Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[CH3:17].Cl[C:19]1[C:24]([N+:25]([O-:27])=[O:26])=[C:23]([CH3:28])[CH:22]=[CH:21][N:20]=1.C(N(CC)CC)C>C(O)C>[CH3:28][C:23]1[CH:22]=[CH:21][N:20]=[C:19]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][N:13]2[CH3:17])[C:24]=1[N+:25]([O-:27])=[O:26]
Reactant: CN1CCC[C@@H]1Cc1c[nH]c2ccc(N)cc12
Reactant: Cc1ccnc(Cl)c1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1ccnc(Nc2ccc3[nH]cc(CC4CCCN4C)c3c2)c1[N+](=O)[O-]
Yield: 34 %

Procedure:
(R)-5-Amino-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole and 2-chloro-4-methyl-3-nitropyridine were used. Triethylamine was used as base, absolute ethanol was used as solvent, and the reaction was heated at reflux for 24 hours. Column chromatography afforded the title compound (34%) as a red amorphous solid: 1H NMR (CDCl3) δ 9.26 (br s, NH), 8.79 (br s, NH), 8.10 (d, J=4.8 Hz, 1H), 7.64 (d, J=1.7 Hz, 1H), 7.29 (d, J=8.5 Hz, 1H)), 7.17 (dd, J=8.5 and 1.9 Hz, 1H), 6.97 (d, J=2.2 Hz, 1H), 6.56 (d, J=4.8 Hz, 1H), 3.25-3.16 (m, 2H), 2.67 (dd, J=13.2 and 9.4 Hz, 1H), 2.64-2.56 (m, 1H), 2.56 (s, 3H), 2.46 (s, 3H), 2.30 (dd, J=17.7 and 9.4 Hz, 1H), 1.90-1.60 (m, 4H); 13C NMR (CDC3) δ 152.2, 151.5, 146.6, 134.3, 131.0, 130.0, 127.9, 123.4, 119.4, 117.1, 114.0, 113.3, 111.6, 67.0, 57.4, 40.7, 31.4, 29.5, 21.8, 21.7; FAB HRMS calculated for [C20H23N5O2.H] 366.1932, found 366.1957.
Reaction SMILES: CC1C=C(N2CCN(CC3C=CC(C(F)(F)F)=CC=3)C2=O)SC=1C(OCC)=O.[F:29][C:30]1[CH:53]=[CH:52][C:33]([CH2:34][N:35]2[CH2:39][CH2:38][N:37]([C:40]3[S:41][C:42]([C:46]([O:48]CC)=[O:47])=[C:43]([CH3:45])[N:44]=3)[C:36]2=[O:51])=[CH:32][CH:31]=1>>[F:29][C:30]1[CH:31]=[CH:32][C:33]([CH2:34][N:35]2[CH2:39][CH2:38][N:37]([C:40]3[S:41][C:42]([C:46]([OH:48])=[O:47])=[C:43]([CH3:45])[N:44]=3)[C:36]2=[O:51])=[CH:52][CH:53]=1
Reactant: CCOC(=O)c1sc(N2CCN(Cc3ccc(F)cc3)C2=O)nc1C
Agent: CCOC(=O)c1sc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)cc1C
Product: Cc1nc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Yield: 80 %

Procedure:
Following the procedure as described in Example 14, making variations as required to replace ethyl 3-methyl-5-(2-oxo-3-(4-(trifluoromethyl)benzyl)imidazolidin-1-yl)thiophene-2-carboxylate with ethyl 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylate, the title compound was obtained as a colorless solid in 80% yield: 1H NMR (300 MHz, DMSO-d6) δ 7.39-7.34 (m, 2H), 7.22-7.17 (m, 2H), 4.43 (s, 2H), 4.01-3.98 (m, 2H), 3.48-3.43 (m, 2H), 2.50 (s 3H): MS (ES+) m/z 336.1 (M+1).
Reaction SMILES: [H-].[Na+].O1CCOCC1.[C:9]1([NH:15][C:16]([NH2:18])=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C[O:20][CH:21](OC)[CH2:22][C:23](OC)=O>C(O)(=O)C>[C:9]1([N:15]2[CH:23]=[CH:22][C:21](=[O:20])[NH:18][C:16]2=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NC(=O)Nc1ccccc1
Reactant: COC(=O)CC(OC)OC
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: O=c1ccn(-c2ccccc2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.05 g NaH (41 mmol as 50% suspension in mineral oil) was added to 55 ml dry dioxane. 3.87 g (28.4 mmol) phenylurea was then added portionwise while keeping the reaction mixture under an argon atmosphere and then was heated for a few minutes to 50° C. After cooling the resulting mixture to room temperature, 6.31 g (42.6 mmol) of methyl 3,3-dimethoxypropionate was added, the mixture then refluxed for 2 hours, after which the resulting mixture was allowed to cool to room temperature. The cooled mixture was then poured into 280 ml 40% acetic acid, stored overnight in a refrigerator and then extracted twice with 140 ml chloroform. The collected chloroform fractions were dried over MgSO4 and evaporated under reduced pressure. The residue was crystallized from methanol using after treatment with activated carbon yielding 0.88 g (16%) of 1-phenyluracil (m.p. 244–245° C., Lit. 244–255° C. (Winckelmann et al., Synthesis 1986, 1041)).
Reaction SMILES: [C:1](Cl)(=[O:7])[O:2][CH2:3][CH2:4][O:5][CH3:6].[NH2:9][C@@H:10]1[CH2:15][CH2:14][N:13]([C:16]2[C:17]([Cl:40])=[C:18]([NH:24][C:25]3[N:30]=[C:29]([NH:31][CH:32]4[CH2:34][CH2:33]4)[C:28]4=[N:35][CH:36]=[C:37]([C:38]#[N:39])[N:27]4[N:26]=3)[CH:19]=[C:20]([C:22]#[N:23])[CH:21]=2)[CH2:12][C@H:11]1[O:41][Si:42]([CH:49]([CH3:51])[CH3:50])([CH:46]([CH3:48])[CH3:47])[CH:43]([CH3:45])[CH3:44].C(N(CC)CC)C>ClCCl>[Cl:40][C:17]1[C:18]([NH:24][C:25]2[N:30]=[C:29]([NH:31][CH:32]3[CH2:33][CH2:34]3)[C:28]3=[N:35][CH:36]=[C:37]([C:38]#[N:39])[N:27]3[N:26]=2)=[CH:19][C:20]([C:22]#[N:23])=[CH:21][C:16]=1[N:13]1[CH2:14][CH2:15][C@@H:10]([NH:9][C:1](=[O:7])[O:2][CH2:3][CH2:4][O:5][CH3:6])[C@H:11]([O:41][Si:42]([CH:46]([CH3:48])[CH3:47])([CH:49]([CH3:51])[CH3:50])[CH:43]([CH3:44])[CH3:45])[CH2:12]1
Reactant: CC(C)[Si](O[C@@H]1CN(c2cc(C#N)cc(Nc3nc(NC4CC4)c4ncc(C#N)n4n3)c2Cl)CC[C@H]1N)(C(C)C)C(C)C
Reactant: COCCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCOC(=O)N[C@@H]1CCN(c2cc(C#N)cc(Nc3nc(NC4CC4)c4ncc(C#N)n4n3)c2Cl)C[C@H]1O[Si](C(C)C)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.5 %

Procedure:
2-methoxyethyl carbonochloridate (5.08 mg, 0.037 mmol) was added to a solution of 2-((3-((3R,4R)-4-amino-3-((triisopropylsilyl)oxy)piperidin-1-yl)-2-chloro-5-cyanophenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Example 174D, 19 mg, 0.031 mmol) and triethylamine (8.53 μl, 0.061 mmol) in dichloromethane (1 mL) and the reaction solution was stirred at room temperature overnight. More 2-methoxyethyl carbonochloridate (5.08 mg, 0.037 mmol) was added and stirring continued over the weekend, still about 30% SM left. More triethylamine (100 μL) and 2-methoxyethyl carbonochloridate (20 μl) was added and stirred for another day. Reaction close to completion. The reaction mixture was diluted with dichloromethane and washed with cold saturated sodium bicarbonate, the organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo, the crude product was purified by flash chromatography on silica gel using an automated ISCO system (24 g column, eluting with 0-40% ethyl acetate/dichloromethane) to give 2-methoxyethyl ((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-((triisopropylsilyl)oxy)piperidin-4-yl)carbamate (12 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=O)[CH:6]=[N:7][CH:8]=1.[F:11][C:12]1[CH:13]=[C:14]([NH:19][CH3:20])[C:15]([NH2:18])=[CH:16][CH:17]=1>CN(C=O)C.O.C(OCC)(=O)C>[F:11][C:12]1[CH:17]=[CH:16][C:15]2[N:18]=[C:9]([C:5]3[CH:6]=[N:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[N:19]([CH3:20])[C:14]=2[CH:13]=1
Reactant: CNc1cc(F)ccc1N
Reactant: COc1cncc(C=O)c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cncc(-c2nc3ccc(F)cc3n2C)c1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
To a solution of 5-methoxypyridine-3-carbaldehyde (0.052 g, 0.378 mmol) in DMF (1.89 mL) were added the title compound from Example 1 Step B (0.053 g, 0.38 mmol) and Na2S2O5 (0.288 g, 1.51 mmol). The resulting mixture was stirred at 120° C. overnight, then cooled to room temperature and diluted with water and ethyl acetate. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, filtered, and concentrated. Purification by flash chromatography on silica gel (50% ethyl acetate in hexanes, then 100% ethyl acetate) provided the title compound: LCMS m/z 258.17 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 8.56 (d, J=1.6 Hz, 1 H), 8.46 (d, J=2.9 Hz, 1 H), 7.66 (dd, J=8.6, 4.8 Hz, 1 H), 7.65 (t, J=2.1, 2.1 Hz, 1 H), 7.12-7.06 (m, 2 H), 3.95 (s, 3 H), 3.88 (s, 3 H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26](O)=[O:27])[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.C1CN([P+](ON2N=[N:56][C:51]3[CH:52]=[CH:53][CH:54]=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C1(N)CCC1>C(Cl)Cl.CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26]([NH:56][CH:51]4[CH2:52][CH2:53][CH2:54]4)=[O:27])[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=C(O)COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1)NC1CCC1
Reaction time: 0.5 h

Procedure:
A suspension of 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid (70 mg, 0.14 mmol), PyBOP® (40 mg, 0.077 mmol), DIEA (24 μL, 0.14 mmol) in dry CH2Cl2:DMF (2:0.1 mL) was stirred at RT for 15 minutes. To this solution of activated acid was added cyclobutanamine (6.5 mg, 0.091 mmol). After 30 minutes, 1.0 equivalent of DIEA and 0.55 equivalents of PyBOP® were added. After stirring the solution for 15 minutes, 0.65 equivalents of cyclobutanamine were added and the mixture was stirred for an additional 30 minutes. The solvent was removed in vacuo and the crude product was purified using prep HPLC (25-50—90 mins) to afford 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-cyclobutylacetamide. (36 mg, 0.077 mmol, 55%).
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[O:11][N:10]=[C:9]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([SH:22])[CH:17]=2)=[O:14])[CH:8]=1)([CH3:6])([CH3:5])[CH3:4].Cl[C:24]1[C:33]2[C:28](=[CH:29][C:30]([O:42][CH3:43])=[C:31]([O:34][CH2:35][CH2:36][CH2:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH:32]=2)[N:27]=[CH:26][N:25]=1>O1CCCC1.C(OCC)(=O)C.O>[C:3]([C:7]1[O:11][N:10]=[C:9]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([S:22][C:24]3[C:33]4[C:28](=[CH:29][C:30]([O:42][CH3:43])=[C:31]([O:34][CH2:35][CH2:36][CH2:37][S:38]([CH3:41])(=[O:39])=[O:40])[CH:32]=4)[N:27]=[CH:26][N:25]=3)[CH:17]=2)=[O:14])[CH:8]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(S)c2)no1
Reactant: COc1cc2ncnc(Cl)c2cc1OCCCS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCCS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 4 %

Procedure:
To a suspension of sodium hydride (11 mg, 0.44 mmol) in anhydrous tetrahydrofuran (2 mL) cooled to 0° C., was added 1-(5-tert-butylisoxazol-3-yl)-3-(3-mercaptophenyl)urea from the previous step (117 mg, 0.40 mmol) as a solution in tetrahydrofuran (1 mL) and the mixture stirred at 0° C. for 30 minutes. To this suspension 4-chloro-7-methoxy-6-(3-(methylsulfonyl)propoxy)quinazoline from Example 41B Step 1 (133 mg, 0.40 mmol) was added and the resulting mixture was stirred at 0° C. and slowly allowed to reach room temperature. After stirring for additional 1 h, the mixture was taken up in ethyl acetate/water and extracted. The combined organic layers were dried (MgSO4) and concentrated under reduced pressure. The residue was purified by preparative HPLC (Phenomenex phenylhexyl reverse phase column) to afford 1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(3-(methylsulfonyl)propoxy)quinazolin-4-ylthio)phenyl)urea (10.30 mg, 4%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 9.73 (bs, 1H), 9.19 (bs, 1H), 8.70 (s, 1H), 7.85 (s, 1H), 7.53-7.27 (m, 5H), 6.49 (s, 1H), 4.32 (bs, 2H), 4.01 (s, 3H), 3.35 (2H), 3.07 (s, 3H), 2.28 (bs, 2H), 1.28 (s, 9H); LC-MS (ESI) m/z 586 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][C:6]([F:12])=[CH:7][CH:8]=2)[N:3]=1.C(O[C:18](=[O:29])[NH:19][C@H:20]1[CH2:25][CH2:24][C@H:23]([CH2:26][CH2:27][OH:28])[CH2:22][CH2:21]1)(C)(C)C.[O:30]=[C:31]1[NH:36][C:35]2[CH:37]=[C:38](C(O)=O)[CH:39]=[CH:40][C:34]=2[S:33][CH2:32]1>>[F:12][C:6]1[CH:5]=[C:4]2[C:9]([N:10]=[CH:11][C:2]([O:28][CH2:27][CH2:26][C@H:23]3[CH2:22][CH2:21][C@H:20]([NH:19][C:18]([C:38]4[CH:39]=[CH:40][C:34]5[S:33][CH2:32][C:31](=[O:30])[NH:36][C:35]=5[CH:37]=4)=[O:29])[CH2:25][CH2:24]3)=[N:3]2)=[CH:8][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCO)CC1
Reactant: Fc1ccc2ncc(Cl)nc2c1
Reactant: O=C1CSc2ccc(C(=O)O)cc2N1
Product: O=C1CSc2ccc(C(=O)N[C@H]3CC[C@H](CCOc4cnc5ccc(F)cc5n4)CC3)cc2N1

Procedure:
The title compound is prepared as a white amorphous lyophilizated solid following Scheme 1 and in analogy to Example 1 using 2-chloro-7-fluoro-quinoxaline, [trans-4-(2-hydroxy-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester and 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid as starting materials.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[S:11](=[O:17])(=[O:16])[NH:12][CH2:13][CH2:14][CH3:15].[Br:18]Br>>[Br:18][CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([S:11](=[O:17])(=[O:16])[NH:12][CH2:13][CH2:14][CH3:15])[CH:4]=1)=[O:10]
Reactant: CCCNS(=O)(=O)c1cc(C(C)=O)ccc1Cl
Reactant: BrBr
Product: CCCNS(=O)(=O)c1cc(C(=O)CBr)ccc1Cl

Procedure:
13.8 g of 4'-chloro-3'-propylsulfamoylacetophenone were reacted as described in Example 1(a) with 8 g of bromine to give the 2-bromo-4'-chloro-3'-propylsulfamoylacetophenone, melting point: 96° C., from isopropanol).
Reaction SMILES: C(OP(=O)(OCC)O[C:6]([CH3:26])([CH3:25])[C:7]#[C:8][C:9]1[CH:24]=[CH:23][C:12]2[C:13]([C:16]3[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=3)=[N:14][S:15][C:11]=2[CH:10]=1)C.[CH2:31]([NH:33][CH2:34][CH2:35][OH:36])[CH3:32].C1COCC1.C([O-])(O)=O.[Na+]>CCOC(C)=O>[Br:22][C:19]1[CH:18]=[CH:17][C:16]([C:13]2[C:12]3[CH:23]=[CH:24][C:9]([C:8]#[C:7][C:6]([N:33]([CH2:31][CH3:32])[CH2:34][CH2:35][OH:36])([CH3:25])[CH3:26])=[CH:10][C:11]=3[S:15][N:14]=2)=[CH:21][CH:20]=1
Reactant: CCNCCO
Reactant: CCOP(=O)(OCC)OC(C)(C)C#Cc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCN(CCO)C(C)(C)C#Cc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Temperature: 50 °C

Procedure:
To 45 mg (0.09 mmol) Phosphoric acid 3-[3-(4-bromo-phenyl)-benzo[d]isothiazol-6-yl]-1,1-dimethyl-prop-2-ynyl ester diethyl ester and 16 μl (0.18 mmol) 2-Ethylaminoethanol in 0.5 ml THF 10.2 mg (0.01 mmol) tetrakis(triphenylphosphine)palladium was added and the suspension stirred at 50° C. over night. The mixture was added to a saturated aqueous solution of NaHCO3 and EtOAc, the phases were separated and the inorganic one was extracted with EtOAc. The combined organic phases were washed with brine and dried over Na2SO4. Column chromatography on silica gel with CH2Cl2:MeOH 95:5 gave 2-((3-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6 yl]-1,1-dimethyl-prop-2-ynyl)-ethyl-amino)-ethanol as yellow semisolid, MS: 443 (MH+, 1Br).
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:11](O)=O)[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[NH2:29][C:30]1[N:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32]([OH:34])=O.[I:39][C:40]1[CH:46]=[CH:45][C:43]([NH2:44])=[CH:42][CH:41]=1>C(Cl)Cl>[I:39][C:40]1[CH:46]=[CH:45][C:43]([N:44]2[C:32](=[O:34])[C:31]3[CH:35]=[CH:36][CH:37]=[N:38][C:30]=3[N:29]=[C:11]2[C@H:9]([NH:8][C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7])[CH3:10])=[CH:42][CH:41]=1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1ccc(I)cc1
Reactant: Nc1ncccc1C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C[C@@H](NC(=O)OC(C)(C)C)c1nc2ncccc2c(=O)n1-c1ccc(I)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 13 %

Procedure:
A solution of Boc-d-alanine, A1 (10.0 g, 52.9 mmol) in CH2Cl2 (140 mL) was cooled to −25° C. (measured internally). N-Methylmorpholine (NMM) (13.8 mL, 125 mmol) followed by iso-butylchloroformate (IBCF) (13.5 mL, 104 mmol) were added at such a rate to maintain the internal temperature below −25° C. After 1.5 h the mixture was transferred via cannula to a 250 mL, three-neck flask equipped with a thermometer and containing dry 2-aminonicotinic acid (7.28 g, 52.7 mmol). After the addition was complete (ca. 10 min.) the internal temperature of the mixture was adjusted to −10° C. The reaction mixture was allowed to warm with vigorous stirring over 17 h reaching a final temperature of 15° C. The mixture was cooled to 0° C. and washed with ice-cold 1N HCl (2×100 mL), brine (100 mL) and dried over Na2SO4. The resulting solution of A2 was charged into a 250 mL three neck, cooled to −25° C. and treated with solid 4-iodoaniline (11.61 g, 53 mmol). The resulting dark mixture was allowed to warm to 15° C. with stirring over 12 h. The solution was washed with 1N HCl (2×100 mL), saturated NaHCO3 (2×100 mL), brine (100 mL) and dried over Na2SO4. The mixture was cooled to −25° C. and treated with NMM (6.8 mL, 61.8 mmol) followed by IBCF (6.7 mL, 56.1) maintaining the internal temperature below −25° C. After stirring for 12 h the reaction mixture was washed with 1N HCl (2×100 mL), saturated NaHCO3 (2×100 mL), brine (100 mL) and dried over Na2SO4 and concentrated. Purification of the concentrate by silica gel chromatography (50×400 mm column; 5% acetone/CH2Cl2 to 25% acetone/CH2Cl2) gave A3 (3.41 g, 13%; purity 96% AUC). Rf=0.37 (15% acetone/CH2Cl2).
Reaction SMILES: C(N(C(C)C)CC)(C)C.C([Li])CCC.[O:15]1[C:19]2([CH2:24][CH2:23][CH:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:21][CH2:20]2)[O:18][CH2:17][CH2:16]1.[C:30]1([Se:36]Br)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O1CCCC1>[C:30]1([Se:36][C:22]2([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:23][CH2:24][C:19]3([O:18][CH2:17][CH2:16][O:15]3)[CH2:20][CH2:21]2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCOC(=O)C1CCC2(CC1)OCCO2
Reactant: Br[Se]c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1([Se]c2ccccc2)CCC2(CC1)OCCO2
Reaction time: 1 h
Yield: 76.4 %

Procedure:
To a solution of diisopropylethyl amine (5.59 g, 55.30 mmol) in anhydrous tetrahydrofuran (150 mL) was added a solution of butyllithium (1.6 M in hexanes, 34.5 mL, 55.30 mmol) at 0° C. The reaction solution was stirred at the same temperature for 1 hour, then added a solution of ethyl 1,4-dioxaspiro[4.5]decane-8-carboxylate (10.80 g, 50.00 mmol) in anhydrous tetrahydrofuran (20 mL) at −78° C. The reaction mixture was stirred at the same temperature for 1 h then added phenylselenium bromide (11.90 g, 50.70 mmol). The mixture was continued to stir at −78° C. for 5 hour, then at ambient temperature for 16 hour. The reaction was quenched with saturated sodium hydrogencarbonate (200 mL), diluted with ethyl acetate (200 mL), saturated ammonium chloride (3×150 mL), brine (3×100 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was purified by column chromatography with ethyl acetate in hexanes (10%) to afford the title compound as a viscous liquid (14.10 g, 76%): 1H NMR (300 MHz, CDCl3) δ 7.54 (d, J=7.6 Hz, 1H), 7.37-7.32 (m, 1H), 7.26 (dd, J=7.0, 7.0 Hz, 2H), 4.05 (dd, J=7.1 Hz, 2H), 3.90 (d, J=3.4 Hz, 4H), 2.20-2.12 (m, 2H), 2.00-1.88 (m, 2H), 1.82-1.70 (m, 2H), 1.57-1.46 (m, 2H), 1.14 (t, J=7.1 Hz, 3H).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:16]=[C:15]([CH3:17])[C:14]([OH:18])=[C:13]2[C:5]=1[CH:6]1[CH:11]([CH:12]2[NH:19][CH3:20])[CH2:10][CH2:9][CH2:8][CH2:7]1.CI.O.[CH:24](Cl)(Cl)[Cl:25]>CN(C)C=O>[ClH:25].[CH3:3][C:4]1[CH:16]=[C:15]([CH3:17])[C:14]([O:18][CH3:24])=[C:13]2[C:5]=1[CH:6]1[CH:11]([CH:12]2[NH:19][CH3:20])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CNC1c2c(O)c(C)cc(C)c2C2CCCCC21
Reactant: ClC(Cl)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: CNC1c2c(OC)c(C)cc(C)c2C2CCCCC21
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.16 Gram of 60% sodium hydride was added to a dimethylformamide solution containing 0.42 g of 5,7-dimethyl-8-hydroxy-9-methylamino-1,2,3,4,4a,9a-hexahydrofluorene in 5 ml of dimethylformamide, followed by stirring at room temperature for 30 minutes. Then, to the mixture was added 0.13 ml of methyl iodide, followed by stirring at the same temperature for 30 minutes. Water was added to the reaction mixture and extraction was carried out with chloroform. The chloroform layer was dried with magnesium sulfate and then the solvent was removed by concentration. The residue was purified by a silica gel column chromatography (eluent: ethyl acetate:n-hexane=1:4), then was dissolved in ethanol and converted to a hydrochloride with saturated hydrochloric acid gas-ethanol solution, which was recrystallized from ethanol to obtain 0.1 g of 5,7-dimethyl-8-methoxy-9-methylamino-1,2,3,4,4a,9a-hexahydrofluorene hydrochloride.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([N:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][OH:19])[CH2:13][CH2:12]3)=[N:9][N:10]=2)[CH:7]=1.CCN(CC)CC.FC(F)(F)S(O[Si:33]([CH:40]([CH3:42])[CH3:41])([CH:37]([CH3:39])[CH3:38])[CH:34]([CH3:36])[CH3:35])(=O)=O>C(Cl)Cl.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([N:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][O:19][Si:33]([CH:40]([CH3:42])[CH3:41])([CH:37]([CH3:39])[CH3:38])[CH:34]([CH3:36])[CH3:35])[CH2:13][CH2:12]3)=[N:9][N:10]=2)[CH:7]=1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: OCCN1CCN(c2nnc3ccc(F)cn23)CC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)[Si](OCCN1CCN(c2nnc3ccc(F)cn23)CC1)(C(C)C)C(C)C
Reaction time: 2.5 h
Yield: 89.7 %

Procedure:
To a solution of Intermediate 94a (169 mg, 0.64 mmol) and Et3N (265 μL, 1.91 mmol) in DCM (6 mL) was added triisopropylsilyl trifluoromethanesulfonate (189 pt, 0.70 mmol). The solution was stirred for 2.5 h, then diluted with water and extracted with DCM. The combined organics were dried and concentrated in vacuo. The residue was purified by FCC, using 0-5% (2M NH3 in MeOH) in DCM, to give the title compound as a pale brown gum (242 mg, 90%). LCMS (Method 3): Rt 2.93 min, m/z 422 [MH+].
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([O:19][CH3:20])=[O:18])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1>C(OCC)(=O)C.CO.O1CCCC1.[Pd]>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: COC(=O)/C=C/c1ccc(-c2ccc(OC)nc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)CCc1ccc(-c2ccc(OC)nc2)cc1
Reaction time: 2.5 h

Procedure:
To a solution of compound obtained from step b above (8.1 g) in a mixture of ethyl acetate/methanol/tetrahydrofuran (˜300 mL), 10% Palladium on charcoal (1.6 g) was added and stirred under hydrogen atmosphere at 30 psi in a Paar apparatus for 2.5 hours. The reaction mixture was filtered through a celite pad, washed with ethyl acetate, and the filtrate was concentrated under reduced pressure to obtain the title compound as a white solid which was used as such for the next step.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([C:10]([N:12]2[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14][CH2:13]2)=[O:11])[CH:7]=[CH:8][CH:9]=1.Cl[C:20]1[N:25]=[CH:24][N:23]=[C:22]2[N:26]([C:29]3[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:31][CH:30]=3)[N:27]=[CH:28][C:21]=12>C1COCC1>[F:3][C:4]1[CH:5]=[C:6]([C:10]([N:12]2[CH2:13][CH2:14][CH:15]([O:18][C:20]3[N:25]=[CH:24][N:23]=[C:22]4[N:26]([C:29]5[CH:30]=[CH:31][C:32]([S:35]([CH3:38])(=[O:36])=[O:37])=[CH:33][CH:34]=5)[N:27]=[CH:28][C:21]=34)[CH2:16][CH2:17]2)=[O:11])[CH:7]=[CH:8][CH:9]=1
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(Cl)ncnc32)cc1
Reactant: O=C(c1cccc(F)c1)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(-n2ncc3c(OC4CCN(C(=O)c5cccc(F)c5)CC4)ncnc32)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a 16 mL reaction vial was placed sodium hydride (48 mg, 60% in oil, 1.2 mmol) and 5 mL of THF. (3-Fluoro-phenyl)-(4-hydroxy-piperidin-1-yl)-methanone (66 mg, 0.3 mmol) was added to the suspension and the mixture was stirred 60 min under N2 at room temperature, followed by the addition of 4-chloro-1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine (60 mg, 0.2 mmol). After stir another 2 hrs under N2 at room temperature, all of the starting chloropyrozolepyrimidines was completely converted as indicated by LCMS. The reaction mixture was then filtered through a syringe filter and purified HPLC to give Compound A8. 1H NMR (CDCl3,400 MHz) δ 1.95 (m, 2H), 2.21 (m, 2H), 3.11 (s, 3H), 3.45 (m, 1H), 3.68 (m, 1H), 3.75 (m, 1H), 4.20 (s, 1H), 5.72 (m, 1H), 7.12 (m, 1H), 7.16 (m, 1H), 7.22 (m, 1H), 7.41 (m, 1H), 8.11 (d, 2H), 8.27 (s, 1H), 8.62 (d, 2H), 8.67 (s, 1H). Exact mass calculated for C24H22FN5O4S 495.14, found 496.3 (MH+)