Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].[CH3:2]C([N-]C(C)C)C.[CH:9]1[C:14]2[C:15]3[C:28](=O)[C:20]4S[C:22]5C=CC=[CH:24][C:23]=5[C:19]=4[C:18](=O)[C:16]=3SC=2C=CC=1.O>C1COCC1>[C:23]([C:19]1[CH:18]=[CH:16][C:15]([C:14]#[CH:9])=[CH:28][CH:20]=1)([CH3:22])([CH3:24])[CH3:2]
Reactant: CC(C)[N-]C(C)C
Reactant: O=C1c2sc3ccccc3c2C(=O)c2sc3ccccc3c21
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1ccc(C(C)(C)C)cc1
Temperature: 24.5 °C
Reaction time: 0.17 h

Procedure:
In another flame dried flask, a solution of 1-tert-butyl-4-ethynyl-benzene (3.56 g, 22.5 mmol) in THF (20 ml) is prepared, and the freshly prepared LDA is added to this solution within 10 minutes. The temperature is maintained in the range between 23-26° C. by cooling, and the solution is stirred for another 10 minutes at ambient temperature. Then dibenzo[d,d′]benzo[1,2-b;4,5-b′]dithiophene-6,12-dione (educt 1) (2.40 g, 7.5 mmol) is added as a solid, and the mixture heated to 50° C. and stirred for 52 hours at this temperature. The clear red solution is poured carefully into water (100 ml), and the product extracted with chloroform (80 ml). The aqueous layer is extracted again with chloroform (80 ml), and the combined organic layers are washed with brine and dried (sodium sulphate). Removal of the solvent leaves the crude product as light brown crystals. The crystals are refluxed in methanol (50 ml) (incompletely dissolved) and the mixture allowed to crystallise over night. The solid is then filtered off and washed with methanol thrice (7 ml each time) and dried in vacuo to give the product as beige crystals. 1H-NMR (CDCl3, 300 MHz) δ 1.29 (s, 9H, C(CH3)3); 3.09 (s, 1H, OH); 7.27, 7.36 (AA′BB′, 4H, Ph H); 7.43, 7.48 (2 “tr”, 1H each), 7.89 pp (d, J=6.5 Hz, 1H), 8.54 (d, J=8.2 Hz, 1H) benzothiophene H. 13C-NMR (CDCl3, 75 MHz) δ 31.47 (C(CH3)3); 35.17 (q, C(CH3)3); 64.79 (q, COH); 87.80, 88.69 (2 q, C≡C); 118.96 (q), 123.03, 124.84, 125.13, 125.77 (benzothiophene CH); 125.46, 131.76 (Ph CH); 130.90 (q), 136.15 (q), 140.37 (q), 144.11 (q), 152.48 (q).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([NH2:7])[CH:3]=1.[CH:8]1([CH2:12][N:13]([CH2:26][CH3:27])[C:14]2[C:23]([CH:24]=O)=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)[CH2:11][CH2:10][CH2:9]1.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[CH:8]1([CH2:12][N:13]([CH2:26][CH3:27])[C:14]2[C:23]([CH2:24][NH:7][C:4]3[CH:3]=[C:2]([CH3:1])[O:6][N:5]=3)=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)[CH2:9][CH2:10][CH2:11]1
Reactant: Cc1cc(N)no1
Reactant: CCN(CC1CCC1)c1nc2ccccc2cc1C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCN(CC1CCC1)c1nc2ccccc2cc1CNc1cc(C)on1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 42.8 %

Procedure:
5-Methyl-isoxazol-3-ylamine (0.098 g, 1 mmol) was added to a solution of 2-(cyclobutylmethyl-ethyl-amino)-quinoline-3-carbaldehyde (0.268 g, 1 mmol) in anhydrous methanol (5 mL) and acetic acid (0.15 mL) under nitrogen. After being stirred for 15 minutes at ambient temperature, sodium cyanoborohydride (0.19 g, 3 mmol) was added slowly, and the reaction mixture was stirred overnight. Afterwards, the solvent was evaporated in vacuo, and water (30 mL) and ethyl acetate (30 mL) were added to the residue. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by chromatography on silica gel, eluting with 1-5% methanol in dichloromethane, to afford the title compound (0.150 g, yield: 43%).
Reaction SMILES: [F:1][CH:2]([F:17])[CH2:3][NH:4][CH:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:19]1[N:24]=[C:23]([NH:25][C@@H:26]2[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]2[NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[C:22]([Cl:37])=[CH:21][N:20]=1>>[Cl:37][C:22]1[C:23]([NH:25][C@@H:26]2[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]2[NH:32][S:33]([CH3:36])(=[O:35])=[O:34])=[N:24][C:19]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][CH:5]([NH:4][CH2:3][CH:2]([F:17])[F:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:20][CH:21]=1
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Reactant: Nc1ccc2c(c1)CCC(NCC(F)F)CC2
Product: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Nc2ccc3c(c2)CCC(NCC(F)F)CC3)ncc1Cl
Yield: 61 %

Procedure:
In an analogous procedure to Example 651, part c, N*7*-(2,2-Difluoro-ethyl)-6,7,8,9-tetrahydro-5H-benzocycloheptene-2,7-diamine was combined with N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide to yield N-((1R,2R)-2-{5-Chloro-2-[7-(2,2-difluoro-ethylamino)-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino]-pyrimidin-4-ylamino}-cyclohexyl)-methanesulfonamide (69.11 mg, 61% yield) as a beige foam. 1H-NMR (CDCl3) δ 7.91 (s, 1H), 7.24 (m, 2H), 7.05 (d, J=7.7 Hz, 1H), 6.85 (s, 1H), 5.83 (m, 1H), 5.39 (m, 2H), 3.86 (m, 1H), 3.23 (m, 1H), 3.02 (m, 2H), 2.78 (m, 2H), 2.68 (m, 2H), 2.20 (br s, 2H), 2.07 (br s, 2H), 1.82 (br s, 2H), 1.36 (m, 7H). LC/MS (ESI+)=542 (M+H).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[CH:31]([NH:34][CH3:35])([CH3:33])[CH3:32]>>[CH:31]([N:34]([CH3:35])[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1)([CH3:33])[CH3:32]
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cc3)ccc2o1
Reactant: CNC(C)C
Product: CC(C)N(C)CCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cc3)ccc2o1

Procedure:
The product from Example 23D and isopropyl(methyl)amine were processed as described in Example 1D to provide the titled compound. 1H NMR (300 MHz, CD3OD) δ 7.82 (m, 1H), 7.74 (d, J=8.1, 2H), 7.58 (m, 2H), 7.52 (d, J=8.1 Hz, 2H), 6.81 (s, 1H), 3.3-3.8 (m, 13H), 2.97 (s, 3H), 1.42 (d, 6.3 Hz, 3H), 1.37 (d, 6.3 Hz, 3H); MS (DCI) m/z 407 (M+H)+;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]3[N:19]=[CH:20][C:21]([C:22](O)=[O:23])=[C:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:25][C:26]1[CH:35]=[CH:34][C:29]([C:30]([NH:32]O)=[NH:31])=[CH:28][N:27]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([C:15]([F:16])([F:18])[F:17])[N:12]3[N:19]=[CH:20][C:21]([C:22]4[O:23][N:32]=[C:30]([C:29]5[CH:34]=[CH:35][C:26]([NH2:25])=[N:27][CH:28]=5)[N:31]=4)=[C:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: N=C(NO)c1ccc(N)nc1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)c(Cl)c3)nc12
Product: Nc1ccc(-c2noc(-c3cnn4c(C(F)(F)F)cc(-c5ccc(Cl)c(Cl)c5)nc34)n2)cn1

Procedure:
The title compound was prepared from 5-(3,4-dichloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.9) (188 mg, 0.5 mmol) and 6-amino-N-hydroxy-nicotinamidine (example B.4) (114 mg, 0.75 mmol) according to general procedure II. Obtained after flash chromatography on silica gel (ethyl acetate/heptane) and further purification by crystallization (dichloromethane/hexane) as a yellow solid (35 mg, 14%). MS (ISP) 492.0 [(M+H)+]; mp 289° C.
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:32][C:33]2[C:34]([CH3:42])=[C:35]3[C:39](=[CH:40][CH:41]=2)[NH:38][CH:37]=[CH:36]3)=[C:5]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][C:15]([CH2:18][N:19]4[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]4)=[CH:14][C:12]=3[CH:13]=2)[CH:6]=[N:7][CH:8]=1)#[N:2]>FC(F)(F)C(O)=O.C(Cl)Cl>[CH3:42][C:34]1[C:33]([NH:32][C:4]2[C:3]([C:1]#[N:2])=[CH:8][N:7]=[CH:6][C:5]=2[C:9]2[O:10][C:11]3[CH:17]=[CH:16][C:15]([CH2:18][N:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)=[CH:14][C:12]=3[CH:13]=2)=[CH:41][CH:40]=[C:39]2[C:35]=1[CH:36]=[CH:37][NH:38]2
Reactant: Cc1c(Nc2c(C#N)cncc2-c2cc3cc(CN4CCN(C(=O)OC(C)(C)C)CC4)ccc3o2)ccc2[nH]ccc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(Nc2c(C#N)cncc2-c2cc3cc(CN4CCNCC4)ccc3o2)ccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.4 %

Procedure:
A mixture of tert-butyl 4-[(2-{5-cyano-4-[(4-methyl-1H-indol-5-yl)amino]pyridin-3-yl}-1-benzofuran-5-yl)methyl]piperazine-1-carboxylate (63 mg, 0.11 mmol) in 10% trifluoroacetic acid/CH2Cl2 was stirred at room temperature for 4 h, concentrated in vacuo, and the residue was purified by preparative HPLC (column: Prodigy ODS3, 4.6×150 mm, from Phenomenex (Torrance, Calif.); mobile phase A: 0.02% trifluoroacetic acid (TFA) in water; mobile phase B: 0.02% TFA in CH3CN, 10-95% B in 25 minutes (min.); flow rate: 1.0 mL/min; column temperature: 40° C.; detection wavelength: 254 and 215 nm) to provide 46 mg (50%) of the trifluoroacetic salt of 4-[(4-methyl-1H-indol-5-yl)amino]-5-[5-(piperazin-1-ylmethyl)-1-benzofuran-2-yl]nicotinonitrile 540 as an orange solid. HPLC retention time: 5.8 min.(g); MS: 463.3 (M+H); melting point: 113-115° C.; and HRMS: 463.2234.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:9](OC(OCC)OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[O:8]1[C:7]2[C:2](=[N:3][CH:4]=[CH:5][CH:6]=2)[N:1]=[CH:9]1
Reactant: Nc1ncccc1O
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: c1cnc2ncoc2c1
Temperature: 140 °C

Procedure:
A mixture of 2-amino-3-hydroxypyridine (25 g, 227 mmol), triethylorthoformate (75 mL) and p-toluenesulfonic acid (61 mg) was heated at 140° C. for 8 h. Excess triethylorthoformate was removed under vacuum. The product was crystallized from ethyl acetate to yield 22.5 g of oxazolo[4,5-b]pyridine.
Reaction SMILES: O[CH2:2][CH2:3][N:4]([C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=1)[CH3:5].[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.C(N(CC)CC)C>C(Cl)Cl>[S:20]([CH2:2][CH2:3][N:4]([C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=1)[CH3:5])([C:17]1[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=1)(=[O:22])=[O:21]
Reactant: CN(CCO)c1ccc(C=O)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)CCN(C)c2ccc(C=O)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 0.5 mol of 4-[N-2-hydroxyethyl-N-methylamino]benzaldehyde in methylene chloride at 0° C. are added 0.51 mol of p-toluenesulfonyl chloride, 0.51 mol of triethylamine, and 0.005 mol of N,N-dimethylaminopyridine, and the reaction medium is warmed slowly to room temperature. After standing at room temperature for one hour, the reaction product medium is washed with cold 1N HCL, saturated sodium bicarbonate solution, and water. The organic solution is separated and dried over molecular sieves, filtered through cotton, and evaporated to yield the 4-[N-2-tosylethyl-N-methylamino]-benzaldehyde as a crystalline product, which then is recrystallized from ethanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[N:11]=[C:10]([NH2:13])[N:9]3[CH2:14][CH2:15][N:16]=[C:8]3[C:7]=2[CH:6]=[CH:5][C:4]=1[O:17][CH2:18][CH2:19][CH2:20][S:21]([N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)(=[O:23])=[O:22].[C:30]([O:34][C:35]([NH:37][C:38]1[N:43]=[CH:42][C:41]([C:44](O)=[O:45])=[CH:40][N:39]=1)=[O:36])([CH3:33])([CH3:32])[CH3:31]>>[C:30]([O:34][C:35](=[O:36])[NH:37][C:38]1[N:43]=[CH:42][C:41]([C:44](=[O:45])[NH:13][C:10]2[N:9]3[CH2:14][CH2:15][N:16]=[C:8]3[C:7]3[CH:6]=[CH:5][C:4]([O:17][CH2:18][CH2:19][CH2:20][S:21]([N:24]4[CH2:25][CH2:26][O:27][CH2:28][CH2:29]4)(=[O:22])=[O:23])=[C:3]([O:2][CH3:1])[C:12]=3[N:11]=2)=[CH:40][N:39]=1)([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)OC(=O)Nc1ncc(C(=O)O)cn1
Reactant: COc1c(OCCCS(=O)(=O)N2CCOCC2)ccc2c1N=C(N)N1CCN=C21
Product: COc1c(OCCCS(=O)(=O)N2CCOCC2)ccc2c1N=C(NC(=O)c1cnc(NC(=O)OC(C)(C)C)nc1)N1CCN=C21

Procedure:
The procedure used for the preparation of Example 16, Step 2 was used to prepare the title compound from 7-methoxy-8-[3-(morpholin-4-ylsulfonyl)propoxy]-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine (Example 22, Step 1) and 2-[(tert-butoxycarbonyl)amino]pyrimidine-5-carboxylic acid. High vacuum drying gave the title compound (227 mg, 74%): HPLC MS RT=2.57 min, MH+=645.1; 1H NMR (DMSO-d6+2 drops TFA-d) δ: 1.46 (9H, s), 2.22-2.27 (2H, m), 3.15-3.18 (4H, m), 3.24-3.29 (2H, m), 3.62-3.65 (4H, m), 4.00 (3H, s), 4.20-4.27 (2H, m), 4.38 (2H, t), 4.52-4.58 (2H, m), 7.47 (1H, d), 8.03 (1H, d), 9.26 (2H, s).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:29])([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:4][CH2:5][CH2:6][CH2:7][S:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([CH3:22])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:14][OH:15].[OH:30]O>C(O)(=O)C.O>[OH:1][CH2:2][C:3]([CH3:29])([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:4][CH2:5][CH2:6][CH2:7][S:8]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]([CH3:22])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:14][OH:15])=[O:30]
Reactant: CC(CO)(CCCCSCCCCC(C)(CO)c1ccccc1)c1ccccc1
Reactant: OO
Solvent: CC(=O)O
Solvent: O
Product: CC(CO)(CCCCS(=O)CCCCC(C)(CO)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 87.2 %

Procedure:
To a solution of 6-(6-hydroxy-5-methyl-5-phenylhexylsulfanyl)-2-methyl-2-phenylhexan-1-ol (3.0 g, 7.0 mmol) in glacial acetic acid (20 mL) was added hydrogen peroxide (50 wt. % in water; 0.5 mL, 7.0 mmol). The reaction mixture was stirred at rt for 22 h, then diluted with water (100 mL), and extracted with chloroform (3×80 mL). The combined organic phases were subsequently washed with saturated NaHCO3 solution (3×80 mL) and saturated NaCl solution (80 mL), dried over MgSO4, concentrated in vacuo, and dried in high vacuo to give crude 6-(6-hydroxy-5-methyl-5-phenylhexylsulfinyl)-2-methyl-2-phenylhexan-1-ol (2.63 g 88%) as an oil. 1H NMR (300 MHz, CDCl3/TMS): δ (ppm): 7.42-7.12 (m, 10 H), 3.78-3.58 (m, 2 H), 3.58-3.45 (m, 2 H), 2.90-2.70 (m, 2 H), 2.68-2.39 (m, 2 H), 1.95-1.50 (m, 8 H), 1.50-1.00 (m, 10 H). 13C NMR (75 MHz, CDCl3/TMS): δ (ppm): 144.5, 144.4, 128.4, 128.3, 126.5, 126.2, 126.1, 72.2, 72.1, 71.9, 52.4, 52.0, 43.2, 37.8, 37.7, 23.2, 22.9, 22.4, 21.7, 21.5. HRMS (LSIMS, nba): Calcd. for C26H39O3S1 (MH+): 431.2620, found: 431.2611.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([Br:25])=[CH:8][C:9]=1[N:10]([CH:20]([CH2:23][OH:24])[CH2:21][OH:22])[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].C=O.[C:28]([O-])(O)=O.[Na+]>O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([Br:25])=[CH:8][C:9]=1[N:10]([CH:20]1[CH2:23][O:24][CH2:28][O:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4]
Reactant: O=C([O-])O
Reactant: COC(=O)c1sc(Br)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C(CO)CO
Agent: C=O
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)c1sc(Br)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1COCOC1
Temperature: 80 °C
Reaction time: 0.23 h

Procedure:
A mixture of 5-bromo-3-[(2-hydroxy-1-hydroxymethyl-ethyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (18 mg, 0.041 mmol), paraformaldehyde (6 mg) and boron trifluoride-diethyl etherate (15 μl, 0.12 mmol) in dry dioxane (0.6 mL) was stirred at 80° C. for 14 min. It was cooled and added to ice and NaHCO3 solution mixture, extracted with ethyl acetate, washed with brine, dried and evaporated. Pure 5-bromo-3-[[1,3]dioxan-5-yl-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester was obtained after chromatography over silica gel (hexane:ethyl acetate—9:1 as eluent) (15 mg; 81%).
Reaction SMILES: [Li]CCCC.Br[C:7]1[C:15]2[C:14]([Cl:16])=[N:13][CH:12]=[N:11][C:10]=2[N:9]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:8]=1.[I:22][C:23]1[CH:24]=[C:25]([CH:32]=[CH:33][CH:34]=1)[C:26](N(OC)C)=[O:27]>C1COCC1>[Cl:16][C:14]1[C:15]2[C:7]([C:26]([C:25]3[CH:32]=[CH:33][CH:34]=[C:23]([I:22])[CH:24]=3)=[O:27])=[CH:8][N:9]([CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[C:10]=2[N:11]=[CH:12][N:13]=1
Reactant: CON(C)C(=O)c1cccc(I)c1
Reactant: Clc1ncnc2c1c(Br)cn2C1CCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(c1cccc(I)c1)c1cn(C2CCCC2)c2ncnc(Cl)c12
Temperature: 25 °C
Yield: 49.4 %

Procedure:
n-BuLi (3.65 mL, 2.5 M in hexanes, 9.14 mmol) was added dropwise to a solution of 5-Bromo-4-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine (2.5 g, 8.31 mmol) in THF (50 mL) at −78° C. After 30 min a solution of 3-Iodo-N-methoxy-N-methyl-benzamide (2.29 g, 7.8 mmol) in THF (10 mL) was added. After 30 min the reaction was quenched with water and allowed to warm to room temperature. The layers were separated and the aqueous layer was extracted with EtOAc (2×). The combined organic layers were washed with water and dried over Na2SO4. Recrystallization from MeOH afforded the title compound as a white solid (1.74 g, 49%). MS: 451.9/453.9 (MH+); HPLC Rf: 7.44 min. (HPLC method 4).
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[O:11])[N:5]=[CH:4][C:3]=1[NH:20][C@@H:21]1[CH2:26][C@@H:25]2[CH2:27][C@@H:23]([C:24]2([CH3:29])[CH3:28])[C@H:22]1[CH3:30].ClC1C=CC=C(C(OO)=[O:39])C=1>O1CCCC1>[Br:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH2:13][C:14]2[CH:15]=[CH:16][N+:17]([O-:39])=[CH:18][CH:19]=2)=[O:11])[N:5]=[CH:4][C:3]=1[NH:20][C@@H:21]1[CH2:26][C@@H:25]2[CH2:27][C@@H:23]([C:24]2([CH3:29])[CH3:28])[C@H:22]1[CH3:30]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(CC(=O)NCc3ccncc3)c(=O)c1Br)C2(C)C
Solvent: C1CCOC1
Product: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(CC(=O)NCc3cc[n+]([O-])cc3)c(=O)c1Br)C2(C)C
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 95.2 %

Procedure:
2-{5-Bromo-6-oxo-4-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}-N-(pyridin-4-ylmethyl)acetamide (50 mg, 0.105 mmol) and m-chloroperbenzoic acid (35 mg, 0.112 mmol) suspended in tetrahydrofuran (1.5 mL) were stirred at room temperature for 5 minutes and at 80° C. for 30 minutes. After cooling, the reaction solution was concentrated, and the resulting residue was purified by silica gel chromatography (chloroform/methanol=5/1) to give the desired product (49 mg, 95% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[C:10](Br)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:21][N:22]1[C:26](B(O)O)=[CH:25][CH:24]=[N:23]1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[C:10]([C:26]2[N:22]([CH3:21])[N:23]=[CH:24][CH:25]=2)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccc(OC(F)(F)F)c(Br)c1
Reactant: Cn1nccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cn1nccc1-c1cc(NC(=O)OC(C)(C)C)ccc1OC(F)(F)F
Temperature: 80 °C
Yield: 36.5 %

Procedure:
A 25-mL round-bottom flask was charged with (3-bromo-4-trifluoromethoxy-phenyl)-carbamic acid tert-butyl ester (230.0 mg, 0.65 mmol), 1-methyl pyrazole-5-boronic acid (392.9 mg, 1.93 mmol), sodium carbonate (137.8 mg, 1.3 mmol), DME (5 mL) and water (0.5 mL) under argon atmosphere. Tetrakis(triphenylphosphine)palladium (75.1 mg, 0.065 mmol) was added and reaction mixture purged with argon again. The reaction mixture was heated at 80° C. overnight then cooled to room temperature. Ethyl acetate (10 mL) was added then washed with brine and water. Organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated to give a residue that was subjected to a purification by flash chromatography (SiO2, Hexanes/EtOAc gradient elution) to afford [3-(2-methyl-2H-pyrazol-3-yl)-4-trifluoromethoxy-phenyl]-carbamic acid tert-butyl ester as an off-white solid in 36.5% yield. LCMS m/z (%)=358 (M+H, 100). 1H NMR (400 MHz, DMSO-d6) δ: 9.83 (bs, 1H), 7.77 (d, J=8.95 Hz, 1H), 7.69 (s, 1H), 7.63 (s, 1H), 7.57 (d, J=8.84 Hz, 1H), 6.45 (s, 1H), 3.78 (s, 3H), 1.60 (s, 9H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[S:13][CH:14]=2)=[CH:4][N:3]=1.[CH3:16][CH:17]1[CH2:21][CH2:20][CH2:19][NH:18]1>CN1C(=O)CCC1>[CH3:16][CH:17]1[CH2:21][CH2:20][CH2:19][N:18]1[C:2]1[N:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[S:13][CH:14]=2)=[CH:4][N:3]=1
Reactant: Cc1nc(C#Cc2cnc(Cl)nc2)cs1
Reactant: CC1CCCN1
Solvent: CN1CCCC1=O
Product: Cc1nc(C#Cc2cnc(N3CCCC3C)nc2)cs1
Temperature: 200 °C

Procedure:
117 mg (0.50 mmol, 1 eq) 2-chloro-5-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyrimidine, 0.50 mL (5 mmol, 10 eq) 2-methylpyrrolidine and 1 mL NMP were combined. The reaction mixture was heated at 200° C. for 15 min, quenched with pH 10 PBS, extracted with DCM. Silica gel chromatography (gradient 10% to 40% EtOAc/Hexanes) gave 2-(2-methylpyrrolidin-1-yl)-5-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyrimidine (L-001152863). LC-MS calculated for C15H16N4S 284, observed m/e 285.3 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:31]=[CH:30][C:16]([CH2:17][NH:18][C:19]3[CH:20]=[CH:21][C:22]([F:29])=[C:23]([CH:28]=3)[C:24]([O:26][CH3:27])=[O:25])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH3:32][C:33]([CH3:38])([CH3:37])[CH2:34][CH:35]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].ClCCl>ClCCCl>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:17][N:18]([CH2:35][CH2:34][C:33]([CH3:38])([CH3:37])[CH3:32])[C:19]3[CH:20]=[CH:21][C:22]([F:29])=[C:23]([CH:28]=3)[C:24]([O:26][CH3:27])=[O:25])=[CH:30][CH:31]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)(C)CC=O
Reactant: CCCCc1ccc(C#Cc2ccc(CNc3ccc(F)c(C(=O)OC)c3)cc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: CCCCc1ccc(C#Cc2ccc(CN(CCC(C)(C)C)c3ccc(F)c(C(=O)OC)c3)cc2)cc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 56.1 %

Procedure:
Methyl 5-({4-[(4-butylphenyl)ethynyl]benzyl}amino)-2-fluorobenzoate (800 mg, 1.93 mmol) was dissolved in DCE (15 mL), then 3,3-dimethyl-butyraldehyde (289 mg, 2.89 mmol) was added followed by sodium triacetoxyborohydride (Aldrich, 1224 mg, 5.78 mmol) and the resulting mixture stirred at 70° C. for 2 h. Reaction was allowed to cool down, dichloromethane (40 mL) was added and the organic layer was washed twice with H2O and once with brine, dried over MgSO4, filtered and concentrated under reduced pressure. Purification on silicagel afforded 541 mg (56%) of the title compound as a colorless oil. HPLC, Rt: 6.42 min, purity: 98.3%); LC/MS, M+(ESI): 500.4; 1H NMR (CDCl3) δ: 7.44 (m, 4H), 7.17 (m, 5H), 6.93 (t, J=9.6 Hz, 1H), 6.73 (m, 1H), 4.46 (s, 2H), 3.88 (s, 3H), 3.40 (m, 2H), 2.60 (t, J=7.7 Hz, 2H), 1.70-1.46 (m, 4H), 1.34 (m, 2H), 0.99-0.87 (m, 12H).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].C([O-])([O-])=O.[K+].[K+]>C1COCC1>[C:4]([CH2:3][CH2:2][C:1]([N:24]1[CH2:23][CH2:22][CH:21]([CH:18]2[CH2:17][CH2:16][N:15]([C:13]([O:12][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:14])[CH2:20][CH2:19]2)[CH2:26][CH2:25]1)=[O:7])([OH:6])=[O:5]
Reactant: CC(C)(C)OC(=O)N1CCC(C2CCNCC2)CC1
Reactant: O=C1CCC(=O)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C2CCN(C(=O)CCC(=O)O)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4.1 g (40.7 mmol) succinic acid anhydride in 50 mL THF was added dropwise at RT to a solution of 10.0 g (37.3 mmol) tert-butyl[4,4′]bipiperidinyl-1-carboxylate in 100 mL THF and the reaction mixture was stirred overnight at RT. To complete the reaction another 2.0 g (19.9 mmol) succinic acid anhydride were added, the mixture was stirred for 4 h at 50° C. and stirred overnight at RT. 200 mL of 7.5% K2CO3 solution was added and the aqueous phase was washed with 200 mL EtOAc. The organic phase was extracted with 200 mL 7.5% K2CO3 solution and the combined aqueous phases were acidified with citric acid. The mixture was extracted exhaustively with EtOAc and the combined organic phases were evaporated down i. vac.