Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN.[NH2:3][C:4]1[C:12]2[O:11][CH2:10][O:9][C:8]=2[CH:7]=[CH:6][C:5]=1[C:13]([OH:15])=O.C[CH2:17][N:18](C(C)C)C(C)C>C(#N)C>[NH2:3][C:4]1[C:12]2[O:11][CH2:10][O:9][C:8]=2[CH:7]=[CH:6][C:5]=1[C:13]([NH:18][CH3:17])=[O:15]
Reactant: CCN(C(C)C)C(C)C
Reactant: Nc1c(C(=O)O)ccc2c1OCO2
Agent: CN
Solvent: CC#N
Product: CNC(=O)c1ccc2c(c1N)OCO2
Temperature: 25 °C
Reaction time: 12 h
Yield: 82 %

Procedure:
To a solution of methylamine (0.43 g, 13.9 mmol, prepared from 33% aqueous solution and sodium hydroxide) in acetonitrile (20 mL) was added 4-aminobenzo[d][1,3]dioxole-5-carboxylic acid (1.68 g, 9.3 mmol), N,N′-diisopropylethylamine (3.24 mL, 18.6 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N″-tetramethyluronium hexafluorophosphate (HATU, 4.28 g, 11.2 mmol). The mixture was stirred at room temperature for 12 hours, and then evaporated. The residue was diluted with dichloromethane, washed by water, dried over anhydrous sodium sulfate, concentrated and purified by silica gel chromatography to afford the product 4-amino-N-methylbenzo[d][1,3]dioxole-5-carboxamide (1.48 g, yield 82%). 1H NMR (400 MHz, CDCl3) δ ppm 6.95-6.98 (d, 1H, J=8.4 Hz), 6.24-6.26 (d, 1H, J=8.0 Hz), 5.97 (s, 2H), 2.94-2.95 (m, 3H).
Reaction SMILES: [CH2:1]([C:5]12[CH2:17][CH2:16][C:15](=[O:18])[C:14]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)=[C:13]1[C:12]1[C:7](=[CH:8][C:9]([O:26][CH3:27])=[CH:10][CH:11]=1)[CH2:6]2)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[Cs+].[Cs+].Cl.Cl[CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>CC(C)=O.CCOC(C)=O>[CH2:1]([C:5]12[CH2:17][CH2:16][C:15](=[O:18])[C:14]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:36][CH2:37][N:38]4[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]4)=[CH:21][CH:20]=3)=[C:13]1[C:12]1[C:7](=[CH:8][C:9]([O:26][CH3:27])=[CH:10][CH:11]=1)[CH2:6]2)[CH2:2][CH2:3][CH3:4]
Reactant: ClCCN1CCCCC1
Reactant: CCCCC12CCC(=O)C(c3ccc(O)cc3)=C1c1ccc(OC)cc1C2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CCCCC12CCC(=O)C(c3ccc(OCCN4CCCCC4)cc3)=C1c1ccc(OC)cc1C2
Temperature: 60 °C
Yield: 96.3 %

Procedure:
A mixture of crude 9a-butyl-4-(4-hydroxyphenyl)-7-methoxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one (787 mg, approx. 2 mmol), cesium carbonate (1.564 g, 4.8 mmol), and 1-(2-chloroethyl)-piperidine monohydrochloride (442 mg, 2.4 mmol) in acetone (5 mL) was stirred and heated in an oil bath at 60° C. for 4 hours. After cooling to room temperature, the mixture was diluted with EtOAc and filtered to remove salts. The filtrate was washed with water and brine, dried over MgSO4, filtered, and evaporated under vacuum to a yellow gum (0.95 g). The crude product was purified by chromatography on EM silica gel 60 (230-400 mesh, 50 mL dry) using 2% MeOH+1% Et3N in EtOAc as eluting solvent. The product containing fractions were evaporated under vacuum and the residue stripped with toluene to provide 9a-butyl-7-methoxy-4-{4-[2-(1-piperidinyl)ethoxy]phenyl}-1,2,9,9a-tetrahydro-3H-fluoren-3-one (912 mg, 96% weight pure) as a pale yellow gum.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:38][N:39]([CH3:46])[CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:43]3[CH2:44][CH2:45][CH:40]([N:39]([CH3:46])[CH3:38])[CH2:41][CH2:42]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CN(C)C1CCNCC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(N(C)C)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with 4-dimethylamino-piperidine (Oakwood) to give the title compound. HR-MS (ES, m/z) calculated for C36H46Cl2N5O2 [(M+H)+] 650.3023, observed 650.3027.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)[OH:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:25][S:26]([O:11][C@H:10]([C:12]1[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=1)[CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])(=[O:28])=[O:27]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](O)c1ccncc1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OC[C@H](OS(C)(=O)=O)c1ccncc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of (R)-2-(tert-butyldimethylsilyloxy)-1-(pyridin-4-yl)ethanol (80 mg, 0.316 mmol), triethylamine (97 μL, 0.695 mmol) and 4-(dimethylamino)pyridine (3.85 mg, 0.032 mmol) in DCM was added methanesulfonyl chloride (36.8 μL, 0.474 mmol) at 0° C. The reaction was stirred at 0° C. for 20 min, then at room temperature overnight. The mixture was washed with a NaHCO3 solution, water and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure to give the title compound without further purification. LCMS m/z=332.3 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:10]=2[O:11][CH2:12][C:13]#[N:14])[C:5]([Cl:20])=[CH:4][N:3]=1.[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([CH:28]2[CH2:33][CH2:32][N:31]([CH:34]3[CH2:40][CH2:39][C:38]4[CH:41]=[C:42]([NH2:45])[CH:43]=[CH:44][C:37]=4[CH2:36][CH2:35]3)[CH2:30][CH2:29]2)[CH2:24][CH2:23]1>>[Cl:20][C:5]1[C:6]([NH:8][C:9]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:10]=2[O:11][CH2:12][C:13]#[N:14])=[N:7][C:2]([NH:45][C:42]2[CH:43]=[CH:44][C:37]3[CH2:36][CH2:35][CH:34]([N:31]4[CH2:32][CH2:33][CH:28]([N:25]5[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]5)[CH2:29][CH2:30]4)[CH2:40][CH2:39][C:38]=3[CH:41]=2)=[N:3][CH:4]=1
Reactant: CN1CCN(C2CCN(C3CCc4ccc(N)cc4CC3)CC2)CC1
Reactant: N#CCOc1cccc(F)c1Nc1nc(Cl)ncc1Cl
Product: CN1CCN(C2CCN(C3CCc4ccc(Nc5ncc(Cl)c(Nc6c(F)cccc6OCC#N)n5)cc4CC3)CC2)CC1

Procedure:
The title compound was prepared by combining [2-(2,5-dichloro-pyrimidin-4-ylamino)-3-fluoro-phenoxy]-acetonitrile (Example N?, 31.3 mg, 0.100 mmol) and 7-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine (Example N?, 25.2 mg, 0.074 mmol) in an analogous manner described in Example 151d. The title product was isolated as described in Example 1475b as a white foam (33 mg, 66%) that had the following properties: m.p: 110-116° C.; LC/MS (m/e): 620 (M+H); 1H-NMR (CDCl3, 400 MHz): δ 8.10 (s, 1H), 7.36 (dd, J=14.7, 7.81H), 7.14 (s, 1H), 7.05 (d, J=6.9, 1H), 7.01 (d, J=8.7, 1H), 6.94-6.90 (m, 2H), 6.88 (s, 1H), 6.50 (s, 1H), 4.73 (s, 2H), 2.90-2.80 (m, 2H), 2.75-2.35 (m, 10H), 2.30 (s, 3H), 2.30-2.18 (m, 2H), 2.10-2.00 (m, 2H), 1.85-1.65 (m, 4H), 1.65-1.45 (m, 2H) 1.40-1.20 (m, 4H).
Reaction SMILES: F[C:2](F)(F)[C:3](O)=O.[CH3:8][O:9][C:10]1[C:19]2[N:18]=[C:17]([NH:20][C:21](=[O:28])[C:22]3[CH:27]=[CH:26][CH:25]=[N:24][CH:23]=3)[N:16]3[CH2:29][CH2:30][N:31]=[C:15]3[C:14]=2[CH:13]=[CH:12][C:11]=1[O:32][CH2:33][CH2:34][CH:35]1[O:40][CH2:39][CH2:38][NH:37][CH2:36]1.C(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.Cl>C1COCC1.CO>[CH2:2]([N:37]1[CH2:38][CH2:39][O:40][CH:35]([CH2:34][CH2:33][O:32][C:11]2[CH:12]=[CH:13][C:14]3[C:15]4[N:16]([CH2:29][CH2:30][N:31]=4)[C:17]([NH:20][C:21](=[O:28])[C:22]4[CH:27]=[CH:26][CH:25]=[N:24][CH:23]=4)=[N:18][C:19]=3[C:10]=2[O:9][CH3:8])[CH2:36]1)[CH3:3]
Reactant: O=C(O)C(F)(F)F
Reactant: COc1c(OCCC2CNCCO2)ccc2c1N=C(NC(=O)c1cccnc1)N1CCN=C21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(=O)O
Product: CCN1CCOC(CCOc2ccc3c(c2OC)N=C(NC(=O)c2cccnc2)N2CCN=C32)C1
Reaction time: 0.5 h
Yield: 0 %

Procedure:
N-[7-Methoxy-8-(2-morpholin-2-ylethoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide trifluoroacetate (100 mg, 0.18 mol) in THF was treated with acetaldehyde (30 μL, 0.53 mmol) and stirred for 30 min. before adding sodium triacetoxyborohydride (113 mg, 0.53 mmol) and acetic acid (13 μL, 0.23 mmol). The reaction mixture was stirred at 60 C overnight after which it was diluted with methanol and a drop of 2 N hydrochloric acid to dissolve all solids. The crude solution was purified by HPLC (Gilson, 5% MeCN/95% H2O to 50% MeCN/50% H2O gradient, 0.1% TFA). The fractions were concentrated under reduced pressure then diluted with a minimum of methanol and pulled through a silica bound NH2 cartridge to give the title compound as a solid (17 mg, 20%): HPLC MS RT=0.21 min, MH+=479.1; 1H NMR (DMSO-d6) δ: 12.75 (1H, s), 9.32 (1H, s), 8.71 (1H, d), 8.45 (1H, d), 7.59 (1H, d), 7.54-7.47 (1H, m), 7.06 (2H, d), 4.23-4.08 (3H, m), 4.06-3.98 (2H, m) 3.92 (3H, s), 3.77 (1H, d), 3.67-3.57 (1H, m), 3.46 (1H, t), 2.84 (1H, d), 2.68 (1H, d), 2.30 (2H, q), 1.99-1.79 (3H, m), 1.74 (1H, t), 0.99 (3H, t).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]=[C:11]([NH:13][C:14]3[CH:15]=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=3)[C:10](I)=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:23][C:24]1[N:29]=[C:28]([S:30][CH3:31])[N:27]=[C:26]([Sn](CCCC)(CCCC)CCCC)[N:25]=1.[F-].[Cs+].O1CCOCC1>O.[Cu]I.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>[CH:1]1([NH:6][C:7]2[N:12]=[C:11]([NH:13][C:14]3[CH:15]=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=3)[C:10]([C:26]3[N:25]=[C:24]([CH3:23])[N:29]=[C:28]([S:30][CH3:31])[N:27]=3)=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(Nc2nc(NC3CCCC3)ncc2I)cn1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(C)nc(SC)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(Nc2nc(NC3CCCC3)ncc2-c2nc(C)nc(SC)n2)cn1
Temperature: 140 °C
Yield: 34.6 %

Procedure:
A glass microwave reaction vessel was charged with N2-cyclopentyl-5-iodo-N4-(6-methoxypyridin-3-yl)pyrimidine-2,4-diamine (145 mg, 0.353 mmol), 2-methyl-4-(methylthio)-6-(tributylstannyl)-1,3,5-triazine (152 mg, 0.353 mmol), copper(I) iodide (14 mg, 0.071 mmol), cesium fluoride (107 mg, 0.705 mmol), tetrakis(triphenylphosphine)palladium(0) (40.7 mg, 0.035 mmol) and dioxane (3 mL). The reaction mixture was stirred and heated in a Emrys Optimizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 140° C. for 20 min. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (2×30 mL). The organic extract was washed with saturated NaCl (5 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as a black solid. The crude product was purified by silica gel chromatography eluting with 50% EtOAc/hexanes to give N2-cyclopentyl-N4-(6-methoxypyridin-3-yl)-5-(4-methyl-6-(methylthio)-1,3,5-triazin-2-yl)pyrimidine-2,4-diamine (52 mg, 0.122 mmol, 34.7% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 11.46-11.87 (m, 1H); 9.15-9.62 (m, 1H); 8.26-8.63 (m, 1H); 7.84-8.26 (m, 1H); 6.77 (d, J=8.77 Hz, 1H); 5.11-5.52 (m, 1H); 4.12-4.56 (m, 1H); 3.95 (s, 3H); 2.59 (d, J=6.87 Hz, 6H); 1.87-2.21 (m, 2H); 1.56-1.87 (m, 4H). m/z (ESI, +ve ion) 425.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[C:12]1[S:16][C:15]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][OH:25])[N:19]=2)=[C:14]([C:26]([NH2:28])=[O:27])[CH:13]=1.[CH3:29][P:30]([CH3:33])(=O)[OH:31].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.C(=O)(O)[O-].[Na+]>CN(C=O)C>[CH3:29][P:30]([CH3:33])(=[O:31])[O:25][CH2:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([NH:17][C:15]2[S:16][C:12]([C:3]3[CH:4]=[CH:5][C:6]([C:8]([OH:11])([CH3:9])[CH3:10])=[CH:7][C:2]=3[F:1])=[CH:13][C:14]=2[C:26]([NH2:28])=[O:27])[N:19]=1
Reactant: CP(C)(=O)O
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(Nc3cccc(CO)n3)s2)c(F)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(Nc3cccc(COP(C)(C)=O)n3)s2)c(F)c1
Temperature: 25 °C

Procedure:
5-[2-Fluoro-4-(1-hydroxy-1-methylethyl)phenyl]-2-{[6-(hydroxymethyl)pyridin-2-yl]amino}thiophene-3-carboxamide (Example 43) (125 mg, 0.31 mmol), dimethylphosphinic acid (32.2 mg, 0.34 mmol), BOP (207 mg, 0.47 mmol) and DIPEA (48.3 mg, 0.37 mmol) were stirred in DMF (1 mL) at room temperature for 6 hours. Additional dimethylphosphinic acid (11.71 mg, 0.13 mmol), BOP (68.9 mg, 0.16 mmol) and DIPEA (0.033 mL, 0.19 mmol) were added and the reaction mixture was maintained at room temperature overnight. Saturated sodium bicarbonate was added and the mixture was extracted with EtOAc (×5). The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by silica gel column chromatography (0-10% MeOH-EtOAc) gave the title compound as a pale yellow solid.
Reaction SMILES: [CH2:1]([C:8]1[CH:17]=[CH:16][C:11]2[NH:12][C:13](=[S:15])[NH:14][C:10]=2[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:19][CH2:20][CH2:21][OH:22].[OH-].[Na+].C(O)C>O>[CH2:1]([C:8]1[CH:17]=[CH:16][C:11]2[N:12]=[C:13]([S:15][CH2:19][CH2:20][CH2:21][OH:22])[NH:14][C:10]=2[CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCCCCl
Reactant: S=c1[nH]c2ccc(Cc3ccccc3)cc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: OCCCSc1nc2ccc(Cc3ccccc3)cc2[nH]1
Yield: 65.4 %

Procedure:
12.02 g (50 mmoles) of 5-benzyl-benzimidazoline-2-thione, 4.72 ml of 3-chloro-1-propanol, 2.0 g (50 mmoles) of sodium hydroxide dissolved in water and ethanol are reacted as described in the above Example. The recovering of the product is carried out similarly. 9.76 g (65.4%) of title product are obtained. M.p.: 103°-105° C.
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]1([C:14]2[CH:15]=[C:16]([C:20]3[N:29]=[C:28]([NH:30][C:31]4[CH:32]=[C:33]5[C:37](=[CH:38][CH:39]=4)[N:36](C([O-])=O)[N:35]=[CH:34]5)[C:27]4[C:22](=[CH:23][C:24]([O:53][CH3:54])=[C:25]([O:43][CH2:44][CH2:45][N:46]5[CH2:51][CH2:50][N:49]([CH3:52])[CH2:48][CH2:47]5)[CH:26]=4)[N:21]=3)[CH:17]=[CH:18][CH:19]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[C:8]1([C:14]2[CH:15]=[C:16]([C:20]3[N:29]=[C:28]([NH:30][C:31]4[CH:32]=[C:33]5[C:37](=[CH:38][CH:39]=4)[NH:36][N:35]=[CH:34]5)[C:27]4[C:22](=[CH:23][C:24]([O:53][CH3:54])=[C:25]([O:43][CH2:44][CH2:45][N:46]5[CH2:47][CH2:48][N:49]([CH3:52])[CH2:50][CH2:51]5)[CH:26]=4)[N:21]=3)[CH:17]=[CH:18][CH:19]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COc1cc2nc(-c3cccc(-c4ccccc4)c3)nc(Nc3ccc4c(cnn4C(=O)[O-])c3)c2cc1OCCN1CCN(C)CC1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2nc(-c3cccc(-c4ccccc4)c3)nc(Nc3ccc4[nH]ncc4c3)c2cc1OCCN1CCN(C)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 64 %

Procedure:
TFA (4 mL) was added to 5-(2-[(3-phenyl)phenyl)-7-methoxy-6-(2-(4-methylpiperazin-1-yl)ethoxy)quinazolin-4-ylamino)-1H-indazole-1-carboxylate and the reaction was stirred at RT for 1.5 h. The solution was concentrated in vacuo and the crude product was triturated with ether and filtered, dried under vacuum to give 2-[(3-phenyl)phenyl)-N-(1H-indazol-5-yl)-7-methoxy-6-(2-(4-methylpiperazin-1-yl)ethoxy)quinazolin-4-amine (0.166 g, 0.283 mmole, 64% over two steps). MS 586.4 (M+1). HPLC retention time 5.06 mins.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:15][CH3:16])[S:14][C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([OH:17])=[CH:5][C:4]=2[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:25][CH2:26][CH2:27][Cl:28].O>CN(C=O)C>[Cl:28][CH2:27][CH2:26][CH2:25][O:17][C:6]1[CH:7]=[CH:8][C:9]2[C:10]3[S:14][C:13]([CH2:15][CH3:16])=[N:12][C:11]=3[C:2]([NH2:1])=[N:3][C:4]=2[CH:5]=1
Reactant: CCc1nc2c(N)nc3cc(O)ccc3c2s1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1nc2c(N)nc3cc(OCCCCl)ccc3c2s1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 59.8 %

Procedure:
A mixture of 4-amino-2-ethylthiazolo[4,5-c]quinolin-7-ol (1.00 mg, 4.08 mmol), cesium carbonate (5.30 g, 16.3 mmol), and DMF (40 mL) was stirred at 50° C. for 10 minutes. A portion (0.05 mL) of a solution (1.1 mL) of 1-bromo-3-chloropropane (705 mg, 4.48 mmol) in DMF was added every 7 minutes. After 2 hours the reaction mixture was poured into water (225 mL). The mixture was stirred for 30 minutes and then filtered. The isolated solid was dried to provide 785 mg of 7-(3-chloropropoxy)-2-ethylthiazolo[4,5-c]quinolin-4-amine as a brown solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[CH2:7][C:8]1[C:9]([CH3:22])=[N:10][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=2)[C:12]=1[CH3:13])([CH3:4])([CH3:3])[CH3:2].[CH:24](N(C(C)C)CC)(C)[CH3:25].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:1]([O:5][C:6](=[O:23])[CH2:7][C:8]1[C:9]([CH3:22])=[N:10][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:24]#[CH:25])=[CH:17][CH:16]=2)[C:12]=1[CH3:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1nn(Cc2ccc(I)cc2)c(C)c1CC(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1ccc(Cn2nc(C)c(CC(=O)OC(C)(C)C)c2C)cc1
Reaction time: 15 h

Procedure:
To a stirred solution of 1-(4-iodobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl-acetic acid tert.-butyl ester (12.2 g) in tetrahydrofuran (100 ml) at room temperature is added diisopropylethylamine (12.3 ml). The solution is degassed and put under argon. Ethynyltrimethylsilane (4.5 ml), copper(I)iodide (543 mg) and bis-(triphenylphosphine)-palladiumdichloride (1.0 g) are added. After 15 h of stirring, the reaction is absorbed onto Extrelute and purified by flash chromatography (4:1 isocratic-cyclohexane:ethyl acetate) to yield a solid (10.7 g; [M+H]=397; HPLC retention time 1.71 min (Method J)). The solid is dissolved in tetrahydrofuran (200 ml) and is stirred together with tetrabutylammonium fluoride (1 M in THF, 28 ml). After 15 h at room temperature, the reaction mixture is concentrated in vacuo. The residue is purified by flash chromatography (4:1 isocratic-cyclohexane:ethyl acetate) to yield 1-(4-ethynylbenzyl)-3,5-dimethyl-1H-pyrazol-4-yl-acetic acid tert.-butyl ester (6.8 g; [M+H]=325; HPLC retention time 1.47 min (Method J)).
Reaction SMILES: [C:1]([C:3]1[N:4]([CH2:21][C:22](O)=[O:23])[C:5]([C:8]2[CH:9]=[CH:10][C:11]3[NH:16][C:15](=[O:17])[O:14][C:13]([CH3:19])([CH3:18])[C:12]=3[CH:20]=2)=[CH:6][CH:7]=1)#[N:2].[CH2:25]([O:27][C:28]1[CH:29]=[C:30]([CH2:36][CH2:37][NH2:38])[CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH3:26].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O.O>[C:1]([C:3]1[N:4]([CH2:21][C:22]([NH:38][CH2:37][CH2:36][C:30]2[CH:31]=[CH:32][C:33]([O:34][CH3:35])=[C:28]([O:27][CH2:25][CH3:26])[CH:29]=2)=[O:23])[C:5]([C:8]2[CH:9]=[CH:10][C:11]3[NH:16][C:15](=[O:17])[O:14][C:13]([CH3:18])([CH3:19])[C:12]=3[CH:20]=2)=[CH:6][CH:7]=1)#[N:2]
Reactant: CC1(C)OC(=O)Nc2ccc(-c3ccc(C#N)n3CC(=O)O)cc21
Reactant: CCOc1cc(CCN)ccc1OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOc1cc(CCNC(=O)Cn2c(C#N)ccc2-c2ccc3c(c2)C(C)(C)OC(=O)N3)ccc1OC

Procedure:
A solution of [2-cyano-5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrol-1-yl]acetic acid (0.6 g, 1.8 mmol), 3-ethoxy-4-methoxyphenylethylamine (0.36 g, 1.9 mmol), diiso-propylethylamine (0.26 g, 2 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.7 g, 1.8 mmol) in dimethylformamide (20 ml) was stirred at room temperature for 20 hours. The mixture was diluted with water and extracted with ethylacetate. The ethylacetate solution was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was recrystallized from ethanol to afford the title compound, m.p. 160–162° C. (0.2 g, 22%): 1H-NMR (DMSO-d6) δ1.3 (t, J=6.9 Hz, 3H), 1.59 (s, 6H), 2.61 (t, 2H, J=7 Hz), 3.29 (q, J=6.9 Hz, 2H), 3.71 (s, 3H), 3.97 (q, J=6.9 Hz, 2H), 4.6 (s, 2H), 6.32 (d, J=5.1 Hz, 1H), 6.65 (dd, J=7.6, 2.0 Hz, 1H), 6.77 (d, J=2.3, 1H), 6.83 (d, J=8.3 Hz, 1H), 6.96 (d, J=8.7 Hz, 1H), 7.05 (d, J=4.1 Hz, 1H), 7.26 (m, 2H), 8.3 (t, J=6 Hz, 1H), 10.42 (s, 1H), MS (APCI (+)) m/z 503 (M+H)+
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:41]=[CH:40][C:25]([O:26][C:27]2[CH:39]=[CH:38][C:30]([O:31][CH2:32][CH2:33][CH2:34][C:35](O)=[O:36])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C[O:44][C:45](=[O:51])[C@H:46]([CH:48]([CH3:50])[CH3:49])[NH2:47]>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]2[CH:28]=[CH:29][C:30]([O:31][CH2:32][CH2:33][CH2:34][C:35]([NH:47][C@H:46]([C:45]([OH:44])=[O:51])[CH:48]([CH3:50])[CH3:49])=[O:36])=[CH:38][CH:39]=2)=[CH:40][CH:41]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(OCCCC(=O)O)cc2)cc1
Reactant: COC(=O)[C@@H](N)C(C)C
Agent: Cl
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(OCCCC(=O)N[C@H](C(=O)O)C(C)C)cc2)cc1

Procedure:
The product from Example 233 and L-valine methyl ester hydrochloride were processed as described in Example 251A and B to provide the titled compound. 1H NMR (500 MHz, DMSO-d6) δ12.18-12.73 (br.s, 1 H), 8.94 (s, 1 H), 7.98 (d, 1 H), 7.23 (m, 7 H), 6.97 (m, 7 H), 6.82 (d, 2 H), 4.14 (m, 1 H), 4.04 (s, 2 H), 4.00 (s, 2 H), 3.94 (t, 2 H), 2.91 (s, 3 H), 2.39 (s, 3 H), 2.34 (m, 2 H), 2.03 (m, 1 H), 1.92 (m, 2 H), 0.87 (dd, 6 H); MS (ESI+) m/z 674 (M+H)+.
Reaction SMILES: C[N:2](C=O)C.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:23]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)=[N:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([S:32]([OH:35])(=O)=[O:33])[CH:20]=3)[N:15]=2)=[CH:10][CH:9]=1>S(Cl)(Cl)=O>[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:23]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)=[N:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([S:32]([NH2:2])(=[O:35])=[O:33])[CH:20]=3)[N:15]=2)=[CH:10][CH:9]=1
Reactant: COc1ccc(-c2nc3ccc(S(=O)(=O)O)cc3nc2-c2ccc(OC)cc2)cc1
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: COc1ccc(-c2nc3ccc(S(N)(=O)=O)cc3nc2-c2ccc(OC)cc2)cc1
Yield: 12 %

Procedure:
DMF (2 mL) was added dropwise with stirring to a solution of 2,3-bis(4-methoxyphenyl)quinoxaline-6-sulfonic acid (137.2 mg, 0.33 mmol, 1.00 equiv) in thionyl chloride (12 mL), stirred at reflux for 3 h in an oil bath, then concentrated under vacuum. The residue was dissolved in acetonitrile (10 mL), and added dropwise to a solution of ammonia (2 g) in acetonitrile (10 mL) at 0° C. The resulting mixture was stirred for overnight at room temperature. The reaction mixture was concentrated under vacuum and purified via Prep-HPLC affording 16 mg (12%) of 2,3-bis(4-methoxyphenyl)quinoxaline-6-sulfonamide as a light yellow solid.
Reaction SMILES: O.O.[Sn](Cl)Cl.[N+:6]([C:9]1[CH:34]=[CH:33][C:12]2[C:13](=[O:32])[C:14]3[CH:21]=[CH:20][C:19]([NH:22][C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=4[O:30][CH3:31])=[CH:18][C:15]=3[O:16][CH2:17][C:11]=2[CH:10]=1)([O-])=O>C(O)C>[NH2:6][C:9]1[CH:34]=[CH:33][C:12]2[C:13](=[O:32])[C:14]3[CH:21]=[CH:20][C:19]([NH:22][C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=4[O:30][CH3:31])=[CH:18][C:15]=3[O:16][CH2:17][C:11]=2[CH:10]=1
Reactant: COc1cc(F)ccc1Nc1ccc2c(c1)OCc1cc([N+](=O)[O-])ccc1C2=O
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: COc1cc(F)ccc1Nc1ccc2c(c1)OCc1cc(N)ccc1C2=O

Procedure:
In accordance with general method Y, 0.30 g (1.32 mmol) of tin(II) chloride dihydrate is dissolved in 15 ml of ethanol, and 0.07 g (0.19 mmol) of (16) is added. Yield: 0.042 g (60.6%); melting point: 38.9° C.; C21H17FN2O3 (Mr=364.38); LC 18.82 min