Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([C:15]3[C:16]([NH:27][C:28]4[CH:29]=[N:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=4)=[N:17][CH:18]=[C:19]([C:21]4[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=4)[CH:20]=3)[N:12]=[C:11]([CH3:36])[N:10]=2)=CC=1>C(O)(C(F)(F)F)=O>[CH3:35][O:34][C:31]1[N:30]=[CH:29][C:28]([NH:27][C:16]2[C:15]([C:13]3[N:12]=[C:11]([CH3:36])[N:10]=[C:9]([NH2:8])[N:14]=3)=[CH:20][C:19]([C:21]3[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=3)=[CH:18][N:17]=2)=[CH:33][CH:32]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(-c4cnn(C)c4)cnc3Nc3ccc(OC)nc3)n2)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Nc2ncc(-c3cnn(C)c3)cc2-c2nc(C)nc(N)n2)cn1
Temperature: 80 °C
Yield: 82.9 %

Procedure:
N,N-bis(4-methoxybenzyl)-4-(2-(6-methoxypyridin-3-ylamino)-5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (140 mg, 0.222 mmol) was treated with TFA (10 mL) and heated at 80° C. with a reflux condenser for 18 h. The TFA was removed in vacuo and the residue was treated with 2 M NH3 in MeOH to pH 7 and dry-packed with silica gel. Purification on the ISCO (12 g column, 1-20% MeOH in DCM) gave 4-(2-(6-methoxypyridin-3-ylamino)-5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (71.7 mg, 0.184 mmol, 83% yield) as an orange crystalline solid. m/z (ESI, +ve ion) 390.0 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 11.69 (1H, s); 8.87 (1H, d, J=2.5 Hz); 8.55 (2H, t, J=3.1 Hz); 8.18 (1H, dd, J=8.8, 2.7 Hz); 8.12 (1H, s); 7.90 (1H, s); 7.82 (1H, s); 7.77 (1H, s); 6.84 (1H, d, J=8.8 Hz); 3.88 (3H, s); 3.85 (3H, s); 2.46 (3H, s).
Reaction SMILES: Cl[CH:2]=[CH:3][C:4](=O)[CH:5]([CH3:7])[CH3:6].[NH2:9][C:10]1[N:14]=[CH:13][NH:12][N:11]=1>C(O)(=O)C>[CH3:6][CH:5]([C:4]1[N:11]2[N:12]=[CH:13][N:14]=[C:10]2[N:9]=[CH:2][CH:3]=1)[CH3:7]
Reactant: CC(C)C(=O)C=CCl
Reactant: Nc1nc[nH]n1
Solvent: CC(=O)O
Product: CC(C)c1ccnc2ncnn12

Procedure:
A mixture of 1-chloro-4-methyl-1-penten-3-one (5.83 g), 3-amino-1,2,4-triazole (3.69 g) and glacial acetic acid was heated under reflux for 1 hour and 30 minutes. The reaction mixture was poured onto ice and extracted with dichloromethane. The organic layer was dried over magnesium sulphate and the solvent was evaporated to give a product which was recrystallised from petroleum ether (b.p. 100°-140° C.), to give 7-(1-methylethyl)-1,2,4-triazolo[1,5-a]pyrimidine. Yield 4.18 g.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].O.Cl[C:16]([O:18][CH2:19][CH3:20])=[O:17].C(=O)([O-])O.[Na+]>CC(C)=O>[CH2:19]([O:18][C:16]([O:1][N:2]=[C:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:17])[CH3:20]
Reactant: CCOC(=O)Cl
Reactant: CCOC(=O)C(=NO)C(=O)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)ON=C(C(=O)OCC)C(=O)OCC
Temperature: 0 °C
Reaction time: 4 h
Yield: 101.7 %

Procedure:
A mixture of diethyl 2-hydroxyiminomalonate (18.9 g), water (50 ml) and acetone (8 ml) is cooled at 0°C, and ethyl chloroformate (9.8 g) is dropwise added thereto. The resulting mixture is, after adjusted to pH 7 to 8 with the addition of an aqueous solution of sodium hydrogencarbonate, stirred at room temperature for 4 hours. The reaction mixture is extracted with ether, and the ether layer is washed with an aqueous solution of sodium chloride, dried and concentrated to give diethyl 2-ethoxycarbonyloxyiminomalonate (24 g) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:10]([CH2:13][NH:14][C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])=[CH:9][C:3]=1[C:4]([N:6]=[C:7]=[O:8])=O.[Cl:21][C:22]1[CH:23]=[C:24]([NH:29][NH:30]C(OC(C)(C)C)=O)[CH:25]=[CH:26][C:27]=1[F:28].FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:12]=[CH:11][C:10]([CH2:13][NH:14][C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])=[CH:9][C:3]=1[C:4]1[NH:6][C:7](=[O:8])[N:29]([C:24]2[CH:25]=[CH:26][C:27]([F:28])=[C:22]([Cl:21])[CH:23]=2)[N:30]=1
Reactant: O=C=NC(=O)c1cc(CNC(=O)C(F)(F)F)ccc1Cl
Reactant: CC(C)(C)OC(=O)NNc1ccc(F)c(Cl)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCc1ccc(Cl)c(-c2nn(-c3ccc(F)c(Cl)c3)c(=O)[nH]2)c1)C(F)(F)F
Yield: 28.7 %

Procedure:
The title compound was prepared according to the procedure described in Example-83 by using 2-chloro-5-((2,2,2-trifluoroacetamido)methyl)benzoyl isocyanate (step-3 of Intermediate-26, 0.500 g, 1.55 mmol), tert-butyl 2-(3-chloro-4-fluorophenyl)hydrazinecarboxylate (Intermediate-85, 0.455 g, 1.55 mmol), DCM (20 mL) and trifluoro acetic acid (5.0 mL) to afford 0.200 g of the desired product.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5]([OH:7])=[O:6].N([O-])=O.[Na+].[I-:18].[K+]>O.S(=O)(=O)(O)O>[I:18][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: Nc1cc(C(=O)O)cc([N+](=O)[O-])c1
Reactant: [I-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: O=C(O)c1cc(I)cc([N+](=O)[O-])c1
Reaction time: 1 h
Yield: 73.1 %

Procedure:
To a suspension of 3-amino-5-nitrobenzoic acid (5.0 g, 27.45 mmol) in water (23 mL) and conc. sulfuric acid (3.15 mL) was added at 0-5° C. sodium nitrite (1.89 g, 27.45 mmol), the mixture was stirred at this temp for 1 h, and potassium iodide (7.59 g, 45.75 mmol) was added. After stirring at room temperature for an additional 2 h, the mixture was extracted, washed with a 10% solution of sodium sulfite, followed by water, then brine, dried over magnesium sulfate, and concentrated to dryness. Purification by flash chromatography gave 5.88 g of 3-iodo-5-nitro-benzoic acid as a yellow solid.
Reaction SMILES: [CH2:1]1[O:24][CH:4]([C:5]2[C:13]3[N:12]=[C:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[N+:20]([O-])=O)[N:10]([CH3:23])[C:9]=3[CH:8]=[CH:7][CH:6]=2)[O:3][CH2:2]1>CO.[Pd]>[CH2:1]1[O:24][CH:4]([C:5]2[C:13]3[N:12]=[C:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[NH2:20])[N:10]([CH3:23])[C:9]=3[CH:8]=[CH:7][CH:6]=2)[O:3][CH2:2]1
Reactant: Cn1c(-c2ccccc2[N+](=O)[O-])nc2c(C3OCCO3)cccc21
Agent: [Pd]
Solvent: CO
Product: Cn1c(-c2ccccc2N)nc2c(C3OCCO3)cccc21
Yield: 99 %

Procedure:
A solution of 6 (0.85 g, 2.6 mmol) in 50 mL MeOH was mixed with 85 mg of Pd/C and hydrogenated with H2 at a pressure of 10 psi for 3 hours. The mixture was then filtered, and the solvent was removed to give 0.76 g (98%) of the title compound as a white solid. 1H NMR (CDCl3): δ 4.44 (s, 3H), 4.69-4.90 (m, 4H), 5.69 (broad s, 2H), 7.44 (d, J=7.8 Hz, 2H), 7.81-8.05 (m, 4H), 8.14 (d, J=1.6, 6.9 Hz, 1H); HRMS: Calcd. for C17H17N3O2 295.1321, found 295.1325.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CO.CS(C)=O.C[CH2:54][O:55][C:56](C)=[O:57].CCCCCC>CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:54][O:55][C:56]([C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:16]2)=[O:57]
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(Br)cc2C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: CS(C)=O
Solvent: CO
Product: COC(=O)c1ccc2c(c1)CN(C(=O)OC(C)(C)C)C2
Temperature: 80 °C
Reaction time: 16 h
Yield: 81 %

Procedure:
A mixture of 5-bromo-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (200 mg, 0.67 mmol), Pd(OAc)2 (30 mg, 0.2 equiv), DPPP (55 mg, 0.2 equiv), TEA (0.93 mL, 10 equiv) and MeOH:DMSO (1:1, 4 mL) was stirred for 16 h under CO (balloon) at 80° C. LC-MS and TLC (20% EtOAc-Hexane) showed completion of the reaction. The Reaction mixture was concentrated to remove MeOH and diluted with EtOAc (10 mL), and washed with water (2×25 mL). The organic layer was dried (Na2SO4), concentrated and purified by silica gel column chromatography (eluent=20% EtOAc-Hexane), giving pure 1,3-dihydro-isoindole-2,5-dicarboxylic acid 2-tert-butyl ester 5-methyl ester (150 mg, 81%). MS (APCI+): m/z 178.1 (MH+−Boc).
Reaction SMILES: [NH2:1][C:2]1[N:7]([C:8]2[C:13]([F:14])=[CH:12][C:11]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Cl)=[CH:10][C:9]=2[F:22])[C:6](=[O:23])[CH:5]=[CH:4][C:3]=1[C:24](=[O:33])[C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32].Cl.[NH2:35][C@H:36]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH:38]([CH3:40])[CH3:39].[I-].[Na+].C(N(CC)C(C)C)(C)C>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[N:7]([C:8]2[C:13]([F:14])=[CH:12][C:11]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:35][C@H:36]([C:41]([O:43][C:44]([CH3:46])([CH3:45])[CH3:47])=[O:42])[CH2:37][CH:38]([CH3:40])[CH3:39])=[CH:10][C:9]=2[F:22])[C:6](=[O:23])[CH:5]=[CH:4][C:3]=1[C:24](=[O:33])[C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32]
Reactant: CC(C)C[C@H](N)C(=O)OC(C)(C)C
Reactant: Nc1c(C(=O)c2ccc(F)cc2F)ccc(=O)n1-c1c(F)cc(OCCCCCCl)cc1F
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)C[C@H](NCCCCCOc1cc(F)c(-n2c(N)c(C(=O)c3ccc(F)cc3F)ccc2=O)c(F)c1)C(=O)OC(C)(C)C
Temperature: 90 °C
Yield: 18 %

Procedure:
From Intermediate 4G. To a solution of 6-Amino-1-{4-[(5-chloropentyl)oxy]-2,6-difluorophenyl}-5-(2,4-difluorobenzoyl)pyridin-2(1H)-one (96 mg, 0.20 mmol) in anhydrous DMF (3 ml) under an atmosphere of nitrogen was added tert-butyl L-leucinate hydrochloride (198 mg, 0.99 mmol, 5 eq), sodium iodide (60 mg, 0.40 mmol, 2 eq) and N,N-diisopropylethylamine (0.072 ml, 0.40 mmol, 2 eq). The mixture was heated at 90° C. for 20 hours, before being allowed to cool to room temperature and diluted with EtOAc (20 ml). The solution was washed with water (2×20 ml) and brine (20 ml). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. Purification by column chromatography (1-3% MeOH in DCM) followed by preparative HPLC afforded the title compound as a white solid (23 mg, 18% yield).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[NH:5][C:4]=1[C:13]1[S:14][CH:15]=[CH:16][CH:17]=1.C(N(C(C)C)CC)(C)C.[C:27]([CH2:31][CH2:32][C:33](Cl)=[O:34])([O:29][CH3:30])=[O:28]>C(Cl)Cl>[C:27]([CH2:31][CH2:32][C:33]([NH:1][CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[NH:5][C:4]=1[C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)=[O:34])([O:29][CH3:30])=[O:28]
Reactant: COC(=O)CCC(=O)Cl
Reactant: NCc1cc(-c2cccs2)[nH]c1-c1cccs1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCC(=O)NCc1cc(-c2cccs2)[nH]c1-c1cccs1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 79.1 %

Procedure:
To a solution of 400 mg (1.54 mmol) of 3-aminomethyl-2,5-dithienylpyrrole (XVIII) and 378 ul (3.07 mmol) of diisopropylethylamine in 15 ml of anhydrous methylene chloride was added 3-carbomethoxypropionyl chloride (1.6 ml, 9.23 mmol). After stirring for 5 minutes at room temperature, the reaction mixture was quenched by the addition of 1 ml of water. The aqueous layer was extracted three times with 5 ml portions of chloroform and the combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude reaction product was chromatographed on 100 g of silica gel. Elution with chloroform:methanol, 95:5, gave 456 mg (39%) of the amide (XXVI) as a greenish solid having a mp of 48°-49° C., and Rf :0.55 (chloroform:methanol, 98:2).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:13]N(C=O)C>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH3:13])=[CH:4][CH:3]=1
Reactant: Brc1ccc2cc[nH]c2c1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: Cn1ccc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 6-bromo-1H-indole (2.5 g, 12.8 mmol) in DMF (10 ml) was slowly added NaH (354 mg, 14.0 mmol) at room temperature. The resulting mixture was stirred for 20 min at RT after which Mel (956 μl, 15.4 mmol) was added. The mixture was stirred for 1 hour at room temperature and then partitioned between DCM and brine. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to provide 6-Bromo-1-methyl-1H-indole CXLII in quantitative yield (2.7 g).
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.C(Cl)Cl.[Br:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]([OH:24])=[O:23].[C:29](O)([CH3:32])([CH3:31])[CH3:30]>CN(C1C=CN=CC=1)C>[C:29]([O:23][C:22](=[O:24])[C:21]1[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=1[Br:19])([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)O
Reactant: O=C(O)c1ccccc1Br
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccccc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 101.8 %

Procedure:
To a solution of DCC (32.8 g, 159 mmol) in DCM (200 mL, 2 mol) was added 2-bromobenzoic acid (32.0 g, 159 mmol) followed by DMAP (1.8 g, 15 mmol) and t-butyl alcohol (15.2 mL, 159 mmol). The mixture was stirred at room temperature for 16 hours, then filtered. The organic was washed with saturated NaHCO3 (200 mL), saturated aqueous NaCl, dried over MgSO4, filtered and concentrated under reduced pressure to yield compound A as an oil (41.6 g).
Reaction SMILES: [Cl:1][C:2]([Cl:7])([Cl:6])[C:3](O)=[O:4].ClC(Cl)(Cl)C([O-])=O.[Na+].C([CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1)=O>CN(C=O)C>[Cl:1][C:2]([Cl:7])([Cl:6])[CH:3]([CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1)[OH:4]
Reactant: O=C(O)C(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: O=C([O-])C(Cl)(Cl)Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C(O)C(Cl)(Cl)Cl)CC1
Reaction time: 0.17 h
Yield: 73.5 %

Procedure:
Placed 2,2,2-trichloroacetic acid (5.746 g, 35.17 mmol) in DMF. (5 mL) and added slowly sodium 2,2,2-trichloroacetate (6.519 g, 35.17 mmol). The reaction was stirred for 10 minutes and tert-butyl 4-formylpiperidine-1-carboxylate (5.00 g, 23.44 mmol) was added. The reaction was stirred for 40 minutes then quenched with saturated sodium bicarbonate and filtered. The solids were washed with water and dried. The product was triturated with water and filtered to give the title compound (5.734 g, 73.53% yield).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Si:12](Cl)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].N1C=CN=C1>CN(C=O)C.CCOC(C)=O>[Si:12]([O:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:9])=[O:10])=[CH:4][CH:3]=1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: NS(=O)(=O)c1ccc(O)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(S(N)(=O)=O)cc1
Reaction time: 20 h

Procedure:
4-Hydroxyphenylsulfonamide (3.46 g, 20 mmol) is dissolved in DMF (40 mL) and treated with tert-butyl-dimethylsilylchloride (3.31 g, 22.0 mmol) and imidazole (1.50 g, 22.0 mmol) at room temperature. After 20 hr, the reaction mixture is diluted with EtOAc (100 mL) and washed with 1.0 N HCl (2×50 mL). The organic phase is dried (MgSO4), filtered, and concentrated to yield an oil. The crude oil is purified by Biotage column chromatography (40M SiO2 column, eluted at 75 mL/min with 1:1 hexanes:EtOAc). A white solid is obtained (4.24 g, 15.4 mmol, 77%). ESI-MS m/e 288.1 (M++H); mp 117–118° C.; 1H NMR (CDCl3) δ 7.78 (d, 2H), 6.89 (d, 2H), 4.86 (br s, 2H), 0.97 (s, 9H), 0.20 (s, 6H).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][CH2:13][CH:14]2[C:19]([F:21])([F:20])[CH2:18][CH2:17][N:16]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:15]2)[C:9]2[C:4](=[N:5][CH:6]=[CH:7][N:8]=2)[CH:3]=1.[CH3:29][N:30]([C:37]1[CH:42]=[CH:41][C:40](B2OC(C)(C)C(C)(C)O2)=[CH:39][CH:38]=1)[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.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>[CH2:35]([O:34][C:32](=[O:33])[CH2:31][N:30]([CH3:29])[C:37]1[CH:42]=[CH:41][C:40]([C:2]2[N:11]=[C:10]([NH:12][CH2:13][CH:14]3[C:19]([F:20])([F:21])[CH2:18][CH2:17][N:16]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[CH2:15]3)[C:9]3[C:4](=[N:5][CH:6]=[CH:7][N:8]=3)[CH:3]=2)=[CH:39][CH:38]=1)[CH3:36]
Reactant: CC(C)(C)OC(=O)N1CCC(F)(F)C(CNc2nc(Cl)cc3nccnc23)C1
Reactant: CCOC(=O)CN(C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
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: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)CN(C)c1ccc(-c2cc3nccnc3c(NCC3CN(C(=O)OC(C)(C)C)CCC3(F)F)n2)cc1
Yield: 155.6 %

Procedure:
A solution of tert-butyl 3-((7-chloropyrido[4,3-b]pyrazin-5-ylamino)methyl)-4,4-difluoropiperidine-1-carboxylate (173 mg, 0.42 mmol), ethyl 2-(methyl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)acetate (200 mg, 0.63 mmol), Pd(PPh3)4 and Cs2CO3 in 4 mL of dioxane and 0.5 mL of water was stirred at 160° C. for 1 hour. The volatiles were removed in vacuo, and the residue was purified by chromatography with MeOH/H2O (1:8˜5:1) to give 373 mg of title compound.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18](=[O:22])[C@@H:19]([OH:21])[CH3:20])[CH2:14][CH2:13]3)=[C:8]([CH3:23])[C:6]=2[N:7]=1.C(O)CC.[NH2:34][C:35]1[N:40]=[CH:39][C:38](B(O)O)=[CH:37][N:36]=1.P([O-])([O-])(O)=O.[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.O>[CH3:23][C:8]1[C:6]2[N:7]=[C:2]([C:38]3[CH:37]=[N:36][C:35]([NH2:34])=[N:40][CH:39]=3)[N:3]=[C:4]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:5]=2[S:10][C:9]=1[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([C:18]([C@@H:19]([OH:21])[CH3:20])=[O:22])[CH2:14][CH2:13]1
Reactant: Cc1c(CN2CCN(C(=O)[C@H](C)O)CC2)sc2c(N3CCOCC3)nc(Cl)nc12
Reactant: Nc1ncc(B(O)O)cn1
Agent: Cl[Pd]Cl
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: O
Solvent: CCCO
Product: Cc1c(CN2CCN(C(=O)[C@H](C)O)CC2)sc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc12
Temperature: 80 °C
Reaction time: 10 h

Procedure:
(S)-1-(4-((2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one II (33.0 g, 75 mmol) was charged to a suitably sized reactor, followed by n-propanol (337 g), water (450 g), 2-aminopyrimidin-5-ylboronic acid III (12.5 g, 90 mmol) and dipotassium hydrogen phosphate (39.2 g, 225 mmol). The resulting mixture was degassed by vacuum/argon purge three times. Bis(triphenylphosphine)palladium (II) chloride (0.079 g, 0.112 mmol) was added and the slurry was again degassed by vacuum/argon purge three times. The mixture was heated within 2 h to 65° C. and stirred for 10 hours. The organic phase was separated and slowly filtered over a preheated pressure filter loaded with a ZETACARBON® R55SP pad (Cuno Inc., a 3M Company, Meriden Conn.). The filter unit was washed with a warm (80° C.) n-propanol (45 mL). Water (750 mL) were added to the filtrate and the resulting suspension was cooled to 10° C., aged for 1 h and filtered. The filter cake was washed with water (150 g) and dried under reduced pressure at 45° C. to afford (S)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one, GDC-0980, Formula I as a white solid (30.1 g, 79%).
Reaction SMILES: [CH2:1]([O:8][C:9]([O:11]N1C(=O)CCC1=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][NH:20][CH2:21][C:22]1[NH:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2.C(N(CC)CC)C>CN(C=O)C>[CH2:1]([O:8][C:9]([N:20]([CH2:21][C:22]1[NH:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH3:19])=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CNCc1cc2ccccc2[nH]1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(Cc1cc2ccccc2[nH]1)C(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 80.6 %

Procedure:
N-(Benzyloxycarbonyloxy)succinimide (17.10 g, 68.6 mmole) was added to a solution of 2-(methylaminomethyl)-1H-indole (10.00 g, 62.4 mmole), from Preparation 33, and triethylamine (9.60 mL, 68.6 mmole) in DMF (100 mL) at RT. The reaction was stirred overnight then was concentrated in vacuo. The residue was diluted with water and the mixture was extracted with ethyl acetate. The combined extracts were dried over K2CO3 and concentrated. Flash chromatography on silica gel (20% ethyl acetate/hexanes) gave the title compound (14.80 g, 80%) as an off-white solid: MS (ES) m/e 295 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([O:10][CH2:11][O:12][CH3:13])[CH:7]=[CH:8][CH:9]=1)([O-])=O>CCOCC>[CH3:13][O:12][CH2:11][O:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([NH2:1])[CH:5]=1
Reactant: COCOc1cccc([N+](=O)[O-])c1
Solvent: CCOCC
Product: COCOc1cccc(N)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.1 %

Procedure:
A solution of 11 (5.68 g, 31 mmol) in 310 mL moist ether (8:2:1 Et2O/EtOH/H2O) was cooled to 0° C., and treated with freshly prepared Al—Hg (5.2 g Al, 217 mmol) in small 1×1 cm pieces. The reaction mixture was stirred vigorously for 0.5 h at 0° C., and 1 h at 25° C. The reaction mixture was filtered through Celite, and the Celite was washed thoroughly with Et2O (5×50 mL). The filtrate was washed with saturated aqueous NaCl (300 mL), dried (Na2SO4), and concentrated under reduced pressure to afford 12 (4.23 g, 89%) as a golden oil, which was immediately carried on to the next step without further purification. For 12: 1H NMR (CDCl3, 250 MHz) δ 7.05 (t, J=8.0 Hz, 1H), 6.38 (m, 3H), 5.12 (s, 2H), 3.70 (br s, 2H), 3.46 (s, 3H); 13C NMR (CDCl3, 250 MHz) δ 158.2, 147.7, 129.9, 108.7, 106.0, 102.9, 94.0, 55.7; IR (film) νmax 3452, 3367, 2955, 2900, 1623, 1601, 1494, 1287, 1147, 1074, 1009 cm−; FABHRMS (NBA/NaI) m/z 153.0786 (C8H11NO2 requires 153.0790).
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:14]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:15]([F:18])([F:17])[F:16])=[CH:9][CH:8]=1)=[N+]=[N-]>CO.[Pd]>[NH2:1][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[C:14]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:15]([F:16])([F:17])[F:18])=[CH:9][CH:8]=1
Reactant: [N-]=[N+]=NCCOc1ccc(C(=C(c2ccc(F)cc2)C(F)(F)F)c2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: NCCOc1ccc(C(=C(c2ccc(F)cc2)C(F)(F)F)c2ccccc2)cc1
Yield: 56.2 %

Procedure:
A solution of 8.54 g (20 mmoles) of 1-[4-(2-azidoethoxy)-phenyl]-1-phenyl-3,3,3-trifluoro-2-(4-fluorophenyl)propene, prepared as described in Example 15, in 170 ml of methanol is hydrogenated for about one hour in the presence of 0.9 g of a 5% palladium-on-carbon catalyst. The solution is evaporated and the product is crystallized from hexane. 4.51 g (56.4%) of the title compound are obtained; m.p.: 83°-89° C.
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:11](=[CH:12][NH:13][N:14]=2)[CH:10]=[C:9]([CH3:16])[C:8]=1[NH:17][C:18]([C:20]1[N:21]([C:27]2[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][N:28]=2)[N:22]=[C:23]([O:25][CH3:26])[CH:24]=1)=[O:19])=[O:6])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:42]([S:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])=[O:43]>ClCCl>[CH2:45]([S:44][C:42]([N:13]1[CH:12]=[C:11]2[C:15]([C:7]([C:5](=[O:6])[NH:4][CH:1]([CH3:3])[CH3:2])=[C:8]([NH:17][C:18]([C:20]3[N:21]([C:27]4[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][N:28]=4)[N:22]=[C:23]([O:25][CH3:26])[CH:24]=3)=[O:19])[C:9]([CH3:16])=[CH:10]2)=[N:14]1)=[O:43])[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52]
Reactant: COc1cc(C(=O)Nc2c(C)cc3c[nH]nc3c2C(=O)NC(C)C)n(-c2ncccc2Cl)n1
Reactant: CCCCCCCCSC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCSC(=O)n1cc2cc(C)c(NC(=O)c3cc(OC)nn3-c3ncccc3Cl)c(C(=O)NC(C)C)c2n1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 6-{[2-(3-chloro-pyridin-2-yl)-5-methoxy-2H-pyrazole-3-carbonyl]-amino}-5-methyl-2H-indazole-7-carboxylic acid isopropylamide (0.300 g, 0.64 mmol) in dichloromethane (3.0 mL) was added triethylamine (90 μL, 0.65 mmol), then S-octyl chlorothioformate (0.133 g, 0.64 mmol). The resulting homogeneous reaction mixture was stirred for 0.5 h at 20° C. The reaction mixture was then concentrated in vacuo and the residue was purified by flash-chromatography (SiO2, CH2Cl2/ethyl acetate 9:1) affording the title compound as yellow crystals with a melting point of 98-102° C.