Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[C:9]([C:14]3[CH:19]=[CH:18][C:17]([C:20](=[O:27])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[C:16]([NH2:28])[CH:15]=3)[C:10]([CH3:13])=[CH:11][CH:12]=2)=[O:6])[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:36](OC(=O)C)(=[O:38])[CH3:37]>C(Cl)Cl.C(OCC)(=O)C>[CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[C:9]([C:14]3[CH:19]=[CH:18][C:17]([C:20](=[O:27])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[C:16]([NH:28][C:36](=[O:38])[CH3:37])[CH:15]=3)[C:10]([CH3:13])=[CH:11][CH:12]=2)=[O:6])[CH2:2][CH2:3]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(C(=O)c2ccccc2)c(N)c1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(=O)Nc1cc(-c2cc(C(=O)NC3CC3)ccc2C)ccc1C(=O)c1ccccc1
Reaction time: 6 h
Yield: 85.1 %

Procedure:
To a solution of the 3′-Amino-4′-benzoyl-6-methyl-biphenyl-3-carboxylic acid cyclopropylamide from Example 14 (21 mg, 0.057 mmol) and triethyl amine (29 mg, 0.284 mmol) in 1.5 mL methylene chloride was added acetic anhydride (8.7 mg, 0.085 mmol) at room temperature. The reaction mixture was stirred at that temperature for 6 hours. The mixture was diluted with 50 mL of ethyl acetate and was washed with sat. aqueous NaHCO3 (10 mL), water (10 mL), and brine (10 mL), dried over MgSO4, and the solvents were evaporated. The residue was purified by preparative TLC sheet (ethyl acetate:hexanes=1:1) to give a colorless solid (20 mg, 85%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([Cl:23])=[CH:4][N:3]=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[C:27]([CH3:32])[CH:26]=1>>[Cl:23][C:5]1[CH:6]=[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[C:2]([O:31][C:28]2[CH:29]=[CH:30][C:25]([Cl:24])=[CH:26][C:27]=2[CH3:32])=[N:3][CH:4]=1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Cl)cc1
Reactant: Cc1cc(Cl)ccc1O
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Oc2ccc(Cl)cc2C)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 45 from methyl 4-((1S)-1-{[(2,5-dichloropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1 of Example 48) and 4-chloro-2-methylphenol: 1H-NMR (CDCl3) δ 8.57 (1H, d, J=2.6 Hz), 8.14 (1H, d, J=7.6 Hz), 8.11 (1H, d, J=2.6 Hz), 8.01 (2H, d, J=8.2 Hz), 7.43 (2H, d, J=8.2 Hz), 7.31 (1H, d, J=2.4 Hz), 7.27 (1H, dd, J=8.6, 2.4 Hz), 7.04 (1H, d, J=8.6 Hz), 5.36 (1H, dq, J=7.6, 7.1 Hz), 3.91 (3H, s), 2.11 (3H, s), 1.60 (3H, d, J=7.1 Hz); MS (ESI) m/z 459 (M+H)+, 457 (M−H)−.
Reaction SMILES: [CH:1]12[CH:7]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([C:15]4[C:16]([NH2:20])=[N:17][O:18][N:19]=4)=[CH:11][CH:10]=3)[CH:4]([CH2:5][CH2:6]1)[CH2:3][NH:2]2.[CH3:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1>>[CH3:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][N:2]2[CH2:3][CH:4]3[CH:7]([NH:8][C:9]4[CH:14]=[CH:13][C:12]([C:15]5[C:16]([NH2:20])=[N:17][O:18][N:19]=5)=[CH:11][CH:10]=4)[CH:1]2[CH2:6][CH2:5]3)=[CH:24][CH:23]=1
Reactant: Nc1nonc1-c1ccc(NC2C3CCC2NC3)cc1
Reactant: Cc1ccc(C=O)cc1
Product: Cc1ccc(CN2CC3CCC2C3Nc2ccc(-c3nonc3N)cc2)cc1

Procedure:
Reaction of Intermediate 40 with 4-methylbenzaldehyde affords the title compound.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([CH:10]=[CH:11][CH:12]=2)[NH2:9])[CH:5]=[CH:4][N:3]=[CH:2]1.[OH-].[Na+].[C:15](OC(=O)C)(=[O:17])[CH3:16]>>[C:15]([NH:9][C:8]1[CH:10]=[CH:11][CH:12]=[C:6]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH:7]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cccc(-n2ccnc2)c1
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)Nc1cccc(-n2ccnc2)c1
Temperature: 0 °C
Yield: 85 %

Procedure:
2d (5.88 g, 37 mmol) is stirred in acetic anhydride (30 ml) at ambient temperature for 1 hour. The mixture is poured into ice-water and rendered alkaline by addition of aqueous sodium hydroxide (12M). The product is filtered off, washed with water and dried to yield 2e (6.34 g, 85%). Mp 181-183° C.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:3]=1[C:4]([CH:6]1[C:11](=[O:12])[CH2:10][CH2:9][CH2:8][C:7]1=[O:13])=[O:5].[C:19](Cl)(=[O:21])[CH3:20].N1C=CC=CC=1>CCOCC>[C:19]([O:12][C:11]1[CH2:10][CH2:9][CH2:8][C:7](=[O:13])[C:6]=1[C:4](=[O:5])[C:3]1[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:2]=1[Cl:1])(=[O:21])[CH3:20]
Reactant: O=C1CCCC(=O)C1C(=O)c1ccc(Cl)cc1Cl
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(=O)OC1=C(C(=O)c2ccc(Cl)cc2Cl)C(=O)CCC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2-(2,4-Dichlorobenzoyl)cyclohexane-1,3-dione (11.4 g, 0.04 mol), acetyl chloride (3.15 g, 0.041 mol) and pyridine (3.2 g, 0.041 mol) were mixed in 100 ml ether and stirred at room temperature for 24 hours. The volatiles were evaporated under reduced pressure, and water and CH2Cl2 were added. The organic layer was then washed three times each with 1N HCl and then 5% Na2CO3, dried with MgSO4 and the solvent evaporated under reduced pressure to yield the product, 8.4 g, 64%. The structure was confirmed as such by nuclear magnetic, infrared and mass spectroscopy.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH:10]([C:12]2[N:17]=[N:16][C:15]([NH:18][C:19]3[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=3)=[N:14][CH:13]=2)[CH3:11])=O)=[CH:4][CH:3]=1.N1C=NC=N1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[Br:1][C:2]1[S:6][C:5]([C:7]2[N:17]3[C:12]([CH:13]=[N:14][C:15]([NH:18][C:19]4[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=4)=[N:16]3)=[C:10]([CH3:11])[N:9]=2)=[CH:4][CH:3]=1
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3ccc(Br)s3)nn2)cc(OC)c1OC
Agent: c1nc[nH]n1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(Nc2ncc3c(C)nc(-c4ccc(Br)s4)n3n2)cc(OC)c1OC
Yield: 7.8 %

Procedure:
In a similar manner as described for Example 9, 5-bromo-N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)thiophene-2-carboxamide (Intermediate 22) (0.35 g, 0.70 mmol) and 1,2,4-triazole (290 mg, 4.2 mmol) in pyridine (5 mL) and phosphorus oxychloride (0.200 mL, 2.1 mmol) gave 7-(5-bromothien-2-yl)-5-methyl-N-(3,4,5-trimethoxyphenyl)imidazo[5,1-f][1,2,4]triazin-2-amine (0.026 g) as a yellow solid. 1H NMR (DMSO-d6): δ9.70 (s, 1H), 9.24 (s, 1H), 7.83 (d, J=4.0 Hz, 1H), 7.38 (d, J=4.0 Hz, 1H), 7.10 (s, 2H), 3.81 (s, 6H), 3.66 (s, 3H), 2.51 (s, 3H). MS m/z 476, 478 (M+1, M+3).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][CH:10]([OH:20])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[C:14]([CH3:19])[CH:13]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH2:1]([O:3][P:4]([CH2:9][C:10](=[O:20])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[C:14]([CH3:19])[CH:13]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP(=O)(CC(O)Cc1ccc(F)c(C)c1)OCC
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CCOP(=O)(CC(=O)Cc1ccc(F)c(C)c1)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of [3-(4-fluoro-3-methyl-phenyl)-2-hydroxy-propyl]-phosphonic acid diethyl ester (1.37 g, 4.51 mmol) in CH2Cl2 (30 mL) was added Dess-Martin reagent (Chemical Abstracts No. 87413-04-0, 2.10 g, 4.96 mmol). The reaction mixture was stirred at room temperature for 2 h and additional CH2Cl2 was added. The organic solution was washed with NaHCO3 (2 times) and once with brine. The organic solution was dried (MgSO4), filtered and concentrated. Purification by medium pressure chromatography (20% EtOAc in hexanes to 70% EtOAc in hexanes) provided the title compound of Preparation 6 (1.1 g).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[CH:13]=2)=[C:8]2[C:3]=1[N:4]=[CH:5][C:6]([OH:22])=[N:7]2.BrC1C=CC(C2C=C(OC)C=C(OC)C=2)=[C:28]2C=1N=C(O)C=[N:29]2.C([Cu])#N>CN1C(=O)CCC1.CCOC(C)=O.C(N)CN>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([C:9]2[C:8]3[N:7]=[C:6]([OH:22])[CH:5]=[N:4][C:3]=3[C:2]([C:28]#[N:29])=[CH:11][CH:10]=2)[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=1
Reactant: COc1cc(OC)cc(-c2ccc(Br)c3nc(O)cnc23)c1
Reactant: COc1cc(OC)cc(-c2ccc(Br)c3ncc(O)nc23)c1
Agent: N#C[Cu]
Solvent: NCCN
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: COc1cc(OC)cc(-c2ccc(C#N)c3ncc(O)nc23)c1
Temperature: 180 °C
Reaction time: 2 h

Procedure:
A mixture of 5-bromo-8-(3,5-dimethoxy-phenyl)-quinoxalin-2-ol and 8-bromo-5-(3,5-dimethoxy-phenyl)-quinoxalin-2-ol (Step 85.6) (609 mg, 1.7 mmol) (Step 1.4) and CuCN (183 mg, 2.0 mmol, 1.2 equiv) in NMP (5 mL) was stirred at 180° C. for 2 h. The reaction mixture was allowed to cool to rt, diluted with EtOAc/10% aqueous solution of ethylenediamine (25 mL) and extracted with EtOAc. The aqueous phase was acidified to pH 5 and extracted with EtOAc. The combined organic extracts were washed with H2O and brine, dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography (Hex/EtOAc, 7:3) to afford 103 mg of the title compound as a yellow solid: ES-MS: 308.1 [M+H]+; tR=4.05 min (System 1); Rf=0.35 (Hex/EtOAc, 7:3).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:12]2[C:13]([C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=3[OH:25])=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:9]=[CH:10][CH:11]=1)=[O:5])[CH3:2].[CH2:26](O)[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.O>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:12]2[C:13]([C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=3[O:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:9]=[CH:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: OCCc1ccccc1
Reactant: CCOC(=O)c1cccc(-c2ccccc2-c2cc(Cl)ccc2O)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cccc(-c2ccccc2-c2cc(Cl)ccc2OCCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
A mixture of 5-chloro-2-hydroxy-[1,1′;2′,1″]terphenyl-3″-carboxylic acid ethyl ester (100 mg, 0.28 mmol), phenethyl alcohol (31 mg, 0.25 mmol), triphenyl phosphine (74 mg, 0.28 mmol), diisopropyl azodicarboxylate (57 mg, 0.28 mmol) in THF (6 ml) was stirred at room temperature overnight. The mixture was then poured into water and extracted with ether, the organic layers were dried over MgSO4 and evaporated. The residue was chromatographed through an SPE column using iso-hexane to yield the title compound (95 mg, 80%) as an oil.
Reaction SMILES: C([N:3]1[CH2:21][CH2:20][C@@:10]23[C:11]4[CH:12]=[C:13]([O:18][CH3:19])[CH:14]=[CH:15][C:16]=4[CH2:17][C@@H:4]1[C@@H:5]2[C@@H:6]([CH2:23][CH3:24])[CH2:7][C:8](=[O:22])[CH2:9]3)#N.[ClH:25]>>[ClH:25].[CH2:23]([C@@H:6]1[C@@H:5]2[C@:10]3([CH2:20][CH2:21][NH:3][C@@H:4]2[CH2:17][C:16]2[CH:15]=[CH:14][C:13]([O:18][CH3:19])=[CH:12][C:11]3=2)[CH2:9][C:8](=[O:22])[CH2:7]1)[CH3:24]
Reactant: CC[C@H]1CC(=O)C[C@]23CCN(C#N)[C@H](Cc4ccc(OC)cc42)[C@H]13
Agent: Cl
Product: CC[C@H]1CC(=O)C[C@]23CCN[C@H](Cc4ccc(OC)cc42)[C@H]13
Yield: 72 %

Procedure:
A sample of 17-cyano-8β-ethyl-3-methoxymorphinan-6-one was treated with 2 N HCl as described in Example 1C. The product was isolated in 72% yield, mp 280° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([CH:8]=O)=[N:6][CH:7]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([NH2:24])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([NH:24][CH2:8][C:5]2[C:4]([CH3:10])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: Cc1cc(Cl)cnc1C=O
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(Cl)cnc1CNC1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Using General Procedure B, reaction of 5-chloro-3-methylpyridine-2-carbaldehyde, 4-aminopiperidine-1-carboxylic acid tert-butyl ester and NaBH(OAc)3 in CH2Cl2 gave 4-[(5-chloro-3-methyl-pyridin-2-ylmethyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester as a beige liquid. 1H NMR (CDCl3): δ 1.39 (m, 2H), 1.45 (s, 9H), 1.89 (d, 2H, J=12.0 Hz), 2.30 (s, 3H), 2.69 (m, 1H), 2.83 (t, 2H, J=12.0 Hz), 3.87 (s, 2H), 4.03 (br, 2H), 7.44 (s, 1H), 8.34 (s, 1H).
Reaction SMILES: [C:1]1([C@H:7]2[CH2:11][C@@H:10]([NH:12][C:13](=[O:15])[CH3:14])[CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16]([Zn]CC)C.ICI.Cl.[O-]S([O-])(=S)=O.[Na+].[Na+]>[Cl-].[Na+].O.CC(OC)(C)C.C(Cl)Cl>[C:1]1([C@@H:7]2[C@H:8]3[C@H:9]([CH2:16]3)[C@H:10]([NH:12][C:13](=[O:15])[CH3:14])[CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC[Zn]CC
Reactant: CC(=O)N[C@H]1C=C[C@@H](c2ccccc2)C1
Agent: Cl
Agent: O=S([O-])([O-])=S
Agent: [Cl-]
Solvent: COC(C)(C)C
Solvent: ICI
Solvent: ClCCl
Product: CC(=O)N[C@@H]1C[C@H](c2ccccc2)[C@@H]2C[C@@H]21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 76.7 %

Procedure:
A solution of Example 55A (100 mg, 0.497 mmol) and CH2Cl2 (5 mL) was cooled to −10° C. and diethylzinc (1M solution, 4.97 mL, 4.97 mmol) was added at <0° C. After 5 minutes, diiodomethane (0.441 mL, 5.47 mmol) was added at <0° C. The mixture was slowly warmed to ambient temperature and the reaction was complete after 3 hours. The mixture was cooled to <0° C., brine (5 mL) and 2N HCl (5 mL) were added, then diluted with MTBE (50 mL) and added saturated aqueous Na2S2O3 (10 mL). The organic layer was washed with brine (10 mL), dried (Na2SO4), and concentrated. The residue was purified by flash column chromatography (50-100% EtOAc/hexanes, gradient elution) to provide the title compound (82 mg, 0.381 mmol, 77% yield). MS (DCI) M/Z 216 [M+H]+.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([O:22][CH3:23])=[C:15]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH:16]=3)[CH:9]=2)[N:4]([S:24]([C:27]2[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH:3]=1.[CH2:34]([N:42]1[CH:46]=[C:45](B2OC(C)(C)C(C)(C)O2)[CH:44]=[N:43]1)[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:23][O:22][C:14]1[CH:13]=[CH:12][C:11]([C:8]2[CH:9]=[C:10]3[C:2]([C:45]4[CH:44]=[N:43][N:42]([CH2:34][CH2:35][C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)[CH:46]=4)=[CH:3][N:4]([S:24]([C:27]4[CH:28]=[CH:29][C:30]([CH3:31])=[CH:32][CH:33]=4)(=[O:26])=[O:25])[C:5]3=[N:6][CH:7]=2)=[CH:16][C:15]=1[NH:17][S:18]([CH3:21])(=[O:20])=[O:19]
Reactant: COc1ccc(-c2cnc3c(c2)c(I)cn3S(=O)(=O)c2ccc(C)cc2)cc1NS(C)(=O)=O
Reactant: CC1(C)OB(c2cnn(CCc3ccccc3)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(-c2cnc3c(c2)c(-c2cnn(CCc4ccccc4)c2)cn3S(=O)(=O)c2ccc(C)cc2)cc1NS(C)(=O)=O
Yield: 103.5 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, N-(5-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-methoxyphenyl)methanesulfonamide (Intermediate 23) (90 mg, 0.1506 mmol) was coupled with 1-phenethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 59) (67 mg, 0.225 mmol) using Pd(PPh3)2Cl2 (6 mg, 0.05 mmol) and sodium carbonate (40 mg, 0.376 mmol) in toluene/ethanol/water (3/2/1 ml) to afford 100 mg of the crude compound. MS: m/z=642.7 (M+1).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]([Si](C(C)C)(C(C)C)C(C)C)[CH:10]=2)=[CH:4][CH:3]=1.[Cl:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32][NH2:33].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(O)(=O)C>[Cl:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32][NH:33][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[CH:6][N:7]=1
Reactant: NCc1cccc(Cl)c1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(Cc2ccc(Br)nc2)c2cccnc21
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: Clc1cccc(CNc2ccc(Cc3c[nH]c4ncccc34)cn2)c1
Temperature: 100 °C

Procedure:
3-(6-bromo-pyridin-3-ylmethyl)-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (6a, mg, 0.023 mmol, prepared as described in Example 2, Scheme 4) was combined with 3-chlorobenzyl amine (543, 13 mg, 0.093 mmol) in dioxane (0.3 mL). Tris(dibenzylideneacetone)-dipalladium(0) (3 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos, 3 mg) and sodium tert-butoxide (15 mg) were added. The mixture was heated at 100° C. overnight. Acetic acid (0.1 mL) was added and the solvents removed under reduced pressure. The remaining residue was dissolved in DMSO and purified by reverse phase HPLC on a YMC-Pack ODS-A C-18 column (50 mm×10 mm ID), eluting with water with 0.1% trifluoroacetic acid and 5-40% acetonitrile with 0.1% trifluoroacetic acid over 13 minutes at a flow rate of 6 mL/minute to provide the desired compound P-0129. MS (ESI) [M+H+]+=349.1.
Reaction SMILES: [C:1]([Si:5]([O:8][CH:9]1[CH2:18][CH2:17][C:16]2[C:11](=[C:12]([N:19]=[C:20]=[S:21])[CH:13]=[CH:14][CH:15]=2)[CH2:10]1)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[NH3:22]>C1COCC1>[Si:5]([O:8][CH:9]1[CH2:10][C:11]2[C:12]([NH:19][C:20]([NH2:22])=[S:21])=[CH:13][CH:14]=[CH:15][C:16]=2[CH2:17][CH2:18]1)([C:1]([CH3:4])([CH3:2])[CH3:3])([CH3:7])[CH3:6]
Reactant: CC(C)(C)[Si](C)(C)OC1CCc2cccc(N=C=S)c2C1
Reactant: N
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC1CCc2cccc(NC(N)=S)c2C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of the product of Example 18C (1.25 g, 3.91 mmol) in THF (50 mL) was treated with 7N methanolic NH3 (5.6 mL, 3, 9.1 mmol), and the mixture was stirred at room temperature for 6 hours. The mixture was partitioned between EtOAc and H2O, and the separated organic phase was washed with brine, dried over Na2SO4, filtered and evaporated under reduced pressure. Silica gel chromatography (98:2 to 95:5 CH2Cl2:CH3OH eluant) provided the title compound as a pale yellow solid, 1.27 g (97%). 1H NMR (300 MHz, DMSO-d6) δ 9.12 (s, 1H), 6.6-7.8 (br, 2H), 6.99-7.13 (m, 3H), 4.08 (m, 1H), 2.73-2.92 (m, 4H), 1.84-1.92 (m, 1H), 1.60-1.68 (m, 1H). MS (ESI+) m/z 337 (M+H).
Reaction SMILES: [C:1]12([CH2:11][NH2:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[OH:13][C@@H:14]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:15](O)=[O:16].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]12([CH2:11][NH:12][C:15](=[O:16])[C@@H:14]([OH:13])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: O=C(O)[C@@H](O)c1ccccc1
Reactant: NCC12CC3CC(CC(C3)C1)C2
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)[C@@H](O)c1ccccc1
Reaction time: 8 h
Yield: 46.5 %

Procedure:
To a solution of (1-adamantyl)methylamine (100 mg, 0.61 mmol), (S)-2-hydroxy-2-phenylacetic acid (92 mg, 0.61 mmol), EDCI (239 mg, 1.22 mmol) and HOBt (164 mg, 1.22 mmol) in CH2Cl2 (15 mL) was added DIEA (391 mg, 3.03 mmol) and the resulting mixture was stirred overnight. The solution was concentrated under vacuum to give the crude product, which was purified by preparative TLC to afford (S)—N-((1-adamantyl)methyl)-2-hydroxy-2-phenylacetamide (85 mg, 47%). 1H NMR (CDCl3, 400 MHz): δ=1.34-1.91 (m, 15H), 2.86 (q, 1H), 3.02 (q, 1H), 5.04 (s, 1H), 5.93 (s, 1H), 7.25-7.43 (m, 5H).
Reaction SMILES: Br[CH2:2][CH:3]=[C:4]([CH3:9])[CH2:5][N+:6]([O-:8])=[O:7].[CH2:10]([O:12][P:13]([O:17]CC)[O:14][CH2:15][CH3:16])[CH3:11]>>[CH2:10]([O:12][P:13]([CH2:2][CH:3]=[C:4]([CH3:9])[CH2:5][N+:6]([O-:8])=[O:7])(=[O:17])[O:14][CH2:15][CH3:16])[CH3:11]
Reactant: CCOP(OCC)OCC
Reactant: CC(=CCBr)C[N+](=O)[O-]
Product: CCOP(=O)(CC=C(C)C[N+](=O)[O-])OCC

Procedure:
To 0.1 Mol of 1-bromo-3-methyl-4-nitro-2-butene was added 0.1 Mol of triethylphosphite. The reaction was started by immersing the mixture into a 50° C. bath and completed under continued removal of bromoethane by distillation. The residue was purified via column chromatography over silica gel using ether as solvent. The product was obtained as a yellowish liquid.
Reaction SMILES: [C:1]([O:4][C@H:5]([CH3:23])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[NH:17][C:16]([Br:21])=[N:15][C:14]=2[N:13]([CH3:22])[C:11]1=[O:12])(=[O:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:43]([O:47][C:48]([NH:50][CH2:51][CH2:52]CO)=[O:49])([CH3:46])([CH3:45])[CH3:44].CCOC(/N=N/C(OCC)=O)=O>ClCCCl>[C:1]([O:4][C@H:5]([CH3:23])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[N:17]([CH2:52][CH2:51][NH:50][C:48]([O:47][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:49])[C:16]([Br:21])=[N:15][C:14]=2[N:13]([CH3:22])[C:11]1=[O:12])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H](C)CCCCn1c(=O)c2[nH]c(Br)nc2n(C)c1=O
Reactant: CC(C)(C)OC(=O)NCCCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCCl
Product: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(nc(Br)n2CCNC(=O)OC(C)(C)C)n(C)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.1 %

Procedure:
To a stirring suspension of (R)-1-(5-acetoxyhexyl)-8-bromo-3-methylxanthine (5.10 g, 13.2 mmol), triphenylphosphine (5.24 g, 20.0 mmol) and 3-(tert-butoxycarbonylamino)-1-propanol (3.2 g, 20.0 mmol) in anhydrous 1,2-dichloroethane (100 ml) at room temperature was added diethylazodicarboxylate (3.48 g, 20.0 mmol) dropwise. The mixture was stirred at room temperature overnight and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with ethyl acetate-hexane (1:1) to provide (R)-1-(5-acetoxyhexyl)-8-bromo-7-(2-(N-tert-butoxycarbonylamino)ethyl)-3-methylxanthine (6.10 g, 85% yield) as a beige oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:5]=[N:6][CH:7]=1.[C:18]1([S:24]([N:27]2[C:35]3[CH:34]=[C:33]([Sn](C)(C)C)[CH:32]=[C:31]([NH2:40])[C:30]=3[CH:29]=[N:28]2)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C.Cl[Pd]C1C=CC=CC=1C1C=CC=CC=1N(C)C.[C@H]12C[C@H](CC1)CC2PC1C[C@H]2C[C@@H]1CC2>[NH2:40][C:31]1[CH:32]=[C:33]([C:2]2[CH:3]=[C:4]([NH:8][S:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)(=[O:11])=[O:10])[CH:5]=[N:6][CH:7]=2)[CH:34]=[C:35]2[C:30]=1[CH:29]=[N:28][N:27]2[S:24]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)(=[O:26])=[O:25]
Reactant: C[Sn](C)(C)c1cc(N)c2cnn(S(=O)(=O)c3ccccc3)c2c1
Reactant: O=S(=O)(Nc1cncc(Br)c1)c1ccccc1
Agent: CN(C)c1ccccc1-c1ccccc1[Pd]Cl
Agent: C1C[C@@H]2C[C@H]1CC2PC1C[C@@H]2CC[C@H]1C2
Solvent: CN(C)C=O
Product: Nc1cc(-c2cncc(NS(=O)(=O)c3ccccc3)c2)cc2c1cnn2S(=O)(=O)c1ccccc1
Temperature: 120 °C

Procedure:
In a separate microwave vial, 1-(phenylsulfonyl)-6-(trimethylstannanyl)-1H-indazol-4-amine (50 mg), N-(5-bromo-3-pyridinyl)benzenesulfonamide (39.5 mg) and chloro[2′-(dimethylamino)-2-biphenylyl]palladium-(1R,4S)-bicyclo[2.2.1]hept-2-yl[(1S,4R)-bicyclo[2.2.1]hept-2-yl]phosphane (1:1) (6.4 mg) were dissolved in DMF (1 ml) and the reaction was heated under microwave irradiation for 15 min at 120° C.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.O.[C:17]([O-])(O)=O.[Na+]>CO>[Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:17])=[O:5]
Reactant: O=C([O-])O
Reactant: O=C(O)c1cccnc1Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1cccnc1Cl
Yield: 40 %

Procedure:
A solution of 2-chloronicotinic acid (1.61 g, 10.2 mmol) and sulfuric acid (0.5 mL) in methanol (30 mL) was stirred at reflux overnight. The solution was poured into water (100 mL) and neutralised with NaHCO3 (s) before being extracted with 1:1 hexane/ethyl acetate (3×40 mL). The solvents were dried (MgSO4) and evaporated and the residue was purified by flash column chromatography (SiO2, 25% ethyl acetate/hexane eluent) to afford the ester as a colourless oil (700 mg, 40%).