Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:4](C(C)C)CC)(C)C.[Br:10][C:11]1[CH:12]=[N:13][C:14]([N:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26]([N:28]([CH2:30][C:31](O)=[O:32])[CH3:29])=[O:27])[CH:24]=3)[C:19]([S:34]([CH3:36])=[O:35])=[CH:18]2)=[N:15][CH:16]=1.BrC1C=NC(N2C3C(=CC=C(C(O)=O)C=3)C(SC)=C2)=NC=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.CNCC(OC)=O>CN(C=O)C>[NH2:4][C:31](=[O:32])[CH2:30][N:28]([CH3:29])[C:26]([C:23]1[CH:24]=[C:25]2[C:20]([C:19]([S:34]([CH3:36])=[O:35])=[CH:18][N:17]2[C:14]2[N:13]=[CH:12][C:11]([Br:10])=[CH:16][N:15]=2)=[CH:21][CH:22]=1)=[O:27]
Reactant: CN(CC(=O)O)C(=O)c1ccc2c(S(C)=O)cn(-c3ncc(Br)cn3)c2c1
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CNCC(=O)OC
Agent: CSc1cn(-c2ncc(Br)cn2)c2cc(C(=O)O)ccc12
Solvent: CN(C)C=O
Product: CN(CC(N)=O)C(=O)c1ccc2c(S(C)=O)cn(-c3ncc(Br)cn3)c2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Diisopropylethylamine (0.34 mL, 1.99 mmol), EDCxHCl (0.19 g, 0.992 mmol) and HOBt ammonium salt (0.15 g, 0.997 mmol) were added to 2-(1-(5-bromopyrimidin-2-yl)-N-methyl-3-(methylsulfinyl)-1H-indole-6-carboxamido)acetic acid (0.3 g, 0.66 mmol, synthesized from 1-(5-bromopyrimidin-2-yl)-3-(methylthio)-1H-indole-6-carboxylic acid in three steps comprising a TBTU mediated amide coupling of methyl 2-(methylamino)acetate hydrochloride, the oxidation of the thioether and the hydrolysis of the methyl ester) in DMF (3.0 mL). The reaction mixture was stirred at room temperature for 16 h, diluted with ice water and extracted with methanol/dichloromethane (5:95; 3×40 mL). The combined organic layers were successively washed with saturated sodium hydrogen carbonate, saturated ammonium chloride solution, and brine, dried over sodium sulfate and concentrated to yield the raw product which was purified by column chromatography [silica; methanol/dichloromethane=5:95]. White solid. Yield: 0.13 g (43% of theory)
Reaction SMILES: [CH3:1][C:2]([CH3:27])([CH3:26])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C:13]3[CH:20]=[C:19]([C@@H:21]([OH:23])[CH3:22])[CH:18]=[CH:17][C:14]=3[C:15]#[N:16])=[CH:10][CH:11]=2)[N:6]([CH3:24])[C:5]1=[O:25].C(N(C(C)C)CC)(C)C>C(Cl)Cl.CS(C)=O.CO>[C:21]([C:19]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[C:13]([C:9]2[N:8]=[C:7]3[N:6]([CH3:24])[C:5](=[O:25])[N:4]([CH2:3][C:2]([CH3:26])([CH3:1])[CH3:27])[C:12]3=[CH:11][CH:10]=2)[CH:20]=1)(=[O:23])[CH3:22]
Reactant: C[C@H](O)c1ccc(C#N)c(-c2ccc3c(n2)n(C)c(=O)n3CC(C)(C)C)c1
Solvent: CS(C)=O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1ccc(C#N)c(-c2ccc3c(n2)n(C)c(=O)n3CC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a microwave vial, 2-[1-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl]-4-[1-hydroxyethyl]benzonitrile (30-2) (35 mg, 0.1 mmol) was dissolved in DCM (0.25 ml) under nitrogen, followed by the addition of Diisopropyl ethyl amine (50 mg, 0.39 mmol). In a separate vial under nitrogen, SO3 Pyridine complex (61 mg, 0.39 mmol) was dissolved in DMSO (0.25 ml). The DMSO solution was then added slowly to DCM solution and allowed to stir at room temperature. After 30 minutes, the mixture was diluted with methanol, and passed through a syringe filter. The solution was purified using reverse phase chromatography (10-100%, 0.1% TFA in H2O/Acetonitrile) and the desired fractions were collected and concentrated to produce 4-acetyl-2-[1-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl]benzonitrile (31-1). HRMS (M+H)+: observed=363.1832, calculated=363.1816.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].N1C=CC=CC=1.[CH3:12][O:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1.Cl>C(Cl)Cl>[CH3:12][O:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18]([NH:21][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc(NS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.2 %

Procedure:
A solution of methanesulfonyl chloride (15.2 g, 132 mmol) in methylene chloride (50 mL) was added dropwise to a stirring slurry of pyridine (41.8 g, 529 mmol) and methyl-4-aminobenzoate (20.0 g, 132 mmol) in methylene chloride (110 mL) cooled by a dry ice/acetone bath. The reaction mixture was allowed to warm to ambient temperature and was stirred overnight. The reaction mixture was added to 400 mL of 4% aqueous HCl solution and the solid that formed was collected by filtration. The orange solid was recrystallized from methanol to give 28.8 g (91.5%) of an orange-pink solid, mp 147°-150° C.
Reaction SMILES: C(=O)(OC)[O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6](Br)=[CH:5][C:4]=1[CH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.CC1(C)C(C)(C)OB([C:29]2[CH2:30][CH2:31][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:33][CH:34]=2)O1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.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>[CH:13]1([C:4]2[C:3]([OH:2])=[CH:8][C:7]([N+:9]([O-:11])=[O:10])=[C:6]([C:29]3[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH:30]=3)[CH:5]=2)[CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: COC(=O)Oc1cc([N+](=O)[O-])c(Br)cc1C1CCCC1
Reactant: CC(C)(C)OC(=O)N1CC=C(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: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(c2cc(C3CCCC3)c(O)cc2[N+](=O)[O-])CC1
Temperature: 90 °C
Yield: 75.6 %

Procedure:
4-Bromo-2-cyclopentyl-5-nitrophenyl methyl carbonate (700 mg, 2.03 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (629 mg, 2.03 mmol), Pd(PPh3)4 (235 mg, 0.20 mmol), and Cs2CO3 (1325 mg, 4.07 mmol) were combined in DMF (10 mL) and heated at 90° C. for 4 h under N2 atmosphere. The reaction was diluted with water and extracted with dichloromethane (3×10 mL). The organic fractions were combined, dried over MgSO4, filtered and concentrated. Purification by silica gel chromatography (0-100% ethyl acetate/hexanes) yielded tert-butyl 4-(5-cyclopentyl-4-hydroxy-2-nitrophenyl)-5,6-dihydropyridine-1(2H)-carboxylate (596 mg, 77% yield). LC/MS m/z 389.4 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[O:6][C@H:5]([C:7]([N:9]2[CH2:14][CH2:13][C:12]([C:15]3[C:20]([F:21])=[CH:19][C:18]([N:22]4[CH2:26][C@H:25]([CH2:27][O:28]C(=O)C)[O:24][C:23]4=[O:32])=[CH:17][C:16]=3[F:33])=[CH:11][CH2:10]2)=[O:8])[CH2:4][O:3]1.C(=O)([O-])[O-].[K+].[K+].C(O)(=O)C.C(=O)(O)[O-].[Na+]>CO>[CH3:1][C:2]1([CH3:34])[O:6][C@H:5]([C:7]([N:9]2[CH2:14][CH2:13][C:12]([C:15]3[C:16]([F:33])=[CH:17][C:18]([N:22]4[CH2:26][C@H:25]([CH2:27][OH:28])[O:24][C:23]4=[O:32])=[CH:19][C:20]=3[F:21])=[CH:11][CH2:10]2)=[O:8])[CH2:4][O:3]1
Reactant: CC(=O)OC[C@H]1CN(c2cc(F)c(C3=CCN(C(=O)[C@@H]4COC(C)(C)O4)CC3)c(F)c2)C(=O)O1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(=O)O
Product: CC1(C)OC[C@@H](C(=O)N2CC=C(c3c(F)cc(N4C[C@H](CO)OC4=O)cc3F)CC2)O1
Temperature: 25 °C
Yield: 92.6 %

Procedure:
3-(4-(1-(2,2-Dimethyl-1,3-dioxolan-4(S)-ylcarbonyl)-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)-5(R)-acetoxymethyloxazolidin-2-one (8.64 g, 18 mM) was suspended in methanol (350 ml) and stirred at ambient temperature under nitrogen. Potassium carbonate (3.73 g, 27 mM) was added, and the mixture stirred for 20 minutes only, then neutralised immediately by the addition of acetic acid (2 ml). Saturated aqueous sodium bicarbonate (50 ml) was added, the methanol evaporated, and the residue diluted with water (100 ml) before extraction of the organics into dichloromethane (250 ml+100 ml). The extract was washed with brine (100 ml), dried (magnesium sulfate), evaporated and crude product purified by chromatography on a 300 g silica vacuum sinter column, eluting with a gradient from 0% to 20% methanol in dichloromethane. Relevant fractions were combined to give the desired product (7.3 g).
Reaction SMILES: Cl.[N:2]1([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[N:15]([O-])=[O:16].[Na+].[OH-].[Na+]>O.ClCCl>[N:15]([N:5]1[CH2:6][CH2:7][N:2]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3][CH2:4]1)=[O:16]
Reactant: O=N[O-]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(N=O)CC1

Procedure:
In a 500 mL round-bottomed flask, 6N aqueous HCl (30 mL) was cooled to −10° C., and tert-butyl piperazine-1-carboxylate (10 g) was added. Sodium nitrite (4.5 g) dissolved in 35 ml water was added slowly. NaOH (10 g in 20 mL water) was used to neutralize the solution. Dichloromethane (3×50 mL) was used to extract the product. After drying over Na2SO4 and filtration, the solution was concentrated. The crude product was added to a silica gel column (Analogix, SF65-400 g) and purified by eluting with 0-30% ethyl acetate in hexane.
Reaction SMILES: [NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([OH:12])=O)[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].Cl.Cl.[NH:25]1[CH2:65][CH2:64][CH2:63][C@H:26]1[C:27]([NH:29][C@H:30]([C:42]([N:44]1[CH2:62][CH2:61][CH2:60][C@H:45]1[C:46]([NH:48][C@H:49]([C:57]([NH2:59])=[O:58])[CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)=[O:47])=[O:43])[CH2:31][C:32](=[O:41])[O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:28].CN1CCOCC1.C(P(=O)(OCC)OCC)#N>CC(N(C)C)=O>[NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([N:25]1[CH2:65][CH2:64][CH2:63][C@H:26]1[C:27]([NH:29][C@H:30]([C:42]([N:44]1[CH2:62][CH2:61][CH2:60][C@H:45]1[C:46]([NH:48][C@H:49]([C:57]([NH2:59])=[O:58])[CH2:50][C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)=[O:47])=[O:43])[CH2:31][C:32](=[O:41])[O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:28])=[O:12])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8]
Reactant: NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CC(=O)OCc1ccccc1)NC(=O)[C@@H]1CCCN1
Reactant: N=C(N)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: CN1CCOCC1
Product: N=C(N)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(N)=O
Reaction time: 4 h

Procedure:
To a stirred solution of Z-Arg.HCl (5.17 g, 15 mmoles) in dimethylacetamide (25 mL) at 25° C. was added a solution of HCl.Pro-Asp(OBzl)-Pro-Phe-NH2 and N-methylmorpholine (1.65 mL, 15 mmoles) in dimethylacetamide (25 mL). To the resulting solution, diethyl cyanophosphonate (2.45 g, 15 mmoles) and N-methylmorpholine (1.65 mL, 15 mmoles) were added and the mixture stirred for 4 hours. The reaction was quenched by the addition of 10% aqueous acetic acid (10 mL) and the solvents were removed on a rotary evaporator under reduced pressure. The resulting solid was triturated with 10% potassium carbonate and then with water and filtered.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]2[N:8]=[C:9]([NH2:11])[S:10][C:4]=2[CH2:3]1.C(N(CC)C(C)C)(C)C.[C:21]([C:23]1[CH:24]=[C:25]([NH:29][C:30]([CH2:32][O:33][C:34]2[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=2)[C:37](O)=[O:38])=[O:31])[CH:26]=[CH:27][CH:28]=1)#[N:22]>CN(C)C=O.O>[C:21]([C:23]1[CH:24]=[C:25]([NH:29][C:30]([CH2:32][O:33][C:34]2[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=2)[C:37]([NH:11][C:9]2[S:10][C:4]3[CH2:3][N:2]([CH3:1])[CH2:7][CH2:6][C:5]=3[N:8]=2)=[O:38])=[O:31])[CH:26]=[CH:27][CH:28]=1)#[N:22]
Reactant: CN1CCc2nc(N)sc2C1
Reactant: N#Cc1cccc(NC(=O)COc2cccc(C(=O)O)c2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCc2nc(NC(=O)c3cccc(OCC(=O)Nc4cccc(C#N)c4)c3)sc2C1
Yield: 26.3 %

Procedure:
Add 5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-ylamine (0.03 g, 0.18 mmol) followed by O-(7-azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyl uranium hexafluorophosphate (0.07 g, 0.18 mmol) and N,N-diisopropylethyl amine (0.10 mL, 0.54 mmol) to a solution of 3-[(3-cyano-phenylcarbamoyl)-methoxy]-benzoic acid (0.05 g, 0.17 mmol) in N,N-dimethylformamide (2 mL). Sir the mixture at room temperature for 15 h then dilute with water causing a solid to precipitate from solution. Collect the solid by filtration, wash with water and dry on the filter pad. Triturate the crude product with methylene chloride and dry on the filter pad to provide 0.020 g of the title compound as a powder. MS, electrospray 448.96 (M+H), rt. 1.13 min.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][O:7][C:8]2[C:9]([OH:16])=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=[O:12])=[C:4]([F:19])[CH:3]=1.[F:20][CH2:21][CH2:22]O.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>O1CCCC1.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][O:7][C:8]2[C:9]([O:16][CH2:22][CH2:21][F:20])=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=[O:12])=[C:4]([F:19])[CH:3]=1
Reactant: OCCF
Reactant: O=Cc1cccc(OCc2ccc(Cl)cc2F)c1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=Cc1cccc(OCc2ccc(Cl)cc2F)c1OCCF
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 53.9 %

Procedure:
To a solution of 3-(4-Chloro-2-fluoro-benzyloxy)-2-hydroxy-benzaldehyde (659, 140 mg, 0.5 mmol, prepared by protocol of Example 43, Steps 1 and 2 of Scheme 71, using 4-chloro-2-fluoro-benzyl bromide in place of 4-chloro-benzyl bromide in Step 1) in tetrahydrofuran (8 mL) was added dropwise a mixture of 2-fluoro-ethanol (64 mg, 1.0 mmol), triphenylphosphine (180 mg, 0.7 mmol), and diisopropyl azodicarboxylate (120 mg, 0.6 mol) in tetrahydrofuran (5 ml) at 0° C. The reaction mixture was stirred at 0° C. for 10 minutes and then at 40° C. for 3 days. The reaction mixture was dissolved in water and ethyl acetate. The organic layers were collected, washed with brine, and dried over magnesium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with ethyl acetate in hexanes to provide the compound as a white solid (660, 88 mg, 54%). MS (ESI) [M+H+]+=327.12.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.[CH:13]([N:16]=[C:17]=[O:18])([CH3:15])[CH3:14]>C1C=CC=CC=1>[CH:13]([NH:16][C:17](=[O:18])[NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2)([CH3:15])[CH3:14]
Reactant: Nc1ccc2c(c1)CCC(=O)N2
Reactant: CC(C)N=C=O
Solvent: c1ccccc1
Product: CC(C)NC(=O)Nc1ccc2c(c1)CCC(=O)N2
Temperature: 25 °C

Procedure:
6-Amino-3,4-dihydrocarbostyril (1.6 g) is suspended in dry benzene (16 ml), and thereto is added dropwise a solution of isopropyl isocyanate (1.2 ml) in dry benzene (10 ml) with stirring at room temperature. The mixture is reacted at 50° to 60° C. for 3 hours. After the reaction, the resulting precipitate is separated by filtration, purified by silica gel column chromatography (solvent; chloroform:methanol=50:1), and recrystallized from ethanol to give 6-(3-isopropylureido)-3,4-dihydrocarbostyril (1.2 g) as colorless prisms, m.p. 252°-254° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][OH:14].O[C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][N:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[Br:22][C:19]1[CH:20]=[CH:21][C:16]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:17][CH:18]=1
Reactant: Cc1onc(-c2ccccc2)c1CO
Reactant: Oc1ccc(Br)cn1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 41.7 %

Procedure:
To a solution of (5-methyl-3-phenyl-isoxazol-4-yl)-methanol (189 mg, 1.0 mmol) in THF (12 mL) was added 2-hydroxy-5-bromopyridine (191 mg, 1.1 mmol) and triphenylphosphine (393 mg, 1.5 mmol) at ambient temperature under an argon atmosphere. Then diethyl azodicarboxylate (233 μL, 1.5 mmol) was added and the reaction mixture was stirred for 3 h at room temperature. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (144 mg, 42%) as a colourless gum. MS: m/e=345.0/347.1 [M+H]+.
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:10]=1[NH:16][C:17]([C@@H:19]1[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]1[C:28](=[O:47])[C@@H:29]([NH:33][C:34](=[O:46])[C@@H:35]([N:37](C)[C:38](=O)OC(C)(C)C)[CH3:36])[CH:30]([CH3:32])[CH3:31])=[O:18]>C(Cl)Cl>[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:10]=1[NH:16][C:17]([C@@H:19]1[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]1[C:28](=[O:47])[C@@H:29]([NH:33][C:34](=[O:46])[C@@H:35]([NH:37][CH3:38])[CH3:36])[CH:30]([CH3:31])[CH3:32])=[O:18]
Reactant: CC(C)[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N1c2ccccc2C[C@H]1C(=O)Nc1c(F)cccc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN[C@@H](C)C(=O)N[C@H](C(=O)N1c2ccccc2C[C@H]1C(=O)Nc1c(F)cccc1F)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.2 %

Procedure:
TFA (2 mL, 26.0 mmol, Eq: 96.7) was added to a solution of tert-butyl (S)-1-((S)-1-((S)-2-(2,6-difluorophenylcarbamoyl)indolin-1-yl)-3-methyl-1-oxobutan-2-ylamino)-1-oxopropan-2-yl(methyl)carbamate (0.15 g, 269 μmol, Eq: 1.00) in DCM (2 mL) and the resulting solution was stirred at rt for 1 hr. The reaction mixture was concentrated in vacuo and treated with minimal ether/hexanes to give (S)-1-[(S)-3-methyl-2-((S)-2-methylamino-propionylamino)-butyryl]-2,3-dihydro-1H-indole-2-carboxylic acid (2,6-difluoro-phenyl)-amide as a white solid (0.11 g), m/z=459 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[CH2:4][N:5]1[C:9]2=[CH:10][N:11]=[C:12]([C:14]([OH:16])=O)[CH:13]=[C:8]2[C:7]([CH2:17][O:18][CH2:19][CH3:20])=[CH:6]1.Cl.[CH3:27][O:28][NH2:29]>>[F:1][C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[CH2:4][N:5]1[C:9]2=[CH:10][N:11]=[C:12]([C:14]([NH:29][O:28][CH3:27])=[O:16])[CH:13]=[C:8]2[C:7]([CH2:17][O:18][CH2:19][CH3:20])=[CH:6]1
Reactant: CCOCc1cn(Cc2ccc(F)cc2F)c2cnc(C(=O)O)cc12
Reactant: CON
Agent: Cl
Product: CCOCc1cn(Cc2ccc(F)cc2F)c2cnc(C(=O)NOC)cc12

Procedure:
The title compound was prepared by coupling of 1-(2,4-difluoro-benzyl)-3-ethoxymethyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid and O-methyl hydroxylamine hydrochloride in a manner similar to step (c) of example 1. 1H NMR (CD3OD) δ: 8.75 (s, 1H), 8.37 (s, 1H), 7.61 (s, 1H), 7.21-7.28 (m, 1H), 6.88-7.00 (m, 2H), 5.54 (s, 2H), 4.70 (s, 2H), 3.82 (s, 3H), 3.59 (q, 2H, J=7.0 Hz), 1.20 (t, 3H, J=7.0 Hz). LCMS (APCI, M+H+): 376.1. HRMS calcd for C19H20F2N3O3 (M+H) 376.1473, found 376.1485. HPLC: 99.24% purity.
Reaction SMILES: N1(CCS(N2CCC(C3[C:25]4[C:20](=[C:21]([C:31](N)=[O:32])[CH:22]=[C:23](C5C=CSC=5)[CH:24]=4)NC=3)CC2)(=O)=O)CCCC1.Br[C:35]1[CH:36]=[C:37]2[C:41](=[C:42]([C:44]([NH2:46])=[O:45])[CH:43]=1)[NH:40][CH:39]=[C:38]2[CH:47]1[CH2:52][CH2:51][N:50]([S:53]([CH2:56][CH2:57][CH2:58][NH:59][CH:60]2[CH2:64][CH2:63][CH2:62][CH2:61]2)(=[O:55])=[O:54])[CH2:49][CH2:48]1.OCC1C=C(B(O)O)C=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>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:60]1([NH:59][CH2:58][CH2:57][CH2:56][S:53]([N:50]2[CH2:49][CH2:48][CH:47]([C:38]3[C:37]4[C:41](=[C:42]([C:44]([NH2:46])=[O:45])[CH:43]=[C:35]([C:25]5[CH:24]=[CH:23][CH:22]=[C:21]([CH2:31][OH:32])[CH:20]=5)[CH:36]=4)[NH:40][CH:39]=3)[CH2:52][CH2:51]2)(=[O:54])=[O:55])[CH2:64][CH2:63][CH2:62][CH2:61]1
Reactant: NC(=O)c1cc(Br)cc2c(C3CCN(S(=O)(=O)CCCNC4CCCC4)CC3)c[nH]c12
Reactant: NC(=O)c1cc(-c2ccsc2)cc2c(C3CCN(S(=O)(=O)CCN4CCCC4)CC3)c[nH]c12
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: OCc1cccc(B(O)O)c1
Product: NC(=O)c1cc(-c2cccc(CO)c2)cc2c(C3CCN(S(=O)(=O)CCCNC4CCCC4)CC3)c[nH]c12
Yield: 34 %

Procedure:
The title compound was prepared according to the general procedure for intermediate 16. Thus, 5-bromo-3-(1-{[3-(cyclopentylamino)propyl]sulfonyl}-4-piperidinyl)-1H-indole-7-carboxamide (46 mg, 0.09 mmol), [3-(hydroxymethyl)phenyl]boronic acid (55 mg, 0.36 mmol), Pd(PPh3)4 (10 mg, 10%) and cesium carbonate (117 mg, 0.36 mmol) were heated in microwave at 160° C. for 40 min to yield the desired product (16.5 mg, 34%), which was purified by reverse phase HPLC eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid)
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([CH3:12])[C:9]([N+:13]([O-])=O)=[CH:8][C:7]=2[CH3:16])[CH2:3][CH2:2]1.C(O)(=O)C>[Fe].O>[CH:1]1([CH2:4][O:5][C:6]2[C:7]([CH3:16])=[CH:8][C:9]([NH2:13])=[C:10]([CH3:12])[CH:11]=2)[CH2:2][CH2:3]1
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1OCC1CC1
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(OCC2CC2)c(C)cc1N
Temperature: 80 °C
Reaction time: 1 h
Yield: 56.2 %

Procedure:
A mixture of 1.73 g of 1-cyclopropylmethoxy-2,5-dimethyl-4-nitrobenzene, 2.18 g of iron powder, 30 mL of acetic acid and 30 mL of water was stirred at 80° C. for 1 hour. The reaction mixture was cooled to around room temperature, and then concentrated under reduced pressure. The resulting residue was converted into basic with an aqueous 1 N sodium hydroxide solution, then ethyl acetate was added, and the mixture was filtered. The filtrate was extracted with ethyl acetate, and then the organic layer was washed with water and saturated salt water, and dried over anhydrous magnesium sulfate. The resulting residue was subjected to silica gel column chromatography to obtain 0.84 g of 4-cyclopropylmethoxy-2,5-dimethylphenylamine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH:27]([NH2:29])[CH3:28].C(N(CC)CC)C.ClCCl>C(#N)C>[F:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH:27]([NH:29][S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:11])=[O:10])[CH3:28]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(N)c1ccccc1-c1cc(F)ccc1F
Solvent: ClCCl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(S(=O)(=O)NC(C)c2ccccc2-c2cc(F)ccc2F)cc1
Yield: 89.2 %

Procedure:
4-Methoxybenzenesulfonyl chloride (326 mg, 1.6 mmol) was added to a solution of 1-(2′,5′-difluoro-1,1′-biphenyl-2-yl)ethylamine (350 mg, 1.5 mmol) and triethylamine (418 uL, 3 mmol) in acetonitrile. The reaction was stirred at ambient temperature for 16 hours, whereupon dichloromethane was added and the reaction washed with water. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by preparative liquid chromatography on a Biotage® 40 Mi column of prepacked silica gel (90 g), eluting with a gradient of 30%-50% methyl tert-butyl ether in hexane (35 min), to afford the product (540 mg, 89%) as a white solid, m.p. 143-144° C.;