Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:3]([CH:7]1[C:11]([Cl:12])=[C:10](Cl)C(=O)O1)[C:4]([NH2:6])=[O:5])#[N:2].Cl.[NH2:16][CH2:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[S:25]([NH2:28])(=[O:27])=[O:26].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[ClH:12].[Cl:12][C:11]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1](=[NH:2])[N:16]([CH2:17][C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[S:25](=[O:26])(=[O:27])[NH2:28])[CH:10]=1
Reactant: NCc1cc(F)ccc1S(N)(=O)=O
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: N=c1c(C(N)=O)cc(Cl)cn1Cc1cc(F)ccc1S(N)(=O)=O
Yield: 8.1 %

Procedure:
(Step 4) 2-Cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide (1.0 g), 2-(aminomethyl)-4-fluorobenzenesulfonamide hydrochloride obtained in Step 3 (1.23 g) and potassium carbonate (1.76 g) were stirred in ethanol (20 ml) overnight at 70° C. The reaction solution was filtered through celite. The solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=7:3→1:0). 4N Hydrochloride-ethyl acetate solution (1 ml) was added to the obtained yellow oil, and the precipitated crystals were collected by filtration, and recrystallized to give the title compound (68 mg).
Reaction SMILES: [CH3:1][C:2]([CH3:22])([O:4][C:5]([NH:7][C@@H:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][C@@H:9]1OS(C)(=O)=O)=[O:6])[CH3:3].[N-:23]=[N+]=[N-].[Na+]>CC(N(C)C)=O.C(OCC)(=O)C>[NH2:23][C@@H:9]1[CH2:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C@H:8]1[NH:7][C:5]([O:4][C:2]([CH3:22])([CH3:3])[CH3:1])=[O:6]
Reactant: CC(C)(C)OC(=O)N[C@@H]1c2ccccc2C[C@@H]1OS(C)(=O)=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H]1c2ccccc2C[C@H]1N
Temperature: 90 °C
Reaction time: 24 h
Yield: 18.9 %

Procedure:
Cis-1-[(1,1-dimethylethoxy)carbonylamino]-2-methanesulphonyloxyindan (18.1 g, 55.3 mmol) was dissolved in dry dimethyl acetamide (100 ml). Sodium azide (5.4 g, 83.0 mmol) was added and the mixture heated to 90° C. for 6 hours. The reaction was cooled, diluted with ethyl acetate (150 ml), washed with water (6×200 ml) and dried over magnesium sulphate. 10% Palladium on activated carbon was added and the mixture stirred under a hydrogen atmosphere for 24 hours. Filtration through celite followed by evaporation gave the title compound (2.6 g, 98%) as a white solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[O:14][N:13]=[C:12]([C:15]([OH:17])=O)[CH:11]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:42]1([CH2:48][NH2:49])[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH:42]1([CH2:48][NH:49][C:15]([C:12]2[CH:11]=[C:10]([C:6]3[CH:5]=[C:4]4[C:9](=[CH:8][CH:7]=3)[NH:1][N:2]=[CH:3]4)[O:14][N:13]=2)=[O:17])[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1
Reactant: NCC1CCCCC1
Reactant: O=C(O)c1cc(-c2ccc3[nH]ncc3c2)on1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC1CCCCC1)c1cc(-c2ccc3[nH]ncc3c2)on1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
5-(1H-Indazol-5-yl)isoxazole-3-carboxylic acid (35 mg, 0.15 mmol, Example 71A), was dissolved in N,N-dimethylformamide (0.8 mL) followed by the addition of HATU (60 mg, 0.15 mmol) dissolved in N,N-dimethylformamide (0.8 mL). Then a solution of 1-cyclohexylmethanamine (17 mg, 0.17 mmol), dissolved in N,N-dimethylformamide (0.8 mL) was added, followed by diisopropylethylamine (56 μL, 0.31 mmol) dissolved in N,N-dimethylformamide (0.8 mL). The resulting mixture was shaken for 3 hours at 40° C. The reaction was filtered, checked by LC/MS and concentrated to dryness. The residues were dissolved in 1:1 dimethyl sulfoxide/methanol and purified by reverse phase HPLC (Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column (30 mm×75 mm), 50 mL/min, 10-100% acetonitrile/0.1% trifluoroacetic acid in water) to provide the title product. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.91-0.97 (m, 2H), 1.12-1.27 (m, 4H), 1.61-1.75 (m, 5H), 3.08-3.16 (m, 2H), 7.22-7.24 (m, 1H), 7.71-7.75 (m, 1H), 7.87-7.92 (m, 1H), 8.23-8.27 (m, 1H), 8.38-8.41 (m, 1H). MS (ESI+) m/z 325 (M+H)+; (ESI−) m/z 323 (M−H)−.
Reaction SMILES: C([O:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)(=O)C1C=CC=CC=1.[CH3:17][C:18]([Si:21](Cl)([CH3:23])[CH3:22])([CH3:20])[CH3:19].N1C=CN=C1.[BH4-].[Na+]>C(Cl)Cl.CO>[C:18]([Si:21]([CH3:23])([CH3:22])[O:9][C:10]1[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=1)([CH3:20])([CH3:19])[CH3:17]
Reactant: O=C(Oc1ccc(O)cc1)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [BH4-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Hydroxyphenyl benzoate (9.0 mmol) was dissolved in CH2Cl2 (9 mL/mmol), TBDMS-Cl (1.5 eq., 13.5 mmol) and imidazole (2.0 eq., 18.0 mmol) were added and the mixture was stirred at r.t. overnight. The mixture was diluted with MeOH (4.5 mL/mmol), and NaBH4 (2.5 eq., 22.5 mmol) was added slowly over 5 min (attention: vigorous gas evolution). The mixture was concentrated by removing CH2Cl2 under reduced pressure and the suspension was heated to 65° C. for 15 h.
Reaction SMILES: [C:1]1([CH:7]2[N:11]([CH:12]([CH3:21])[CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17]C=3)[CH2:10][CH:9]([CH2:22][OH:23])[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[C:27]1[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][N:28]=1.[CH3:34]N(C)C=O>>[CH3:33][C:32]1([O:23][CH2:22][CH:9]2[O:8][CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:11]([CH:12]([CH2:13][C:14]3[CH:15]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:21][CH3:34])[CH2:10]2)[CH:31]=[CH:30][CH:29]=[N:28][CH2:27]1
Reactant: Cc1cccnc1Br
Reactant: CN(C)C=O
Reactant: CC(CCc1ccccc1)N1CC(CO)OC1c1ccccc1
Agent: [H-]
Agent: [Na+]
Product: CCC(Cc1ccccc1)N1CC(COC2(C)C=CC=NC2)OC1c1ccccc1

Procedure:
31.1 g of 2-phenyl-3-(1-phenyl-3-butyl)-5-hydroxymethyl-oxazolidine, dissolved in 150 ml of dimethylformamide, are reacted with 6.5 g of sodium hydride dispersion (55% strength) and subsequently with 34.4 g of 2-bromo-3-methyl-pyridine over the course of 18 hours. Crude 3-methyl-3-{[2-phenyl-3-(4-phenyl-3-butyl)-oxazolidin-5-yl]-methoxy}-pyridine is thus obtained.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([N:10]([CH2:21][CH3:22])[S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].CO[CH:25](OC)[N:26]([CH3:28])[CH3:27]>>[CH3:25][N:26]([CH3:28])[CH:27]=[CH:2][C:1]([C:4]1[CH:5]=[C:6]([N:10]([CH2:21][CH3:22])[S:11]([C:14]2[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=2)(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: COC(OC)N(C)C
Reactant: CCN(c1cccc(C(C)=O)c1)S(=O)(=O)c1ccc(C)cc1
Product: CCN(c1cccc(C(=O)C=CN(C)C)c1)S(=O)(=O)c1ccc(C)cc1
Temperature: -10 °C
Reaction time: 18 h

Procedure:
A 31.2 g portion of N-(3-acetylphenyl)-N-ethyl-4-methylbenzenesulfonamide and 50 ml of dimethylformamide dimethylacetal were combined and stirred on a steam bath for 18 hours, then evaporated in vacuo to an oil. This oil was triturated with hexane at -10° C. The hexane was decanted and the residue dissolved in 125 ml of boiling dichloromethane and then filtered. The filtrate was reheated to boiling, 200 ml of hexane was added and the mixture cooled to -10° C. The precipitate was collected, washed with hexane and dried, giving 21.6 g of N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-N-ethyl-4-methylbenzenesulfonamide.
Reaction SMILES: [OH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:11][C:12]([NH:14][C:15]1[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=1[CH3:23])=S>C(#N)C.C(OCC)(=O)C.[Hg](Cl)Cl>[C:16]1([CH3:23])[CH:17]=[C:18]([CH3:22])[CH:19]=[C:20]([CH3:21])[C:15]=1[NH:14][C:12]1[O:1][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=2[N:11]=1
Reactant: Cc1cc(C)c(NC(=S)Nc2cccc([N+](=O)[O-])c2O)c(C)c1
Agent: Cl[Hg]Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(Nc2nc3cccc([N+](=O)[O-])c3o2)c(C)c1
Reaction time: 1 h
Yield: 87.8 %

Procedure:
To a solution containing 0.06 g (0.18 mmol) of 1-(2-hydroxy-3-nitrophenyl)-3-mesitylthiourea in acetonitrile was added 0.10 g (0.36 mmol) of mercury (II) chloride, and the mixture was then stirred for 1 h. The reaction mixture was diluted with ethyl acetate (2 ml) and filtered through a prepacked celite column. The filtrate was concentrated under reduced pressure and the residue was purified via Biotage chromatography eluting with 20% ethyl acetate/dichloromethane to afford 0.047 g (90%) of product.
Reaction SMILES: [CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:15]=2)[NH:10][C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:26])=O.C(N(CC)C(C)C)(C)C>>[CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:15]=2)[N:10]=[C:9]1[Cl:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2c(=O)n(Cc3ccccc3)c(=O)[nH]c2c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2c(=O)n(Cc3ccccc3)c(Cl)nc2c1
Temperature: 120 °C
Reaction time: 48 h
Yield: 95.1 %

Procedure:
Into a round bottom flask was added methyl 3-benzyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-7-carboxylate (1.0 g, 3.2 mmol) dissolved in phosphoryl chloride (15.0 mL, 161 mmol) and N,N-diisopropylethylamine (1.2 mL, 7.1 mmol). The reaction mixture was heated to 120° C. and stirred for 2 d. The mixture was then cooled to rt and concentrated. The residue was poured over ice and the resulting solid was filtered and washed with water to afford methyl 3-benzyl-2-chloro-4-oxo-3,4-dihydroquinazoline-7-carboxylate (1.0 g, 94%). LC-MS: (FA) ES+ 329.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[C:8](=[O:21])[NH:9][C:10]2[C:15]([N:16]=1)=[CH:14][C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=2.N1C=CC=CC=1.[O:28](S(C(F)(F)F)(=O)=O)[S:29]([C:32]([F:35])([F:34])[F:33])(=O)=[O:30]>ClCCl>[CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[C:8]([O:21][S:29]([C:32]([F:35])([F:34])[F:33])(=[O:30])=[O:28])=[N:9][C:10]2[C:15]([N:16]=1)=[CH:14][C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=2
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1ccc2[nH]c(=O)c(N3CCC[C@H]3C)nc2c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N3CCC[C@H]3C)nc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-methyl 3-(2-methylpyrrolidin-1-yl)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (200 mg, 0.70 mmol) in dichloromethane (30 mL) was added pyridine (221 mg, 2.79 mmol) and then Tf2O (395 mg, 1.40 mmol) dropwise with stifling at 0° C. The resulting solution was stirred overnight at room temperature, then quenched by the addition of ice-water (50 mL), extracted with dichloromethane (3×20 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to afford (R)-methyl 3-(2-methylpyrrolidin-1-yl)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate as red oil (250 mg, crude).
Reaction SMILES: [O:1]1[C@@H:13]2[C@@:14]34[CH2:16][CH2:17][N:18]([CH3:19])[C@@H:8]([C@:9]3([O:38][CH3:39])[CH2:10][CH2:11][C@H:12]2[N:20](C(OC(C)(C)C)=O)[C:21]([NH:23]C(OC(C)(C)C)=O)=[NH:22])[CH2:7][C:6]2=[C:15]4[C:2]1=[C:3]([OH:40])[CH:4]=[CH:5]2.[ClH:41]>CCOCC.O>[ClH:41].[ClH:41].[O:1]1[C@@H:13]2[C@@:14]34[CH2:16][CH2:17][N:18]([CH3:19])[C@@H:8]([C@:9]3([O:38][CH3:39])[CH2:10][CH2:11][C@H:12]2[NH:20][C:21]([NH2:23])=[NH:22])[CH2:7][C:6]2=[C:15]4[C:2]1=[C:3]([OH:40])[CH:4]=[CH:5]2
Reactant: CO[C@@]12CC[C@@H](N(C(=N)NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)[C@@H]3Oc4c(O)ccc5c4[C@@]31CCN(C)[C@@H]2C5
Agent: Cl
Solvent: CCOCC
Solvent: O
Product: CO[C@@]12CC[C@@H](NC(=N)N)[C@@H]3Oc4c(O)ccc5c4[C@@]31CCN(C)[C@@H]2C5

Procedure:
A solution of Compound 16 (50 mg, 0.089 mmol) in Et2O (3 ml) was mixed through to a clear acidic reaction with ethereal HCl and with 4 drops of H2O. The mixture was subjected to ultrasound for one hour at room temperature and then evaporated. The residue (40 mg of white foam resin) was dissolved in H2O and freeze dried. Yield: 30 mg (79%) 17.2 HCl as white lyophilisate: 1H-NMR (CDCl3): δ 9.59 (s, OH—C(3)); 9.29 (s, br, NH+); 8.53 (d, J=8.0, C(6)-NH—); 7.29 (s, br, C(6)-NH—C(NH2)2+), 6.78 (d, J=8.1, 1 arom. H); 6.69 (d, J=8.1, 1 arom. H); 4.49 (d, J=7.2, H—C(5)); 3.26 (s, CH3O—C(14)); 2.84 (s, CH3N).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]([CH:20]([CH3:22])[CH3:21])[C:12]2=[O:23])=[O:10])[CH2:3][CH2:2]1.[Cl:24][CH2:25][CH2:26][C:27]([C:29]1[CH:34]=[CH:33][C:32](Cl)=[CH:31][CH:30]=1)=[O:28]>>[NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]([CH:20]3[CH2:21][CH2:22]3)[C:12]2=[O:23])=[O:10])[CH2:3][CH2:2]1.[Cl:24][CH2:25][CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:28]
Reactant: CC(C)n1c(=O)n(C(=O)NCC2CCNCC2)c2ccccc21
Reactant: O=C(CCCl)c1ccc(Cl)cc1
Product: O=C(CCCl)c1ccccc1
Product: O=C(NCC1CCNCC1)n1c(=O)n(C2CC2)c2ccccc21

Procedure:
The procedure given in Example 135 was followed using 3-isopropyl-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid (piperidin-4-ylmethyl)-amide and 3-chloro-4′-chloropropiophenone as a reactant, instead of 3-cyclopropyl-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid (piperidin-4-ylmethyl)-amide and 3-chloropropiophenone, to give the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:12]3[CH:13]=[C:14]([NH:17][CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]4[OH:24])[CH:15]=[CH:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[O:25]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26]1>>[O:25]1[CH:29]=[CH:28][C:27]([C:2]2[CH:7]=[C:6]([C:8]3[N:12]4[CH:13]=[C:14]([NH:17][CH:18]5[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]5[OH:24])[CH:15]=[CH:16][C:11]4=[N:10][CH:9]=3)[CH:5]=[CH:4][N:3]=2)=[CH:26]1
Reactant: OB(O)c1ccoc1
Reactant: OC1CCCCC1Nc1ccc2ncc(-c3ccnc(Cl)c3)n2c1
Product: OC1CCCCC1Nc1ccc2ncc(-c3ccnc(-c4ccoc4)c3)n2c1

Procedure:
The title compound is prepared from (1SR,2SR)-2-[3-(2-Chloro-pyridin-4-yl)-imidazo[1,2-a]pyridin-6-ylamino]-cyclohexanol (Intermediate K) and 3-furyl boronic acid using a procedure analogous to that described in Example 2.3.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:9]1[CH:13]=[CH:12][S:11][C:10]=1[CH:14]=[O:15]>>[C:1]1([S:7][C:9]2[CH:13]=[CH:12][S:11][C:10]=2[CH:14]=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1sccc1Br
Reactant: Sc1ccccc1
Product: O=Cc1sccc1Sc1ccccc1

Procedure:
The title compound was prepared by the method of Preparation 1a using benzenethiol and 3-bromothiophene-2-carbaldehyde.
Reaction SMILES: Cl[C:2]1[N:3]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[C:4](=[O:14])[C:5]2[C:6]([N:13]=1)=[N:7][C:8]([S:11][CH3:12])=[N:9][CH:10]=2.[C:22]([NH:25][NH2:26])(=O)[CH3:23]>C(#N)C>[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[N:3]1[C:4](=[O:14])[C:5]2[C:6](=[N:7][C:8]([S:11][CH3:12])=[N:9][CH:10]=2)[N:13]2[C:22]([CH3:23])=[N:25][N:26]=[C:2]12
Reactant: CSc1ncc2c(=O)n(-c3ccccc3Cl)c(Cl)nc2n1
Reactant: CC(=O)NN
Solvent: CC#N
Product: CSc1ncc2c(=O)n(-c3ccccc3Cl)c3nnc(C)n3c2n1

Procedure:
A mixture of Example 1B (0.150 g, 0.442 mmol) and acetohydrazide (0.072 g, 0.973 mmol) in acetonitrile (5 mL) was heated at 150° C. for 15 minutes in a Biotage microwave reactor. The solid was filtered. The filtrate was concentrated, treated with saturated aqueous NaHCO3 and extracted with ethyl acetate (2×). The combined organic layers were dried over MgSO4, filtered, concentrated, and purified on a 12 g column using the ISCO Companion flash system eluting with CH2Cl2/ethyl acetate (3:7 to 2:8) to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:36]=[CH:35][CH:34]=[CH:33][C:3]=1[O:4][C:5]1[CH2:9][N:8]([CH:10]([CH2:27][C:28]([F:31])([F:30])[F:29])[C:11]([NH:13][C:14]2[CH:18]=[CH:17][N:16]([CH2:19][C@@H:20]3[CH2:24][O:23]C(C)(C)[O:21]3)[N:15]=2)=[O:12])[C:7](=[O:32])[CH:6]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[Cl:1][C:2]1[CH:36]=[CH:35][CH:34]=[CH:33][C:3]=1[O:4][C:5]1[CH2:9][N:8]([CH:10]([CH2:27][C:28]([F:31])([F:29])[F:30])[C:11]([NH:13][C:14]2[CH:18]=[CH:17][N:16]([CH2:19][C@@H:20]([OH:21])[CH2:24][OH:23])[N:15]=2)=[O:12])[C:7](=[O:32])[CH:6]=1
Reactant: CC1(C)OC[C@@H](Cn2ccc(NC(=O)C(CC(F)(F)F)N3CC(Oc4ccccc4Cl)=CC3=O)n2)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: O=C(Nc1ccn(C[C@@H](O)CO)n1)C(CC(F)(F)F)N1CC(Oc2ccccc2Cl)=CC1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.5 %

Procedure:
In a round bottom flask was placed 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1-H-pyrazol-3-yl]-4,4,4-trifluoro-butyramide (164 mg, 0.31 mmol), methanol (5 mL) and p-toluenesulfonic acid monohydrate (15 mg). The mixture was stirred at 25° C. for 16 h and then concentrated in vacuo with silica gel (1.3 g). Purification by Biotage flash chromatography (Aspire column, 100% ethyl acetate to 5% methanol/ethyl acetate) afforded 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-4,4,4-trifluoro-butyramide (116 mg, 77%) as a white foam: HR-ES-MS m/z calculated for C20H20N4O5ClF3 [M+H]+ 489.1147, observed 489.1148; 1H NMR (300 MHz, DMSO-d6) δ ppm 2.80-3.13 (m, 2H), 3.20-3.32 (m, 2H), 3.70-3.81 (m, 1H), 3.87 (dd, J=13.4, 7.5 Hz, 1H), 4.10 (dd, J=13.4, 3.9 Hz, 1H), 4.38 (s, 2H), 4.72 (t, J=5.6 Hz, 1H), 4.84 (s, 1H), 4.95 (d, J=5.4 Hz, 1H), 5.18 (dd, J=9.4, 3.9 Hz, 1H), 6.43 (d, J=2.1 Hz, 1H), 7.31-7.41 (m, 1H), 7.42-7.53 (m, 2H), 7.56 (d, J=2.1 Hz, 1H), 7.65 (d, J=8.2 Hz, 1H), 10.92 (s, 1H).
Reaction SMILES: [C:1]([C:3]1([C:8]2[CH:13]=[CH:12][C:11]([N:14]([CH3:16])[CH3:15])=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1)#[N:2].N.[H][H]>[Ni].CO>[CH3:15][N:14]([CH3:16])[C:11]1[CH:12]=[CH:13][C:8]([C:3]2([CH2:1][NH2:2])[CH2:7][CH2:6][CH2:5][CH2:4]2)=[CH:9][CH:10]=1
Reactant: [H][H]
Reactant: CN(C)c1ccc(C2(C#N)CCCC2)cc1
Agent: [Ni]
Agent: N
Solvent: CO
Product: CN(C)c1ccc(C2(CN)CCCC2)cc1
Yield: 100.2 %

Procedure:
In a pressure reactor was placed 281.2 g (1.3 mole) of 1-cyano-1-(4-dimethylaminophenyl)cyclopentane, 3500 ml of methanol, 600 g of anhydrous ammonia, and 200 g of Raney nickel. Hydrogen was charged into the stirred reaction vessel. The reaction was stirred at room temperature until the theoretical amount of hydrogen had been taken up. The reaction mixture was filtered and the filtrate concentrated in vacuo to yield 284.4 g of the title compound, melting point 87°-89° C.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]2[C:6]([CH2:9][C:10]([O:12]C)=[O:11])=[CH:7][O:8][C:4]=2[CH:3]=1.Cl[CH2:17][C:18]1[CH:19]=[C:20]([C:24]2[C:29]([CH3:30])=[CH:28][C:27]([O:31][CH2:32][CH2:33][CH2:34][S:35]([CH3:38])(=[O:37])=[O:36])=[CH:26][C:25]=2[CH3:39])[CH:21]=[CH:22][CH:23]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(C)C=CC=CC=1>CN(C)C=O.O>[CH3:39][C:25]1[CH:26]=[C:27]([O:31][CH2:32][CH2:33][CH2:34][S:35]([CH3:38])(=[O:36])=[O:37])[CH:28]=[C:29]([CH3:30])[C:24]=1[C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([CH2:17][O:1][C:2]2[CH:15]=[CH:14][C:5]3[C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:7][O:8][C:4]=3[CH:3]=2)[CH:19]=1
Reactant: Cc1cc(OCCCS(C)(=O)=O)cc(C)c1-c1cccc(CCl)c1
Reactant: COC(=O)Cc1coc2cc(O)ccc12
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Cc1cc(OCCCS(C)(=O)=O)cc(C)c1-c1cccc(COc2ccc3c(CC(=O)O)coc3c2)c1
Temperature: 70 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
To a solution of methyl (6-hydroxy-1-benzofuran-3-yl)acetate (17.7 g) and 3′-(chloromethyl)-2,6-dimethyl-4-[3-(methylsulfonyl)propoxy]biphenyl (31.5 g) in N,N-dimethylformamide (60 mL) was added tripotassium phosphate (27.4 g), and the mixture was stirred at 70° C. for 3 hr. The mixture was allowed to cool to room temperature, toluene (240 mL) and water (240 mL) were added, and an extraction operation was performed. The aqueous phase was extracted with toluene (240 mL), and the extract was washed with water (240 mL) and saturated brine (240 mL), and concentrated. The obtained solid was dissolved in dimethyl sulfoxide (100 mL), and 2N sodium hydroxide (47.2 mL) was added at room temperature. After stirring at 70° C. for 1 hr and at 25° C. for 20 hr, the aqueous layer was acidified with 6N hydrochloric acid to pH 1-2, water (240 mL) and ethyl acetate (240 mL) were added, and an extraction operation was performed. The aqueous layer was extracted with ethyl acetate (200 mL), and the combined organic layer was washed with water (240 mL) and concentrated. The crude product was recrystallized from acetone (120 mL)-water (240 mL), and the obtained solid was dried at 60° C. under reduced pressure to give the title compound (34.1 g) as white crystals.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][C:13]([OH:15])=O)=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([C@H:25]([NH2:27])[CH3:26])=[N:23][CH:24]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([C@H:25]([NH:27][C:13](=[O:15])[CH2:12][C:9]2[CH:8]=[CH:7][C:6]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[CH:11][CH:10]=2)[CH3:26])=[N:23][CH:24]=1
Reactant: COc1ccc([C@@H](C)N)nc1
Reactant: O=C(O)Cc1ccc(N2CCCC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc([C@@H](C)NC(=O)Cc2ccc(N3CCCC3)cc2)nc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of (4-pyrrolidin-1-ylphenyl)acetic acid (U.S. Pat. No. 3,641,040) (0.50 g, 2.4 mmol), (1R)-1-(5-methoxypyridin-2-yl)ethylamine hydrochloride (0.57 g, 3.0 mmol), and HATU (1.2 g, 3.1 mmol) in DMF (3 mL) was added N,N-diisopropylethylamine (1.7 mL, 9.7 mmol) and the mixture was stirred at room temperature for 16 h. The solution was concentrated and the crude residue was partitioned between water and EtOAc. The organic layer was washed with brine and water, dried over MgSO4, and purified by normal phase chromatography (10-100% EtOAc/hexanes) to give N-[(1R)-1-(5-methoxypyridin-2-yl)ethyl]-2-(4-pyrrolidin-1-ylphenyl)acetamide as a tan solid. 1H NMR (400 MHz, CDCl3) δ 8.16 (m, 1H), 7.11 (m, 4H), 6.54 (m, 3H), 5.09 (m, 1H), 3.83 (s, 3H), 3.48 (d, J=3.2 Hz, 2H), 3.28 (t, J=6.4 Hz, 4H), 2.01 (m, 4H), 1.36 (d, J=6.4 Hz, 3H); MS (Electrospray): m/z 340.4 (M+H)
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:12]([C:13]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=3[F:20])[N:11]=[C:10]([C:21]3[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][CH:22]=3)[C:4]=2[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.CO.[OH-].[Na+].Cl>C1COCC1>[Cl:1][C:2]1[C:3]2[N:12]([C:13]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=3[F:20])[N:11]=[C:10]([C:21]3[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:29][CH:30]=3)[C:4]=2[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COC(=O)c1ccc(-c2nn(-c3c(F)cccc3F)c3c(Cl)cnc(OC)c23)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ncc(Cl)c2c1c(-c1ccc(C(=O)O)cc1)nn2-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 68.3 %

Procedure:
To a mixture of methyl 4-(7-chloro-1-(2,6-difluorophenyl)-4-methoxy-1H-pyrazolo[4.3-c]pyridin-3-yl)benzoate (118 mg) in a mixed solvent of methanol (2 mL) and THF (1 mL) was added 1N aqueous sodium hydroxide solution (1 mL) at room temperature, and the mixture was stirred at room temperature for 4 hr. The reaction mixture was neutralized with 1N hydrochloric acid under ice-cooling, and the mixture was concentrated under reduced pressure. The obtained solid was washed with water to give the title compound (78.0 mg).