Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]2[NH:9][N:8]=[CH:7][C:6]=2[C:5]2[CH2:11][N:12]([CH2:21][C:22]([F:25])([F:24])[F:23])[C:13](=[O:20])[C@H:14]([CH2:16][C:17](O)=[O:18])[CH2:15][C:4]=2[CH:3]=1.[Cl:26][C:27]1[CH:28]=[CH:29][C:30]([C:35]2[CH2:36][CH2:37][NH:38][CH2:39][CH:40]=2)=[C:31]([CH:34]=1)[C:32]#[N:33].CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:26][C:27]1[CH:28]=[CH:29][C:30]([C:35]2[CH2:40][CH2:39][N:38]([C:17](=[O:18])[CH2:16][C@H:14]3[C:13](=[O:20])[N:12]([CH2:21][C:22]([F:23])([F:25])[F:24])[CH2:11][C:5]4[C:6]5[CH:7]=[N:8][NH:9][C:10]=5[C:2]([Cl:1])=[CH:3][C:4]=4[CH2:15]3)[CH2:37][CH:36]=2)=[C:31]([CH:34]=1)[C:32]#[N:33]
Reactant: N#Cc1cc(Cl)ccc1C1=CCNCC1
Reactant: O=C(O)C[C@@H]1Cc2cc(Cl)c3[nH]ncc3c2CN(CC(F)(F)F)C1=O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#Cc1cc(Cl)ccc1C1=CCN(C(=O)C[C@@H]2Cc3cc(Cl)c4[nH]ncc4c3CN(CC(F)(F)F)C2=O)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.9 %

Procedure:
In an oven-dried round bottom flask, (S)-2-(4-chloro-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetic acid (50 mg, 0.133 mmol) and 5-chloro-2-(1,2,3,6-tetrahydropyridin-4-yl)benzonitrile (44.1 mg, 0.173 mmol) were dissolved in DMF (2 ml). To this solution was added DIEA (0.093 ml, 0.532 mmol) followed by PyBOP (69.3 mg, 0.133 mmol). The reaction mixture was allowed to stir at room temperature under a nitrogen atmosphere for 3 hours during which time it became dark red in color. The DMF was evaporated under high vacuum. The residue was subjected to column chromatography (silica, 20:1 CH2Cl2/2M NH3 in MeOH). The most pure fractions were collected, evaporated and again subjected to column chromatography (silica, 40:1 CH2Cl2/2M NH3 in MeOH). The fractions were collected, evaporated and dried overnight under vacuum to give (S)-5-chloro-2-(1-(2-(4-chloro-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetyl)-1,2,3,6-tetrahydropyridin-4-yl)benzonitrile (40 mg, 0.069 mmol, 52.1% yield) as a light tan solid. 1H NMR (500 MHz, MeOD) δ ppm 1.24-1.34 (m, 1H) 2.50-2.60 (m, 3H) 2.60-2.76 (m, 2H) 2.95-3.05 (m, 1H) 3.14-3.23 (m, 2H) 3.82-3.91 (m, 1H) 3.90-4.02 (m, 1H) 4.05-4.14 (m, 1H) 4.53-4.62 (m, 2H) 5.54 (d, J=17.4 Hz, 1H) 6.07 (d, J=13.7 Hz, 1H) 7.21 (s, 1H) 7.46 (d, J=8.3 Hz, 1H) 7.64 (d, J =8.5 Hz, 1H) 7.78 (s, 1H) 8.24 (s, 1H); MS (ESI): 575 (M-1H); Rf=1.90 (4 min run).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][CH2:11][CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=2)[CH:3]=1.[C:22]([NH:25][NH2:26])(=[O:24])[CH3:23].C(N(CC)CC)C.F[B-](F)(F)F.N1(OC(=[N+](C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[C:22]([NH:25][NH:26][C:17](=[O:19])[C:16]1[CH:15]=[CH:14][C:13]([CH2:12][CH2:11][NH:10][C:4]2[CH:3]=[C:2]([Cl:1])[N:7]=[C:6]([O:8][CH3:9])[N:5]=2)=[CH:21][CH:20]=1)(=[O:24])[CH3:23]
Reactant: COc1nc(Cl)cc(NCCc2ccc(C(=O)O)cc2)n1
Reactant: CC(=O)NN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1nc(Cl)cc(NCCc2ccc(C(=O)NNC(C)=O)cc2)n1
Reaction time: 15 h
Yield: 55.2 %

Procedure:
To a solution of 4-[2-(6-chloro-2-methoxy-pyrimidin-4-ylamino)-ethyl]-benzoic acid (0.41 g, 1.33 mmol), acetic acid hydrazide (0.1 g, 2 mmol), and triethylamine (0.7 mL, 3.99 mmol) in DMF (3 mL) is added [(benzotriazol-1-yloxy)-dimethylamino-methylene]-dimethyl-ammonium tetrafluoro borate (0.51 g, 1.6 mmol) at room temperature. After 15 h at 20° C., the solid is filtered, and washed with water to afford 4-[2-(6-chloro-2-methoxy-pyrimidin-4-ylamino)-ethyl]-benzoic acid N′-acetyl-hydrazide (267 mg). The filtrate is extracted with EtOAc, and concentrated to afford additional amount of 4-[2-(6-chloro-2-methoxy-pyrimidin-4-ylamino)-ethyl]-benzoic acid N′-acetyl-hydrazide (100 mg). LCMS: RT=2 minutes; MS: 364 (M+H).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([CH3:18])[C:9]=1[SH:19].[CH:20]1([CH2:23]Br)[CH2:22][CH2:21]1>C(#N)C>[Cl:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([CH3:18])[C:9]=1[S:19][CH2:23][CH:20]1[CH2:22][CH2:21]1
Reactant: COC(=O)c1ccc(Cl)c(S)c1C
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)c1ccc(Cl)c(SCC2CC2)c1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1.66 g (5.09 mmol) of cesium carbonate in 20 ml of acetonitrile were added to 1.05 g (4.85 mmol) of methyl 4-chloro-3-mercapto-2-methylbenzoate. 687 mg (5.09 mmol) of cyclopropylmethyl bromide were slowly added dropwise, and the reaction mixture was stirred at RT for 16 h. For work-up, the solvent was removed, and water was added to the residue. The mixture was extracted three times with ethyl acetate, the combined organic phases were dried and filtered and the solvent was removed. What was isolated were 1.2 g of pure product.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([S:10]([N:13]2[CH2:17][CH2:16][S:15][C@H:14]2[C:18]([O:20][C@H:21]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH:39]([F:41])[F:40])=[C:34]([O:42][CH2:43][CH:44]3[CH2:46][CH2:45]3)[CH:33]=2)[CH2:22][C:23]2[C:28]([Cl:29])=[CH:27][N+:26]([O-:30])=[CH:25][C:24]=2[Cl:31])=[O:19])(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([OH:3])=O.[NH2:47][CH2:48][CH2:49][NH:50][C:51](=[O:57])[O:52][C:53]([CH3:56])([CH3:55])[CH3:54].C(Cl)CCl>CN(C1C=CN=CC=1)C.CN(C=O)C.O>[C:53]([O:52][C:51]([NH:50][CH2:49][CH2:48][NH:47][C:1]([C:4]1[CH:5]=[C:6]([S:10]([N:13]2[CH2:17][CH2:16][S:15][C@H:14]2[C:18]([O:20][C@H:21]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH:39]([F:40])[F:41])=[C:34]([O:42][CH2:43][CH:44]3[CH2:46][CH2:45]3)[CH:33]=2)[CH2:22][C:23]2[C:24]([Cl:31])=[CH:25][N+:26]([O-:30])=[CH:27][C:28]=2[Cl:29])=[O:19])(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)=[O:3])=[O:57])([CH3:56])([CH3:55])[CH3:54]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCS[C@H]2C(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCNC(=O)c1cccc(S(=O)(=O)N2CCS[C@H]2C(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.1 %

Procedure:
4-((S)-2-((S)-3-(3-Carboxyphenylsulfonyl)thiazolidine-2-carbonyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (200 mg, 0.278 mmol), tert-butyl 2-aminoethylcarbamate (89 mg, 0.556 mmol), DMAP (40.7 mg, 0.334 mmol) and EDC (160 mg, 0.834 mmol) were dissolved in DMF. The reaction was stirred at room temperature overnight to achieve completion. The reaction mixture was diluted with water, and the precipitate was washed with water, dissolved in ethyl acetate and extracted with HCl 1N, NaHCO3 5% and brine. The organic phase was dried over Na2SO4 and concentrated under vacuum to give 4-((S)-2-((S)-3-(3-(2-(tert-butoxycarbonylamino)ethylcarbamoyl)phenylsulfonyl)thiazolidine-2-carbonyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (211 mg, 0.245 mmol, 88% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@:9]([NH:38][CH3:39])([CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][C:25]3([C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH2:30][C:29](=[O:37])[NH:28]3)[CH2:24][CH2:23]2)[CH2:10][N:11]([CH3:19])[C:12](=[O:18])[CH2:13][C:14]([F:17])([F:16])[F:15])[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)CC)C.[C:47](Cl)(=[O:54])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.O>C(#N)C>[F:16][C:14]([F:15])([F:17])[CH2:13][C:12]([N:11]([CH2:10][C@@:9]([N:38]([CH3:39])[C:47](=[O:54])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[CH2:20][CH2:21][N:22]1[CH2:23][CH2:24][C:25]2([C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:30][C:29](=[O:37])[NH:28]2)[CH2:26][CH2:27]1)[CH3:19])=[O:18]
Reactant: O=C(Cl)c1ccccc1
Reactant: CN[C@](CCN1CCC2(CC1)NC(=O)Cc1ccccc12)(CN(C)C(=O)CC(F)(F)F)c1ccc(Cl)c(Cl)c1
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN(C[C@](CCN1CCC2(CC1)NC(=O)Cc1ccccc12)(c1ccc(Cl)c(Cl)c1)N(C)C(=O)c1ccccc1)C(=O)CC(F)(F)F
Reaction time: 1 h
Yield: 85.5 %

Procedure:
N-{2-(S)-(3,4-Dichlorophenyl)-2-methylamino-4-[3-oxo-3,4-dihydro-2H-spiro(isoquinoline-1,4′-piperidin)-1′-yl]butyl}-3,3,3-trifluoro-N-methylpropanamide (440 mg) was dissolved in acetonitrile (5 mL). Under cooling with ice, triethylamine (314 μL) and benzoyl chloride (174 μL) were added thereto, and the mixture was stirred for 1 hour at the same temperature. Water was added to the reaction mixture, and the resultant mixture was extracted with ethyl acetate, sequentially washed with 0.5N aqueous hydrochloric acid, water, saturated aqueous sodium bicarbonate, and saturated brine, and dried over sodium sulfate anhydrate. The solvent was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography (n-hexane ethyl acetate=1:1→ethyl acetate→ethyl acetate:methanol=10:1), to thereby give the title compound (442 mg, 85.5%) as white powder.
Reaction SMILES: [C:1]([C:4]1[C:9]2[CH2:10][C:11](=O)[C:12]3[CH:18]=[CH:17][CH:16]=[C:15](F)[C:13]=3[S:14][C:8]=2[CH:7]=[CH:6][CH:5]=1)([OH:3])=[O:2].[OH2:21].NN>C(O)C.O1CCOCC1>[C:1]([C:4]1[C:9]2[CH2:10][CH2:11][C:12]3[CH:18]=[CH:17][CH:16]=[C:15]([OH:21])[C:13]=3[S:14][C:8]=2[CH:7]=[CH:6][CH:5]=1)([OH:3])=[O:2]
Reactant: O
Reactant: O=C(O)c1cccc2c1CC(=O)c1cccc(F)c1S2
Agent: NN
Solvent: C1COCCO1
Solvent: CCO
Product: O=C(O)c1cccc2c1CCc1cccc(O)c1S2
Reaction time: 2 h
Yield: 12.7 %

Procedure:
5.0 g of 9-carboxy-4-fluoro-10,11-dihydrodibenzo[b,f]thiepin-11-one and 5.0 g of 100% hydrazine hydrate were dissolved in the mixed solvent of 50 ml of ethanol and 50 ml of dioxane. The resulting mixture was heated under reflux for 5 hours. The solvent was evaporated under reduced pressure to obtain the residue, which was washed with ethanol. To this was added 5.0 g of sodium hydroxide in 100 ml of diethylene glycol and the resulting mixture was heated with stirring at 180°-200° C. for 2 hours. After cooling, water was added to the mixture, which was extracted with benzene. The aqueous layer was acidified with hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated to obtain a glutinous residue which was chromatographed over silica gel, and eluted with benzene-ethyl acetate (1:1). Recrystallization of the thus obtained crude product from methanol-water afforded 600 mg of 9-carboxy-4-hydroxy-10,11-dihydrodibenzo[b,f] thiepin having a melting point of 171°-173° C.
Reaction SMILES: Cl[C:2]1[N:3]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[CH3:19][C:16]1[CH:17]=[CH:18][C:13]([N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]([CH:11]=[O:12])=[C:2]2[N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:14][C:15]=1[N+:20]([O-:22])=[O:21]
Reactant: C1CNCCN1
Reactant: Cc1ccc(-n2c(Cl)c(C=O)c3ccccc32)cc1[N+](=O)[O-]
Product: Cc1ccc(-n2c(N3CCNCC3)c(C=O)c3ccccc32)cc1[N+](=O)[O-]
Yield: 68 %

Procedure:
2-chloro-1-(4-methyl-3-nitrophenyl)-1H-indole-3-carboxaldehyde is reacted with piperazine as described in Step 2 of Example 29 to afford 1-(4-methyl-3-nitrophenyl)-2-(piperazin-1-yl)-1H-indole-3-carboxaldehyde (68% yield). ESI/MS 365 (M+H); RT=2.65 min; NMR (CDCl3) 10.35 (1H, s); 8.31 (1H, d, J=9 Hz); 8.11 (1H, s); 7.61 (2H); 7.31 (2H); 7.01 (1H, d, J=9 Hz); 3.31 (4H, m); 2.88 (4H, m); 2.74 (3H, s).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)=[CH:5][CH:4]=1.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CO>[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([B:9]3[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]3)=[CH:5][CH:4]=2)[CH2:21][CH2:20]1
Reactant: CN1CCNCC1
Reactant: CC1(C)OB(c2ccc(CBr)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: CN1CCN(Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1

Procedure:
2-(4-Bromomethyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (300 mg; 1.01 mmol), N-methylpiperazine (132 mg; 1.32 mmol) and K2CO3 (168 mg; 1.22 mmol) in DMF (4 ml) are heated to 80° C. for 45 minutes. The reaction mixture was diluted with MeOH, filtered and purified via chromatography (SiO2; CH2Cl2/MeOH/NH3conc 95:5:0.5) to yield the title compound as yellow resin. 1H-NMR (400 MHz; DMSO-d6): 7.63 (d, 2H); 7.33 (d, 2H); 3.47 (s, 1H); 2.34 (bs, 8H); 2.16 (s, 3H); 1.30 (s, 12H). MS (m/z) ES+: 317 (MH+).
Reaction SMILES: CC([O-])(C)C.[K+].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([Cl:15])[CH:9]=1.[Cl:16][C:17]1[CH:22]=[C:21](Cl)[CH:20]=[CH:19][N:18]=1>CN(C=O)C.O.CCOC(C)=O>[Cl:15][C:10]1[CH:9]=[C:8]([NH2:7])[CH:13]=[CH:12][C:11]=1[O:14][C:21]1[CH:20]=[CH:19][N:18]=[C:17]([Cl:16])[CH:22]=1
Reactant: Clc1ccnc(Cl)c1
Reactant: Nc1ccc(O)c(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc(Oc2ccnc(Cl)c2)c(Cl)c1
Temperature: 90 °C
Yield: 50.1 %

Procedure:
KOtBu (1.016 g, 9.05 mmol) was added to a solution of 4-amino-2-chlorophenol (1.00 g, 6.97 mmol) in DMF (35 ml) at RT and the resultant mixture was stirred 45 min. 2,4-Dichloropyridine (1.340 g, 9.05 mmol) was then added and the reaction was stirred with heating at 90° C. overnight. The reaction was cooled to RT and diluted generously with H2O and EtOAc. The layers were separated. The aqueous was extracted with EtOAc (3×). The combined organics were washed with H2O (1×) and brine (2×), dried (MgSO4), concentrated in vacuo and purified by silica gel chromatography (EtOAc/hexanes) to afford 3-chloro-4-(2-chloropyridin-4-yloxy)benzenamine (0.89 g, 50% yield) as a waxy yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 8.24 (d, J=5.7 Hz, 1H), 7.02 (d, J=8.7 Hz, 1H), 6.87-6.82 (m, 2H), 6.73-6.72 (m, 1H), 6.58-6.56 (m, 1H), 5.50 (br s, 2H); MS (ESI) m/z: 254.9 (M+H+); 256.9 (M+2+H+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1.[F:12][C:13]([F:25])([F:24])[C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.C(N(C(C)C)CC)(C)C.C(=O)([O-])O.[Na+]>C(Cl)Cl>[F:25][C:13]([F:12])([F:24])[C:14]1[CH:15]=[CH:16][C:17]([S:20]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]([CH:10]=[O:11])=[CH:2]2)(=[O:22])=[O:21])=[CH:18][CH:19]=1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: O=Cc1c[nH]c2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=Cc1cn(S(=O)(=O)c2ccc(C(F)(F)F)cc2)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
A solution of 1H-indole-3-carboxaldehyde (0.290 g, 2.00 mmol) in methylene chloride (4 mL) was added with 4-(trifluoromethyl)phenylsulfonyl chloride (0.587 g, 2.40 mmol) and diisopropylethylamine (0.310 g, 2.40 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate to terminate the reaction, and then extracted three times with methylene chloride. The organic layer was dried over anhydrous magnesium sulfate, then the solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain 1-[4′ (trifluoromethyl)phenylsulfonyl]-1H-indole-3-carboxaldehyde (0.650 g, 92%).
Reaction SMILES: C([Cl:4])(=O)C.[CH3:5][S:6][C:7]1[CH:31]=[CH:30][C:10]([CH2:11][C:12]2[N:16]=[C:15]([CH:17]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]3)[O:14][N:13]=2)=[CH:9][CH:8]=1>CO>[ClH:4].[CH3:5][S:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:11][C:12]2[N:16]=[C:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[O:14][N:13]=2)=[CH:30][CH:31]=1
Reactant: CSc1ccc(Cc2noc(C3CCN(C(=O)OC(C)(C)C)CC3)n2)cc1
Reactant: CC(=O)Cl
Solvent: CO
Product: CSc1ccc(Cc2noc(C3CCNCC3)n2)cc1
Product: Cl
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 100.1 %

Procedure:
Acetyl chloride (86 μL, 1.21 mmol) was added dropwise to methanol (0.5 mL) and stirred for 10 minutes then added to tert-butyl 4-{3-[4-(methylthio)benzyl]-1,2,4-oxadiazol-5-yl}piperidine-1-carboxylate (237 mg, 0.61 mmol) in MeOH (5 mL) and the mixture heated to 60° C. for 1 hour and the solvents evaporated to give a the title compound as a yellow powder, (199 mg, 100%); MS: 290 (MH+).
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([I:9])=[CH:7][CH:6]=[C:5]([Cl:10])[N:4]=1.C([O-])([O-])=[O:12].[Ca+2]>O1CCOCC1.O>[Cl:10][C:5]1[N:4]=[C:3]([CH2:2][OH:12])[C:8]([I:9])=[CH:7][CH:6]=1.[Cl:10][C:5]1[N:4]=[C:3]([CH3:2])[C:8]([I:9])=[CH:7][CH:6]=1
Reactant: O=C([O-])[O-]
Reactant: Clc1ccc(I)c(CBr)n1
Agent: [Ca+2]
Solvent: C1COCCO1
Solvent: O
Product: Cc1nc(Cl)ccc1I
Product: OCc1nc(Cl)ccc1I
Temperature: 25 °C
Yield: 18 %

Procedure:
To a stirred solution of 2-bromomethyl-6-chloro-3-iodo-pyridine (20 g, crude, 60 mmol, 1 eq) in 1,4-dioxane (200 mL) was added suspension of CaCO3 (31.4 g, 313 mmol, 5.2 eq) in water (200 mL) at room temperature. Resulting reaction mixture was refluxed for 10 hours. After complete consumption of starting material, reaction mixture was cooled to room temperature and filtered through celite bed over Buchner funnel. Celite bed was washed with EtOAc (2×100 mL). Combined filtrate was washed with water (100 mL) and aqueous sodium bicarbonate (50 mL), dried over sodium sulfate and concentrated under reduced pressure to afford brown solid (21 g, crude). Crude was purified by column chromatography using silica gel (100-200 mesh). Desired compound was eluted at 20% EtOAc in hexane to get title compound as faint yellow solid (2.9 g, 18%) and also 9 g of 6-chloro-3-iodo-2-methyl-pyridine was recovered. 1H NMR (400 MHz, CDCl3) δ: 3.87 (t, J=4.9 Hz, 1H), 4.63 (d, J=4.96 Hz, 2H), 7.04 (d, J=4 Hz, 1H), 8.0 (d, J=8.2 Hz, 1H). LC-MS (m/z): 270.1 (M+H).
Reaction SMILES: C(B(CC)CC)C.[CH3:8][O:9][C:10](=[O:28])[CH:11](I)[CH2:12][CH2:13][N:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CS(C)=O.CCCCCC.[Cl-].[Na+].O>[CH3:8][O:9][C:10]([CH:11]1[CH2:12][CH2:13][N:14]2[C:15]([C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][CH:17]=[C:18]12)=[O:28]
Reactant: COC(=O)C(I)CCn1cccc1C(=O)c1ccccc1
Agent: CCB(CC)CC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Solvent: CS(C)=O
Product: COC(=O)C1CCn2c(C(=O)c3ccccc3)ccc21
Reaction time: 1 h
Yield: 62.8 %

Procedure:
A 1.0N solution of triethylborane in hexane (1.6 mL, 1.6 mmoles) was added to a stirred solution of 4-(2-benzoylpyrrol-1-yl)-2-iodobutyric acid methyl ester (IV, 530 mg, 1.3 mmoles) in dimethylsulfoxide (5 mL) under normal air atmosphere. After 1 hour, additional triethylborane (1.0 mL, 1.0 mmole) in hexane was added and the reaction was stirred. After 30 minutes, the reaction was diluted with brine (50 mL) and extracted with diethyl ether (2×50 mL). The organic layer was dried over NaSO4 and evaporated. The crude product was purified by flash chromatography on silica eluting with 1:4 ethyl acetate/hexane to give pure 5-benzoyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid methyl ester (V, 220 mg, 61%) as an amber oil. 1H NMR (CDCl3): delta 2.75-3.0 (m, 2H); 3.76 (s, 3H); 4.07 (dd, 1H); 4.38-4.61 (m, 2H); 6.09 (d, 1H); 6.81 (d, 1H); 7.4-7.55 (m, 3H); 7.80 (dd, 2H). 13C NMR (CDCl3): delta 30.9, 42.3, 7.4, 52.5, 103.0, 124.8, 127.0,128.0, 128.8, 131.3, 139.1, 142.2, 171.6, 184.8.
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:8]1[C:9](=[O:21])[N:10](C2CCCCO2)[N:11]=[CH:12][C:13]=1Cl.C[O:23][C:24](=[O:33])[CH:25](Br)[CH2:26][CH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH:27]1([CH2:26][CH:25]([N:10]2[C:9](=[O:21])[CH:8]=[C:13]([O:6][CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:12]=[N:11]2)[C:24]([OH:23])=[O:33])[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: OC1CCCC1
Reactant: COC(=O)C(Br)CC1CCCC1
Reactant: O=c1c(Cl)c(Cl)cnn1C1CCCCO1
Product: O=C(O)C(CC1CCCC1)n1ncc(OC2CCCC2)cc1=O

Procedure:
In an analogous manner to the stepwise sequence outlined in Intermediate 59, starting from cyclopentanol and 4,5-dichloro-2-(tetrahydro-pyran-2-yl)-2H-pyridazin-3-one (Intermediate 20) and 2-bromo-3-cyclopentyl-propionic acid methyl ester (Intermediate 10) afforded 3-cyclopentyl-2-(4-cyclopentyloxy-6-oxo-6H-pyridazin-1-yl)-propionic acid as a white solid (244.7 mg, 88%, total or for last step); ES+-HRMS m/e calcd for C17H24N2O4 [M+H+] 321.1809, found 321.1808. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.96-1.17 (m, 2H), 1.35-1.78 (m, 13H), 1.87-2.01 (m, 3H), 2.15 (ddd, J=13.8, 11.0, 5.0 Hz, 1H), 4.81-4.90 (m, 1H), 5.31 (dd, J=11.0, 4.2 Hz, 1H), 6.26 (d, J=2.8 Hz, 1H), 7.75 (d, J=2.8 Hz, 1H), 12.92 (br s, 1H).
Reaction SMILES: O[CH:2]([C:4]1[O:5][C:6](=[O:27])[C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:16][CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:3].[F:28][C:29]1[CH:30]=[C:31]([C:37]2[C:45]3[C:40](=[N:41][CH:42]=[N:43][C:44]=3[NH2:46])[NH:39][N:38]=2)[CH:32]=[C:33]([O:35][CH3:36])[CH:34]=1>>[NH2:46][C:44]1[N:43]=[CH:42][N:41]=[C:40]2[N:39]([CH:2]([C:4]3[O:5][C:6](=[O:27])[C:7]4[C:12]([C:13]=3[C:14]3[CH:15]=[CH:16][C:17]([CH2:20][N:21]5[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]5)=[CH:18][CH:19]=3)=[CH:11][CH:10]=[CH:9][CH:8]=4)[CH3:3])[N:38]=[C:37]([C:31]3[CH:32]=[C:33]([O:35][CH3:36])[CH:34]=[C:29]([F:28])[CH:30]=3)[C:45]=12
Reactant: COc1cc(F)cc(-c2n[nH]c3ncnc(N)c23)c1
Reactant: CC(O)c1oc(=O)c2ccccc2c1-c1ccc(CN2CCCCC2)cc1
Product: COc1cc(F)cc(-c2nn(C(C)c3oc(=O)c4ccccc4c3-c3ccc(CN4CCCCC4)cc3)c3ncnc(N)c23)c1
Yield: 70.7 %

Procedure:
The title compound was made in a similar way as that of the example 134, step a, from 3-(1-hydroxyethyl)-4-(4-(piperidin-1-ylmethyl)phenyl)-1H-isochromen-1-one (Intermediate B48, 720 mg, 1.981 mmol) and 3-(3-fluoro-5-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Intermediate G1, 565 mg, 2.17 mmol) to give 3-(1-(4-amino-3-(3-fluoro-5-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-4-(4-(piperidin-1-ylmethyl)phenyl)-1H-isochromen-1-one (850 mg, 1.40 mmol, 71.0% yield) as a brown solid.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:41])[CH2:6][C:7]1[CH:8]=[C:9]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH2:38][CH3:39])([C:23]3[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][CH:31]([OH:36])[C:32]([CH3:35])([CH3:34])[CH3:33])=[C:25]([CH3:37])[CH:24]=3)[CH2:21][CH3:22])=[CH:16][C:15]=2[CH3:40])[CH:10]=[C:11]([OH:13])[CH:12]=1.Cl>CO>[CH2:21]([C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:9]2[CH:10]=[C:11]([OH:13])[CH:12]=[C:7]([CH2:6][C:5]([OH:41])=[O:4])[CH:8]=2)=[C:15]([CH3:40])[CH:16]=1)([C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][CH:31]([OH:36])[C:32]([CH3:34])([CH3:35])[CH3:33])=[C:25]([CH3:37])[CH:24]=1)[CH2:38][CH3:39])[CH3:22]
Reactant: CCC(CC)(c1ccc(CCC(O)C(C)(C)C)c(C)c1)c1ccc(-c2cc(O)cc(CC(=O)OC)c2)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCC(CC)(c1ccc(CCC(O)C(C)(C)C)c(C)c1)c1ccc(-c2cc(O)cc(CC(=O)O)c2)c(C)c1
Temperature: 25 °C
Reaction time: 9 h
Yield: 100.6 %

Procedure:
A 2 N sodium hydroxide aqueous solution (0.06 mL) was added to a solution of (4′-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-5-hydroxy-2′-methyl-biphenyl-3-yl)acetic acid methyl ester (Example 164-(4); 11.5 mg, 0.0202 mmol) in methanol (0.30 mL) at room temperature, and the mixture was stirred at room temperature for nine hours. The mixture was acidified with dilute hydrochloric acid aqueous solution, followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to give the title compound (10.5 mg, 100%).