Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][CH:37]=1)[CH:5]([OH:34])[CH2:6][NH:7][CH:8]([CH3:33])[CH2:9][C:10]1[CH:32]=[CH:31][C:13]([O:14][CH2:15][C:16]2O[CH:18]=[C:19]([O:23]CC3C=CC=CC=3)[C:20](=[O:22])[CH:21]=2)=[CH:12][CH:11]=1.[CH3:38][NH2:39]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][CH:37]=1)[CH:5]([OH:34])[CH2:6][NH:7][CH:8]([CH3:33])[CH2:9][C:10]1[CH:32]=[CH:31][C:13]([O:14][CH2:15][C:16]2[N:39]([CH3:38])[CH:18]=[C:19]([OH:23])[C:20](=[O:22])[CH:21]=2)=[CH:12][CH:11]=1
Reactant: CC(Cc1ccc(OCc2cc(=O)c(OCc3ccccc3)co2)cc1)NCC(O)c1cccc(Cl)c1
Reactant: CN
Product: CC(Cc1ccc(OCc2cc(=O)c(O)cn2C)cc1)NCC(O)c1cccc(Cl)c1

Procedure:
A suspension of 2-[4-[2 [(3-chloro-β-hydroxyphenethyl)amino]propyl]phenoxymethyl]-5-benzyloxy-4H-pyran-4-one (1.0 g) in 33% ethanolic methylamine solution (15 ml), was heated to 120° in a sealed vessel for 18 hours. The solvent was evaporated in vacuo and the residue purified by column chromatography on silica using chloroform, then 10% methanol:chloroform as eluent. The resulting gum was dissolved in methanol and 2M hydrochloric acid was added dropwise to bring the pH to 1.5-2.0. The solution was then hydrogenated at room temperature and pressure over 10% palladium on charcoal. After filtration and evaporation of solvent in vacuo the residue was treated with 1.2M sodium hydrogen carbonate solution (5 ml), and extracted with ethyl acetate (3×50 ml), and dried (MgSO4). After filtration and evaporation of solvent the residue was triturated with acetone to give 2-[4-[2-[(3-chloro-β-hydroxyphenethyl)amino]propyl]phenoxymethyl]-5-hydroxy-1-methyl-1H-pyrid-4-one (0.7 g) as a (40:60) mixture of diastereoisomers.
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:12]/[C:13]1[NH:14][CH:15]=[CH:16][CH:17]=1)/[C:5](=[O:11])[NH:6]2.CCN(CC)CC.[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C)C=O.CC([O-])=O.CC([O-])=O.[Pd+2].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[C:25]1([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2/[C:4](=[CH:12]/[C:13]2[NH:14][CH:15]=[CH:16][CH:17]=2)/[C:5](=[O:11])[NH:6]3)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C1Nc2cccc(I)c2/C1=C/c1ccc[nH]1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1Nc2cccc(-c3ccccc3)c2/C1=C/c1ccc[nH]1
Temperature: 25 °C
Yield: 85 %

Procedure:
A solution of (Z)-1,3-dihydro-4-iodo-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (30.4 mg, 0.090 mmol) (Starting Material 1), Et3N (38 μL, 0.271 mmol), tri-o-tolylphosphine (1.7 mg, 0.006 mmol) (Aldrich), Pd(OAc)2 (0.6 mg, 0.003 mmol)(Aldrich), and phenylboronic acid (16.5 mg, 0.136 mmol) (Aldrich) in 362 μL of dry N,N-dimethylformamide (Fisher Scientific) was heated at 100° C. for 24 h. The reaction mixture was allowed to cool to room temperature, concentrated in vacuo to remove N,N-dimethylformamide, and then directly purified by flash chromatography (Merck Silica gel 60, 70-230 mesh, 10% ethyl acetate-hexanes then 25% ethyl acetate-hexanes elution) to provide pure (Z)-1,3-dihydro-4-phenyl-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (Yield 21.9 mg, 85%) as an orange solid (mp 184-185° C.).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[S:10][C:9]([C:11]#[CH:12])=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:13][Si:14]([CH2:17][N:18]=[N+:19]=[N-:20])([CH3:16])[CH3:15].CCN(C(C)C)C(C)C>CN(C=O)C.[Cu]I>[Cl:1][C:2]1[C:3]2[S:10][C:9]([C:11]3[N:20]=[N:19][N:18]([CH2:17][Si:14]([CH3:16])([CH3:15])[CH3:13])[CH:12]=3)=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: C#Cc1cc2ncnc(Cl)c2s1
Reactant: C[Si](C)(C)CN=[N+]=[N-]
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)Cn1cc(-c2cc3ncnc(Cl)c3s2)nn1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of compound 48.2 (1.0 mmol), trimethylsilylmethyl azide (5.0 mmol), CuI (0.2 mmol), and DIEA (1.0 mmol) in DMF (10 mL) was stirred at room temperature for 24 hours. The solvent was removed and the residue was diluted with water and extracted with EtOAc. The organic layer was washed with dilute aqueous ammonium hydroxide, brine, dried, concentrated and purified by flash column chromatography to provide 4-chloro-6-(1-trimethylsilanylmethyl-1H-[1,2,3]triazol-4-yl)-thieno[3,2-d]pyrimidine (compound 48.3) in 80% yield. EIMS (m/z): calcd. for C12H14ClN5SSi (M+)+H 324.04. found 324.00.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][CH:13]=[C:14]([C:16]([O:18]CC)=[O:17])[N:15]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]>CO.O>[NH2:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=2)=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CCOC(=O)c1csc(-c2ccc(S(N)(=O)=O)cc2)n1
Solvent: O
Solvent: CO
Product: NS(=O)(=O)c1ccc(-c2nc(C(=O)O)cs2)cc1
Temperature: 75 °C

Procedure:
In an oven-dried, 100-mL, round-bottomed flask was placed ethyl 2-(4-aminosulfonylphenyl)thiazole-4-carboxylate (1300 mg, 4.2 mmol), LiOH monohydrate (350 mg, 8.3 mmol) in MeOH (40 mL) and H2O (4 mL). The solution was heated to 75° C. for 3 h, cooled to RT, and concentrated. The resulted yellow solid was dissolved in H2O (10 mL), extracted with EtOAc (1×15 mL). The aqueous layer was acidified with 2N aqueous HCl (4.15 mL). The precipitate was filtered, and washed with H2O (10 mL) to afford the title compound as a light-yellow solid. MS m/z: 285 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=1)[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[OH:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:29]1([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]Br)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[C:1]([O:5][C:6]([N:8]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:27][CH:28]=1)[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: BrCCCCCc1ccccc1
Reactant: COC(=O)c1ccc(CN(CCc2ccccc2O)C(=O)OC(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COC(=O)c1ccc(CN(CCc2ccccc2OCCCCCc2ccccc2)C(=O)OC(C)(C)C)cc1

Procedure:
1.78 g (4.63 mmol) of methyl 4-{[(tert-butoxycarbonyl)-(2-hydroxyphenethyl)-amino]methyl}benzoate from Ex.V.2, 1.05 g (4.63 mmol) of 5-phenyl-1-bromopentane and 0.77 g (5.55 mmol) of potassium carbonate in 15 ml of acetonitrile are heated at reflux for 18 hours. The reaction mixture is poured into water, extracted with ethyl acetate and dried over magnesium sulphate and the solvent is distilled off under reduced pressure. A solid is obtained which is reacted further without purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH3:19])=[O:5])[CH3:2].B(Br)(Br)Br>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=2)=[N:8][C:7]=1[CH3:19])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(-c2ccc(OC)cc2)nc1C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)c1sc(-c2ccc(O)cc2)nc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.9 %

Procedure:
To a solution of 2-(4-methoxy-phenyl)-4-methyl-thiazole-5-carboxylic acid ethyl ester (550 mg, 2 mmol) in dichloromethane (20 mL) at −80° C. is added BBr3 (5 mL, 1M solution in dichloromethane). The reaction is stirred at ambient temperature overnight. The reaction is quenched by addition of methanol and is concentrated under reduced pressure. The residue is partitioned between EtOAc and 1N HCl. The organic layer is concentrated and the residue is purified by chromatography (0 to 30% EtOAc in hexanes) to give the title compound as a tan solid (500 mg, 95%). LC-ES/MS m/e 264 (M+1), 1H NMR (400 MHz, DMSO-d6) δ 10.22 (s, 1H), 7.82 (d, 2H), 6.86 (d, 2H), 4.27 (q, 2H), 2.64 (s, 3H), 1.29 (t, 3H).
Reaction SMILES: [Na].[Br:2][C:3]1[S:7][C:6]([CH:8]=O)=[CH:5][CH:4]=1.[N:10]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N+:11]=[N-:12]>CCO>[N:10]([C:13](=[CH:8][C:6]1[S:7][C:3]([Br:2])=[CH:4][CH:5]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N+:11]=[N-:12]
Reactant: CCOC(=O)CN=[N+]=[N-]
Reactant: O=Cc1ccc(Br)s1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(=Cc1ccc(Br)s1)N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42 %

Procedure:
A solution of sodium (2.76 g, 120 mmol) in absolute EtOH (120 mL) was cooled in an ice-bath and a mixture of 5-bromo-2-formylthiophene (5.73 g, 30 mmol) and ethyl azidoacetate (15.49 g, 120 mmol) was added dropwise during 30 min period. The bath was removed and the reaction mixture was stirred at room temperature for another 30 min. A cold solution of saturated aqueous NH4Cl solution (100 mL) was added and the resulting solution was extracted with diethyl ether (3×100 mL) and the combined organic layers were washed with brine (200 mL), dried over Na2SO4. After removing diethyl ether under reduced pressure, the crude product was purified by column chromatography (EtOAc/Hexane: 1/50) to give acrylate 60 (3.81 g, 42%) as a light yellow solid.
Reaction SMILES: C1(CO[C:9]2[CH:10]=[CH:11][CH:12]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[C:13]3[C:17]=2[N:16]=[C:15]2CCCC[C:14]=32)C=CC=CC=1.[O:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>C(OCC)(=O)C>[F:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][CH:12]2[C:13]3[C:31]4[CH:32]=[CH:33][C:34]([OH:30])=[CH:14][C:15]=4[NH:16][C:17]=3[CH2:9][CH2:10][CH2:11]2)=[CH:28][CH:27]=1
Reactant: Fc1ccc(CC2C=CC(OCc3ccccc3)=C3N=C4CCCCC4=C32)cc1
Reactant: C1CCOC1
Solvent: CCOC(C)=O
Product: Oc1ccc2c3c([nH]c2c1)CCCC3Cc1ccc(F)cc1

Procedure:
The hydrogenation of 2.8 g of 1,2,3,4-tetrahydro-6-phenylmethoxy -9-[(4-fluorophenyl)methyl]-9H-dibenzo[b,d]pyrrole from Example 77 was carried out by using the procedure described in Example 86 except that 1:1 tetrahydrofuran-absolute ethyl alcohol was used instead of 1:1 ethyl acetate-absolute ethyl alcohol mixture as a solvent. The crude 5,6,7,8-tetrahydro-9-[(3-fluorophenyl)methyl]-9H-dibenzo[b,d]pyrrol-3-ol was used without further purification.
Reaction SMILES: [C:1]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([Cl:15])[CH:11]=[C:10]([Cl:16])[CH:9]=2)([O:3][CH2:4][CH3:5])=[O:2].CN(C)[CH:19]=[O:20].P(Cl)(Cl)(Cl)=O>ClC(Cl)C>[CH:19]([C:14]1[C:13]2[C:8](=[CH:9][C:10]([Cl:16])=[CH:11][C:12]=2[Cl:15])[NH:7][C:6]=1[C:1]([O:3][CH2:4][CH3:5])=[O:2])=[O:20]
Reactant: CCOC(=O)c1cc2c(Cl)cc(Cl)cc2[nH]1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Product: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1C=O
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
Combine 2-carboethoxy-4,6-dichloroindole (20.0 g, 0.077 mol), and dimethylformamide (9.0 mL, 0.117 mol) in dichloroethane (100 mL). Add phosphoryl chloride (18.0 g, 0.117 mmol). Heat to reflux. After 3.5 hours, cool the reaction mixture to ambient temperature to obtain a solid. Collect the solid by filtration, rinse with dichloromethane. Combine the solid with aqueous 1 M sodium acetate solution and stir. After 1 hour, filter, rinse with water, and dry to give the title compound.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[Cl:7][C:8]1[C:15]([CH3:16])=[C:14](F)[CH:13]=[CH:12][C:9]=1[C:10]#[N:11].Cl.[NH2:19][C@H:20]([C@H:24]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]([F:28])([F:27])[F:26])[C:21]([OH:23])=[O:22]>CS(C)=O>[CH2:30]([O:29][C@H:24]([C:25]([F:26])([F:28])[F:27])[C@@H:20]([NH:19][C:14]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[C:8]([Cl:7])[C:15]=1[CH3:16])[C:21]([OH:23])=[O:22])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: Cc1c(F)ccc(C#N)c1Cl
Reactant: N[C@@H](C(=O)O)[C@H](OCc1ccccc1)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: Cc1c(N[C@@H](C(=O)O)[C@H](OCc2ccccc2)C(F)(F)F)ccc(C#N)c1Cl
Temperature: 80 °C
Reaction time: 48 h
Yield: 21.9 %

Procedure:
Cs2CO3 (3.5 g, 10.7 mmol) was added to a mixture of 2-chloro-4-fluoro-3-methylbenzonitrile (0.79 g, 4.65 mmol) and (2R,3S)-2-amino-3-(benzyloxy)-4,4,4-trifluorobutanoic acid hydrochloride salt (0.93 g, 3.1 mmol) in DMSO (18 mL) at room temperature. The resulting mixture was heated to 80° C. and stirred for 2 days. After cooling to room temperature, the reaction mixture was poured into ice-water (150 mL) and extracted with 10% EtOAc in hexanes (2×50 mL). The aqueous phase was acidified to pH=2˜3 with 2N HCl and extracted with EtOAc (2×100 mL). The EtOAc extracts were washed with water, brine and dried over Na2SO4. Removal of the solvent gave a residue, which was purified by flash chromatography to afford the crude (2R,3S)-3-(benzyloxy)-2-(3-chloro-4-cyano-2-methylphenylamino)-4,4,4-trifluorobutanoic acid (280 mg) as a mixture.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[C:15]([F:17])[C:14]([C:18]3[CH2:19][CH2:20][N:21]([CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:22][CH:23]=3)=[C:13]([F:31])[CH:12]=2)[CH2:6]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C.O>[NH2:1][CH2:4][C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[C:15]([F:17])[C:14]([C:18]3[CH2:19][CH2:20][N:21]([CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:22][CH:23]=3)=[C:13]([F:31])[CH:12]=2)[CH2:6]1
Reactant: [N-]=[N+]=NC[C@H]1CN(c2cc(F)c(C3=CCN(Cc4ccccc4)CC3)c(F)c2)C(=O)O1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: O
Product: NC[C@H]1CN(c2cc(F)c(C3=CCN(Cc4ccccc4)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.5 %

Procedure:
(5R)-5-(Azidomethyl)-3-[4-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)-3,5-difluorophenyl]-1,3-oxazolidin-2-one (WO 0181350) (10.60 g, 24.97 mmol) was dissolved in acetonitrile (250 ml) and water (25 ml). Triphenylphosphine (7.86 g, 29.96 mmol) was added and the suspension was stirred at room temperature for approximately 16 h. The reaction mixture was concentrated under vacuum. The crude material was purified by chromatography on silica gel using 2.5-5% methanol in dichloromethane to give 7.03 g of the title product.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][N:7](C(OC(C)(C)C)=O)[C@H:6]([C:16]2[NH:20][C:19]3[C:21]4[C:26]([CH:27]=[CH:28][C:18]=3[N:17]=2)=[CH:25][C:24]2[C:29]3[C:34]([CH2:35][O:36][C:23]=2[CH:22]=4)=[CH:33][C:32]([B:37]2[O:41][C:40]([CH3:43])([CH3:42])[C:39]([CH3:45])([CH3:44])[O:38]2)=[CH:31][CH:30]=3)[CH2:5]1.Cl>C(O)C>[CH3:1][O:2][CH2:3][CH:4]1[CH2:8][NH:7][CH:6]([C:16]2[NH:20][C:19]3[C:21]4[C:26]([CH:27]=[CH:28][C:18]=3[N:17]=2)=[CH:25][C:24]2[C:29]3[C:34]([CH2:35][O:36][C:23]=2[CH:22]=4)=[CH:33][C:32]([B:37]2[O:41][C:40]([CH3:43])([CH3:42])[C:39]([CH3:45])([CH3:44])[O:38]2)=[CH:31][CH:30]=3)[CH2:5]1
Reactant: COC[C@H]1C[C@@H](c2nc3ccc4cc5c(cc4c3[nH]2)OCc2cc(B3OC(C)(C)C(C)(C)O3)ccc2-5)N(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CCO
Product: COCC1CNC(c2nc3ccc4cc5c(cc4c3[nH]2)OCc2cc(B3OC(C)(C)C(C)(C)O3)ccc2-5)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Tert-butyl (2S,4S)-4-(methoxymethyl)-2-[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]pyrrolidine-1-carboxylate (310 mg, 0.507 mmol) was treated with 2 mL 1.25N HCl in ethanol and stirred at room temperature for 2 h then at 50° C. for 2 h. The reaction mixture was concentrated under reduced pressure to give a dark yellow solid that was directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2([OH:23])[CH2:22][O:21][CH2:20]2)=[CH:15][CH:14]=1.CC(=CC)C.Cl([O-])=[O:30].[Na+].O.OP([O-])(O)=O.[Na+]>CC#N.O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:30])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2([OH:23])[CH2:22][O:21][CH2:20]2)=[CH:15][CH:14]=1
Reactant: O=Cc1c[nH]c2cc(Cl)c(-c3ccc(C4(O)COC4)cc3)cc12
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=C(O)c1c[nH]c2cc(Cl)c(-c3ccc(C4(O)COC4)cc3)cc12
Temperature: 25 °C
Reaction time: 20 h
Yield: 34.9 %

Procedure:
To the mixture of 6-chloro-5-[4-(3-hydroxy-oxetan-3-yl)-phenyl]-1H-indole-3-carbaldehyde (50.0 mg, 0.15 mmol) in MeCN (2 mL) was added 2-methyl-2-butene (2.0 mL, 13.7 mmol), followed by sodium chlorite (138 mg, 1.53 mmol) and sodium phosphate monobasic hydrate (211.0 mg, 1.53 mmol) in water (1 mL). The reaction mixture was stirred at room temperature for 20 hours, and concentrated in vacuo. The residue was acidified with 1N aqueous citric acid (1 mL) and extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (34-80% EtOAc/heptanes, with 0.2% formic acid modifier) to afford the title compound (18 mg, 34%) as a brown solid. MS (ES−) 342.3 (M−H)−. 1H NMR (400 MHz, CD3OD) δ 8.02 (s, 1H), 7.98 (s, 1H), 7.66 (d, J=8.20 Hz, 2H), 7.56 (s, 1H), 7.47 (d, J=8.20 Hz, 2H), 4.87-4.80 (m, 4H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([CH:24]([CH3:26])[CH3:25])[C:5]1([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][C:6]1=[O:15].[CH:27]1([C:31](O)=[O:32])[CH2:30][CH2:29][CH2:28]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:14][C:10]1[CH:9]=[C:8]2[C:13]([C:5]([N:4]([CH:24]([CH3:26])[CH3:25])[CH2:3][CH2:2][NH:1][C:31]([CH:27]3[CH2:30][CH2:29][CH2:28]3)=[O:32])([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=3)[C:6](=[O:15])[NH:7]2)=[CH:12][CH:11]=1
Reactant: CC(C)N(CCN)C1(Cc2cccc(Cl)c2)C(=O)Nc2cc(Cl)ccc21
Reactant: O=C(O)C1CCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)N(CCNC(=O)C1CCC1)C1(Cc2cccc(Cl)c2)C(=O)Nc2cc(Cl)ccc21
Reaction time: 2 h
Yield: 84.3 %

Procedure:
The mixture of rac-3-[(2-Amino-ethyl)-isopropyl-amino]-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one (60 mg, 0.15 mmol), cyclobutanecarboxylic acid (18.4 mg, 0.18 mmol), EDCl (37 mg, 0.19 mmol), HOBt (30 mg, 0.19 mmol) and DIPEA (40 uL, 0.225) in DCM (2 mL) was stirred at root temperature for 2 hr. The mixture was purified by flash column chromatography to give 60 mg rac-Cyclobutanecarboxylic acid (2-{[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-isopropyl-amino}-ethyl)-amide. MS: [M+H]+=474
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:15]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:20]=CC=C[CH:16]=1.CC(O)C.C(OC(N=NC(OC(C)C)=O)=O)(C)C>C1COCC1>[CH:15]([O:1][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])([CH3:20])[CH3:16]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: C1CCOC1
Solvent: CC(C)O
Product: COC(=O)c1cc([N+](=O)[O-])ccc1OC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.2 %

Procedure:
Methyl 2-hydroxy-5-nitrobenzoate (11.82 g, 60 mmol), triphenylphosphine (17.29 g, 66 mmol) and iPrOH (3.96 g, 5 ml, 66 mmol) were taken up in THF (150 ml) and cooled in ice. Di-isopropyl-azodicarboxylate (8.31 g, 10 ml, 66 mmol) was added carefully, and the reaction was stirred at RT overnight. The volatiles were removed in vacuo and the residue treated with EtOAc (50 ml). The solids that didn't dissolve were removed by filtration, and the filtrate evaporated to dryness in vacuo. The residue was purified by column chromatography to give methyl 2-isopropoxy-5-nitrobenzoate (6.92 g, 48.5%) as a yellow oil.
Reaction SMILES: [C:1]([C:10]1[CH:22]=[CH:21][C:20]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][C:12]=2[CH:11]=1)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].O.NN.[OH-].[K+].C(O)COCCO>O>[CH2:1]([C:10]1[CH:22]=[CH:21][C:20]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][C:12]=2[CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCC(=O)c1ccc2c(c1)Cc1ccccc1-2
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: O
Product: CCCCCCCCc1ccc2c(c1)Cc1ccccc1-2
Temperature: 130 °C
Reaction time: 0.67 h
Yield: 80.2 %

Procedure:
In a 200 ml-three-necked flask, 6.00 g (20.5 mM) of 2-octanoylfluorene, 3.06 ml (50.4 mM) of hydrazine hydrate (80% aqueous solution), 4.20 g (63.6 mM) of potassium hydroxide and 60 ml of diethyleneglycol were placed, followed by heating to about 130° C. to dissolve the mixture. Then, the mixture was gradually heated to 210°-217° C., followed by stirring for 3 hours and 40 minutes under heating. After the reaction, the reaction mixture was cooled and poured into 250 ml of water to precipitate a crystal. The crystal was recovered by filtration and dissolved in toluene, followed by washing with water, drying with anhydrous sodium sulfate and distilling-off of the solvent. The residue was purified by silica gel column chromatography (eluent: toluene/hexane=1/2) to obtain 4.58 g of 2-octylfluorene.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:15])=[C:6]([NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])[CH:7]=1.[CH3:16][Si:17]([C:20]#[CH:21])([CH3:19])[CH3:18]>>[F:11][C:10]([F:13])([F:12])[C:9]([NH:8][C:6]1[CH:7]=[C:2]([C:21]#[C:20][Si:17]([CH3:19])([CH3:18])[CH3:16])[CH:3]=[CH:4][C:5]=1[F:15])=[O:14]
Reactant: O=C(Nc1cc(Br)ccc1F)C(F)(F)F
Reactant: C#C[Si](C)(C)C
Product: C[Si](C)(C)C#Cc1ccc(F)c(NC(=O)C(F)(F)F)c1
Yield: 78.4 %

Procedure:
N-(5-Bromo-2-fluorophenyl)-2,2,2-trifluoroacetamide (8.04 g, 28 mmol) and (trimethylsilyl)acetylene (6 mL, 42 mmol) were coupled according to the procedure of Example 56, Step B to give the desired product (6.66 g, 78%). 1H NMR (400 MHz, d6-DMSO) δ 11.32 (s, 1H), 7.62-7.60 (m, 1H), 7.47-7.44 (m, 1H), 7.39-7.33 (m, 1H), 0.21 (s, 9H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[Br:12]Br>ClCCl.C(O)(=O)C>[Br:12][C:7]1[CH:8]=[C:2]([F:1])[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]=1[NH2:6]
Reactant: BrBr
Reactant: Nc1ccc(F)cc1[N+](=O)[O-]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Nc1c(Br)cc(F)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 20 h
Yield: 76 %

Procedure:
To a solution of 4-fluoro-2-nitroaniline (19.76 g, 126 mmol) in a mixture of dichloromethane (600 mL) and acetic acid (200 mL) was slowly added bromine (15 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1 hour and at ambient temperature for 20 hrs. The mixture was concentrated and the residue partitioned between ethyl acetate and sodium bicarbonate solution. The organic phase was separated, washed with sodium bisulphite solution and concentrated. The residue was recrystallized from hexanes containing some dichloromethane to provide 22.7 g (76%) of the title compound. MS (DCI/NH3) m/z 236 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[CH:4][C:3]=1[OH:14].C([O-])([O-])=O.[Cs+].[Cs+].ClC[C:23]1[CH2:27][CH2:26][CH2:25][CH:24]=1>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[CH:4][C:3]=1[O:14][C:23]1[CH2:27][CH2:26][CH2:25][CH:24]=1
Reactant: Oc1cc(Nc2nccs2)ccc1Cl
Reactant: ClCC1=CCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: Clc1ccc(Nc2nccs2)cc1OC1=CCCC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 25 %

Procedure:
Following the general procedure for O-allylation, Method B, a mixture 2-chloro-5-(thiazol-2-ylamino)phenol (88 mg, 0.39 mmol) and Cs2CO3 (127 mg, 0.39 mmol) in acetone was treated with 1-(chloromethyl)cyclopentene (60 mg, 0.39 mmol) at 0° C. The reaction mixture was heated to 60° C. and stirred for 3 h. The title compound was obtained after purification by flash chromatography on silica gel (hexane:EtOAc 8/2) in 25% yield (29 mg).