Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][N:6]([C:11](C1C=C(C(C)C)C(OC)=CC=1OC)=[O:12])[CH2:5]2.C([O-])([O-])=O.[Na+].[Na+].[C:32]1(C)C=CC=C[CH:33]=1>CO.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:32]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][N:6]([CH:11]=[O:12])[CH2:5]2)=[CH2:33]
Reactant: Cc1ccccc1
Reactant: COc1cc(OC)c(C(C)C)cc1C(=O)N1Cc2ccc(Br)cc2C1
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: [Na+]
Solvent: O
Solvent: CO
Product: C=Cc1ccc2c(c1)CN(C=O)C2
Temperature: 80 °C

Procedure:
To (5-bromo-1,3-dihydro-isoindol-2-yl)-(5-isopropyl-2,4-dimethoxyphenyl)methanone (2.2 g, 5.44 mmol), and 2-vinyl-4,4,5,5-tetramethyl-1,3,2-dioxaboralane (1.2 ml, 6.53 mmol) in MeOH (25 ml) and toluene (25 ml) was added Na2CO3 in water (25 ml). The reaction was degassed, Pd(PPh3)4 (0.38 g, 0.05 mmol) added then heated at 80° C. overnight. The reaction was worked up by adding water and extracting with EtOAc (×3). The combined organic layers were washed with brine and dried over MgSO4. The product was filtered and evaporated to dryness then purified by flash column chromatography, gradient elution (ether:petrol) to yield 5-isopropyl-2,4-dimethoxy-phenyl)-(5-vinyl-1,3-dihydro-isoindol-2-yl)-methanone as a yellow oil (1.6 g). 1H NMR (Me-d3-OD) 7.47-7.15 (3H, m), 7.15 (1H, s), 6.82-6.72 (1H, m), 6.71 (1H, s), 5.79 (1H, dd), 5.24 (1H, dd), 4.90 (2H, d), 4.64 (2H, d), 3.93 (3H, s), 3.91 (3H, s), 3.27 (1H, sept), 1.23 (6H, d). MS: [M+H]+ 352.
Reaction SMILES: [OH:1][CH2:2][CH2:3][P:4](=[O:9])([O:7][CH3:8])[O:5][CH3:6].N1C=CC=CC=1.[Br:16][CH2:17][CH2:18][CH2:19][S:20](Cl)(=[O:22])=[O:21]>C(OCC)C>[Br:16][CH2:17][CH2:18][CH2:19][S:20]([O:1][CH2:2][CH2:3][P:4](=[O:9])([O:7][CH3:8])[O:5][CH3:6])(=[O:22])=[O:21]
Reactant: COP(=O)(CCO)OC
Reactant: O=S(=O)(Cl)CCCBr
Solvent: c1ccncc1
Solvent: CCOCC
Product: COP(=O)(CCOS(=O)(=O)CCCBr)OC
Reaction time: 24 h

Procedure:
3.9 g. of dimethyl 2-hydroxyethylphosphonate and 5.9 g of pyridine were dissolved in 40 ml. of dry diethyl ether, and the solution was cooled with ice to -5° C. A solution of 6.0 g of γ-bromopropylsulfonyl chloride in 30 ml. of dry diethyl ether was added dropwise to the cooled solution by means of a dropping funnel. After the addition, the mixed solution was allowed to stand for 24 hours at 0° to 5° C. The reaction mixture was poured into 50 ml. of 5% hydrochloric acid, and extracted with diethyl ether. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off at reduced pressure. The product was further dried at room temperature at 0.7 mmHg for 18 hours to afford dimethyl 2-(3-bromopropyl-sulfonyloxy)ethylphosphonate as a colorless oil in a yield of 75 mol %. The product showed the following characteristic values.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=[O:11].C(C(O)=O)(F)(F)F.[F:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33]Br)=[CH:28][CH:27]=1.[OH-].[Na+]>[Br-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(Cl)Cl.O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([CH:12]1[CH2:17][CH2:16][N:15]([CH2:33][CH2:32][C:29]2[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=2)[CH2:14][CH2:13]1)=[O:11]
Reactant: O=C(c1nc2ccccc2s1)C1CCNCC1
Reactant: Fc1ccc(CCBr)cc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Br-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: O=C(c1nc2ccccc2s1)C1CCN(CCc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Mix (2-benzothiazolyl)(4-piperidinyl)methanone. CF3CO2H (1.95 g, 5.43 mmol), 2-(4-fluorophenyl)ethyl bromide (1.70 g, 8.35 mmol), benzyltriethylammonium bromide (149 mg, 0.54 mmol), sodium hydroxide (5 g), water (25 mL) and methylene chloride (25 mL). Stir at room temperature under an argon atmosphere overnight, then heat at reflux overnight. Cool the reaction to room temperature, separate the organic phase and extract the aqueous phase with methylene chloride (50 mL). Combine the organic phases, dry (Na2SO4) and evaporate the solvent in vacuo. Purify by chromatography (20% ethyl acetate/hexane with 2% triethylamine) and recrystallize (hexane) to give the title compound as pale yellow needles; mp 97°-98° C.
Reaction SMILES: Br[C:2]1[C:18]([F:19])=[CH:17][C:5]2[O:6][CH2:7][CH2:8][C:9]3[S:13][C:12]([C:14]([NH2:16])=[O:15])=[N:11][C:10]=3[C:4]=2[CH:3]=1.[CH3:20][N:21]1[CH:25]=[C:24]([C:26]([OH:30])([C:28]#[CH:29])[CH3:27])[N:23]=[CH:22]1>>[F:19][C:18]1[C:2]([C:29]#[C:28][C:26]([OH:30])([C:24]2[N:23]=[CH:22][N:21]([CH3:20])[CH:25]=2)[CH3:27])=[CH:3][C:4]2[C:10]3[N:11]=[C:12]([C:14]([NH2:16])=[O:15])[S:13][C:9]=3[CH2:8][CH2:7][O:6][C:5]=2[CH:17]=1
Reactant: C#CC(C)(O)c1cn(C)cn1
Reactant: NC(=O)c1nc2c(s1)CCOc1cc(F)c(Br)cc1-2
Product: Cn1cnc(C(C)(O)C#Cc2cc3c(cc2F)OCCc2sc(C(N)=O)nc2-3)c1
Yield: 9 %

Procedure:
Similar to as described in General Procedure G, 9-bromo-8-fluoro-4,5-dihydrobenzo[2,3]oxepino[4,5-d]thiazole-2-carboxamide was reacted with 2-(1-methyl-1H-imidazol-4-yl)but-3-yn-2-ol (WO2009/158011 A1) to give the titled compound as colorless solid (19 mg, 9%).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[N:16]1([C:21](N)=[O:22])[CH:20]=[CH:19][N:18]=[CH:17]1>>[N:18]1([CH2:19][CH2:20][NH:16][C:21]([NH:2][CH2:3][CH2:4][NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:22])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:17]1
Reactant: NC(=O)n1ccnc1
Reactant: NCCNC(=O)OCc1ccccc1
Agent: Cl
Product: O=C(NCCNC(=O)OCc1ccccc1)NCCN1CCCCC1

Procedure:
Prepared from benzyl 2-aminoethylcarbamate hydrochloride and N-[2-1-piperidinyl)ethyl]-1H-imidazole-1-carboxamide (Preparation 18) by a similar procedure to Preparation 50. The title compound was obtained as a yellow oil.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([NH:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:21]=1[NH:20][C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:18]2)(=[O:11])=[O:10].[C:29](=O)([O-])[O-].[K+].[K+].CI.CCCCCC>CN(C)C=O.C(OCC)(=O)C>[CH3:29][N:12]([S:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:2]([F:27])([F:1])[F:28])(=[O:11])=[O:10])[C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:21]=1[NH:20][C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:18]2
Reactant: CCOC(=O)c1cc2cccc(NS(=O)(=O)c3ccccc3C(F)(F)F)c2[nH]1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CI
Product: CCOC(=O)c1cc2cccc(N(C)S(=O)(=O)c3ccccc3C(F)(F)F)c2[nH]1
Temperature: 25 °C
Yield: 71.6 %

Procedure:
To a solution of ethyl 7-({[2-(trifluoromethyl)phenyl]sulfonyl}amino)-1H-indole-2-carboxylate (5.0 g) and potassium carbonate (2.0 g) in N,N-dimethylformamide (50 mL) was added methyl iodide (0.75 mL) under ice-cooling, and the mixture was stirred from under ice-cooling to room temperature for 18 hr. The reaction solution was ice-cooled, methyl iodide (0.75 mL) was added again, and the mixture was stirred from under ice-cooling to room temperature for 18 hr. The reaction solution was diluted with ethyl acetate, washed with water, aqueous citric acid solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to basic silica gel column chromatography (ethyl acetate:hexane=20:80-35:65), and the obtained crude product was subjected three times to silica gel column chromatography (ethyl acetate:hexane=5:95-10:90) to give the title compound (3.7 g, yield: 72%) as a pale-yellow oil. MS: 427(MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:16](=[O:18])[CH3:17])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:19]1([S:25](Cl)(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>N1C=CC=CC=1.C(Cl)Cl>[C:16]([C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:2]([NH:1][S:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:27])=[O:26])[CH:3]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)c1ccc(OCc2ccccc2)c(N)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)c1ccc(OCc2ccccc2)c(NS(=O)(=O)c2ccccc2)c1
Reaction time: 18 h
Yield: 47 %

Procedure:
To a stirred solution of 1-(3-amino-4-benzyloxy-phenyl)-ethanone (EP 0 659 737) (16.98 g, 70.0 mmol) in pyridine (50 mL) was added dropwise benzenesulfonyl chloride (13.09 g, 73.5 mmol) in 100 mL of pyridine at room temperature. The reaction was stirred for 18 hours under nitrogen atmosphere. The mixture was diluted with CH2Cl2 (700 mL) and washed with 1N hydrochloric acid, water, dried over Na2SO4, and concentrated. The product was purified by flash silica gel chromatography eluting with CH2Cl2 to give the title compound as a tan solid (12.55 g, 47%); 1H NMR (300 MHz, DMSO-d6) δ 3.33(s, 3 H), 5.03(s, 2 H), 7.02(d, J=8.7 Hz, 1 H), 7.35(m, 3 H), 7.44(t, J=15 Hz, 2 H), 7.58(m, 1 H), 7.50 (m, 3 H), 7.81(d, 1 H), 9.83(s, 1 H); MS (ES) m/z: 381.9 (MH+, 100%); HRMS Calcd. for C21H19NO4S(MH+): 382.1107. Found: 382.1100.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[O:16])[CH:10]=2)=[C:4]([CH3:17])[CH:3]=1.CO.[BH4-].[Na+]>O1CCCC1>[OH:16][CH2:15][C:11]1[CH:10]=[C:9]([C:5]2[C:4]([CH3:17])=[CH:3][C:2]([OH:1])=[CH:7][C:6]=2[CH3:8])[CH:14]=[CH:13][CH:12]=1
Reactant: Cc1cc(O)cc(C)c1-c1cccc(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(O)cc(C)c1-c1cccc(CO)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 93.6 %

Procedure:
A solution of 4′-hydroxy-2′,6′-dimethylbiphenyl-3-carbaldehyde (6.95 q, 30.7 mmol) in a mixed solvent of methanol (30 mL) and tetrahydrofuran (60 mL) was ice-cooled, sodium borohydride (90%, 1.29 g, 30.7 mmol) was added, and the mixture was stirred for 20 hr under nitrogen atmosphere, during which the mixture was allowed to gradually warm to room temperature. The reaction mixture was concentrated under reduced pressure, the residue was treated with diluted hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crystals were recrystallized from heptane-ethyl acetate to give the title compound (6.56 g, yield 93%) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[S:11])[S-:10])[CH:5]=[CH:4][CH:3]=1.C([NH+](CC)CC)C.Cl[CH2:20][C:21](=[O:26])[CH2:22][CH:23]([CH3:25])[CH3:24]>C(#N)C>[OH:26][C:21]1([CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:20][S:11][C:9](=[S:10])[N:8]1[C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=1
Reactant: CC(C)CC(=O)CCl
Reactant: Cc1cccc(NC(=S)[S-])n1
Agent: CC[NH+](CC)CC
Solvent: CC#N
Product: Cc1cccc(N2C(=S)SCC2(O)CC(C)C)n1
Reaction time: 2 h
Yield: 59.8 %

Procedure:
The procedure of Example 4 is followed but starting with triethylammonium (6-methylpyrid-2-yl)dithiocarbamate (28.5 g) and 1-chloro-4-methylpentan-2-one (13.4 g) in anhydrous acetonitrile (200 cc) at a temperature between 20 and 25° C. The reaction is continued for 2 hours at 20°-25° C. After recrystallisation of the product from diisopropyl ether (390 cc) and filtration of the boiling solution, there is obtained 4-hydroxy-4-isobutyl-3-(6-methylpyrid-2-yl)-thiazolidine-2-thione (16.8 g) melting at 95° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]([CH2:34][C:35]2[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=2)[C@H:13]([C@H:24]2[CH2:29][CH2:28][C@H:27]([O:30][CH2:31][CH2:32][CH3:33])[CH2:26][CH2:25]2)[C:14]([O:16]CC2C=CC=CC=2)=[O:15])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[ClH:41]>C(O)C.[Pd]>[ClH:41].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]([CH2:34][C:35]2[CH:36]=[CH:37][N:38]=[CH:39][CH:40]=2)[C@H:13]([C@H:24]2[CH2:29][CH2:28][C@H:27]([O:30][CH2:31][CH2:32][CH3:33])[CH2:26][CH2:25]2)[C:14]([OH:16])=[O:15])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: CCCO[C@H]1CC[C@H]([C@H](C(=O)OCc2ccccc2)N(Cc2ccncc2)S(=O)(=O)c2ccc(OC)cc2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCCO[C@H]1CC[C@H]([C@H](C(=O)O)N(Cc2ccncc2)S(=O)(=O)c2ccc(OC)cc2)CC1

Procedure:
A solution of benzyl 2(R)-[(4-methoxybenzenesulfonyl)(4-picolyl)amino]-2-(trans-4-propoxycyclohexyl)-acetate (3.0 g, 5 mmol) in ethanol (50 mL) containing 3 N hydrochloric acid (5 mL, 15 mmol) is hydrogenated at 50 psi in the presence of 5% palladium on charcoal (200 mg) at room temperature for 4 hours. The reaction mixture is filtered through celite washing with ethanol and concentrated in vacuo to provide 2(R)-[(4-methoxybenzenesulfonyl)(4-picolyl)amino]-2-(trans-4-propoxycyclohexyl) acetic acid hydrochloride as a crude product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:21]([N+:22]([O-])=O)=[C:20]([CH3:25])[CH:19]=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1.C(O)(=O)C.O.[Zn]>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:21]([NH2:22])=[C:20]([CH3:25])[CH:19]=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccnc(Nc2ccc(OCc3ccccc3)cc2)c1[N+](=O)[O-]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccnc(Nc2ccc(OCc3ccccc3)cc2)c1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.4 %

Procedure:
To a solution of N-[4-(benzyloxy)phenyl]-4-methyl-3-nitropyridin-2-amine (154.5 g) in THF (1300 mL), acetic acid (260 mL) and water (13 mL) was slowly added zinc powder (300 g) over 35 min. After zinc was added, the mixture was stirred at room temperature for 1 h. The reaction mixture was filtered through celite, and insoluble materials were washed with THF (3 L). The filtrate was combined and concentrated. To the residue were added EtOAc (1.2 L) and 2.5 N NaOH (1.2 L) under ice cooling, and then the mixture was stirred at room temperature for 30 min. The mixture was filtered through celite, and insoluble materials were washed with EtOAc (3 L). The organic layer was separated, washed with water (300 mL) and brine (300 mL×2), dried over MgSO4 and concentrated to give a crude N2-[4-(benzyloxy)phenyl]-4-methylpyridine-2,3-diamine (137 g) as black oil. This product was subjected to the next reaction without further purification.
Reaction SMILES: C1(CC2C(C=COC)=C(C(F)(F)F)N=C(C(F)F)C=2C(OC)=O)CC1.BrBr.C(=O)([O-])[O-].[K+].[K+].[Br:34][CH:35]([C:41]1[C:42]([CH2:58][CH:59]2[CH2:61][CH2:60]2)=[C:43]([C:54]([O:56][CH3:57])=[O:55])[C:44]([CH:51]([F:53])[F:52])=[N:45][C:46]=1[C:47]([F:50])([F:49])[F:48])[CH:36](OC)[O:37][CH3:38]>CCOCC.CO>[Br:34][C:35]([C:41]1[C:42]([CH2:58][CH:59]2[CH2:60][CH2:61]2)=[C:43]([C:54]([O:56][CH3:57])=[O:55])[C:44]([CH:51]([F:52])[F:53])=[N:45][C:46]=1[C:47]([F:48])([F:49])[F:50])=[CH:36][O:37][CH3:38]
Reactant: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(Br)C(OC)OC)c1CC1CC1
Agent: BrBr
Agent: COC=Cc1c(C(F)(F)F)nc(C(F)F)c(C(=O)OC)c1CC1CC1
Agent: O=C([O-])[O-]
Solvent: CCOCC
Solvent: CO
Product: COC=C(Br)c1c(C(F)(F)F)nc(C(F)F)c(C(=O)OC)c1CC1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To a solution of 18.0 g (49.3 mmol) of methyl 4-(cyclopropylmethyl)-2-(difluoromethyl)-5-(2-methoxyethenyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (example 127 of U.S. Pat. No. 6,169,432) in 250 ml of ether was added 7.9 g (49.4 mmol) of bromine. The reaction mixture was stirred at room temperature for 2 h and to the mixture was added 6.8 g of freshly ground potassium carbonate and 100 ml of methanol. The reaction mixture was stirred for another 45 min and was washed with water and brine. The organic layer was dried (MgSO4), filtered through celite, and concentrated in vacuo. The residue was kugelrohr distilled and the distillate was purified by chromatography (7% EtOAc in hexane) to give 18.7 g (80% yield) of 1:1 mixture of methyl 5-(1-bromo-2,2-dimethoxy-ethyl)-4-(cyclopropylmethyl)-2-(difluoromethyl)-6-(trifluoromethyl)-3-pyridinecarboxylate and product. HPLC purification (10% EtOAc in hexane) gave 4.1 g of the desired product as a colorless oil which crystallized and was recrystallized from hexane to give crystals, mp 79-79.5° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8](O)[CH2:9][CH2:10][CH:11]=[CH2:12])[CH:5]=[CH:6][CH:7]=1.CCN(S(F)(F)[F:20])CC>C(Cl)Cl>[F:20][CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([I:1])[CH:3]=1)[CH2:9][CH2:10][CH:11]=[CH2:12]
Reactant: CCN(CC)S(F)(F)F
Reactant: C=CCCC(O)c1cccc(I)c1
Solvent: ClCCl
Product: C=CCCC(F)c1cccc(I)c1
Temperature: 25 °C

Procedure:
To a stirred solution of 1-(3-Iodo-phenyl)-pent-4-en-1-ol (0.51 g, 1.77 mmol), in dry methylene chloride (10 mL) at −78° C. and under a nitrogen atmosphere was added DAST (0.28 mL, 2.1 mmol). The cooling bath was removed and the mixture was warmed to room temperature for 1 h, and then quenched with sat sodium bicarbonate (4 mL). The mixture was partitioned between methylene chloride and H2O, and the aqueous layer was extracted with methylene chloride (2×10 mL). The organic layer was washed with brine and dried over MgSO4, filtered and concentrated in vacuo to a clear oil (0.46 g, 90%) and used directly in the next step.
Reaction SMILES: C(C1[C:8]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:7]=2[O:6][C:5]([CH2:18][F:19])([CH2:16][F:17])[CH:4]=1)#N.[C:20]([OH:23])(=[O:22])[CH3:21].S(=O)(=O)(O)O>O>[F:17][CH2:16][C:5]1([CH2:18][F:19])[CH:4]=[C:21]([C:20]([OH:23])=[O:22])[C:12]2[CH:11]=[C:10]([N+:13]([O-:15])=[O:14])[CH:9]=[CH:8][C:7]=2[O:6]1
Reactant: N#CC1=CC(CF)(CF)Oc2ccc([N+](=O)[O-])cc21
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)C1=CC(CF)(CF)Oc2ccc([N+](=O)[O-])cc21
Temperature: 0 °C

Procedure:
A mixture of 0.93 g of 4-cyano-2,2-bis(fluoromethyl)-6-nitro-2H-1-benzopyran, 20 ml of acetic acid, 10 ml of water and 10 ml of concentrated sulfuric acid was refluxed with heating for 4.5 hours. When the reaction mixture was poured into ice water, crystals were separated out. Said crystals were dissolved with a sodium hydrogen carbonate solution and washed with methylene chloride. A water layer was acidified to be hydrochloric acid and extracted with methylene chloride. An organic layer was washed with water and dried, and the solvent was distilled to obtain 0.83 g of 2,2-bis(fluoromethyl)-6-nitro-2H-1-benzopyran-4-carboxylic acid with a melting point of 171°-172° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[C:6]([N+:12]([O-])=O)=[CH:5][C:4]=1[O:15][CH3:16].[O:17]=[CH:18][C:19](OCC)=O>C(O)C.C(O)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][C:4]=1[O:15][CH3:16])[NH:12][C:18](=[O:17])[CH:19]=[N:9]2
Reactant: CCOC(=O)C=O
Reactant: COc1cc([N+](=O)[O-])c([N+](=O)[O-])cc1OC
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: COc1cc2ncc(=O)[nH]c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.8 %

Procedure:
A mixture of 1,2-dimethoxy-4,5-dinitrobenzene (5.7 g, 25.0 mmol) in ethanol/acetic acid (140 mL, 1:1) was hydrogenated over palladium on carbon (10%, 1 g) at normal pressure and room temperature for 3 hours, then filtered through a pad of celite. The filtrate containing the crude diamine was treated with ethyl oxoacetate (50 wt % in toluene, 10 mL, 50 mmol) and the reaction was stirred at room temperature overnight. The resulting precipitate was collected by filtration. This material was suspended in a mixture of methanol/dichloromethane and solvent was removed under reduced pressure to remove traces of acetic acid to give 2.0 g (38%) of product as a solid.
Reaction SMILES: Br[C:2]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:3]=1[O:4][CH:5]([CH3:10])[C:6]([O:8]C)=[O:7].[C:16]([C:18]1[CH:23]=[C:22]([S:24]([CH2:27][CH2:28][CH3:29])(=[O:26])=[O:25])[CH:21]=[CH:20][C:19]=1[F:30])#[CH:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl>CCOC(C)=O.O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[Cl:15][C:13]1[CH:12]=[CH:11][C:3]([O:4][CH:5]([CH3:10])[C:6]([OH:8])=[O:7])=[C:2]([C:17]#[C:16][C:18]2[CH:23]=[C:22]([S:24]([CH2:27][CH2:28][CH3:29])(=[O:26])=[O:25])[CH:21]=[CH:20][C:19]=2[F:30])[CH:14]=1
Reactant: COC(=O)C(C)Oc1ccc(Cl)cc1Br
Reactant: C#Cc1cc(S(=O)(=O)CCC)ccc1F
Agent: Cl[Pd]Cl
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CCCS(=O)(=O)c1ccc(F)c(C#Cc2cc(Cl)ccc2OC(C)C(=O)O)c1
Temperature: 80 °C

Procedure:
A solution of methyl 2-(2-bromo-4-chlorophenoxy)propanoate (Intermediate 263 ; 130 mg; 0.44 mmol), 2-ethynyl-1-fluoro-4-(propane-1-sulfonyl)-benzene (Intermediate 109 ; 110 mg; 0.49 mmol), bis(triphenylphosphine)palladium (II) chloride (9.3 mg; 0.01 mmol), triphenylphosphine (23.2 mg; 0.09 mmol) and cuprous iodide (2.5 mg; 0.01 mmol) in TEA (985 μl) was degassed with nitrogen. The reaction mixture was heated overnight at 80° C., diluted with EtOAc and washed with sat. ammonium chloride solution and brine. The organic phase was dried over MgSO4, filtered and concentrated to dryness affording a dark brown sticky solid, which was purified by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc. The intermediate thus obtained was dissolved in a mixture of dioxane (2.6 ml) and water (2.6 ml) and treated with a 4 N solution of HCl in dioxane (1.33 ml). After heating at 100° C. for 16 hours, water was added and the reaction mixture was extracted 3 times with EtOAC. The organic phase was dried over MgSO4, filtered and concentrated to dryness affording a yellow sticky solid, which was triturated in diethylether/pentane to afford the title compound as a white solid.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[C:22]1[CH:30]=O>>[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[C:22]1[CH2:30][N:1]1[CH:2]([C:11]2[C:12]([O:19][CH3:20])=[CH:13][CH:14]=[CH:15][C:16]=2[O:17][CH3:18])[CH2:3][CH:4]([CH3:10])[C:5]1=[O:7]
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Reactant: O=Cc1cc2ccccc2[nH]1
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1cc2ccccc2[nH]1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with commercially available 1H-indole-2-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.87 min.; [M+H]+: 365.03 g/mol.
Reaction SMILES: C1[O:11][C:10]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[O:2]1.C([N-]C(C)C)(C)C.[Li+].CN1CCN(C)C1=O>>[OH:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[OH:11])[C:6]#[N:7]
Reactant: N#Cc1ccc2c(c1)OCO2
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN1CCN(C)C1=O
Product: N#Cc1ccc(O)c(O)c1
Yield: 94 %

Procedure:
As a conventional process for producing 3,4-dihydroxybenzonitrile from 3,4-methylenedioxybenzonitrile, for example, J. Org. Chem., 62, 4097 (1977) discloses a process in which 3,4-methylenedioxybenzonitrile is reacted with lithium diisopropylamide in an excess molar amount (five times by mole or more) in a reaction medium consisting of 1,3-dimethyl-2-imidazolidinone at a high temperature of 185° C., to produce 3,4-dihydroxybenzonitrile with a yield of 94%. This process is, however, disadvantageous as an industrial process in that lithium diisopropylamide, which has a high ignition property, must be employed, and the reaction conditions are very severe and a complicated after-treatment is necessary.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]([N:17]3[CH2:22][CH2:21][N:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[F:29])[CH2:19][CH2:18]3)=[O:16])=[CH:7][N:8]2[CH2:11][C:12](O)=[O:13])=[CH:4][CH:3]=1.[NH3:30]>C1COCC1>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]([N:17]3[CH2:22][CH2:21][N:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[F:29])[CH2:19][CH2:18]3)=[O:16])=[CH:7][N:8]2[CH2:11][C:12]([NH2:30])=[O:13])=[CH:4][CH:3]=1
Reactant: O=C(O)Cn1cc(C(=O)N2CCN(c3ccccc3F)CC2)c2ccc(Cl)cc21
Reactant: N
Solvent: C1CCOC1
Product: NC(=O)Cn1cc(C(=O)N2CCN(c3ccccc3F)CC2)c2ccc(Cl)cc21

Procedure:
Following general procedure I, the coupling of {6-chloro-3-[4-(2-fluoro-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-acetic acid (preparation described herein), with (commercially available) ammonia in THF gave the title compound.