Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([OH:13])=O)=[CH:9][N:10]=2)[CH:7]=1.C(Cl)(=O)C(Cl)=O.[CH2:20]([N:27]1[C:35]2[CH:34]=[CH:33][CH:32]=[C:31]([NH2:36])[C:30]=2[CH:29]=[N:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(NC(C)CC(C)C)C>ClCCl>[CH2:20]([N:27]1[C:35]2[C:30](=[C:31]([NH:36][C:11]([C:8]3[N:6]4[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]4=[N:10][CH:9]=3)=[O:13])[CH:32]=[CH:33][CH:34]=2)[CH:29]=[N:28]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(O)c1cnc2ccc(F)cn12
Reactant: Nc1cccc2c1cnn2Cc1ccccc1
Agent: CCNC(C)CC(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: O=C(Nc1cccc2c1cnn2Cc1ccccc1)c1cnc2ccc(F)cn12
Reaction time: 0.17 h

Procedure:
6-Fluoroimidazo[1,2-a]pyridine-3-carboxylic acid (0.083 g, 0.46 mmol) was added as a suspension to dichloromethane, and then oxalyl dichloride (0.28 mL, 0.55 mmol) was added slowly. The mixture was allowed to stir for 10 minutes, then a solution of 1-benzyl-1H-indazole-4-amine (0.10 g, 0.46 mmol, above, step D) and N-ethyl-isopropylpropan-2-amine (0.11 mL, 0.60 mmol) were added and the reaction stirred for 2 hours. The solvent was concentrated and the resulting crude material was purified on silica gel using ethyl acetate and methanol (Rf=0.18 in 5% MeOH in ethyl acetate) to provide 20 mg of the desired product. MS (ES+APCI) m/z=386.4 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[F:10].N1C=CC=CC=1.Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>C1COCC1.[OH-].[Na+]>[CH2:21]([O:20][C:18](=[O:19])[NH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[F:10])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Nc1ccc(CO)cc1F
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(CO)cc1F)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a mixture of 4-amino-3-fluorobenzylalcohol (20.7 g, 147 mmol) and pyridine (35.5 ml, 79 mmol) in THF (320 ml) and 2N NaOH (80 mL) was added benzyl chloroformate (24.8 mL, 170.6 mmol) at 0° C. over a period of 15 min. The reaction mixture was stirred for 20 min at 0° C. and for 2 h at room temperature. The reaction was quenched with water and diluted with EtOAc. The phases were separated and the organic phase was washed with 5% NaHSO4, saturated aq. NaHCO3 and brine, dried over Na2SO4, filtered and evaporated. The title compound was crystallized from EtOAc and cyclohexane: TLC (cyclohexane-EtOAc 3:1) Rf=0.45; HPLC RtE=1.02 min; ESIMS [M+NH4]+=293; ESIMS [M−H]−=274; 1H NMR (360 MHz, CDCl3): δ 8.00 (t, 1H), 7.40-7.25 (m, 5H), 7.10-7.00 (m, 2H), 6.82 (s broad, 1H), 5.15 (s, 2H), 4.55 (d, 2H).
Reaction SMILES: [C:1]([C:4]1[C:9]([Cl:10])=[CH:8][C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][N:5]=1)(=[O:3])[CH3:2].CO[C:17](OC)([N:19]([CH3:21])[CH3:20])[CH3:18]>C1(C)C=CC=CC=1>[Cl:10][C:9]1[C:4]([C:1](=[O:3])[CH:2]=[C:17]([N:19]([CH3:21])[CH3:20])[CH3:18])=[N:5][CH:6]=[C:7]([C:11]([F:13])([F:14])[F:12])[CH:8]=1
Reactant: CC(=O)c1ncc(C(F)(F)F)cc1Cl
Reactant: COC(C)(OC)N(C)C
Solvent: Cc1ccccc1
Product: CC(=CC(=O)c1ncc(C(F)(F)F)cc1Cl)N(C)C
Yield: 66.4 %

Procedure:
1.0 g of 2-acetyl-3-chloro-5-(trifluoromethyl)pyridine and 715 mg of N,N-dimethylacetamide dimethyl acetal were reacted in 6 mL of toluene at 100° C. for 14 hours. The reaction liquid was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate) to obtain 869 mg of 1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-3-(dimethylamino)-2-buten-1-one (after-mentioned intermediate No. IV-1).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([Cl:11])[N:3]=1.[H-].[Na+].I[CH:15]([CH3:17])[CH3:16].O>CN(C=O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:15]([CH3:17])[CH3:16])=[C:4]([Cl:11])[N:3]=1
Reactant: Clc1nc(Cl)c2nc[nH]c2n1
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)n1cnc2c(Cl)nc(Cl)nc21
Temperature: 10 °C
Reaction time: 1 h

Procedure:
To 2,6-dichloro-9H-purine (a) (998 g, 5.28 mol) dissolved in anhydrous DMF (5.0 L) was added sodium hydride (60% dispersion, 254 g, 6.35 mol) with stirring at 10° C. over 1 hr. 2-iodopropane (1595 g) was added and the mixture was stirred at rt for 24 hr. Water (5.0 L) was added, and the resulting solid precipitate was collected and washed with water (500 ml) and heptane (2×2.5 L). The crude solid was crystallized from isopropyl acetate (2.1 L) to provide the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:18]=[C:17]([CH2:19][CH3:20])[S:16][C:10]=2[NH:11][C:12](=S)[CH2:13][N:14]=1.[CH2:21]([O:23][C:24]([NH:26][NH2:27])=[O:25])[CH3:22]>C(O)C>[CH2:21]([O:23][C:24]([NH:26][NH:27][C:12]1[CH2:13][N:14]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:9]2[CH:18]=[C:17]([CH2:19][CH3:20])[S:16][C:10]=2[N:11]=1)=[O:25])[CH3:22]
Reactant: CCc1cc2c(s1)NC(=S)CN=C2c1ccccc1Cl
Reactant: CCOC(=O)NN
Solvent: CCO
Product: CCOC(=O)NNC1=Nc2sc(CC)cc2C(c2ccccc2Cl)=NC1
Yield: 73 %

Procedure:
A solution of 1.3 g of 5-o-chlorophenyl-7-ethyl-1,2-dihydro-3H-thieno[2,3-e] [1,4]diazepine-2-thione and 0.5 g of ethoxycarbonylhydrazine in 30 ml of ethanol is refluxed for 5 hours. Then the ethanol is removed under reduced pressure, and the residue is crystallized from ligroin to give 2-ethoxycarbonylhydrazino-5-o-chlorophenyl-7-ethyl-3H-thieno[ 2,3-e] [1,4]diazepine appearing as orange crystals. The product is recrystallized from ethanol to give the pure substance melting at 207° C, in 73% yield.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]1[O:15][C:14]2[C:9](=[C:10]([OH:16])[CH:11]=[CH:12][CH:13]=2)[O:8]1.Cl[C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH2:31][CH2:32][CH2:33][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1>CN(C=O)C.O>[CH3:29][O:28][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][C:24]=1[O:30][CH2:31][CH2:32][CH2:33][N:34]1[CH2:35][CH2:36][O:37][CH2:38][CH2:39]1)[N:21]=[CH:20][N:19]=[C:18]2[O:16][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[O:15][CH2:7][O:8][C:9]=12
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Reactant: Oc1cccc2c1OCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3cccc4c3OCO4)ncnc2cc1OCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82 %

Procedure:
Potassium carbonate (0.092 g) was added to a solution of 2,3-methylenedioxyphenol (0.067 g) in DMF (3 ml) and the mixture was stirred at ambient temperature for 10 minutes. 4-Chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (0.15 g) was added and the mixture was heated to 70° C. for 3 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and with brine, dried over magnesium sulphate and evaporated. There was thus obtained the title compound as a solid (0.16 g); NMR Spectrum: (DMSOd6 and CF3CO2D) 2.3 (m, 2H), 3.15 (m, 2H), 3.35 (m, 2H), 3.55 (d, 1H), 3.7 (t, 2H), 4.0 (s, 3H), 4.05 (m, 2H), 4.35 (t, 2H), 6.05 (s, 2H), 6.95 (m, 3H), 7.5 (s, 1H), 7.6 (s, 1H), 8.7 (s, 1H); Mass Spectrum: M+H+ 440; Elemental Analysis: Found C, 62.66; H, 5.78; N, 9.48; C23H25N3O6 requires C, 62.86; H, 5.73; N, 9.56%.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=O)=[CH:7][NH:8]2)=[CH:4][C:3]=1[F:13].C([O-])(=O)C.[NH4+].[N+:19]([CH2:22][CH3:23])([O-:21])=[O:20]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[C:22]([N+:19]([O-:21])=[O:20])[CH3:23])=[CH:7][NH:8]2)=[CH:4][C:3]=1[F:13]
Reactant: O=Cc1c[nH]c2cc(Cl)c(F)cc12
Reactant: CC[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: CC(=Cc1c[nH]c2cc(Cl)c(F)cc12)[N+](=O)[O-]
Yield: 97 %

Procedure:
The solution (0.2 M) of 6-chloro-5-fluoro-1H-indole-3-carbaldehyde (4.0 g, 20.24 mmol) in nitroethane (100 mL) was refluxed with ammonium acetate (1.32 g, 0.85 mmol) for 4 hours. The reaction mixture was concentrated under vacuum to remove nitroethane, diluted with ethylacetate and washed with brine. The organic layer was concentrated to give 6-chloro-5-fluoro-3-(2-nitro-propenyl)-1H-indole (5.0 g, 97%) as a reddish orange solid. 1H NMR (500 MHz, CDCl3): δ 8.77 (s, 1H), 8.32 (s, 1H), 7.58 (d, 1H, J=2.5 Hz), 7.54 (d, 1H, J=9 Hz), 7.50 (d, 1H, J=5.9 Hz), 2.52 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([F:12])[C:3]=1[C:13]1[S:17][C:16]([NH:18][C:19]2[N:20]=[N:21][C:22]([O:25]CC[Si](C)(C)C)=[CH:23][CH:24]=2)=[C:15]([C:32]([NH2:34])=[O:33])[CH:14]=1.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:12][C:4]1[CH:5]=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:7]=[C:2]([F:1])[C:3]=1[C:13]1[S:17][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22](=[O:25])[NH:21][N:20]=2)=[C:15]([C:32]([NH2:34])=[O:33])[CH:14]=1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3ccc(OCC[Si](C)(C)C)nn3)s2)c(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3ccc(=O)[nH]n3)s2)c(F)c1
Reaction time: 0.5 h

Procedure:
5-[2,6-Difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-2-({6-[2-(trimethylsilyl)ethoxy]pyridazin-3-yl}amino)thiophene-3-carboxamide (0.61 g, 1.20 mmol) was taken up in DCM (12 mL) and TFA (0.4 mL) was added. After 30 minutes at room temperature, saturated NaHCO3 was added. The resulting precipitate was collected by filtration and triturated in DCM to give the title compound as a yellow solid.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]#[N:11])[C:4]=2[CH:3]=[N:2]1.[H-].[Na+].Br[CH2:15][C:16]([CH3:23])([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>CN(C)C=O>[C:10]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[CH:3]=[N:2][N:1]2[CH2:15][C:16]([CH3:23])([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])#[N:11]
Reactant: CCOC(=O)C(C)(C)CBr
Reactant: N#Cc1cccc2[nH]ncc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Cn1ncc2c(C#N)cccc21
Temperature: 80 °C
Yield: 86 %

Procedure:
1H-indazole-4-carbonitrile (commercially available from Insight Chemical Solutions Ltd., 298 mg, 1.957 mmol) in dry N,N-Dimethylformamide (DMF) (1 ml), under nitrogen was treated with NaH (94 mg, 2.348 mmol). A solution of ethyl 3-bromo-2,2-dimethylpropanoate (D98) (450 mg, 2.153 mmol), in DMF (2 ml), was then added to the dark brown mixture. The reaction mixture was heated to 80° C. overnight then concentrated in vacuo. The residue was dissolved in EtOAc and the organic phase was washed with water then brine, dried and concentrated to give a brown gum. Purification of the residue by flash chromatography on silica gel [gradient ethyl acetate/cyclohexane] gave the title compound (217 mg, 86%) as a yellow oil. MS (ES) C15H15N3O2 requires 271, found 272 [M+H]+
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:17][N:18](C=O)C>CC#N.C([O-])(O)=O.[Na+]>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1([C:11]2[O:12][C:13]([C:17]#[N:18])=[CH:14][CH:15]=2)[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccco2)CC1
Reactant: CN(C)C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC1(c2ccc(C#N)o2)CC1
Temperature: -40 °C
Reaction time: 0.75 h

Procedure:
(1-Furan-2-yl-cyclopropyl)-carbamic acid tert-butyl ester (765 mg, 3.43 mmol) was dissolved in MeCN (7.7 mL) and cooled to −40° C. in an acetone/dry ice bath. Chloroulfonyl isocyante (0.45 mL, 5.1 mmol) was added in one portion via syringe and the reaction was allowed to stir at a temperature between −40 and −30° C. for 45 min. Anhydrous DMF (1.2 mL) was then added and stirring continued at room temperature for 30 min. The reaction was diluted with saturated aqueous NaHCO3 (100 ml) and extracted with EtOAc (3×50 mL). The combined organic layers were concentrated to a red liquid and chromatographed (silica, 5→25% EtOAc/hexanes) to give 400 mg of the title compound as a white solid, m/z 234.35 [M-t-Bu+MeCN]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13])[C:5]([OH:7])=O.C1C=CC2N(O)N=NC=2C=1.[F:25][C:26]1[CH:27]=[C:28](/[C:42](/[NH:45]O)=[N:43]/[H])[CH:29]=[C:30]2[C:34]=1[NH:33][C:32]([CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:31]2.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O1CCCC1.C(Cl)CCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[O:7][N:43]=[C:42]([C:28]3[CH:29]=[C:30]4[C:34](=[C:26]([F:25])[CH:27]=3)[NH:33][C:32]([CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:31]4)[N:45]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)Oc1ccc(C(=O)O)cc1Cl
Reactant: [H]/N=C(\NO)c1cc(F)c2[nH]c(CCC(=O)OCC)cc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: On1nnc2ccccc21
Agent: [F-]
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CCOC(=O)CCc1cc2cc(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cc(F)c2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.6 %

Procedure:
To a solution of 3-chloro-4-[(1-methylethyl)oxy]benzoic acid (307 mg) in tetrahydrofuran (30 mL) stirred at room temperature was added EDC (549 mg) and HOBT (439 mg). The reaction mixture was stirred at room temperature for 0.5 h. Then ethyl 3-{7-fluoro-5-[(Z)-(hydroxyamino)(imino)methyl]-1H-indol-2-yl}propanoate (D163) (420 mg) was added. The reaction mixture was stirred at room temperature for an hour, and then TBAF (3.7 g) was added. The reaction mixture was heated at reflux overnight. The organic solvent was evaporated off in vacuo and purified by column chromatography to give ethyl 3-[5-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-7-fluoro-1H-indol-2-yl]propanoate (D164) (240 mg) as white solid. MS (ES): C24H23ClFN3O4 requires 471; found 472.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([CH3:44])=[N:22][N:23](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[CH:24]=4)=[CH:16][CH:15]=3)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1>Cl.C1COCC1.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([CH3:44])=[N:22][NH:23][CH:24]=4)=[CH:16][CH:15]=3)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: Cc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1-c1ccc(C2(c3ccc(Cl)cc3)CCNCC2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: Cc1n[nH]cc1-c1ccc(C2(c3ccc(Cl)cc3)CCNCC2)cc1
Reaction time: 2.33 h

Procedure:
A suspension of 4-(4-chloro-phenyl)-4-[4-(3-methyl-1-trityl-1H-pyrazol-4-yl)-phenyl]-piperidine (178 mg, 0.30 mmol) in 5N hydrochloric acid (5 mL), THF (5 mL) and methanol (5 mL) was stirred for 140 minutes. The organic solvents were removed in vacuo then the resulting solution was diluted with 2N HCl and washed with ether. The aqueous phase was basified by addition of sodium hydroxide pellets then extracted with ethyl acetate. This organic extract was washed with brine, dried (MgSO4), filtered and concentrated to give a residue which was purified by column chromatography (SiO2), eluting with a gradient of 2M ammonia in methanol (5% to 7.5%) and dichloromethane. The product was further purified by preparative HPLC to give the title compound which was converted to its dihydrochloride salt (84 mg, 80%); LCMS (PS-A3) Rt 6.86 min [M+H]+ 352. 1H NMR (Me-d3-OD) δ 2.55 (3H, s), 2.70-2.75 (4H, m), 3.22-3.27 (4H, m), 7.35-7.41 (4H, m), 7.47-7.54 (4H, m), 8.32 (2H, s).
Reaction SMILES: O.[NH3:2].[F:3][CH:4]([F:16])[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12](Cl)(=[O:14])=[O:13]>C(Cl)Cl>[F:3][CH:4]([F:16])[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([NH2:2])(=[O:14])=[O:13]
Reactant: O=S(=O)(Cl)c1ccccc1OC(F)F
Reactant: N
Solvent: ClCCl
Solvent: O
Product: NS(=O)(=O)c1ccccc1OC(F)F

Procedure:
To a mixture of 250 ml of methylene chloride, 250 ml of water and 250 ml of 30% ammonia solution is slowly added a solution of 80.3 g of crude 2-difluoromethoxyphenylsulfonyl chloride in 50 ml of methylene chloride. After the exothermic reaction had subsided, the reaction mixture is refluxed for 2 hours. The organic phase is washed with water, dried over sodium sulfate, and evaporated to dryness. Recrystallisation from methanol yielded 40.5 g of 2-difluoromethoxyphenylsulfonamide with a melting point of 128°-130° C.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N+:14]([O-])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>C(O)C.ClCCl.[C].[Pd]>[NH2:14][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:8]=1[NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cnccc1Nc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Product: Nc1cnccc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 88.7 %

Procedure:
4-Phenylamino-3-nitropyridine (1.40 g, 6.51 mmol) was dissolved in the mixed solvent of 15 ml of ethanol and 10 ml of dichloromethane. After the atmosphere was replaced with nitrogen, 0.10 g of 10% palladium-carbon was added thereto. After the atmosphere was replaced with hydrogen, hydrogen addition was conducted with stirring at room temperature for about 15 hours. Palladium-carbon was removed by filtration and the filtered cake was washed with ethanol. The filtrate and the washings were combined and then concentrated. The residue was purified by silica gel column chromatography [eluent: dichloromethane: methanol=2:1 (v/v)] to obtain 1.07 g of a light brown solid (yield: 88.7%).
Reaction SMILES: [C:1]([O:7]C(=O)C(C)(C)C)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[C-]#N.[Na+].[CH3:17][Si:18](C#N)([CH3:20])[CH3:19]>>[CH3:17][Si:18]([O:7][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])([CH3:20])[CH3:19]
Reactant: CC(C)(C)C(=O)OC(=O)C(C)(C)C
Reactant: C[Si](C)(C)C#N
Agent: [C-]#N
Agent: [Na+]
Product: CC(C)(C)C(=O)O[Si](C)(C)C

Procedure:
93 g (0.5 mol) of pivalic acid anhydride and 1 g of sodium cyanide are initially introduced and 49.5 g (0.5 mol) of trimethylsilyl cyanide are added dropwise. The reaction mixture is worked up by distillation. Yield: 56 g of pivaloyl cyanide (=98.9% of theory). Boiling point: 121°-125° C. In addition, pivalic acid-trimethylsilyl ester is obtained in a corresponding amount (98% of theory).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])=[C:13]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:12]=[C:11]([C:33]2[CH:34]=[C:35]3[C:39](=[CH:40][CH:41]=2)[N:38]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C:37](B(O)O)=[CH:36]3)[C:10]=1[CH2:52][CH3:53])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:54]([C:56]1[CH:61]=[CH:60][C:59](I)=[CH:58][CH:57]=1)#[N:55].C([O-])([O-])=O.[Na+].[Na+].COCCOC>O>[CH2:1]([O:8][C:9]1[C:14]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])=[C:13]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:12]=[C:11]([C:33]2[CH:34]=[C:35]3[C:39](=[CH:40][CH:41]=2)[N:38]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C:37]([C:59]2[CH:60]=[CH:61][C:56]([C:54]#[N:55])=[CH:57][CH:58]=2)=[CH:36]3)[C:10]=1[CH2:52][CH3:53])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(I)cc1
Reactant: CCc1c(-c2ccc3c(c2)cc(B(O)O)n3C(=O)OC(C)(C)C)nc(OCc2ccccc2)c(C(=O)OCc2ccccc2)c1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCc1c(-c2ccc3c(c2)cc(-c2ccc(C#N)cc2)n3C(=O)OC(C)(C)C)nc(OCc2ccccc2)c(C(=O)OCc2ccccc2)c1OCc1ccccc1
Temperature: 85 °C
Reaction time: 2 h
Yield: 54.6 %

Procedure:
A mixture of the boronic acid obtained in Step 1 (75 mg, 0.10 mmol), 4-cyanoiodobenzene (24 mg, 0.10 mmol) Pd(PPh3)4 (12 mg, 0.01 mmol), Na2CO3 (33 mg, 0.30 mmol), DME (0.9 mL) and H2O (0.1 mL) was stirred under argon at 85° C. for 2 hr. The mixture was then concentrated to dryness and chromatographed (silica gel, ethyl acetate in hexanes 0-15% gradient) to provide tert-butyl 5-(4,6-bis(benzyloxy)-5-((benzyloxy)carbonyl)-3-ethylpyridin-2-yl)-2-(4-cyanophenyl)-1H-indole-1-carboxylate (42 mg, yield: 55%). LC-MS 770.6 [M+H]+, RT 1.16 min. (1 min. Method). This was dissolved in diphenyl ether (1 mL) and heated to 210° C. for 0.5 hr. After cooling the mixture was chromatographed (silica gel, ethyl acetate in hexanes 0-50% gradient) to furnish 6-(2-(4-cyanophenyl)-1H-indol-5-yl)-5-ethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylic acid (29 mg, yield: 80%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][Si](C(C)(C)C)(C)C)=[CH:4][C:3]=1[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[CH:19]=1)=O.[CH3:25][CH:26]([CH3:33])[CH2:27][C:28](=O)[CH2:29][C:30]#[N:31].CS(O)(=O)=O>C1(C)C=CC=CC=1>[OH:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[N:1]=[C:28]([CH2:27][CH:26]([CH3:33])[CH3:25])[C:29]([C:30]#[N:31])=[C:16]2[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[CH:19]=1
Reactant: CC(C)CC(=O)CC#N
Reactant: Cc1cccc(C(=O)c2cc(O[Si](C)(C)C(C)(C)C)ccc2N)c1
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Product: Cc1cccc(-c2c(C#N)c(CC(C)C)nc3ccc(O)cc23)c1
Yield: 56.3 %

Procedure:
To a solution of 2-amino-5-{[tert-butyl(dimethyl)silyl]oxy}-N-methoxy-N-methylbenzamide (2.0 g, 6.4 mmol) in diethyl ether (50 ml) was added dropwise 1.0 M solution of m-tolylmagnesium bromide in tetrahydrofuran (30 ml, 30 mmol) under ice-cooling over 30 min. Ice water (250 g) was added to the reaction mixture 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 residue was purified by silica gel column chromatography to give (2-amino-5-{[tert-butyl(dimethyl)silyl]oxy}phenyl)(3-methylphenyl)methanone as a mixture. To a solution of the obtained mixture (1.4 g) of (2-amino-5-{[tert-butyl(dimethyl)silyl]oxy}phenyl)(3-methylphenyl)methanone and 5-methyl-3-oxohexanenitrile (0.60 g, 4.7 mmol) in toluene (50 ml) was added methanesulfonic acid (0.38 g, 4.0 mmol), and the mixture was heated under reflux for 6 hrs. The reaction mixture was partitioned between ethyl acetate (100 ml) and saturated aqueous sodium hydrogen carbonate (100 ml), and the organic layer was washed with saturated brine (50 ml) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained crude crystals were recrystallized from n-hexane-ethyl acetate to give 6-hydroxy-2-isobutyl-4-(3-methylphenyl)quinoline-3-carbonitrile (0.73 g, yield 36%) as pale-yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:39]=[CH:40][C:41]=1[Cl:42])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C@H:13]2[CH2:38][O:37][C:16]3=[CH:17][C:18]4[CH2:19][C@@H:20]([C:34](O)=[O:35])[N:21]([C@H:25]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[CH2:26][CH3:27])[CH2:22][C:23]=4[CH:24]=[C:15]3[O:14]2)=[CH:9][CH:8]=1.Cl.C[O:45][C:46](=[O:64])[C@@H:47]([NH2:63])[CH2:48][C:49]1[CH:54]=[CH:53][C:52]([C:55]2[CH:60]=[CH:59][C:58]([C:61]#[N:62])=[CH:57][CH:56]=2)=[CH:51][CH:50]=1>>[C:61]([C:58]1[CH:57]=[CH:56][C:55]([C:52]2[CH:51]=[CH:50][C:49]([CH2:48][C@H:47]([NH:63][C:34]([C@@H:20]3[CH2:19][C:18]4[CH:17]=[C:16]5[O:37][CH2:38][C@H:13]([C:10]6[CH:9]=[CH:8][C:7]([O:6][CH2:5][C:4]7[CH:39]=[CH:40][C:41]([Cl:42])=[C:2]([Cl:1])[CH:3]=7)=[CH:12][CH:11]=6)[O:14][C:15]5=[CH:24][C:23]=4[CH2:22][N:21]3[C@H:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:26][CH3:27])=[O:35])[C:46]([OH:45])=[O:64])=[CH:54][CH:53]=2)=[CH:60][CH:59]=1)#[N:62]
Reactant: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)O)OC[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccc(C#N)cc2)cc1
Agent: Cl
Product: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)C(=O)O)OC[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3

Procedure:
The title compound (193 mg) was prepared from (3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid (272 mg) and (S)-2-amino-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester hydrochloride according to General Procedures L and B. LCMS (m/z): 853.