Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH:7]([O:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)([CH2:9][CH3:10])[CH3:8].Cl[CH2:20][C:21]1[O:25][N:24]=[C:23]([CH3:26])[CH:22]=1>CN(C)C=O>[CH:7]([O:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:20][C:21]2[O:25][N:24]=[C:23]([CH3:26])[CH:22]=2)=[CH:16][CH:17]=1)([CH2:9][CH3:10])[CH3:8]
Reactant: CCC(C)Oc1ccc(O)cc1
Reactant: Cc1cc(CCl)on1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC(C)Oc1ccc(OCc2cc(C)no2)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 85.2 %

Procedure:
4.6 g of anhydrous potassium carbonate is added to 5.0 g of 4-sec-butyloxyphenol in 80 ml of absolute dimethylformamide, and the mixture is stirred for one hour at 80° C. At this temperature, 3.9 g of 5-chloromethyl-3-methylisoxazole is dripped in and the mixture is stirred for a further seven hours at 90° C. The batch is then stirred into 300 ml of ice water, extracted three times, each time with 100 ml of methyl tert-butyl ether and the organic phase is washed twice with 2N sodium hydroxide solution (50 ml in each instance) and then three times with water (50 ml in each instance). Drying over sodium sulfate and removal of the solvent under reduced pressure give 6.6 g of 5-[4-(sec-butyloxy)-phenoxymethyl]-3-methylisoxazole, which is obtained, after chromatography over silica gel using toluene/ethyl acetate(1:1) as eluant, as a viscous oil. According to 1H-NMR spectroscopy, the oil is pure.
Reaction SMILES: CC1C=CC(S([NH:11][CH:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=3)=[CH:14][N:13]2[CH2:28][C:29]([NH2:31])=O)(=O)=O)=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl>[N+:25]([C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[O:18][C:15]1[CH:16]=[CH:17][C:12]2[N:13]([CH:28]=[C:29]([NH2:31])[N:11]=2)[CH:14]=1)([O-:27])=[O:26]
Reactant: Cc1ccc(S(=O)(=O)NC2C=CC(Oc3cccc([N+](=O)[O-])c3)=CN2CC(N)=O)cc1
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Nc1cn2cc(Oc3cccc([N+](=O)[O-])c3)ccc2n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 48.9 %

Procedure:
A mixture of 2-[2-{[(4-methylphenyl)sulfonyl]amino}-5-(3-nitrophenoxy)pyridin-1(2H)-yl]acetamide (4.70 g, 10.6 mmol), trifluoroacetic anhydride (30 mL) and dichloromethane (40 mL) was stirred at room temperature for 5 hr. The reaction solution was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the residue and the mixture was extracted with ethyl acetate (×3). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, 8N aqueous sodium hydroxide solution (10 mL) and ethanol (30 mL) were added to the residue and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with water and extracted with ethyl acetate (×3). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, ethyl acetate) to give the title compound (1.40 g, 49%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19])(O)[CH3:10].C(OC(=O)C)(=O)C.S(=O)(=O)(O)O>CCOCC>[CH3:19][O:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])=[CH2:10]
Reactant: COc1ccccc1C(C)(O)c1ccccc1OC
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: CC(=O)OC(C)=O
Product: C=C(c1ccccc1OC)c1ccccc1OC
Reaction time: 0.17 h
Yield: 58.8 %

Procedure:
1,1-Bis(2-methoxyphenyl)ethanol (25.6 g) was combined with 250 ml of acetic anhydride and the mixture was heated at reflux for 4 hours. A drop of concentrated sulfuric acid was added and the heating continued for 10 min. The opaque brown mixture obtained was allowed to cool and was diluted with ether. The resulting solution was extracted twice with water, dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure to obtain a brownish-black solid. This was recrystallized from methanol to obtain 14.0 g of the title compound as tan crystals melting at 88-90° C. The proton NMR spectrum was consistent with the assigned structure.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[C:13]([Si](C)(C)C)[N:12]=[N:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C1C(=O)N([Cl:26])C(=O)C1>CC#N>[Cl:26][C:13]1[N:12]=[N:11][N:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH:14]=1
Reactant: C[Si](C)(C)c1cn(-c2ccc([N+](=O)[O-])cc2)nn1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(-n2cc(Cl)nn2)cc1
Temperature: 80 °C

Procedure:
To a mixture of 1-(4-nitrophenyl)-4-(trimethylsilyl)-1H-1,2,3-triazole (0.5 g, 1.9 mmol) and silica gel (2.9 g) in anhydrous CH3CN (10 mL) was added NCS (1.1 g, 6.7 mmol). The mixture was heated to 80° C. for 24 h. The reaction was cooled, filtered and concentrated in vacuo. The resulting crude residue was purified by chromatography on silica gel (EtOAc/hexanes) to give 4-chloro-1-(4-nitrophenyl)-1H-1,2,3-triazole. 1H NMR (CDCl3, 400 MHz) δ 8.39 (dd, 2H), 8.02 (s, 1H), 7.89 (dd, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([CH2:14][C:15]3[CH:16]=[C:17]([CH:37]=[CH:38][CH:39]=3)[C:18]([NH:20][C:21]3[S:22][C:23]4[CH2:29][C@@H:28]([NH:30][CH2:31][CH2:32][C:33]([F:36])([F:35])[F:34])[CH2:27][CH2:26][C:24]=4[N:25]=3)=[O:19])[CH:13]=2)=[CH:5][CH:4]=1)#[N:2].C=O.[C:42]([BH3-])#N.[Na+]>CO.C(Cl)Cl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([CH2:14][C:15]3[CH:16]=[C:17]([CH:37]=[CH:38][CH:39]=3)[C:18]([NH:20][C:21]3[S:22][C:23]4[CH2:29][C@@H:28]([N:30]([CH3:42])[CH2:31][CH2:32][C:33]([F:36])([F:35])[F:34])[CH2:27][CH2:26][C:24]=4[N:25]=3)=[O:19])[CH:13]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: [BH3-]C#N
Reactant: N#Cc1ccc(-c2cnn(Cc3cccc(C(=O)Nc4nc5c(s4)C[C@@H](NCCC(F)(F)F)CC5)c3)c2)cc1
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CN(CCC(F)(F)F)[C@H]1CCc2nc(NC(=O)c3cccc(Cn4cc(-c5ccc(C#N)cc5)cn4)c3)sc2C1
Yield: 83.7 %

Procedure:
Stir a solution of 3-[4-(4-cyano-phenyl)-pyrazol-1-ylmethyl]-N—[(S)-6-(3,3,3-trifluoro-propylamino)-4,5,6,7-tetrahydro-benzothiazol-2-yl]-benzamide (0.063 g, 0.11 mmol) and formaldehyde solution (0.08 mL, 1.14 mmol, 37 wt % in H2O) and sodium cyanoborohydride (0.014 g, 0.23 mmol) in 1 mL 20% MeOH/CH2Cl2 overnight at room temperature in a capped flask. Concentrate the mixture, add aq. H2O and extract the product 4×EtOAc, washed 3×H2O. Dry the mixture with a drying agent and concentrate. Purify the product on a prep plate eluting with 5% MeOH/CH2Cl2 which affords 0.052 g, 80% yield of 3-[4-(4-cyano-phenyl)-pyrazol-1-ylmethyl]-N-{(S)-6-[methyl-(3,3,3-trifluoro-propyl)-amino]-4,5,6,7-tetrahydro-benzothiazol-2-yl}-benzamide as a clear resin. MS, electrospray 565.71 (M+H), room temperature 1.60 min. The following compound is prepared analogously (Example 11)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:12]#[N:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].[H][H]>[Ni].C(O)C>[CH2:1]([O:3][C:4]([C:6]1([CH2:12][NH2:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C1(C#N)CCCCC1
Agent: [Ni]
Solvent: CCO
Product: CCOC(=O)C1(CN)CCCCC1
Reaction time: 8 h
Yield: 80 %

Procedure:
Excess Raney Nickel in an ethanol slurry was added to a solution of 1-cyano-cyclohexanecarboxylic acid ethyl ester in ethanol under a nitrogen atmosphere. The nitrogen atmosphere was replaced with excess hydrogen gas and the mixture was allowed to stir overnight. The reaction mixture was filtered through celite and the solvent was removed. The compound was clean enough to continue without purification. 80% yield. MH+=186.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[N:32]=[CH:31][N:30]=[C:29]5[C:25]=4[N:26]=[CH:27][N:28]5C4CCCCO4)=[CH:19][CH:18]=3)=[O:15])[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.Cl>O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[N:32]=[CH:31][N:30]=[C:29]5[C:25]=4[N:26]=[CH:27][NH:28]5)=[CH:19][CH:18]=3)=[O:15])[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc(F)cc1)C1(C(=O)Nc2ccc(Oc3ncnc4c3ncn4C3CCCCO3)cc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(Nc1ccc(F)cc1)C1(C(=O)Nc2ccc(Oc3ncnc4[nH]cnc34)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.6 %

Procedure:
To a solution of N-(4-fluorophenyl)-N′-(4-{[9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl]oxy}phenyl)-cyclopropane-1,1-dicarboxamide (430 mg, 0.83 mmol) in 30 mL of dioxane was added 3 mL of 4N HCl in dioxane. The reaction mixture was stirred at room temperature for 1 h. After removal of solvent in vacuo, the reaction mixture triturated with ether, affording N-(4-fluorophenyl)-N′-[4-(9H-purin-6-yloxy)phenyl]cyclopropane-1,1-dicarboxamide (300 mg, 83% yield) as a colorless solid. 1H NMR (400 MHz, DMSO, d6): δ 10.20 (s, 1H), 10.10 (s, 1H), 8.6 (s, 1H), 8.4 (s, 1H), 7.6-7.8 (m, 4H), 7.1-7.3 (m, 4H), 1.45 (s, 4H). MS (ESI) for C22H17FN6O3: 433 (MH+).
Reaction SMILES: Br[C:2]1([NH:7][CH2:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)([CH3:11])[CH3:10])[S:6][NH:5][CH:4]=[N:3]1.[C:19]([Cu])#[N:20]>>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:9]([CH3:11])([CH3:10])[CH2:8][NH:7][C:2]2[S:6][N:5]=[C:4]([C:19]#[N:20])[N:3]=2)=[CH:13][CH:14]=1
Reactant: CC(C)(CNC1(Br)N=CNS1)c1ccc(F)cc1
Reactant: N#C[Cu]
Product: CC(C)(CNc1nc(C#N)ns1)c1ccc(F)cc1
Temperature: 120 °C
Yield: 8.9 %

Procedure:
5-Bromo-N-(2-(4-fluorophenyl)-2-methylpropyl)-1,2,4-thiadiazol-5-amine (635 mg, 1.92 mmol, 1.0 equiv) and CuCN (224 mg, 2.5 mmol, 1.3 equiv) were added to a microwave vial equipped with a stirbar. A septum was affixed to the vial, and the vial was purged with nitrogen for ˜5 min. DMF (2.5 mL) was then added, and the vial was sealed and heated for 20 min at 120° C. in a microwave. The reaction mixture was diluted with EtOAc and washed with sat'd. aq. NaHCO3 and brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. Purification by reverse phase HPLC provided the title compound (47 mg, 9%). m/z=275.0 [M−H]−.
Reaction SMILES: Cl[C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[OH-].[K+].Cl.C(O)(C(F)(F)F)=[O:18]>O.O.CO>[OH:18][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: O=C(O)C(F)(F)F
Reactant: O=C(O)c1cccc(Cl)c1[N+](=O)[O-]
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cccc(O)c1[N+](=O)[O-]
Yield: 66 %

Procedure:
To a 250 mL flask were added 3-chloro-2-nitrobenzoic acid (10 g, 49.6 mmol) and a potassium hydroxide solution (40 g, 727 mmol) in water (70 mL). The thick slurry was heated to reflux for 12 hours. The solution was cooled in ice and cautiously brought to pH 3 with concentrated HCl. The aqueous mixture was extracted with EtOAc (3×). The organic layers were combined, washed with brine, dried with sodium sulfate and concentrated in vacuo. The crude product mixture was dissolved in dichloromethane and the resulting yellow precipitate was filtered to afford Intermediate A-15A (6 g, 32.8 mmol, 66.0% yield). HPLC: RT=0.85 min (H2O/MeOH with TFA, Sunfire C18 3.5 μm, 2.1×30 mm, gradient=4 min, wavelength=220 nm); MS(ES): m/z=206 [M+Na]+; 1H NMR (400 MHz, chloroform-d) δ 7.56-7.35 (m, 1H), 7.23 (dd, J=7.9, 1.5 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:6][C:5]=1[N+:18]([O-])=O.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:6][C:5]=1[NH2:18]
Reactant: COC(=O)c1ccc(NC(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Reactant: BrCc1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(N(Cc2ccccc2)C(=O)OC(C)(C)C)cc1N
Temperature: 25 °C
Reaction time: 12 h
Yield: 57.5 %

Procedure:
To a suspension of CsCO3 (4.9 g, 15 mmoles) and (4-tert-Butoxycarbonylamino-2-nitro-benzoic acid methyl ester (2.96 g, 10 mmoles) in anhydrous DMF (100 mL) was added benzyl bromide (2.57 g, 15 mmoles) and the resulting mixture was stirred at room temperature for 12 hrs. The reaction mixture was filtered, concentrated, diluted with ethyl acetate, and washed with 5% citric acid, saturated NaHCO3 solution and water. The organic phase was hydrogenated over 10% Pd/C in EtOAc. After 12 hr, the mixture was filtered through a celite pad, and the filtrate was concentrated in vacuo to give a crude oil which was purified by column chromatography to furnish the desired product as an off-white solid (2.05 g, 57% yield). ES+ MS showed 357 m/z, the correct mass for the product. 1H NMR (400 MHz, DMSO-d6) showed β=1.34 (s, 9H), 3.71 (s, 3H), 4.74 (s, 2H), 6.39 (d, J=9 Hz, 1H), 6.62 (s, 1+2H), 7.19 (d, J=7 Hz, 2H), 7.24 (d, J=7 Hz, 1H), 7.32 (dd, J1=J2=7 Hz, 2H),.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]2[N:9]=[C:10]([O:31][C@H:32]3[CH2:35][C@H:34]([NH:36]C(=O)OC(C)(C)C)[CH2:33]3)[C:11]3[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)=[CH:15][N:14]([CH2:23][O:24]CC[Si](C)(C)C)[C:12]=3[N:13]=2)[CH:4]=[N:3]1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:36][C@H:34]1[CH2:33][C@H:32]([O:31][C:10]2[C:11]3[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)=[CH:15][N:14]([CH2:23][OH:24])[C:12]=3[N:13]=[C:8]([NH:7][C:5]3[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=3)[N:9]=2)[CH2:35]1
Reactant: Cn1cc(Nc2nc(O[C@H]3C[C@H](NC(=O)OC(C)(C)C)C3)c3c(-c4ccccn4)cn(COCC[Si](C)(C)C)c3n2)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1cc(Nc2nc(O[C@H]3C[C@H](N)C3)c3c(-c4ccccn4)cn(CO)c3n2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution tert-butyl {trans-3-[(2-[(1-methyl-1H-pyrazol-4-yl)amino]-5-(pyridin-2-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy]cyclobutyl}carbamate (359 mg, 0.592 mmol) in DCM (3 mL) was added trifluoroacetic acid (2 mL) and stirred at ambient temperature for 2 hrs. The reaction was concentrated down to a dark oil to give the title compound that was used as is for next step. m/z (ESI+) for C20H22N8O2 407.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[N:13]([CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[C:12]3[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:11]=3[N:10]=2)=[C:6]([OH:8])[CH:7]=1.Br[CH2:28][C:29]1[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][C:30]=1[F:37]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[N:13]([CH2:14][CH:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)[C:12]3[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:11]=3[N:10]=2)=[C:6]([CH:7]=1)[O:8][CH2:28][C:29]1[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][C:30]=1[F:37]
Reactant: Oc1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2n1CC1CCOCC1
Reactant: N#Cc1ccc(CBr)c(F)c1
Product: N#Cc1ccc(COc2cc(Cl)ccc2-c2nc3cc(F)c(F)cc3n2CC2CCOCC2)c(F)c1

Procedure:
The title compound was prepared in analogy to Example 5, intermediate a, from 5-chloro-2-[5,6-difluoro-1-(tetrahydro-pyran-4-ylmethyl)-1H-benzoimidazol-2-yl]-phenol and 4-bromomethyl-3-fluoro-benzonitrile (CAS Reg. No. 105942-09-4). Light brown solid (95%). MS (Turbo Spray): m/z=511.9 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19](O)=[O:20])[CH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.[NH2:53][CH2:54][CH:55]([OH:67])[CH2:56][N:57]1[CH2:66][CH2:65][C:64]2[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=2)[CH2:58]1>C(Cl)Cl>[CH2:58]1[C:59]2[C:64](=[CH:63][CH:62]=[CH:61][CH:60]=2)[CH2:65][CH2:66][N:57]1[CH2:56][CH:55]([OH:67])[CH2:54][NH:53][C:19]([C:18]1[CH:17]=[C:16]([CH:24]=[CH:23][CH:22]=1)[CH2:15][N:8]([CH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:20]
Reactant: CC(C)(C)OC(=O)N(Cc1cccc(C(=O)O)c1)C1CCOCC1
Reactant: NCC(O)CN1CCc2ccccc2C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N(Cc1cccc(C(=O)NCC(O)CN2CCc3ccccc3C2)c1)C1CCOCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.1 %

Procedure:
To a solution of 3-(((tert-butoxycarbonyl)(tetrahydro-2H-pyran-4-yl)amino)methyl)benzoic acid (300 mg, 0.89 mmol) in DCM (8 mL) was added EDCI (257 mg, 1.34 mmol), HOBt (181 mg, 1.34 mmol), Et3N (270 mg, 2.67 mmol) and 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (183 mg, 0.89 mmol). The mixture was stirred at 25° C. for 16 h. The reaction solution was washed with water and extracted with DCM. The organic layer was concentrated to give the title product (350 mg, Yield 65%). LCMS (m/z): 524.3 (M+1).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:8]=[C:7]2[S:9][C:10]3[CH2:15][S:14](=[O:16])[CH2:13][CH2:12][C:11]=3[C:6]2=[C:5]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[C:4]=1[Cl:25]>CO>[NH2:1][CH2:2][C:3]1[N:8]=[C:7]2[S:9][C:10]3[CH2:15][S@@:14](=[O:16])[CH2:13][CH2:12][C:11]=3[C:6]2=[C:5]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[C:4]=1[Cl:25]
Reactant: COc1ccc(-c2c(Cl)c(CN)nc3sc4c(c23)CCS(=O)C4)cc1
Solvent: CO
Product: COc1ccc(-c2c(Cl)c(CN)nc3sc4c(c23)CC[S@](=O)C4)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To methanol heated to 60° C. (63 L) was added 2-(aminomethyl)-3-chloro-4-(4-methoxyphenyl)-7-oxido-5,8-dihydro-6H-thiopyrano[4′,3′:4,5]thieno[2,3-b]pyridine (6.5 kg) and the mixture was stirred for 5 minutes, followed by addition of (R)-(−)-hydrogenphosphate-1,1′-bihaphthyl-2,2′-diyl (3.455 kg). The mixture was stirred at 60° C. for 10 minutes, slowly cooled to 25° C. After stirring for 1 hours, crystals were filtered off and washed with methanol (13L). Methanol-ethanol (1:3, 63 L) was heated to 75° C. and the resultant crystals were added thereto. The mixture was slowly cooled to 25° C. and stirred for 1 hours. Crystals deposited were filtered off and washed with methanol-ethanol (1:1, 13 L). The crystals were dissolved in tetrahydrofuran-water (3:1, 121.4 L) and active carbon (242 g) was added thereto. The mixture was stirred at room temperature for 15 minutes and the active carbon was filtered off. The tetrahydrofuran layer was distilled off under reduced pressure and the resultant aqueous layer was stirred at 25° C. to deposit crystals. The crystals were filtered off to obtain a diastereomer salt of (S)-2-(aminomethyl)-3-chloro-4-(4-methoxyphenyl)-7-oxido-5,8-dihydro-6H-thiopyrano[4′,3′:4,5]thieno[2,3-b]pyridine with (R)-(−)-hydrogenphosphate-1,1′-binaphthyl-2,2′-diyl (4.618 kg, 37.7%). 1H-NMR (DMSO-d6)δ: 1.98–2.04 (1H, m), 2.35–2.43 (1H, m), 2.71–2.81 (1H, m), 3.01–3.06 (1H, m), 3.83 (3H, s), 3.18 (1H, d, J=17.1 Hz), 4.26 (1H, d, J=17.1 Hz), 4.35 (2H, s), 0.07–7.43 (12H, m), 7.96–8.10 (4H, m), 8.64 (3H, bs).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](N2CCCC2)=[O:9])=[N:6][CH:5]=[CH:4][N:3]=1.[C:15]1([Mg]Br)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O1CCCC1>O>[NH2:1][C:2]1[C:7]([C:8](=[O:9])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:6][CH:5]=[CH:4][N:3]=1
Reactant: Nc1nccnc1C(=O)N1CCCC1
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: Nc1nccnc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Aminopyrazine-3-carboxylic acid pyrrolidide (63.4 g. or 0.33 mol) was added to a solution of freshly prepared phenylmagnesium bromide (305 g.) in 1 l. of tetrahydrofuran while the temperature was kept at 20°-30° by cooling with an ice bath. After stirring at room temperature for 2 hours, the mixture was hydrolyzed by addition of 2 l. of water. The aqueous layer was extracted twice with 500 ml. of methylene chloride. The extracts were combined with the organic layer, dried over sodium sulfate and evaporated. The brown residue was slurried with ether to yield 37.5 g. (56%) of yellow crystals of the above-named product.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[OH:17].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[O:17][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1Br
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1ccc(OCc2ccccc2)c(Br)c1
Reaction time: 72 h

Procedure:
Benzyl bromide (13.1 ml) was added to a stirred mixture of 2-bromo-4-chlorophenol (20.7 g) and potassium carbonate (27.6 g) in DMF (200 ml). After 72 h, the mixture was partitioned between diethylether and water, the organic layer washed with water, dried and the solvent evaporated under reduced pressure. The residue was purified by chromatography (silica, EtOAc/isohexane as eluent). to give the sub-title compound (18.1 g).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C:6]1[CH:15]=[C:14]([CH2:16][N:17]2[C:25]3[C:20](=[CH:21][C:22]([C:26]([OH:28])=O)=[CH:23][CH:24]=3)[CH:19]=[CH:18]2)[C:13]2[CH2:12][CH:11]=[CH:10][CH2:9][C:8]=2[N:7]=1>C(Cl)Cl>[CH3:5][C:6]1[CH:15]=[C:14]([CH2:16][N:17]2[C:25]3[C:20](=[CH:21][C:22]([C:26]([Cl:3])=[O:28])=[CH:23][CH:24]=3)[CH:19]=[CH:18]2)[C:13]2[CH2:12][CH:11]=[CH:10][CH2:9][C:8]=2[N:7]=1
Reactant: Cc1cc(Cn2ccc3cc(C(=O)O)ccc32)c2c(n1)CC=CC2
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1cc(Cn2ccc3cc(C(=O)Cl)ccc32)c2c(n1)CC=CC2
Temperature: 25 °C
Yield: 80 %

Procedure:
Thionyl chloride (5 ml) was added to a suspension of the 1-[(2-methyl-5,8-dihydro-4-quinolinyl)methyl]-1H-indole-5-carboxylic acid from step (402a) (0.67 g, 2.1 mmol) in methylene chloride (15 ml) and was heated to reflux for 2 hs. The reaction was cooled to room temperature, concentrated in vacuo to give the 1-[(2-methyl-5,8-dihydro-4-quinolinyl)methyl]-1H-indole-5-carbonyl chloride (0.68 g, 80%) as a yellow solid.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([N+:10]([O-:12])=[O:11])=[CH:6][C:7]=1[O:8][CH3:9].C(O)(=O)C.[BrH:18].N([O-])=O.[Na+]>O>[Br:18][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([N+:10]([O-:12])=[O:11])=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1cc([N+](=O)[O-])c(C)cc1N
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc([N+](=O)[O-])c(C)cc1Br
Reaction time: 0.17 h
Yield: 72 %

Procedure:
A slurry of 3-amino-4-methoxy-6-nitrotoluene (18 g) in water (20 ml) containing acetic acid (20 ml) and hydrobromic acid (47%, 35 ml) is stirred until a fine suspension of the hydrobromide is formed, cooled to 0°, and treated with a solution of sodium nitrite (7 g) in water (20 ml) added over 20 min. After a further 10 min., the yellow-brown solution is stirred into a mixture of cuprous bromide (30 g) and hydrobromic acid (47%, 30 ml) in water (50 ml), the mixture warmed on the steam bath until an effervescence commences and then at 70° for 1 hr. The mixture is cooled, diluted with water (500 ml), and the solid collected and recrystallized from aqueous ethanol to give a 3-bromo-4-methoxy-6-nitrotoluene (I) as pale yellow needles (18 g, 72%): mp 91-92°.
Reaction SMILES: [C:1]([CH2:4][C:5]1[N:6]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH:35]([CH3:37])[CH3:36])=[CH:30][CH:29]=2)[C:7]2[C:12]([C:13]=1[C:14]([OH:16])=[O:15])=[CH:11][C:10]([O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][N:19]=1)=[CH:9][CH:8]=2)([OH:3])=[O:2].Cl.[CH3:39][CH2:40]O>>[CH2:39]([O:2][C:1]([CH2:4][C:5]1[N:6]([C:28]2[CH:29]=[CH:30][C:31]([O:34][CH:35]([CH3:37])[CH3:36])=[CH:32][CH:33]=2)[C:7]2[C:12]([C:13]=1[C:14]([OH:16])=[O:15])=[CH:11][C:10]([O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][N:19]=1)=[CH:9][CH:8]=2)=[O:3])[CH3:40]
Reactant: CC(C)Oc1ccc(-n2c(CC(=O)O)c(C(=O)O)c3cc(Oc4ccc(C(F)(F)F)cn4)ccc32)cc1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)Cc1c(C(=O)O)c2cc(Oc3ccc(C(F)(F)F)cn3)ccc2n1-c1ccc(OC(C)C)cc1

Procedure:
A mixture of 2-carboxymethyl-1-(4-isopropoxyphenyl)-5-(5-trifluoromethyl-2-pyridinyloxy)indole-3-carboxylic acid (85 mg, 0.16 mmol, see Example 26), EtOH (0.8 mL) and HCl (1 M in EtOH, 0.1 mL) was heated at reflux for 20 min, concentrated, diluted with water, neutralized with NaHCO3 (aq, sat) and extracted with EtOAc. The organic layer was washed with brine, dried (Na2SO4), concentrated and purified by chromatography to give the title compound. Yield 45 mg (52%), mp 202° C.