Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][S:17]([N:20]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[Cl:40])[CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH:26]([O:29]COC)[CH2:25][CH2:24]3)(=[O:19])=[O:18])[CH:8]=2)[N:3]=1.C[OH:42].Cl.[OH-].[K+]>C(O)(=O)C>[Cl:40][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=1[CH2:33][N:20]([CH2:21][CH2:22][N:23]1[CH2:24][CH2:25][CH:26]([OH:29])[CH2:27][CH2:28]1)[S:17]([CH2:16][CH2:15][CH2:14][CH2:13][O:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[NH:3][C:2](=[O:42])[CH:11]=[CH:10]2)(=[O:18])=[O:19]
Reactant: COCOC1CCN(CCN(Cc2ccccc2Cl)S(=O)(=O)CCCCOc2ccc3nc(Cl)ccc3c2)CC1
Reactant: CO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Product: O=c1ccc2cc(OCCCCS(=O)(=O)N(CCN3CCC(O)CC3)Cc3ccccc3Cl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 2.63 g of 2-chloro-6-[4-{N-(2-chlorobenzyl)-N-[2-(4-methoxymethoxy-1-piperidinyl)ethyl]aminosulfonyl}butoxy]quinoline dissolved in 50 ml of acetic acid was refluxed for 3.5 hours. The solvent was removed by distillation under reduced pressure to obtain crude 6-[4-{N-(2-chlorobenzyl)-N-[2-(4-methoxymethoxy-1-piperidinyl)ethyl]aminosulfonyl}butoxy]carbostyril. To the substance were added 10 ml of methanol and 10 ml of a 5% aqueous hydrochloric acid solution. The mixture was stirred at room temperature for 1 day and then made alkaline with an aqueous potassium hydroxide solution, followed by extraction with ethyl acetate. The extract was washed with water and dried with magnesium sulfate. The solvent was removed by distillation. The resulting residue was purified by silica gel column chromatography (eluant: 10% methanol/dichloromethane) to obtain 1.4 g of 6-[4-{N-(2-chlorobenzyl)-N-[2-(4-hydroxy-1-piperidinyl)ethyl]aminosulfonyl}butoxy]carbostyril.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH:24]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C(=O)(O)[O-].[K+].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.O1CCOCC1>[C:13]([O:17][C:18]([N:20]1[CH2:21][CH:22]=[C:23]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=2)[CH2:24][CH2:25]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: COc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(C2=CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 90 %

Procedure:
4-Chloro-2-methoxy-1-nitro-benzene (1.12 g, 5.96 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.84 g, 5.95 mmol), tetrakis(triphenylphosphine)palladium(0) (380 mg, 0.33 mmol), a 2 M solution of potassium bicarbonate in water (7.45 mL, 14.9 mmol), and 1,4-dioxane (18 mL) were combined in a sealed tube, and the mixture was stirred and heated at 80° C. overnight. HPLC indicated the complete conversion of the starting material. The product, 4-(3-methoxy-4-nitro-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester was isolated by flash chromatography (Silicagel, EtOAc/Hexanes 25-50%) in 90% yield.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[H-].[Na+].[NH2:8][C:9]1[C:18]2[C:13](=[C:14](F)[C:15]([N:19]3[C:27]4[CH2:26][C:25]([CH3:29])([CH3:28])[CH2:24][C:23](=[O:30])[C:22]=4[C:21]([CH3:31])=[CH:20]3)=[CH:16][CH:17]=2)[N:12]=[CH:11][N:10]=1>CN(C=O)C>[NH2:8][C:9]1[C:18]2[C:13](=[C:14]([O:5][CH2:4][CH2:3][O:2][CH3:1])[C:15]([N:19]3[C:27]4[CH2:26][C:25]([CH3:29])([CH3:28])[CH2:24][C:23](=[O:30])[C:22]=4[C:21]([CH3:31])=[CH:20]3)=[CH:16][CH:17]=2)[N:12]=[CH:11][N:10]=1
Reactant: COCCO
Reactant: Cc1cn(-c2ccc3c(N)ncnc3c2F)c2c1C(=O)CC(C)(C)C2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOc1c(-n2cc(C)c3c2CC(C)(C)CC3=O)ccc2c(N)ncnc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 80.5 %

Procedure:
In a small microwave vial with a stir bar, 2-methoxyethanol (19.3 mg, 0.253 mmol) is dissolved in DMF (1 mL). To this solution is added sodium hydride (60% suspension in mineral oil, 10.13 mg, 0.2532 mmol) and the mixture is stirred at room temperature for 5 minutes and 1-(4-Amino-8-fluoro-quinazolin-7-yl)-3,6,6-trimethyl-1,5,6,7-tetrahydro-indol-4-one (42.8 mg, 0.126 mmol) is added. The reaction is sealed and placed in the microwave reactor where it is heated to 150° C. for 30 minutes. The reaction is cooled, quenched by adding 5 mL sat. NH4Cl (aq) and extracted with CH2Cl2 (3×1 mL). The combined organics are purified by silica gel chromatography by two gradient runs on the same column, the first 0% to 100% ethyl acetate in hexanes and the second 0% to 50% methanol in ethyl acetate. This gives the desired 1-[4-Amino-8-(2-methoxy-ethoxy)-quinazolin-7-yl]-3,6,6-trimethyl-1,5,6,7-tetrahydro-indol-4-one as a tan powder (40 mg, 80% yield) (LC/MS m/z=395 [M+H]+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:21]/[CH:22]=[CH:23]/[C:24]([O:26][CH3:27])=[O:25]>CN(C)C=O>[CH3:27][O:26][C:24](=[O:25])[CH:23]=[CH:22][CH2:21][N:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: COC(=O)/C=C/CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C=CCN1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 92 %

Procedure:
To a ice chilled solution of 1-benylpiperazine (25.0 g, 0.14 moles) in 140 mL dimethylformamide was added potassium carbonate (24.0 g, 1.25 eq.) and methyl 4-bromocrotonate (18.6 mL, 0.99 eq.). The solution was warmed to room temperature and stirred 24 h. The solution was filtered. Water was added and extracted with ethyl acetate. The organics were washed with water twice and brine, dried over sodium sulfate, filtered and evaportated to afford methyl -4-(4-benzylpiperazin-1-yl)but-2-enoate (35.2 g, 92%) as a brown-orange liquid. MS (ESI+) for m/z 275 (M+H)+.
Reaction SMILES: [CH3:1][Mg]Br.[C:4]([C:7]1[S:8][C:9]([Cl:12])=[CH:10][CH:11]=1)(=O)[CH3:5].[NH4+].[Cl-]>CCOCC>[Cl:12][C:9]1[S:8][C:7]([C:4]([CH3:1])=[CH2:5])=[CH:11][CH:10]=1
Reactant: C[Mg]Br
Reactant: CC(=O)c1ccc(Cl)s1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: C=C(C)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 80 mL of 3M methyl magnesium bromide in ether was added to a solution of 32 g of 2-acetyl-5-chlorothiophene in 400 mL of ether at 0° to 10° C. After being stirred for 1 hour at 25° C., the reaction mixture was poured onto saturated aq NH4Cl, washed with brine, dried (MgSO4), and concentrated. The crude carbinol was dissolved in 400 mL of 1-chlorobutane, 0.5 g of potassium hydrogen sulfate was added, and the mixture was heated at reflux with a water separator until the distillate was clear. The reaction mixture was washed with aq. NaHCO3, dried (MgSO4), and concentrated after first adding 0.1 g of 4-t-butyl catechol. Distillation at 90° at aspirator pressure afforded the title compound as a yellow oil. 1H NMR (CDCl3): δ2.08 (s, 3H), 4.95 (s, 1H), 5.25 (s, 1H), 6.77 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([O:32][CH3:33])([C:28]([F:31])([F:30])[F:29])[CH2:4][CH2:5][C:6]1[CH:27]=[CH:26][C:9]([O:10][CH2:11][CH2:12][NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:8][CH:7]=1.I[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40].C(N(CCCCCCCCCCCC)CCOC1C=CC(CCC(OC)(OC)C(F)(F)F)=CC=1)CC>>[CH2:35]([N:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:12][CH2:11][O:10][C:9]1[CH:8]=[CH:7][C:6]([CH2:5][CH2:4][C:3]([O:2][CH3:1])([O:32][CH3:33])[C:28]([F:30])([F:31])[F:29])=[CH:27][CH:26]=1)[CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]
Reactant: CCCCCCI
Reactant: CCCCCCCCCCCCNCCOc1ccc(CCC(OC)(OC)C(F)(F)F)cc1
Agent: CCCCCCCCCCCCN(CCC)CCOc1ccc(CCC(OC)(OC)C(F)(F)F)cc1
Product: CCCCCCCCCCCCN(CCCCCC)CCOc1ccc(CCC(OC)(OC)C(F)(F)F)cc1
Yield: 66.4 %

Procedure:
N-[2-[4-(3,3-Dimethoxy-4,4,4-trifluorobut-1-yl)phenoxy]ethyl]dodecylamine (500 mg, 1.05 mmol) and 1-iodohexane (0.186 ml, 1.26 mmol) were reacted as described in the preparation of N-propyl-N-[2-[4-(3,3-dimethoxy-4,4,4-trifluorobut-1-yl)phenoxy]ethyl]dodecylamine and afforded the title compound (390 mg, g, 67%) as a liquid.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9](=[O:13])[CH2:10][O:11][CH3:12])=[C:4]([CH3:14])[CH:3]=1.Br[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1/[C:23](=[CH:28]\[O:29][CH3:30])/[C:24]([O:26][CH3:27])=[O:25].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:30][O:29]/[CH:28]=[C:23](\[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH2:16][O:1][C:2]1[CH:3]=[C:4]([CH3:14])[C:5]([C:9](=[O:13])[CH2:10][O:11][CH3:12])=[CH:6][C:7]=1[CH3:8])/[C:24]([O:26][CH3:27])=[O:25]
Reactant: CO/C=C(/C(=O)OC)c1ccccc1CBr
Reactant: COCC(=O)c1cc(C)c(O)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CO/C=C(/C(=O)OC)c1ccccc1COc1cc(C)c(C(=O)COC)cc1C
Yield: 76.1 %

Procedure:
In 30 mL of acetonitrile (CH3CN), 0.3 g (1.55 mmol) of 1-(4-hydroxy-2,5-dimethylphenyl)-2-methoxyethanone obtained in Step 1 was reacted for 4 hours with 0.44 g (1.55 mmol) of (E)-methyl 2-(2-(bromomethyl)phenyl)-3-methoxyacrylate in the presence of 20.45 g (2.1 eq) of potassium carbonate under reflux. After completion of the reaction, the solvent was removed at a reduced pressure and the residue was stirred in water (30 mL) and extracted twice with 30 mL of dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and concentrated in a vacuum, followed by purification with silica gel to afford 0.47 g of (E)-methyl 3-methoxy-2-(2-((4-(2-methoxyacetyl)-2,5-dimethylphenoxy)methyl)phenyl)acrylate as a white solid (yield: 76%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.[C:8]1([S:14]([CH:17]=[C:18]2[CH2:21][O:20][CH2:19]2)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CO>[C:8]1([S:14]([CH2:17][C:18]2([N:1]3[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]3)[CH2:21][O:20][CH2:19]2)(=[O:16])=[O:15])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=S(=O)(C=C1COC1)c1ccccc1
Reactant: OC1CCNCC1
Solvent: CO
Product: O=S(=O)(CC1(N2CCC(O)CC2)COC1)c1ccccc1

Procedure:
A solution of piperidin-4-ol (100 mg, 0.989 mmol) and 3-((phenylsulfonyl)methylene)oxetane (prepared according to a published literature procedure: Wuitschik et al. J. Med. Chem. 53(8) 3227-3246, 2010, 416 mg, 1.977 mmol) in methanol (5 mL) was heated at 50° C. for 20 h. Solvent was evaporated in vacuo and the crude product was purified by flash chromatography on silica gel using an automated ISCO system (40 g column, eluting with 0-8% 2 N ammonia in methanol/dichloromethane). 1-(3-((phenylsulfonyl)methyl)oxetan-3-yl)piperidin-4-ol (300 mg) was obtained as a colorless oil.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[N:5]([CH2:19][CH2:20][CH2:21][O:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][CH:24]=2)[C:4]=1[C:33]([O:35]C)=[O:34])#[N:2].[OH-].[Na+].Cl>O1CCCC1.CO>[C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[N:5]([CH2:19][CH2:20][CH2:21][O:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][CH:24]=2)[C:4]=1[C:33]([OH:35])=[O:34])#[N:2]
Reactant: COC(=O)c1c(C#N)c2c(-c3ccccc3C)cccc2n1CCCOc1cccc2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccccc1-c1cccc2c1c(C#N)c(C(=O)O)n2CCCOc1cccc2ccccc12

Procedure:
A mixture of EXAMPLE 133A (16 mg) and sodium hydroxide (200 μl) in tetrahydrofuran (0.5 ml) and methanol (0.5 ml) was stirred overnight, neutralized with diluted HCl, and concentrated. The residue was purified by RPHPLC to provide the desired product. 1H NMR (500 MHz, dimethyl sulfoxide-d6) δ 14.24 (s, 1H), 8.14 (d, J=8.54 Hz, 1H), 7.86 (dd, J=7.48, 5.65 Hz, 2H), 7.35-7.61 (m, 5H), 7.18-7.36 (m, 3H), 7.12 (d, J=7.32 Hz, 1H), 7.06 (d, J=7.02 Hz, 1H), 6.89 (d, J=7.32 Hz, 1H), 4.77-5.18 (m, 2H), 4.24 (t, J=5.03 Hz, 2H), 2.30-2.47 (m, 2H), 1.99 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=O)[NH:7][N:6]=[C:5]2[CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:8]1[C:9]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:11][CH:10]=2)[C:5]([CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[N:6][N:7]=1
Reactant: O=c1[nH]nc(Cc2cccnc2)c2cc(Cl)ccc12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ccc2c(Cl)nnc(Cc3cccnc3)c2c1

Procedure:
6-Chloro-4-(3-pyridylmethyl)-1(2H)-phthalazinone (0.86 g) was suspended in 10 ml of phosphorus oxychloride. The obtained suspension was heated under reflux for 2 hours and freed from the phosphorus oxychloride by vacuum distillation. The residue was dissolved in tetrahydrofuran. The obtained solution was neutralized with triethylamine, followed by the addition of water. The obtained mixture was extracted with ethyl acetate. The organic phase was washed with water and a saturated aqueous solution of common salt, dried over anhydrous magnesium sulfate and freed from the solvent by vacuum distillation. The residue was purified by silica gel column chromatography to give 0.49 g of the title compound as a pale yellow crystal.
Reaction SMILES: [OH-].[K+].C(O)C.Br[CH2:7][CH2:8][C:9]1([F:16])[C:11]([F:13])([F:12])[C:10]1([F:15])[F:14]>O>[CH:8]([C:9]1([F:16])[C:11]([F:13])([F:12])[C:10]1([F:15])[F:14])=[CH2:7]
Reactant: FC1(F)C(F)(F)C1(F)CCBr
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C=CC1(F)C(F)(F)C1(F)F
Temperature: 70 °C
Reaction time: 2 h
Yield: 57.3 %

Procedure:
To a stirred solution of 18.0 g of KOH, 15 mL of ethanol and 20 mL of water was slowly added 24.0 g of 2-bromo-1-(pentafluorocyclopropyl)ethane at 70° C. During the addition, volatiles were collected in a -78° C. trap. After the addition was complete, the reaction mixture was stirred at 70° C. for an additional two hours until collection of all volatiles, which was distilled to give 9.1 g of product, bp 30° C. 19F NMR: -152.3 (dt, J =195.4 Hz, J=9.8 Hz, 2F), -156.0 (dm, J=195.6 Hz, 2F), -210.7 (t, J=7.7 Hz, 1F) . 1H NMR: 5.86-5.73 (m, 2H), 5.70-5.65 (m, 1H).
Reaction SMILES: [CH3:1][C:2]([CH3:8])=[CH:3][CH2:4][CH2:5][Mg]Br.[CH3:9][Si:10]([CH3:19])([CH3:18])[C:11]1[O:15][CH:14]=[C:13]([CH:16]=[O:17])[CH:12]=1.S(=O)(=O)(O)O>C(OCC)C>[OH:17][CH:16]([C:13]1[CH:12]=[C:11]([Si:10]([CH3:19])([CH3:18])[CH3:9])[O:15][CH:14]=1)[CH2:5][CH2:4][CH:3]=[C:2]([CH3:8])[CH3:1]
Reactant: CC(C)=CCC[Mg]Br
Reactant: C[Si](C)(C)c1cc(C=O)co1
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: CC(C)=CCCC(O)c1coc([Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4-methyl-3-pentenylmagnesium bromide (0.74 mmol, prepared from 0.74 mmol 5-bromo-2-methyl-2-pentene and 1.46 mmol magnesium) in two ml anhydrous ethyl ether at 0° under argon was added dropwise 5-trimethylsilyl-3-furaldehyde (0.124 g., 0.74 mmol) in 1.5 ml ethyl ether. This solution was allowed to warm to room temperature, stirred for 30 minutes, and then poured over crushed ice containing several drops of concentrated sulfuric acid. The resulting mixture was partitioned between ethyl ether and 5% sodium bicarbonate. The organic portion was washed with water, saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give a colorless oil. This material was purified by flash chromatography (silica, 10% ethyl acetate/hexane) to give the desired alcohol.
Reaction SMILES: COC1C=CC([C@H]([N:11]2[CH2:15][CH2:14][CH2:13][C@H:12]2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]([N:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:24][CH2:23]3)[CH:17]=2)C)=CC=1>C(O)(C(F)(F)F)=O>[NH:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([N:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:24][CH2:23]2)[CH:17]=1
Reactant: COc1ccc([C@@H](C)N2CCC[C@H]2c2ccnc(N3CCc4ccccc43)c2)cc1
Solvent: O=C(O)C(F)(F)F
Product: c1ccc2c(c1)CCN2c1cc([C@@H]2CCCN2)ccn1

Procedure:
A solution of (1-(4-{(S)-1-[(R)-1-(4-Methoxy-phenyl)-ethyl]-pyrrolidin-2-yl}-pyridin-2-yl)-2,3-dihydro-1H-indole (140 mg, 0.35 mmol) in TFA (10 mL) is heated in microwave at 100° C. for 30 min and concentrated down to give crude 1-((S)-4-pyrrolidin-2-yl-pyridin-2-yl)-2,3-dihydro-1H-indole (6), which is used in next step without further purification.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:10][C@H:9]1[C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:28])[CH:21]=2)=[O:19])=[CH:13][CH:12]=1)(C)(C)C.[ClH:36].C(OCC)(=O)C>>[ClH:36].[NH2:7][C@@H:8]1[CH2:10][C@H:9]1[C:11]1[CH:12]=[CH:13][C:14]([NH:17][C:18](=[O:19])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][C:27]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[O:28])[CH:21]=2)=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(NC(=O)c2cccc(NC(=O)c3ccccc3)c2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: N[C@@H]1C[C@H]1c1ccc(NC(=O)c2cccc(NC(=O)c3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl(trans-2-{4-[({3-[(phenylcarbonyl)amino]phenyl}carbonyl)amino]phenyl}-cyclopropyl)carbamate (188 mg) was dissolved in 4N hydrochloric acid/ethyl acetate solution (2 mL), and the mixture was stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure to give the title compound (107 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[F:27])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([O:21][CH3:22])[C:10](=O)[N:11](C)[C:12]=2C(O)=O)[C:7]1=[O:23].C(Cl)(=O)C(Cl)=O.CC(N=NC(C#N)(C)C)(C#N)C.[N+]1([O-])C(S)=CC=CC=1.[Br:54]C(Cl)(Cl)Cl>ClCCl.CN(C=O)C.ClC(Cl)C>[Br:54][C:12]1[N:11]=[CH:10][C:9]([O:21][CH3:22])=[C:8]2[C:13]=1[CH2:14][CH2:15][N:6]([CH2:5][C:4]1[CH:24]=[CH:25][C:26]([F:27])=[C:2]([Cl:1])[CH:3]=1)[C:7]2=[O:23]
Reactant: ClC(Cl)(Cl)Br
Reactant: COc1c2c(c(C(=O)O)n(C)c1=O)CCN(Cc1ccc(F)c(Cl)c1)C2=O
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C(Cl)C(=O)Cl
Agent: [O-][n+]1ccccc1S
Solvent: CC(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cnc(Br)c2c1C(=O)N(Cc1ccc(F)c(Cl)c1)CC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 6-(3-chloro-4-fluorobenzyl)-4-methoxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylic acid (3.5 g, 9.59 mmol; Example 12, step 12) in anhydrous dichloromethane (60 mL) and anhydrous DMF (0.45 mL) at room temperature was treated with oxalyl chloride (1.7 mL, 19.2 mmol). The reaction mixture was stirred at room temperature for 2 hours and concentrated under vacuum. A solution of the residue and AIBN (0.47 g, 2.88 mmol) in anhydrous dichloromethane (30 mL) was added portionwise to a solution of 2-pyridinethiol-N-oxide (2.4 g, 19.2 mmol) in a mixture of bromotrichloromethane (90 mL) and dichloroethane (30 mL) at 100° C. over a period of 20 minutes (Barton et al, Tetrahedron Lett., 5939, 1985). The mixture was heated at the same temperature for 20 minutes, cooled to room temperature, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 2% methanol in dichloromethane. Collection and concentration of appropriate fractions provided the titled compound.
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].[H-].[Na+].Cl[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([S:19](=[O:22])(=[O:21])[NH2:20])[CH:17]=2)[C:12]([Cl:23])=[CH:11][N:10]=1>CS(C)=O>[Cl:23][C:12]1[C:13]2[C:18](=[CH:17][C:16]([S:19](=[O:22])(=[O:21])[NH2:20])=[CH:15][CH:14]=2)[C:9]([NH:4][C:3]([NH2:5])=[NH:2])=[N:10][CH:11]=1
Reactant: N=C(N)N
Reactant: NS(=O)(=O)c1ccc2c(Cl)cnc(Cl)c2c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: N=C(N)Nc1ncc(Cl)c2ccc(S(N)(=O)=O)cc12
Temperature: 50 °C
Yield: 66.8 %

Procedure:
Guanidine hydrochloride (70 mg, 0.73 mmol) was added in one portion to a suspension of NaH (21 mg, 80% dispersion by wt in mineral oil, 0.66 mmol) in DMSO (2.0 mL) and the mixture was heated at 50° C. under N2 for 30 min. 1,4-Dichloro-7-sulphamoylisoquinoline (70 mg, 0.25 mmol) was added and the mixture heated at 90° C. for 18 h. The cooled mixture was partitioned between ethyl acetate (EtOAc) and water, and the organic phase was washed with brine, dried (MgSO4) and evaporated in vacuo. The residue was purified by column chromatography upon silica gel using CH2Cl2—MeOH-0.880NH3 (95:5:0.5 to 90:10:1) as eluant to give 4-chloro-1-guanidino-7-sulphamoylisoquinoline (50 mg, 0.167 mmol) as a white solid.
Reaction SMILES: [N:1]1([C:5]([C:7]2[CH:8]=[C:9]([NH:13]C(=O)OC(C)(C)C)[CH:10]=[CH:11][CH:12]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:13][C:9]1[CH:8]=[C:7]([C:5]([N:1]2[CH2:4][CH2:3][CH2:2]2)=[O:6])[CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(C(=O)N2CCC2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1cccc(C(=O)N2CCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
To a stirred solution of tert-butyl (3-(azetidine-1-carbonyl)phenyl)carbamate (600 mg, 2.171 mmol) in DCM (5.0 ml) was added trifluoroacetic acid (0.167 ml, 2.171 mmol) at 0° C. under nitrogen atmosphere. Reaction was stirred at room temperature for 1 hr. Solvent evaporated up to dryness and the residual solid was dissolved in DCM (20 ml) and washed with saturated solution of NaHCO3. DCM layer was dried over sodium sulphate and evaporated under vacuum. Resulting solid was washed with pentane and ether to give the titled compound (310 mg).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.[CH3:12][C:13]1([CH3:16])[CH2:15][S:14]1.O>C1C=CC=CC=1>[CH3:12][C:13]([SH:14])([CH3:16])[CH2:15][N:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1
Reactant: CCOC(=O)C1CCNCC1
Reactant: CC1(C)CS1
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)C1CCN(CC(C)(C)S)CC1
Temperature: 80 °C
Reaction time: 20 h
Yield: 97 %

Procedure:
Ethyl piperidine-4-carboxylate (3.6 g, 22.9 mmol) was dissolved in benzene (5 mL), and 2,2-dimethylthiirane (5.04 g, 57.3 mmol) was added. The reaction mixture was stirred at 80° C. for 20 hours, poured into water and extracted several times with EtOAc. The combined organic extracts were washed with brine and dried over anhydrous sodium sulfate. The volatiles were evaporated and the residue was dried under vacuum to afford 5.45 g (97%) of the title compound. 1H NMR (300 MHz, CD3OD) δ 4.12 (q, J=7.1 Hz, 2H), 2.92-2.96 (d, J=11.9 Hz, 2H), 2.19-2.40 (m, 6H), 1.61-1.86 (m, 4H), 1.29 (s, 6H), 1.25 (t, J=7.1 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[C:10]2[O:9][CH2:8][CH:7](O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.O=S(Cl)Cl>N1C=CC=CC=1.C(Cl)Cl>[F:1][C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: OC1COc2c(F)cccc21
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: Fc1cccc2ccoc12
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 235.1 %

Procedure:
To a solution of 7-fluoro-2,3-dihydrobenzofuran-3-ol (4.6 g, 29 8 mmol) in pyridine (93 mL) at 0° C. was added SOCl2 (21.7 mL, 298 mmol) dropwise. Upon completion of addition, the mixture was stirred at 0° C. for 1.5 h. At the conclusion of this period, the reaction mixture was carefully quenched with aqueous NaHCO3 (saturated, 100 mL) to reach a pH=9. Once at the prescribed pH, the reaction mixture was extracted with CH2Cl2 (4×15 mL). The combined organic layers were washed with aqueous NaHCO3 (5%, 40 mL), water (40 mL), and then concentrated to yield the crude product. The crude product was dissolved in CH2Cl2 (50 mL), washed with aqueous HCl (1 N, 5×10 mL), and then water (40 mL). The organic layer was separated, dried (MgSO4), filtered, and concentrated to afford Compound 1C as a brown oil (2.56 g). 1H NMR (500 MHz, CDCl3) δ ppm 7.67 (d, J=2.2 Hz, 1 H), 7.33-7.40 (m, 1 H), 7.17 (td, J=8.0, 4.4 Hz, 1 H), 7.04 (dd, J=10.7, 8.0 Hz, 1 H), 6.79-6.85 (m, 1 H).