Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[F:19][C:20]([F:34])([F:33])[O:21][C:22]1[CH:23]=[C:24](/[CH:28]=[CH:29]/[C:30](O)=[O:31])[CH:25]=[CH:26][CH:27]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:30](=[O:31])/[CH:29]=[CH:28]/[C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([O:21][C:20]([F:33])([F:34])[F:19])[CH:23]=3)=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)/C=C/c1cccc(OC(F)(F)F)c1
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)/C=C/c3cccc(OC(F)(F)F)c3)n2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and (E)-3-(3-trifluoromethoxy-phenyl)-acrylic acid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8](Cl)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:12][C:13]1[CH:14]=[C:15]([CH:17]=[C:18]([CH3:20])[CH:19]=1)[NH2:16]>O1CCOCC1>[Cl:1][C:2]1[C:7]([S:8]([NH:16][C:15]2[CH:17]=[C:18]([CH3:20])[CH:19]=[C:13]([CH3:12])[CH:14]=2)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Cl)c1cccnc1Cl
Reactant: Cc1cc(C)cc(N)c1
Solvent: C1COCCO1
Product: Cc1cc(C)cc(NS(=O)(=O)c2cccnc2Cl)c1
Yield: 52.1 %

Procedure:
The title compound (791 mg, 2.67 mmol) was prepared from 2-chloropyridine-3-sulfonyl chloride (1.09 g, 5.12 mmol) and 3,5-dimethylaniline (709 uL, 5.65 mmol) in 1,4-dioxane (30 mL) using the methods of (IntC1).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][N:11]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH2:1]([O:16][C:14](=[O:15])[C:13]1[CH:17]=[CH:18][C:10]([NH2:9])=[N:11][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: Nc1ccc(C(=O)O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc(C(=O)OCc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 53.5 %

Procedure:
Benzyl bromide (0.86 ml, 7.9 mmol) was added to a mixture of 6-aminonicotinic acid (1.0 g, 7.2 mmol) and potassium carbonate (1.5 g, 10.8 mmol) in DMF (4 mL). The mixture was stirred at room temperature for 16 hr and diluted with water (50 mL). The aqueous mixture was extracted with ethyl acetate (1×). The EtOAc layer was washed with brine, dried over MgSO4 and concentrated to provide crude solid product. Recrystallization from diethyl ether provided the title compound as a pale yellow solid (0.88 g, 53%).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:18])=[CH:4][C:5]2[C:6]([CH3:17])([CH3:16])[CH2:7][CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=2[CH:11]=1.[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([O:18][C:3]1[CH:4]=[C:5]2[C:10]([C:9]([C:12]([CH3:13])([CH3:15])[CH3:14])=[CH:8][CH2:7][C:6]2([CH3:17])[CH3:16])=[CH:11][C:2]=1[Br:1])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)C1=CCC(C)(C)c2cc(O)c(Br)cc21
Reactant: BrCc1ccccc1
Product: CC(C)(C)C1=CCC(C)(C)c2cc(OCc3ccccc3)c(Br)cc21
Yield: 100 %

Procedure:
Following General Procedure O, 3-bromo-5-t-butyl-8,8-dimethyl-7,8-dihydronaphthalen-2-ol (Compound 98, 0.18 g, 0.58 mmol) was reacted with benzyl bromide to afford 0.23 g (100%) of the title compound as a yellow oil.
Reaction SMILES: [Cl-].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]([C:13]2([Cl:16])[CH2:15][CH2:14]2)=[O:12])=[CH:5][CH:4]=1.[H][H]>C1(C)C=CC=CC=1>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][C:11]([C:13]2([Cl:16])[CH2:15][CH2:14]2)=[O:12])=[CH:7][CH:8]=1
Reactant: [H][H]
Reactant: O=C(C=Cc1ccc(Cl)cc1)C1(Cl)CC1
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: O=C(CCc1ccc(Cl)cc1)C1(Cl)CC1
Temperature: 50 °C
Yield: 90.5 %

Procedure:
460 mg (0.5 mmol) of tris-triphenylphosphinerhodium chloride (=1 mol %, with respect to the reaction component) are added to a 100 ml autoclave. After purging with nitrogen, an air-free solution of 12 g (0.05 mol) of 1-chlorocyclopropyl 4-chlorophenyl-ethenyl ketone in 40 ml of toluene is added and the mixture is heated to 50° C. under a hydrogen pressure of 30 bar. The hydrogen pressure is held between 40 and 50 bar until gas uptake has ended (after about 1 hour). The mixture is then allowed to react for a further hour. For working up, the solvent is stripped off under reduced pressure and the remaining residue is purified on silica gel using dichloromethane as eluant. 11 g (90% of theory) of 1-chlorocyclopropyl 4-chlorophenylethyl ketone are obtained in the form of an oily product.
Reaction SMILES: [OH-].[Na+].CO.[Cl:5][C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[CH2:16][CH2:17][CH2:18][C:19]1([C:33]([O:35]CC)=[O:34])[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][S:27][C:28]3[S:29][CH:30]=[CH:31][CH:32]=3)[CH2:21][CH2:20]1)=[CH:13][C:12]([O:38][CH3:39])=[C:11]([O:40][CH3:41])[CH:10]=2>O1CCOCC1>[Cl:5][C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[CH2:16][CH2:17][CH2:18][C:19]1([C:33]([OH:35])=[O:34])[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][S:27][C:28]3[S:29][CH:30]=[CH:31][CH:32]=3)[CH2:21][CH2:20]1)=[CH:13][C:12]([O:38][CH3:39])=[C:11]([O:40][CH3:41])[CH:10]=2
Reactant: CCOC(=O)C1(CCCc2c(Cl)cnc3cc(OC)c(OC)cc23)CCN(CCSc2cccs2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: COc1cc2ncc(Cl)c(CCCC3(C(=O)O)CCN(CCSc4cccs4)CC3)c2cc1OC
Temperature: 20 °C
Yield: 73.7 %

Procedure:
26 cm3 of aqueous 5N sodium hydroxide and 20 cm3 of methanol were added to a solution of 1.47 g of ethyl 4-[3-(3-chloro-6,7-dimethoxyquinolin-4-yl)propyl]-1-[2-(thiophen-2-ylthio)ethyl]piperidine-4-carboxylate in 20 cm3 of dioxane, with stirring and at a temperature in the region of 20° C., and the mixture was then maintained at a temperature of about 70° C. for 21 hours. The reaction mixture was concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue obtained was purified by chromatography under a pressure of 50 kPa of argon, on a column of silica gel (particle size 40-63μ; mass 60 g), eluting with a mixture of dichloromethane/methanol/aqueous ammonia (12/3/0.5 by volume). Fractions 11 to 25 were combined and then concentrated to dryness under the above conditions. 1.03 g of 4-[3-(3-chloro-6,7-dimethoxy-quinolin-4-yl)propyl]-1-[2-(thiophen-2-ylthio)ethyl]-piperidine-4-carboxylic acid was obtained in the form of a white solid melting at 214° C.
Reaction SMILES: [C:1]1([CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH:11]=[N:10][C:9]([C:12]([O:14]CC)=[O:13])=[N:8]1.[Li+].[OH-].CO.Cl>C1COCC1>[C:1]1([CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH:11]=[N:10][C:9]([C:12]([OH:14])=[O:13])=[N:8]1
Reactant: CCOC(=O)c1ncn(-c2ccccc2C)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccccc1-n1cnc(C(=O)O)n1
Temperature: 50 °C
Reaction time: 0.08 h

Procedure:
To a solution of ethyl 1-(o-tolyl)-1,2,4-triazole-3-carboxylate (400 mg, 1.7 mmol) in 3 mL THF was added 4 M LiOH (2 mL, 8 mmol) followed by 3 mL of MeOH. The reaction mixture was stirred at 50° C. for 5 minutes, after which the pH was adjusted to 4 with the addition of conc. HCl. After extraction, drying (MgSO4), filtration and drying under reduced pressure, 43 mg of residue was recovered (12%) and used in the subsequent step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]2[NH:6][C:7]([C:12]3[C:13](=[O:28])[N:14]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:15]4[C:20]([C:21]=3[OH:22])=[CH:19][CH:18]=[CH:17][N:16]=4)=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.[CH3:31][S:32]([C:35]1[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:37][CH:36]=1)(=[O:34])=[O:33]>N1C=CC=CC=1.C(OCC)(=O)C>[OH:22][C:21]1[C:20]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:13](=[O:28])[C:12]=1[C:7]1[NH:6][C:5]2[CH:29]=[CH:30][C:2]([NH:1][S:41]([C:38]3[CH:37]=[CH:36][C:35]([S:32]([CH3:31])(=[O:34])=[O:33])=[CH:40][CH:39]=3)(=[O:43])=[O:42])=[CH:3][C:4]=2[S:9](=[O:11])(=[O:10])[N:8]=1
Reactant: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(N)ccc3N2)c(O)c2cccnc21
Reactant: CS(=O)(=O)c1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(NS(=O)(=O)c4ccc(S(C)(=O)=O)cc4)ccc3N2)c(O)c2cccnc21
Temperature: 100 °C
Yield: 49.4 %

Procedure:
To the product of Example 205 (0.020 g, 0.047 mmol) in pyridine (0.2 mL) was added 4-methylsulfonylbenzenesulfonyl chloride (0.014 g, 0.056 mmol). The reaction mixture was heated in a microwave reactor at 100° C. for 30 minutes. The reaction was cooled to 25° C. and diluted with ethyl acetate (40 mL), washed with water and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated. The residue was chromatographed on silica gel eluting with 99: 1dichloromethane:methanol to give the title compound (15 mg, 50%). 1H NMR (300 MHz, DMSO-d6) δ 0.97 (d, J=6.25 Hz, 6 H) 1.56 (m, 2 H) 1.68 (m, 1 H) 3.28 (s, 3 H) 4.46 (m, 2 H) 7.48 (m, 3 H) 7.65 (d, J=8.82 Hz, 1 H) 8.04 (d, J=8.82 Hz, 2 H) 8.15 (d, J=8.46 Hz, 2 H) 8.54 (dd, J=8.09, 1.84 Hz, 1 H) 8.86 (dd, J=4.60, 1.65 Hz, 1 H) 11.11 (s, 1 H) 14.14 (s, 1 H). MS (ESI−) m/z 644 (M−H)−.
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH3:31])[CH2:3][N:4]1[C:8]2[N:9]=[C:10]([C:13]#[N:14])[N:11]=[CH:12][C:7]=2[CH:6]=[C:5]1[CH2:15][N:16]1[CH2:30][CH2:29][C:19]2([NH:23][C:22](=[O:24])[N:21]([CH2:25][CH2:26][CH3:27])[C:20]2=[O:28])[CH2:18][CH2:17]1.[H-].[Na+].[CH3:35]I>CN(C=O)C>[CH3:32][C:2]([CH3:31])([CH3:1])[CH2:3][N:4]1[C:8]2[N:9]=[C:10]([C:13]#[N:14])[N:11]=[CH:12][C:7]=2[CH:6]=[C:5]1[CH2:15][N:16]1[CH2:17][CH2:18][C:19]2([N:23]([CH3:35])[C:22](=[O:24])[N:21]([CH2:25][CH2:26][CH3:27])[C:20]2=[O:28])[CH2:29][CH2:30]1
Reactant: CI
Reactant: CCCN1C(=O)NC2(CCN(Cc3cc4cnc(C#N)nc4n3CC(C)(C)C)CC2)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCN1C(=O)N(C)C2(CCN(Cc3cc4cnc(C#N)nc4n3CC(C)(C)C)CC2)C1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 32.8 %

Procedure:
To a solution of 7-(2,2-dimethyl-propyl)-6-(2,4-dioxo-3-propyl-1,3,8-triaza-spiro[4.5]dec-8-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (0.2 g, 0.48 mmol) in DMF (2 ml), NaH (22 mg, 0.55 mmol) and MeI (50 □1, 0.55 mmol) are added at 0° C. The reaction mixture is stirred at ambient temperature for 4 h, quenched with saturated ammonium chloride and extracted with AcOEt. The organic layer is washed with brine, dried over magnesium sulfate and filtrated The combined extracts are concentrated and the residue is purified by column chromatography on silica gel using CH2Cl2:MeOH=25:1 (v/v) and CH2Cl2:MeOH=15:1 (v/v) to give 71 mg of desired product in 34% yield.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][C:3]=1[CH:4]=O.O.[NH2:17][NH2:18]>N1C=CC=CC=1>[N:17](=[CH:4][C:3]1[CH:6]=[CH:7][C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:9][C:2]=1[OH:1])[NH2:18]
Reactant: NN
Reactant: O=Cc1ccc(N2CCOCC2)cc1O
Solvent: O
Solvent: c1ccncc1
Product: NN=Cc1ccc(N2CCOCC2)cc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.8 %

Procedure:
A solution of 2-hydroxy-4-morpholin-4-yl-benzaldehyde (0.135 g, 0.65 mmol) in pyridine (5 mL) was treated with hydrazine hydrate (33 mg, 0.65 mmol) and stirred for 3 h at room temperature. The reaction mixture was concentrated in vacuo and the residue was partitioned between EtOAc and 5% sodium bicarbonate. The organic layer was dried over Na2SO4 and concentrated in vacuo to afford the product as a pale yellow solid (96 mg, 67%)
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]#[N:7].[N-:8]=[N+:9]=[N-:10].[Na+].[Cl-].[Al+3].[Cl-].[Cl-].Cl>O1CCCC1.CCCCC>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[NH:10][N:9]=[N:8][N:7]=1
Reactant: N#CCCCCCl
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCCCC
Solvent: C1CCOC1
Product: ClCCCCc1nnn[nH]1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
100mmol of 5-chlorovaleronitrile are placed under an inert atmosphere in 100 ml of anhydrous tetrahydrofuran on an ice bath. 445 mmol of sodium azide and then 100 mmol of aluminum chloride are then added in small fractions. The reaction mixture is heated to 80° C. and left under reflux, with stirring, for 16 hours. The complex formed is then hydrolyzed by addition, dropwise, of 150 cm3 of 5% hydrochloric acid. The resulting aqueous phase is extracted with ethyl acetate and after washing the organic phase with water, then with a saturated sodium chloride solution, drying and evaporation, the residue obtained is taken up in pentane. The expected product is then obtained after filtration of the precipitate formed.
Reaction SMILES: C([O:3][C:4](=O)[C:5]([NH2:28])([C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][C@H:18]3[CH2:23][CH2:22][C@H:21]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19]3)[CH:13]=2)[N:8]=1)[CH3:6])C.[BH4-].[Na+]>CO.O1CCCC1>[NH2:28][C:5]([C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][C@H:18]3[CH2:19][CH2:20][C@H:21]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:22][CH2:23]3)[CH:13]=2)[N:8]=1)([CH3:6])[CH2:4][OH:3]
Reactant: CCOC(=O)C(C)(N)c1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(N)(CO)c1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2n1
Reaction time: 2 h

Procedure:
2-Amino-2-[6-(trans-4-tert-butyl-cyclohexyloxy)-quinolin-2-yl]-propionic acid ethyl ester (18 mg as TFA salt, 0.000035 mol) was dissolved in a mixture of methanol (2.0 mL, Acros) and tetrahydrofuran (2.0 mL, Acros), then sodium tetrahydroborate (3.8 mg, 0.00010 mol, Aldrich) was added. After 2 h, additional sodium tetrahydroborate (8.1 mg, 0.00021 mol, Aldrich) was added. After an additional 2 h, the reaction mixture was quenched with 250 uL of to saturated NH4Cl, and solvents were removed under vacuum. DMSO (½ mL) was added to the residue but it did not completely solubilize. The material was partitioned between methylene chloride and water. The emulsion was broken up by adding saturated sodium chloride and solid sodium chloride. The organics were dried with magnesium sulfate, filtered and evaporated. The residue was purified via preparative HPLC to give pure product (6.3 mg, 38%) as TFA salt. MS: m/z=357.20 [M+H]+. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm: 8.19 (d, J=8.5 Hz, 1H), 7.96 (d, J=9.3 Hz, 1H), 7.39-7.46 (m, 2H), 7.13 (d, J=2.8 Hz, 1H), 4.24-4.36 (m, 1H), 4.12-4.21 (m, 2H), 2.23-2.32 (m, 2H), 1.88-1.96 (m, 2H), 1.78 (s, 3H), 1.41-1.54 (m, 2H), 1.10-1.27 (m, 3H), 0.91 (s, 9H).
Reaction SMILES: [N:1]1[C:6]2[CH:7]=[CH:8][NH:9][C:5]=2[C:4]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][C:12]=2[F:18])=[N:3][CH:2]=1.[CH:19]1[CH:24]=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=C[CH:20]=1.CCOC(/N=N/C(OCC)=O)=O.C(O)(C)C.Cl>C1COCC1.CO.C(Cl)Cl.CCOC(C)=O.CCCCCC>[F:18][C:12]1[CH:13]=[C:14]([NH2:17])[CH:15]=[CH:16][C:11]=1[O:10][C:4]1[C:5]2[N:9]([CH:19]([CH3:24])[CH3:20])[CH:8]=[CH:7][C:6]=2[N:1]=[CH:2][N:3]=1
Reactant: Nc1ccc(Oc2ncnc3cc[nH]c23)c(F)c1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: Cl
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)n1ccc2ncnc(Oc3ccc(N)cc3F)c21
Reaction time: 48 h
Yield: 20.3 %

Procedure:
To a suspension of 247 (80 mg, 0.327 mmol) in THF (4 mL), was added PPh3 (258 mg, 0.983 mmol), DEAD (0.155 mL, 0.983 mmol) and isopropanol (0.075 mL, 0.983 mmol), and the reaction mixture was allowed to stir for 48 hours. 3N HCl solution (1.0 mL) was added and the mixture was extracted with DCM. Aqueous phase was collected, neutralized with NaOH 10% (pH˜11) and extracted with DCM. The organic phase was collected, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified twice by column chromatography: eluents EtOAc/hexane (3:7) and MeOH/DCM (1:20), to afford title compound 248 (19 mg, 31% yield) as yellow solid. MS (m/z): 287.1 (M+1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+].CCCCCC>CC(=O)CC>[CH3:24][C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:1]2[C:9]3[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)c1ccc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCC(C)=O
Product: COC(=O)c1ccc2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1
Reaction time: 18 h
Yield: 56.4 %

Procedure:
A solution of methyl indole-5-carboxylate, (21.7 g), p-toluenesulfonyl chloride (47.3 g), and K2CO3 (68.4 g) in 2-butanone (310 ml) was refluxed under a nitrogen atmosphere for 18 hr. Additional p-toluenesulfonyl chloride (12.0 g) and K2CO3 (17 g) was added to the reaction mixture and reflux was continued for 18 hr. The reaction mixture was filtered hot and the filtrate was evaporated to give an ivory solid that was tritrated with hexane to give methyl 1-(4-methylphenylsulfonyl)indole-5-carboxylate (23.0 g, 56%) as an ivory solid: NMR (80 MHz, CDCl3): 2.34 (s, 3H, ArCH3), 3.91 (s, 3H, OCH3), 6.7 (d, 1H, H2 -indole).
Reaction SMILES: Br[C:2]1[C:7]([N:8]([CH2:23][O:24][CH3:25])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:26])=[CH:4][N:3]=1.C([Mg]Cl)(C)C.CON(C)[C:35](=[O:47])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[C:42]1[O:43][CH:44]=[CH:45][N:46]=1>C1COCC1>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([S:9]([N:8]([C:7]2[C:2]([C:35](=[O:47])[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[C:42]3[O:43][CH:44]=[CH:45][N:46]=3)=[N:3][CH:4]=[C:5]([Cl:26])[CH:6]=2)[CH2:23][O:24][CH3:25])(=[O:11])=[O:10])=[CH:13][C:14]=1[C:19]([F:22])([F:21])[F:20]
Reactant: CON(C)C(=O)c1ccccc1-c1ncco1
Reactant: COCN(c1cc(Cl)cnc1Br)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COCN(c1cc(Cl)cnc1C(=O)c1ccccc1-c1ncco1)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 20.5 %

Procedure:
To a solution of N-(2-Bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (125 mg, 0.25 mmol) in 2.0 mL of THF under nitrogen atmosphere at 0° C. was added drop-wise 0.3 ml (0.6 mmol) of isopropylmagnesium chloride. The mixture was then stirred for 20 min at 0° C. followed by addition of N-Methoxy-N-methyl-2-oxazol-2-yl-benzamide (100 mg, 0.43 mmol). The mixture was stirred at room temperature overnight, quenched with saturated ammonium chloride and extracted with ethyl acetate. After concentration the residue was purified by flash chromatograph (30% ethyl acetate in hexane) to afford 30 mg of title compound as an off white solid. MS: (M+H)/z=586.1.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C(N(CC)CC)C.[Cl:19][CH2:20][C:21](Cl)=[O:22]>C1COCC1>[Cl:19][CH2:20][C:21]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([CH3:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1)=[O:22]
Reactant: O=C(Cl)CCl
Reactant: Cc1ccc(N)cc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)CCl)cc1[N+](=O)[O-]
Yield: 89.7 %

Procedure:
A solution of 4-methyl-3-nitroaniline (1.0 g, 6.58 mmol, Lancaster), triethylamine (2.00 g, 19.7 mmol, Aldrich), and chloroacetyl chloride (0.96 g, 8.55 mmol) in THF (50 mL) was stirred overnight at rt. The reaction was washed with 1M HCl (50 mL), concentrated by rotary evaporation, and placed under high vacuum to give 2-chloro-N-(4-methyl-3-nitrophenyl)acetamide (1.35 g, 90%). ESIMS (M+H)+=229.
Reaction SMILES: [N:1]([CH2:4][CH:5]([CH2:24][C:25]#[N:26])[CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[N+]=[N-].C(OC(C)CC(COC(=O)NCCCCCCCCCCCCCCCCCC)CN)(=O)C1C=CC=CC=1.C(OC(NC(COC(=O)NCCCCCCCCCCCCCCCCCC)CN)=O)(C)(C)C>[Pd].CO>[C:25]([CH2:24][CH:5]([CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:4][NH2:1])#[N:26]
Reactant: CCCCCCCCCCCCCCCCOCC(CC#N)CN=[N+]=[N-]
Agent: [Pd]
Agent: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CN)CC(C)OC(=O)c1ccccc1
Agent: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CN)NC(=O)OC(C)(C)C
Solvent: CO
Product: CCCCCCCCCCCCCCCCOCC(CN)CC#N

Procedure:
A suspension of 3.00 g (23 mM) of 1-azido-2-cyanomethyl-3-hexadecyloxypropane V n1b and 300 mg of 10% palladium on charcoal in 100 ml of methanol is hydrogenated as described in (129) and the crude product of the titled compound IV n1 is obtained.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([F:17])[CH:3]=2)=[CH:21][CH:20]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: O=C1NCCCn2c1cc1cc(F)cc(Br)c12
Product: O=C1NCCCn2c1cc1cc(F)cc(-c3ccc(Cl)cc3)c12

Procedure:
The title compound, light grey solid (78 mg, 95%), MS (ISP) m/z=329.2 [(M+H)+], mp 263.5° C., was prepared in accordance with the general method of example 1 from 7-bromo-9-fluoro-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indol-1-one (intermediate 2) (74.3 mg, 0.25 mmol) and commercially available 4-chloro-phenylboronic acid (50.8 mg, 0.325 mmol).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:22][C:21]([C:28]([NH:30][C:31]4[CH:36]=[CH:35][C:34]([S:37][CH2:38][C:39]5[N:40]([CH2:44][CH2:45][CH3:46])[CH:41]=[CH:42][N:43]=5)=[CH:33][CH:32]=4)=[O:29])=[CH:20][C:19]=3[CH:47]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:56])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:22][C:21]([C:28]([NH:30][C:31]4[CH:32]=[CH:33][C:34]([S:37]([CH2:38][C:39]5[N:40]([CH2:44][CH2:45][CH3:46])[CH:41]=[CH:42][N:43]=5)=[O:56])=[CH:35][CH:36]=4)=[O:29])=[CH:20][C:19]=3[CH:47]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nccn4CCC)cc2)CCN3CCC)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nccn4CCC)cc2)CCN3CCC)cc1
Reaction time: 0.5 h
Yield: 64.9 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[4-[[(1-propylimidazol-2-yl)methyl]sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (1.52 g) in dichloromethane (20 ml) was added dropwise 70% solution of 3-chloroperbenzoic acid (861 mg) in dichloromethane (20 ml) at −78° C. To the mixture was added an aqueous solution of sodium thiosulfate, and the mixture was allowed to be at room temperature, stirred for 30 minutes, and extracted with ethyl acetate. The organic layer was washed with an aqueous solution of saturated sodium bicarbonate, and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (ethyl acetate→methanol:ethyl acetate=1:8), to give 7-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[4-[[(1-propylimidazol-2-yl)methyl]sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (1.01 g) (Compound 340) as yellow amorphous.