Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:15]([OH:17])=[O:16])[C:14]2[C:5](=[CH:6][C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[Cl:18]N1C(=O)CCC1=O>CN1CCCC1=O.O>[Cl:18][C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:13]=[C:14]2[C:5]=1[CH:4]=[CH:3][CH:2]=[C:1]2[C:15]([OH:17])=[O:16]
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C(O)c1cccc2cc3ccccc3cc12
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C(O)c1cccc2c(Cl)c3ccccc3cc12
Yield: 59.2 %

Procedure:
Anthracene-1-carboxylic acid (15B, 24 g, 0.108 mol) was treated with N-chlorosuccinimide (Aldrich, 24 g, 0.18 mol) in N-methylpyrrolidinone (Eastman, 600 mL) and heated under N2 at 90° for 1.5 h. The reaction mixture was diluted with H2O (3.5 L), filtered, dried, and the precipitate recrystallized from EtOAc to afford 16.41 g (59%) of 10-chloroanthracene-1-carboxylic acid mp 275°-277°, (C,H,Cl).
Reaction SMILES: [SH:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=O.Cl.Cl[CH2:14][CH2:15][NH2:16].[H-].[Na+]>O1CCCC1.CN(C)C=O>[S:1]1[C:2]2[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=2[C:4](=[O:6])[NH:16][CH2:15][CH2:14]1
Reactant: COC(=O)c1ccccc1S
Reactant: NCCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C1NCCSc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.9 %

Procedure:
To a cooled solution of methyl 2-sulfanylbenzoate (200 g, 1.19 mol) in tetrahydrofuran and N,N-dimethylformamide (2 L, V/V=1/1) was added 2-chloroethanamine hydrochloride (138 g, 1.19 mol) at 0° C. followed by sodium hydride (143 g, 3.57 mol, 60% in mineral oil) in portions. After being stirred at room temperature overnight, the reaction mixture was poured into ice-water and extracted with ethyl acetate (900 mL×4). The organic layers were combined, washed with brine (900 mL×3), dried over sodium sulfate and concentrated in vacuo. The residue was stirred in a mixture solution of ethyl acetate and petroleum ether (300 mL, V/V=1/1) for 1 hour. The solid was collected by filtration and dried in vacuo to afford 100 g of 3,4-dihydro-1,4-benzothiazepin-5(2H)-one (yield was 47%).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([O:8][C@H:9]2[CH:14]3[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]3)[CH2:10]2)=[CH:4][CH:3]=1.[NH:17]1[C:25]2[C:20](=[CH:21][C:22](B(O)O)=[CH:23][CH:24]=2)[CH:19]=[CH:18]1>>[NH:17]1[C:25]2[C:20](=[CH:21][C:22]([C:2]3[N:7]=[N:6][C:5]([O:8][C@H:9]4[CH:14]5[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]5)[CH2:10]4)=[CH:4][CH:3]=3)=[CH:23][CH:24]=2)[CH:19]=[CH:18]1
Reactant: OB(O)c1ccc2[nH]ccc2c1
Reactant: Clc1ccc(O[C@@H]2CN3CCC2CC3)nn1
Product: c1cc2cc(-c3ccc(O[C@@H]4CN5CCC4CC5)nn3)ccc2[nH]1

Procedure:
The product of Example 30A (270 mg, 1.1 mmol) was coupled with 5-indolylboronic acid (215 mg, 1.4 mmol) according to the procedure of Example 20B. The title compound was purified by preparative HPLC (Xterra™, column, Xterra RP-18 5 μm, 30×100 mm. Eluting Solvent, MeCN/H2O (NH4HCO3, 0.1 M, PH=10) (v. 90/10 to 10/90 over 20 min.) Flow rate, 75 mL/min., uv, 250 nm) as solid (200 mg, 57%). 1H NMR (300 MHz, MeOH-D4) δ 1.49-1.63 (m, 1H), 1.67-1.92 (m, 2H), 1.99-2.14 (m, 1H), 2.28-2.36 (m, 1H), 2.76-3.04 (m, 5H), 3.48 (ddd, J=14.7, 8.2, 1.9 Hz, 1H), 5.24-5.34 (m, 1H), 6.56 (d, J=4.1 Hz, 1H), 7.24 (d, J=9.5 Hz, 1H), 7.30 (d, J=3.4 Hz, 1H), 7.50 (d, J=8.5 Hz, 1H), 7.73 (dd, J=8.6, 1.9 Hz, 1H), 8.07 (d, J=9.5 Hz, 1H), 8.13 (s, 1H) ppm. MS (DCI/NH3) m/z 321 (M+H)+.
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:28])[C@H:9]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[NH:10]C(OCC2C=CC=CC=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1CCCCC=1>C(O)C.[Pd]>[C:1]1([NH:7][C:8](=[O:28])[C@H:9]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[NH2:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)Nc1ccccc1)OCc1ccccc1
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCO
Product: N[C@@H](Cc1ccccc1)C(=O)Nc1ccccc1

Procedure:
Nα -Benzyloxycarbonyl-L-phenylalanine-N-phenylamide (2.50 g, 6.68 mmol) was dissolved in ethanol (20 ml) and cyclohexene (5 ml) and 10% palladium on charcoal (250 mg) was added. The mixture was heated at reflux for 1 hour after which time no starting material was detectable (as indicated by TLC analysis). The catalyst was removed by filtration and the solvent evaporated to leave the title compound contaminated with residual ethanol (1.74 g). 1H-NMR; d (CD3OD), 7.45 (2H, m), 7.18 (7H, m), 7.04 (1H, m), 3.56 (1H, m), 3.04 (1H, dd, J=6.4, 13.3 Hz) and 2.85 (1H, dd, J=7.2, 13.3 Hz).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22](O)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1[NH:34][C:35]1[S:36][C:37]([CH3:40])=[N:38][N:39]=1>>[F:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][NH:25][C:22]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:19])[C:9]=2[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:21])[CH3:20])=[O:23])=[C:28]([NH:34][C:35]2[S:36][C:37]([CH3:40])=[N:38][N:39]=2)[CH:29]=1
Reactant: Cc1nnc(Nc2cc(F)ccc2CN)s1
Reactant: CC1(C)OCCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Product: Cc1nnc(Nc2cc(F)ccc2CNC(=O)c2nc3n(c(=O)c2OCc2ccccc2)CCOC3(C)C)s1

Procedure:
The title compound can be prepared from intermediate 27, 3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylic acid and N-(2-(aminomethyl)-5-fluorophenyl)-5-methyl-1,3,4-thiadiazol-2-amine, derived from reduction of intermediate 124, 4-fluoro-2-(5-methyl-1,3,4-thiadiazol-2-ylamino)benzonitrile. LCMS (+ESI, M+H+) m/z 551.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[CH2:8][C:9]1[C:14]2[O:15][C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:17][C:13]=2[CH:12]=[CH:11][CH:10]=1.[CH3:24][O:25][C:26](=[O:45])[C@H:27]([CH2:35][C:36]1[CH:41]=[C:40]([Cl:42])[C:39]([OH:43])=[C:38]([Cl:44])[CH:37]=1)[NH:28][C:29](=[O:34])[C:30]([F:33])([F:32])[F:31].CN(C)C=O>CC(C)=O>[CH3:24][O:25][C:26](=[O:45])[C@H:27]([CH2:35][C:36]1[CH:37]=[C:38]([Cl:44])[C:39]([O:43][CH2:8][C:9]2[C:14]3[O:15][C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:17][C:13]=3[CH:12]=[CH:11][CH:10]=2)=[C:40]([Cl:42])[CH:41]=1)[NH:28][C:29](=[O:34])[C:30]([F:33])([F:31])[F:32]
Reactant: COC(=O)[C@H](Cc1cc(Cl)c(O)c(Cl)c1)NC(=O)C(F)(F)F
Reactant: ClCc1cccc2cc(-c3ccccc3)oc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1cc(Cl)c(OCc2cccc3cc(-c4ccccc4)oc23)c(Cl)c1)NC(=O)C(F)(F)F
Temperature: 0 °C
Yield: 52 %

Procedure:
Potassium carbonate (180 mg, 1.30 mmol) and 7-chloromethyl-2-phenylbenzo[b]furan. (171 mg, 0.705 mmol) were added in turn to a solution of 3,5-dichloro-N-trifluoroacetyl-L-tyrosine methyl ester (221 mg, 0.614 mmol) in acetone (3 ml) with stirring under ice cooling and the mixture was stirred under argon atmosphere at the same temperature for 5 hrs. Dimethylformamide (2 ml) and n-tetrabutylammonium iodide (23 mg, 0.062 mmol) were added to the mixture and stirred at room temperature for 21 hrs. The reaction mixture was poured into ice-water (50 ml) and extracted with ethyl acetate. The extract was washed with water and saturated brine solution in turn and dried. The solvent was distilled off under reduced pressure. The residue was purified by flash column chromatography on silica gel (n-hexane/ethyl acetate=5) to give 3,5-dichloro-N-trifluoroacetyl-O-[(2-phenylbenzo[b]fur-7-yl)methyl]-L-tyrosine methyl ester (182 mg, 52%) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][N:9]2[CH:21]=1)=[O:4].ClC1C=CC=C(C(OO)=[O:30])C=1>C(Cl)Cl>[CH3:1][O:2][C:3]([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([S:14]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[O:30])=[CH:10][N:9]2[CH:21]=1)=[O:4]
Reactant: COC(=O)Nc1cn2cc(Sc3ccccc3)ccc2n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COC(=O)Nc1cn2cc(S(=O)c3ccccc3)ccc2n1

Procedure:
Alternatively, 0.599 g. (0.002 mole) of the product of Example 3 is combined with 0.406 g. (0.002 moles) of metachloroperbenzoic acid (85%) in 300 ml. of methylene chloride and stirred at room temperature overnight. The solution is washed with saturated aqueous sodium bicarbonate and evaporated to dryness affording 0.75 g. of crude product which is recrystallized from methylene chloride affording 2-(methoxycarbonylamino) 6-(phenylsulfinyl) imidazo [1,2-a] pyridine m.p. 247°-248° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:5][CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)[CH:5]=[C:4]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:3]=1
Reactant: CCOC(=O)C1=C(C)NC(c2ccccc2)=CC1c1cccc([N+](=O)[O-])c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1c(-c2cccc([N+](=O)[O-])c2)cc(-c2ccccc2)nc1C
Temperature: 25 °C
Yield: 50.3 %

Procedure:
To a solution of ethyl 1,4-dihydro-2-methyl-4(3-nitrophenyl)-6-phenyl-3-pyridinecarboxylate (0.5 g) in chloroform (5 ml) was added activated manganese dioxide (2 g) and the mixture was refluxed for 1 hour with stirring vigorously. After allowing to cool to ambient temperature, manganese dioxide was filtered off and the filtrate was evaporated in vacuo. The residual precipitates were recrystallized from ethanol, washed with ethanol and dried in vacuo to give ethyl 2-methyl-4-(3-nitrophenyl)-6-phenyl-3-pyridinecarboxylate (0.25 g)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[C:12]2[NH:16][C@@H:15]([CH:17]([CH2:19][CH3:20])[CH3:18])[CH2:14][S:13]2)=[C:7]([CH3:21])[CH:6]=1)=[O:4].[CH2:22](Br)[CH:23]([CH3:25])[CH3:24]>>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[C:12]2[N:16]([CH2:22][CH:23]([CH3:25])[CH3:24])[C@@H:15]([CH:17]([CH2:19][CH3:20])[CH3:18])[CH2:14][S:13]2)=[C:7]([CH3:21])[CH:6]=1)=[O:4]
Reactant: CCC(C)[C@H]1CSC(=Nc2ccc(C(=O)OC)cc2C)N1
Reactant: CC(C)CBr
Product: CCC(C)[C@H]1CSC(=Nc2ccc(C(=O)OC)cc2C)N1CC(C)C

Procedure:
(1S)-1-(Hydroxymethyl)-2-methylbutylamine was made from (L)-isoleucine methyl ester as described in Method B1b. The 2-hydroxyethylamine was converted to (1S)-1-(chloromethyl)-2-methylbutanammonium chloride as described in Method B7a. 4-Methoxycarbonyl-2-methylphenyl isothiocyanate was reacted with (1S)-1-(chloromethyl)-2-methylbutanammonium chloride to Method C1a to give (4S)-2-(4-methoxycarbonyl-2-methylphenylimino)-4-(2-butyl)-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford (4S)-2-(4-methoxycarbonyl-2-methylphenylimino)-4-(2-butyl)-3-isobutyl-1,3-thiazolidine.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=O.[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([NH2:19])=[N:17][CH:18]=1.O>CN(C)C=O>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=3)[N:19]=2)[CH:18]=1
Reactant: Nc1ccc(Cl)cn1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ccc(-c2cn3cc(Cl)ccc3n2)cc1
Yield: 8.8 %

Procedure:
2-Bromo-1-(4-chlorophenyl)ethanone (9.08 g, 39 mmol) was added to a solution of 5-chloro-2-pyridinamine (5.0 g, 39 mmol) in dimethylformamide (100 mL) and the mixture was heated under reflux for 20 h. The mixture was cooled and poured into water (400 mL) and the solid was collected. The solid was dissolved in dichloromethane (300 mL), washed with water (50 mL) and brine (50 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was recrystallised from ethanol/water and the solid was collected and dried in vacuo to give the title compound (0.9 g, 9%). 1H NMR (360 MHz, CDCl3) δ 8.17 (1H, d, J 2.0 Hz), 7.87 (2H, d, J 8.9 Hz), 7.81 (1H, s), 7.56 (1H, d, J 9.5 Hz), 7.41 (2H, d, J 8.9 Hz), and 7.16 (1H, dd, J 9.5, 2.0 Hz). n/z (ES+) 263, 265 (M+1).
Reaction SMILES: C([O:5][C:6]([CH2:8][CH2:9][CH:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:6]([CH2:8][CH2:9][CH:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:16]([O:18][CH2:19][CH3:20])=[O:17])([OH:7])=[O:5]
Reactant: CCOC(=O)C(CCC(=O)OC(C)(C)C)C(=O)OCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(CCC(=O)O)C(=O)OCC
Temperature: 25 °C
Reaction time: 48 h
Yield: 100 %

Procedure:
To a solution of compound 10 (19.6 g, 68.05 mmol), in 400 mL CH2Cl2 is added 400 mL of TFA. The mixture is stirred under during 48 h at room temperature. The reaction mixture is concentrated under vacuum, coevaporated two times with cyclohexane to eliminate excess TFA yielded 15.8 g compound 11 as oil used without further purification.
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH:6]1[O:10][CH2:9][CH2:8][O:7]1)[CH:2]=[CH2:3].C(N(CC)CC)C.[N+:18]([C:21]1[CH:32]=[CH:31][C:30]([O:33][C:34]2[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][C:35]=2[Cl:44])=[CH:29][C:22]=1[O:23][CH:24]([CH3:28])[C:25](Cl)=[O:26])([O-:20])=[O:19]>C1(C)C=CC=CC=1>[CH2:1]([N:4]([CH2:5][CH:6]1[O:10][CH2:9][CH2:8][O:7]1)[C:25](=[O:26])[CH:24]([O:23][C:22]1[CH:29]=[C:30]([O:33][C:34]2[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][C:35]=2[Cl:44])[CH:31]=[CH:32][C:21]=1[N+:18]([O-:20])=[O:19])[CH3:28])[CH:2]=[CH2:3]
Reactant: CC(Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])C(=O)Cl
Reactant: C=CCNCC1OCCO1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C=CCN(CC1OCCO1)C(=O)C(C)Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 10 °C
Reaction time: 1.5 h

Procedure:
N-Allyl-N-(1,3-dioxolan-2-ylmethyl)amine (1.32 grams; 0.0092 mole), dry toluene (70 ml) and triethylamine (3.0 ml) were charged into a glass reaction vessel equipped with a magnetic stirrer, thermometer, gas inlet tube and addition funnel. The mixture was blanketed with nitrogen gas, cooled to 10° C. and a solution of 2-[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenoxy]propionyl chloride (3.8 grams; 0.0092 mole) in toluene (40 ml) was added dropwise with stirring. After the addition was completed the mixture was allowed to warm to room temperature and stirring was continued for a period of about 1.5 hours. After this time the reaction mixture was transferred to a separatory funnel and was washed with water and with aqueous sodium bicarbonate. The washed solution was dried by passing it through phase separation paper. The dried solution was then chromatographed through a clay column using mixtures of ethyl acetate and hexane as the eluant. Nine fractions were collected. Fraction five was stripped of solvents and thereafter further dried by letting the residue stand under vacuum at 110° C. for a period of four hours to yield the desired product N-allyl-N-(1,3-dioxolan-2-ylmethyl)-2-[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenoxy]propionamide as an amber gum.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[N:59]1[CH:64]=[CH:63][N:62]=[CH:61][C:60]=1[CH2:65]O>C(OCC)(=O)C.O1CCCC1>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:65][C:60]2[CH:61]=[N:62][CH:63]=[CH:64][N:59]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: OCc1cnccn1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCc1nc(C)n(Cc2cnccn2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.2 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), 1,1′-(azodicarbonyl)dipiperidine (1.41 g), tributylphosphine (1.56 mL), pyrazin-2-ylmethanol (0.46 g) and tetrahydrofuran (50 mL) was stirred at room temperature for 4 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.87 g, 69%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[C:19]([C:21]([O-:23])=[O:22])[CH:18]=[C:17]2[C:4]=1[C@H:5]1[C@H:14]([CH2:15][S:16]2(=[O:25])=[O:24])[C@:13]2([CH3:26])[C@H:8]([C:9]([CH3:28])([CH3:27])[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1.O[Li].O.[CH2:32]1COCC1>O>[CH3:1][O:2][C:3]1[CH:20]=[C:19]([C:21]([OH:23])=[O:22])[CH:18]=[C:17]2[C:4]=1[C@@:5]1([CH3:32])[C@H:14]([CH2:15][S:16]2(=[O:25])=[O:24])[C@:13]2([CH3:26])[C@H:8]([C:9]([CH3:28])([CH3:27])[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1
Reactant: C1CCOC1
Reactant: COc1cc(C(=O)[O-])cc2c1[C@@H]1CC[C@H]3C(C)(C)CCC[C@]3(C)[C@H]1CS2(=O)=O
Agent: [Li]O
Solvent: O
Product: COc1cc(C(=O)O)cc2c1[C@]1(C)CC[C@H]3C(C)(C)CCC[C@]3(C)[C@H]1CS2(=O)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 98 %

Procedure:
A mixture of (1R,10S,11S,16S)-3-methoxy-11,15,15-trimethyl-8,8-dioxo-8λ6-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene-5-carboxylate (59) (0.29 g, 0.66 mmol) and LiOH.H2O (0.08 g, 3.3 mmol) in THF (15 mL) and water (5.0 mL) was stirred at room temperature for 18 h. The mixture was concentrated under reduced pressure and the residue was acidified with 1 M HCl. The resulting solid was collected by filtration to give (1R,10R,11S,16S)-3-methoxy-1,11,15,15-tetramethyl-8,8-dioxo-8λ6-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene-5-carboxylic acid (80) (0.27 g, 98%) as a white solid. 1H NMR (CD3OD): δ 8.04 (d, 1H), 7.74 (d, 1H), 3.94 (s, 3H), 3.47-3.35 (m, 3H), 2.26 (d, 1H), 1.86-1.16 (m, 11H), 1.10-1.00 (m, 5H), 0.89 (s, 3H), 0.87 (s, 3H). MS m/z 421 (O23H32O5S+H+).
Reaction SMILES: CC(C(CC)C)(CO)[CH2:3][OH:4].C1(C)C=CC(S(O)(=O)=O)=CC=1.C[C:23]1[CH2:24][CH:25]([CH:30]=O)[CH2:26][CH:27]([CH3:29])[CH:28]=1>C1CCCCC1>[CH3:29][CH:27]1[CH:28]([CH:3]=[O:4])[CH2:23][CH2:24][C:25]([CH3:30])=[CH:26]1
Reactant: CC1=CC(C)CC(C=O)C1
Reactant: CCC(C)C(C)(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCCCC1
Product: CC1=CC(C)C(C=O)CC1

Procedure:
A 3-necked round bottom flask (250 ml capacity) was fitted with a mechanical stirrer, thermometer and Dean and Stark apparatus, the latter was equipped with a double surface water condenser. Privetal (0.1 mole, 14.6 g) and 2-methyl-2-sec.butylpropane-1,3 diol (0.1 mole 14.6 g) were charged into the flask together with cyclohexane (50 ml) as solvent and a catalytic amount of p-toluenesulphonic acid (0.35 g). Privetal was a mixture of 2,4-dimethyl-and 3,5-dimethyl-cyclohex-3-ene-1-carboxaldehyde obtained from PPF International, Ashford, England; now obtained under the trade name Ligustral from Quest International, Ashford, Kent the successor company to PPF International. (The 1,3-diol was obtained from Hoechst GmbH of West Germany.)
Reaction SMILES: C(O)CC.Cl.[CH3:6][O:7][NH2:8].[O:9]1[CH:13]=[CH:12][C:11]([C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:22][O:23][C:24]2[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][C:25]=2[CH3:31])=O)=[N:10]1>O>[CH3:6][O:7][N:8]=[C:14]([C:11]1[CH:12]=[CH:13][O:9][N:10]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][O:23][C:24]1[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][C:25]=1[CH3:31]
Reactant: CON
Reactant: Cc1ccc(C)c(OCc2ccccc2C(=O)c2ccon2)c1
Agent: Cl
Solvent: O
Solvent: CCCO
Product: CON=C(c1ccon1)c1ccccc1COc1cc(C)ccc1C

Procedure:
n-Propanol (2 ml) and methoxyamine hydrochloride (0.50 g, 6 mmol) were added to 2-(2,5-dimethylphenoxymethyl)phenyl isoxazol-3-yl ketone (0.64 g, 2 mmol), and the mixture was stirred under reflux for 17 hours. After completion of the reaction, water (100 ml) was added, the mixture was extracted with dichloromethane. The dichloromethane layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel chromatography (benzene/n-hexane) to give 2-(2,5-dimethylphenoxymethyl)phenyl isoxazol-3-yl ketone O-methyloxime (a mixture of isomers A/B) (0.55 g, 81.8%) as colorless crystals. mp. 104-108° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]([S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH:18]=[C:17]3I)[CH:10]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:40]([Cu])#[N:41]>O1CCOCC1.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]([S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH:18]=[C:17]3[C:40]#[N:41])[CH:10]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3c(c2)c(I)cn3S(=O)(=O)c2ccccc2)C(Cc2ccccc2)C1
Reactant: N#C[Cu]
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3c(c2)c(C#N)cn3S(=O)(=O)c2ccccc2)C(Cc2ccccc2)C1
Temperature: 25 °C
Yield: 89.8 %

Procedure:
A mixture of 4-(1-benzenesulfonyl-3-iodo-1H-indol-5-yl)-3-benzyl-piperazine-1-carboxylic acid tert-butyl ester (0.23 g, 0.4 mmol), CuCN (0.13 g, 1.4 mmol), Pd2(dibenzylideneacetone)3 (0.017 g, 0.02 mmol), 1,1′-bis(diphenylphosphino)ferrocene (0.040 g, 0.07 mmol) was taken up in 5 mL 1,4 dioxane and warmed to reflux for one hour. The mixture was cooled to room temperature and filtered through a pad of celite. The filter cake was washed with EtOAc and the filtrate was concentrated under reduced pressure. Purification via flash chromatography (gradient: 15 to 25% EtOAc in hexanes) afforded 4-(1-benzenesulfonyl-3-cyano-1H-indol-5-yl)-3-benzyl-piperazine-1-carboxylic acid tert-butyl ester (0.20 g, 97%) as a white foam; MS (M+H)=557.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([NH:19][C:20]([C:22]4[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=4[C:24]([OH:26])=[O:25])=[O:21])[CH:18]=[C:13]3[C:12]([C:31]3[S:35][CH:34]=[N:33][CH:32]=3)=[CH:11]2)(=O)=O)C=CC=CC=1.[OH-].[Na+].C(O)(=O)C>CCO>[S:35]1[C:31]([C:12]2[C:13]3[C:14](=[N:15][CH:16]=[C:17]([NH:19][C:20]([C:22]4[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=4[C:24]([OH:26])=[O:25])=[O:21])[CH:18]=3)[NH:10][CH:11]=2)=[CH:32][N:33]=[CH:34]1
Reactant: O=C(O)c1ccccc1C(=O)Nc1cnc2c(c1)c(-c1cncs1)cn2S(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: O=C(O)c1ccccc1C(=O)Nc1cnc2[nH]cc(-c3cncs3)c2c1
Yield: 26.6 %

Procedure:
Sulfonamide 44 (20 mg, 40 μmol), 10% aqueous NaOH solution (0.36 mL, 0.9 mmol) in EtOH (1.0 mL) was refluxed for 30 min. The mixture was cooled, concentrated, treated with glacial acetic acid (0.72 mL, 12 mmol), and concentrated again. The residue was separated by LCMS (column LUNA 10 μ C18(2) 00G-4253-V0 250×50 mm) using water—MeCN (0.11% AcOH) as eluent (in gradient; flow 80 mL/min) to afford 45 (3.88 mg, 27%). 1H NMR (400 MHz; CDCl3+3 drops of CD3OD) δ 7.36 (dd, J=7.5, 2.5 Hz, 1H), 7.57 (s, 2H), 7.78 (s, 1H), 8.02 (d, J=2.0 Hz, 1H), 8.15 (d, J=1.8 Hz, 1H), 8.20 (d, J=1.9 Hz, 1H), 8.39 (d, J=2.1 Hz, 1H), 8.50 (s, 1H); MS (ES) m/z 406.3 (MH++MeCN).