Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:17]=[C:6]2[C:7]3[C:12]([CH2:13][CH2:14][N:5]2[C:4](=[O:18])[N:3]=1)=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=3.[NH2:19][C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[CH:22]=[CH:23][CH:24]=[N:25]2>>[CH3:16][O:15][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[C:6]1=[CH:17][C:2]([NH:19][C:20]3[CH:29]=[CH:28][CH:27]=[C:26]4[C:21]=3[CH:22]=[CH:23][CH:24]=[N:25]4)=[N:3][C:4](=[O:18])[N:5]1[CH2:14][CH2:13]2
Reactant: COc1ccc2c(c1)CCn1c-2cc(Cl)nc1=O
Reactant: Nc1cccc2ncccc12
Product: COc1ccc2c(c1)CCn1c-2cc(Nc2cccc3ncccc23)nc1=O

Procedure:
The title compound was prepared from 2-chloro-9-methoxy-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one (4) and 5-amino-quinoline as in Example 1 d. 1H-NMR (400 MHz, d6-DMSO) δ 9.68 (br, 1H), 8.93 (dd, 1H), 8.47 (d, 1H), 7.89 (2H), 7.79 (t, 1H), 7.70 (d, 1H), 7.57 (dd, 1H), 7.03-6.97 (2H), 6.49 (br, 1H), 3.97 (t, 2H), 3.84 (s, 3H) and 2.97 (t, 2H); MS (ESI) (M+H)+ 371.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[C:20]([Cl:22])[CH:21]=1)[CH2:5][O:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:9]([C:10]([OH:12])=O)[C:8]=1[C:16]([OH:18])=O.Cl.[NH2:24][CH:25]1[CH2:31][CH2:30][C:29](=[O:32])[NH:28][C:26]1=[O:27]>N1C=CC=CC=1>[Cl:22][C:20]1[CH:19]=[C:4]([CH:3]=[C:2]([Cl:1])[CH:21]=1)[CH2:5][O:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:9]2[C:8]=1[C:16](=[O:18])[N:24]([CH:25]1[CH2:31][CH2:30][C:29](=[O:32])[NH:28][C:26]1=[O:27])[C:10]2=[O:12]
Reactant: NC1CCC(=O)NC1=O
Reactant: O=C(O)c1cccc(OCc2cc(Cl)cc(Cl)c2)c1C(=O)O
Agent: Cl
Solvent: c1ccncc1
Product: O=C1CCC(N2C(=O)c3cccc(OCc4cc(Cl)cc(Cl)c4)c3C2=O)C(=O)N1
Yield: 76.9 %

Procedure:
A mixture of 3-(3,5-dichloro-benzyloxy)-phthalic acid (0.3 g, 0.9 mmol), alpha-amino-glutarimide hydrochloride (0.15 g, 0.92 mmol) in pyridine (10 mL) was refluxed overnight. The mixture was evaporated and the residue was purified by flash column chromatography (methanol/methylene chloride) to give 4-(3,5-dichloro-benzyloxy)-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione as a white solid (0.30 g, 84% yield); HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 70/30 CH3CN/0.1% H3PO4, 3.6 min (98.0%); mp, 278-280° C.; 1HNMR (DMSO-d6) δ 2.01-2.08 (m, 1H, CHH), 2.54-2.63 (m, 2H, CH2), 2.84-2.96 (m, 1H, CHH), 5.13 (dd, J=6, 12 Hz, 1H, CH), 5.40 (s, 2H, CH2), 7.50-7.89 (m, 6H, Ar), 11.12 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.95, 30.92, 48.79, 68.37, 115.90, 116.79, 120.02, 125.58, 127.45, 133.25, 134.18, 137.14, 140.61, 154.93, 165.34, 166.73, 169.88, 172.73. Anal Calcd For C20H14N2O5Cl2: C, 55.45; H, 3.26; N, 6.47; Cl, 16.37. Found: C, 55.20; H, 3.13; N, 6.38; Cl, 16.63.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20]CC)=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[CH2:6][C@@H:5]1[CH3:33])(=[O:3])[CH3:2].[OH-].[Na+].Cl>C(O)C>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:24]=[CH:23][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:25][C:26]2[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=2)[CH2:6][C@@H:5]1[CH3:33])(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1ccc(-c2ccc3c(c2)[C@H](Nc2ccc(Cl)cc2)C[C@H](C)N3C(C)=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)O)cc3)cc2[C@H](Nc2ccc(Cl)cc2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
Ethyl 4-{(2S,4R)-1-acetyl-4-[(4-chlorophenyl)amino]-2-methyl-1,2,3,4-tetrahydro-6-quinolinyl}benzoate (for a preparation see Example 158) (5.41 g, 11.69 mmol) was dissolved in ethanol (100 mL) and the solution was treated with 2M NaOH aqueous solution (50 mL, 100 mmol). The resulting mixture was stirred at room temperature (air atmosphere) for approximately 2 h then most of the ethanol was removed in vacuo. The resulting yellow solution was diluted with water (resulting in the formation of an oily yellow precipitate). The aqueous phase was washed twice with DCM (which didn't dissolve the precipitate previously formed) then was acidified with a 2N hydrochloric acid aqueous solution to pH 1 and extracted twice with AcOEt. The combined AcOEt phases were washed with brine, dried using a hydrophobic frit and concentrated in vacuo. The residual yellow foam was triturated with Et2O over approximately 1 h. The resulting solid was isolated by filtration, washed with Et2O and air-dried to give 4-{(2S,4R)-1-acetyl-4-[(4-chlorophenyl)amino]-2-methyl-1,2,3,4-tetrahydro-6-quinolinyl}benzoic acid (4.41 g, 10.1 mmol, 87%) as a cream solid.
Reaction SMILES: [C:1]([C:3]1[O:7][C:6]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([O:18][C@H:19]([CH3:41])[CH2:20][O:21]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:15]=[C:14]([S:42][CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[C:46]([F:50])[C:45]=3[F:51])[N:13]=2)(=[O:10])=[O:9])=[CH:5][CH:4]=1)#[N:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(OC)C=CC=CC=1.O>CO>[C:1]([C:3]1[O:7][C:6]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([O:18][C@H:19]([CH3:41])[CH2:20][OH:21])[N:15]=[C:14]([S:42][CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[C:46]([F:50])[C:45]=3[F:51])[N:13]=2)(=[O:10])=[O:9])=[CH:5][CH:4]=1)#[N:2]
Reactant: C[C@H](COC(c1ccccc1)(c1ccccc1)c1ccccc1)Oc1cc(NS(=O)(=O)c2ccc(C#N)o2)nc(SCc2cccc(F)c2F)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COc1ccccc1
Solvent: CO
Solvent: O
Product: C[C@H](CO)Oc1cc(NS(=O)(=O)c2ccc(C#N)o2)nc(SCc2cccc(F)c2F)n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 5-cyano-N-{2-[(2,3-difluorobenzyl)thio]-6-[(1R)-1-methyl-2-(triphenylmethyloxy)ethoxy]pyrimidin-4-yl}furan-2-sulfonamide (the product of step ii) (0.15 g) in methanol (5 mL) was added para-toluenesulfonic acid hydrate (39 mg) and anisole (0.23 mL). After stirring at room temperature for 5 h, H2O (5 mL) was added and the mixture extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (10 mL), dried (MgSO4), filtered and evaporated to dryness in vacuo. The resulting crude solid was purified by reverse phase HPLC (75% to 5% gradient of 0.1% aqueous ammonium acetate in acetonitrile as eluent) to give the title compound as a white solid. Yield: 20 mg.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:23])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([NH:13][C:14](=[O:22])[C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)[CH:7]=2)[CH2:3][CH2:2]1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][N:29]=[C:28]([CH2:32]O)[CH:27]=1.C(P(CCCC)CCCC)CCC.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH:1]1([NH:4][C:5](=[O:23])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([NH:13][C:14](=[O:22])[C:15]3[CH:16]=[CH:17][C:18]([O:21][CH2:32][C:28]4[CH:27]=[C:26]([O:25][CH3:24])[CH:31]=[CH:30][N:29]=4)=[CH:19][CH:20]=3)[CH:7]=2)[CH2:2][CH2:3]1
Reactant: COc1ccnc(CO)c1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(O)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: COc1ccnc(COc2ccc(C(=O)Nc3cc(C(=O)NC4CC4)ccc3C)cc2)c1
Temperature: 20 °C
Reaction time: 16 h
Yield: 36.2 %

Procedure:
To a stirred solution of N-cyclopropyl-3-[(4-hydroxybenzoyl)amino]-4-methylbenzamide (200 mg, 0.64 mmol) and 4-methoxy-2-hydroxymethylpyridine (500 mg, 3.6 mmol) in dry THF (25 mL) under an argon atmosphere was added successively tributylphosphine (500 mg, 2.5 mmol) and di-isopropyl azodicarboxylate (500 mg, 2.5 mmol). The mixture was stirred at 20° C. for 16 hours, then the solvent was evaporated at reduced pressure and the residue purified by silica column chromatography, eluting with a gradient of 0 to 10% methanol in ethyl acetate to give the title compound as a white solid (100 mg); NMR Spectrum: (DMSOd6) 1.55 (m, 2H), 1.65 (m, 2H), 2.25 (s, 3H), 2.85 (m, 1H), 3.85 (s, 3H), 5.20 (s, 2H), 6.95 (dd, 1H), 7.05 (d, 1H), 7.15 (d, 2H), 7.30 (d, 1H), 7.60 (dd, 1H), 7.80 (s, 1H), 7.95 (d, 2H), 8.35 (d, 1H), 8.40 (broad s, 1H), 9.80 (s, 1H); Mass Spectrum: M+H+ 432.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([S:14]C(=O)C)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].Br[C:21]([CH3:28])([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23]>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([S:14][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])([CH3:28])[CH3:27])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: CC(=O)SC1CCN(C(=O)OC(C)(C)C)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C(C)(C)SC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91259.9 %

Procedure:
A solution of 5.41 g (0.02 mmol) of 4-acetylsulfanyl-piperidine-1-carboxylic acid tert-butyl ester in ethanol (50 mL) is degassed with nitrogen over 0.5 h and 2.34 g (0.04 mol) of KOH are added, followed by 8.14 g (0.04 mol) of ethyl α-bromoisobutyrate. The reaction is stirred for 18 h at room temperature under a nitrogen atmosphere. The reaction mixture is concentrated under reduced pressure. The residue is partitioned between DCM (100 mL) and water (100 mL). The organic layer is washed with water (50 mL), brine (250 mL), dried over Na2SO4 and filtered. The filtrate is concentrated under reduced pressure and purified by column chromatography (silica, eluent heptanes, 50% ethyl acetate) to afford 6.05 g of 4-(1-ethoxycarbonyl-1-methyl-ethylsulfanyl)-piperidine-1-carboxylic acid tert-butyl ester as a brown oil. Yield: 87%; ES-MS: m/z 354 [M+Na], 232 [[M+H—C5H9O2]; 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.25-1.35 (3H, m), 1.46 (9H, s), 1.48-1.53 (2H, m), 1.55 (6H, s), 1.88 (2H, dd, J=13.31, 3.47 Hz), 2.94-3.04 (3H, m), 3.81-3.92 (2H, m), 4.19 (2H, q, J=7.10 Hz)
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]#[N:6].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([N:14]2[CH2:19][CH2:18][N:17]([CH2:2][CH2:3][CH2:4][C:5]#[N:6])[CH2:16][CH2:15]2)=[CH:12][CH:13]=1
Reactant: N#CCCCBr
Reactant: Clc1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCCCN1CCN(c2ccc(Cl)cc2)CC1
Reaction time: 3 h
Yield: 86.5 %

Procedure:
To a solution of 4-bromobutanenitrile (1.50 g, 10.17 mmol) in dimethyl formamide (20 ml) were added 1-(4-chlorophenyl)piperazine (2.0 g, 10.17 mmol) and potassium carbonate (2.81 g, 20.34 mmol) at room temperature and the reaction mixture was stirred for 3 h at same temperature. The progress of the reaction was monitored by TLC. The reaction mixture was diluted with water (50 ml) and the aqueous layer was extracted with ethyl acetate (3×50 ml). The combined organic layer was dried over anhydrous sodium sulphate. The solvent in the organic layer was removed under reduced pressure to obtain a crude product, which was purified by column chromatography over silica gel (100-200 mesh) using 10% ethyl acetate in hexane to yield the title compound (2.32 g, 86% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:21])[C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[CH:12]=[N:11][N:10]=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:21])[C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[CH2:12][NH:11][N:10]=1
Reactant: COc1ccc2c(Cc3c(Cl)cncc3Cl)nncc2c1
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CNN=C2Cc1c(Cl)cncc1Cl
Yield: 100.6 %

Procedure:
A suspension of 1-(3,5-dichloro-pyridin-4-ylmethyl)-6-methoxy-phthalazine (23.5 g, 73.4 mmoles), prepared as described in example 5, and PtO2 hydrate (0.5 g, 2.2 mmoles) in THF (600 ml) was put in a hydrogenator at room temperature and 2 atmospheres. After 22 hours the mixture was filtered over celite and brought to dryness to give 23.8 g of the title compound (stoichiometric yield). m.p.: 181-183° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[CH2:10][C:11]([F:14])([F:13])[F:12])=[C:4]([F:16])[CH:3]=1.[N+:17]([O-])([OH:19])=[O:18]>OS(O)(=O)=O>[Cl:1][C:2]1[CH:7]=[C:6]([N+:17]([O-:19])=[O:18])[C:5]([NH:8][C:9](=[O:15])[CH2:10][C:11]([F:13])([F:14])[F:12])=[C:4]([F:16])[CH:3]=1
Reactant: O=C(CC(F)(F)F)Nc1ccc(Cl)cc1F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C(CC(F)(F)F)Nc1c(F)cc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 17 %

Procedure:
A solution of N-(4-chloro-2-fluorophenyl)-3,3,3-trifluoropropanamide (2 g, 7.8 mmol) in 15 mL of concentrated H2SO4 was added 1 mL of concentrated nitric acid and stirred at room temperature overnight. The reaction was monitored by LC-MS. The reaction mixture was poured into 20 mL of ice-water. The mixture was filtered to give the solid crude N-(4-chloro-2-fluoro-6-nitrophenyl)-3,3,3-trifluoropropanamide (600 mg, yield: 17%) which was further purified by column chromatography (PE/EtOAc=6/1). MS obsd. (ESI+) [(M+H)+] 301.
Reaction SMILES: [C:1](Cl)(=O)C.CO.[CH2:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH:9]([C:17]([OH:19])=[O:18])[NH:8]1>CN(C=O)C>[CH3:1][O:18][C:17]([CH:9]1[CH2:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][NH:8]1)=[O:19]
Reactant: O=C(O)C1Cc2ccccc2CN1
Reactant: CC(=O)Cl
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)C1Cc2ccccc2CN1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 46.6 %

Procedure:
Acetyl chloride (0.88 g) was added to methanol (100 ml) with stirring at 0° C. After 10 minutes, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (J. Am. Chem. Soc., 1962, 48, 4487-4494) (2.0 g) was added; the reaction was allowed to warm to room temperature and stirred overnight. DMF (1 ml) was then added and stirring was then continued for a further 24 h. The solvent was removed in vacuo; dichloromethane was added and the solid thus formed was filtered off and partitioned between dichloromethane (50 ml) and saturated aqueous sodium hydrogen carbonate solution (50 ml). The organic phase was dried (magnesium sulphate), filtered, and the filtrate evaporated in vacuo to yield the title compound as a pale yellow oil (1.0 g).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][C:8](O)=[O:9])=[C:5]([CH3:11])[N:4]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:31])[C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)=[CH:15][CH:14]=2)[N:3]=1.[CH3:32][C:33]([S:36]([NH2:39])(=[O:38])=[O:37])([CH3:35])[CH3:34].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:1][C:2]1[C:6]([CH2:7][C:8](=[O:9])[NH:39][S:36]([C:33]([CH3:35])([CH3:34])[CH3:32])(=[O:38])=[O:37])=[C:5]([CH3:11])[N:4]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:31])[C:21]3[CH:22]=[CH:23][C:24]([C:27]([F:29])([F:28])[F:30])=[CH:25][CH:26]=3)=[CH:15][CH:14]=2)[N:3]=1
Reactant: Cc1nn(Cc2ccc(NC(=O)c3ccc(C(F)(F)F)cc3)cc2)c(C)c1CC(=O)O
Reactant: CC(C)(C)S(N)(=O)=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1nn(Cc2ccc(NC(=O)c3ccc(C(F)(F)F)cc3)cc2)c(C)c1CC(=O)NS(=O)(=O)C(C)(C)C

Procedure:
{3,5-Dimethyl-1-[4-(4-trifluoromethyl-benzoylamino)-benzyl]-1H-pyrazol-4-yl}-acetic acid (example 1.1, 250 mg, 0.58 mmol), 2-methylpropane-2-sulfonamide (95 mg, 0.70 mmol), 1,3-dicyclohexylcarbodiimid (143 mg, 0.70 mmol) and 4-dimethylaminopyridine (85 mg, 0.70 mmol) in 2.5 ml dichloromethane were stirred for 3 h at 30° C. The solvent was removed under reduced pressure and the residue was purified by MPLC (silica gel, CH2Cl2/methanol 95:5).
Reaction SMILES: N[C@@H:2]([C:7]([OH:9])=[O:8])[C:3]([SH:6])([CH3:5])[CH3:4].[OH-].[Na+].Br[CH2:13][CH2:14][OH:15].C(=O)([O-])[O-].[Na+].[Na+].C(OC1C=CC(S(Cl)(=O)=O)=CC=1)#CCC>CO.CN(C=O)C>[OH:15][CH2:14][CH2:13][S:6][C:3]([CH3:5])([CH3:4])[CH2:2][C:7]([OH:9])=[O:8]
Reactant: CC(C)(S)[C@@H](N)C(=O)O
Reactant: OCCBr
Agent: CCC#COc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CC(C)(CC(=O)O)SCCO
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.6 %

Procedure:
A solution of D-penicillamine (0.5 g, 3.35 mmol) in methanol (5 ml) was cooled 0° C. and crushed sodium hydroxide (0.28 g, 6.87 mmol) was added to give a clear solution. 2-Bromoethanol (0.26 ml, 3.71 mmol) was added and the reaction was stirred at 0° C. for 1 hour and then at room temperature for an additional 1.5 hours. The solvent was evaporated and the oily residue was dissolved in 3 mL water and 6 mL DMF and stirred with sodium carbonate (0.82 g 7.2 mmol) and 4-butynyloxy-benzenesufonyl chloride (0.78 g, 3.18 mmol) at room temperature overnight. After evaporating the solvent, the residue was diluted with ethyl acetate and water. The aqueous layer was acidified to pH˜3 with concentrated HCl and extracted with dichloromethane. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated to obtain 1.2 g of (2S)-2-{[4-(2 butynyloxy)phenyl]sulfonyl}amino)-3-[(2-hydroxyethyl)sulfanyl]-3-methylbutanoic acid as an oil. Yield 89.6%. Electrospray Mass Spec 400.1 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10](=[O:23])[CH2:11][CH2:12][C:13]1[C:18](Br)=[CH:17][C:16]([O:20][CH3:21])=[CH:15][C:14]=1[Br:22].C([O-])([O-])=O.[K+].[K+]>N1C=CC=CC=1.[Cu]I>[Br:22][C:14]1[CH:15]=[C:16]([O:20][CH3:21])[CH:17]=[C:18]2[C:13]=1[CH2:12][CH2:11][C:10](=[O:23])[N:9]2[C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[Cl:8]
Reactant: COc1cc(Br)c(CCC(=O)Nc2c(Cl)cccc2Cl)c(Br)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: COc1cc(Br)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)CC2
Temperature: 160 °C

Procedure:
To a suspension of 340 mg of N-(2,6-dichlorophenyl)-3-(2,6-dibromo-4-methoxyphenyl)-propionamide in 20 mL of pyridine was added CuI (137 mg) and powdered, dried K2CO3 (99 mg). The resulting mixture was heated to 160° C. in a sealed tube overnight (20 h), then concentrated. The reside was purified by flash chromatography on a Biotage 40S column, eluting with 100% CH2Cl2, to yield 5-Bromo-1-(2,6-dichlorophenyl)-3,4-dihydro-7-methoxy-2(1H)-quinolinone as a white solid. Mass spectrum (ESI) 402.0 (M+1). 1H NMR (500 MHz, CDCl3): δ 7.48 (d, J=8.0 Hz, 2H); 7.34 (t, J=8.0 Hz, 1H); 6.83 (d, J=2.5 Hz, 1H); 5.77 (d, J=2.5 Hz, 1H); 3.67 (s, 3H); 3.18 (m, 2H); 2.84 (m, 2H).
Reaction SMILES: [C:1]([O:7][CH2:8][C@@H:9]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[C:10]1[C:11]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]=[C:15](OS(C(F)(F)F)(=O)=O)[CH:14]=[CH:13]2)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[NH2:41][NH2:42].C1COCC1>>[C:1]([O:7][CH2:8][C@@H:9]([O:36][C:37]([CH3:40])([CH3:38])[CH3:39])[C:10]1[C:11]([C:29]2[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]=[C:15]([NH:41][NH2:42])[CH:14]=[CH:13]2)(=[O:6])[C:2]([CH3:3])([CH3:4])[CH3:5]
Reactant: Cc1cc2nc(OS(=O)(=O)C(F)(F)F)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Reactant: NN
Solvent: C1CCOC1
Product: Cc1cc2nc(NN)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Temperature: 80 °C

Procedure:
The mixture of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(trifluoromethylsulfonyloxy)quinolin-6-yl)ethyl pivalate (compound of Example 26) (10 mg) and hydrazine in THF (1.0 N, 1 mL, 1 mmol) was heated at 80° C. for 12 hours. Concentration under reduced pressure gave (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-hydrazinyl-7-methylquinolin-6-yl)ethyl pivalate, which was used for next step without purification. LCMS-ESI+ (m/z): [M+H]+ calcd for C27H35ClN3O3: 484.2. Found: 484.3.
Reaction SMILES: [O:1]1[C@H:13]2[CH2:14][C@@H:15]([C:27]([O:29]C)=[O:28])[C@@H:16](/[CH:17]=[CH:18]/[C@@H:19]([OH:26])[CH:20]([F:25])[CH2:21][CH2:22][CH2:23][CH3:24])[C@H:12]2[CH2:11][C@@H:2]1[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=[O:8].O1C2C[C@@H](C(O)=O)[C@@H](/C=C/[C@@H](O)C(F)CCCC)[C@H]2C[C@@H]1CCCCC(O)=O>>[O:1]1[C@H:13]2[CH2:14][C@@H:15]([C:27]([OH:29])=[O:28])[C@@H:16](/[CH:17]=[CH:18]/[C@@H:19]([OH:26])[CH:20]([F:25])[CH2:21][CH2:22][CH2:23][CH3:24])[C@H:12]2[CH2:11][C@@H:2]1[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8]
Reactant: CCCCC(F)[C@H](O)/C=C/[C@H]1[C@H]2C[C@H](CCCCC(=O)OC)O[C@H]2C[C@H]1C(=O)OC
Agent: CCCCC(F)[C@H](O)/C=C/[C@@H]1[C@H](C(=O)O)CC2O[C@@H](CCCCC(=O)O)C[C@@H]21
Product: CCCCC(F)[C@H](O)/C=C/[C@H]1[C@H]2C[C@H](CCCCC(=O)O)O[C@H]2C[C@H]1C(=O)O

Procedure:
By the procedure of Example 3, [6S,8R,9S,11R,12S,15R]methyl 6,9-epoxy-11-carbomethoxy-16-fluoro-15-hydroxyprost-(13E)-enoate was converted to [6S,8R,11R,12S,15R]-6,9-epoxy-11-carboxy-16-fluoro-15-hydroxyprost-(13E)-enoic acid.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[C:10](\[CH3:14])/[C:11]([OH:13])=[O:12])=[CH:5][CH:4]=1.[CH2:16]([Li])[CH2:17]CC.CN(C)C1C=CC(C=O)=CC=1.O>CCCCCC>[CH3:15][N:2]([CH3:1])[C:3]1[CH:4]=[CH:5][C:6](/[CH:9]=[C:10](\[CH3:14])/[C:11]([O:13][CH2:16][CH3:17])=[O:12])=[CH:7][CH:8]=1
Reactant: [Li]CCCC
Reactant: C/C(=C\c1ccc(N(C)C)cc1)C(=O)O
Agent: CN(C)c1ccc(C=O)cc1
Solvent: CCCCCC
Solvent: O
Product: CCOC(=O)/C(C)=C/c1ccc(N(C)C)cc1

Procedure:
E-3-(4-Dimethylaminophenyl)-2-methyl-propenoic acid guanidide hydrochloride ##STR6## 1 a) 1 eq. of triethyl phosphonopropionate was deprotonated with 1 eq. of n-butyllithium in hexane at 0° C., and 1 eq. of 4-dimethylaminobenzaldehyd was then added at RT. After the aldehyde had reacted completely, the mixture was worked up with water and extracted three times by shaking with toluene. After the combined organic phases had been dried over magnesium sulfate, the solvent was removed in vacuo and the crude product which remained was separated by chromatography over silica gel using EA/HEP mixtures as the eluent. Ethyl E-3-(4-dimethylamino-phenyl)-2-methyl-acrylate was isolated. orange-yellowish oil MS 233 (M+)
Reaction SMILES: [OH:1][CH:2]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)[CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1.[H-].[Na+].[CH3:22]I.O>CN(C)P(N(C)C)(N(C)C)=O.ClCCl.CO>[CH3:22][O:1][CH:2]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)[CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1
Reactant: OC(CCn1ccnc1)c1ccc2ccccc2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: COC(CCn1ccnc1)c1ccc2ccccc2c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A solution of 1.2 g of 1-[3-hydroxy-3-(2-naphthyl)-n-propyl]imidazole in 20 ml of dry hexamethylphosphoramide is treated between 5°-10° C. with stirring under nitrogen with 0.24 g of a 50% dispersion of sodium hydride in mineral oil. The mixture is stirred one hour at 10° C., one hour at 50° C., and then cooled in ice. Methyl iodide (0.8 g.) in 2 ml of hexamethylphosphoramide is added with stirring maintaining the temperature below 10° C. and the mixture stirred at 5° C. for 1 hour and overnight at room temperature. The resulting mixture is poured into water, the product extracted with ether and the extracts washed, dried (MgSO4) and evaporated to give a yellow oil. Chromatography on silica gel eluting with 10% methanol in dichloromethane gives pure 1-[3-methoxy-3-(2-naphthyl)-n-propyl]imidazole. This is converted to its hydrogen sulfate addition salt by dropwise addition of sulfuric acid to a solution in ether and recrystallized from methanol/ethyl acetate to give 1-[3-methoxy-3-(2-naphthyl)-n-propyl]imidazole hydrogen sulfate, m.p. 122°-122.5° C.