Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH:27]([CH3:29])[CH3:28])[CH:19]=2)[C:10]2[C:5](=[CH:6][C:7]([O:32][CH3:33])=[C:8]([O:30][CH3:31])[CH:9]=2)[N:4]=1.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.C(O)C>ClCCl>[CH:27]([O:26][C:20]1[CH:19]=[C:18]([C:11]2[C:10]3[C:5](=[CH:6][C:7]([O:32][CH3:33])=[C:8]([O:30][CH3:31])[CH:9]=3)[N:4]=[C:3]([CH2:2][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:23]=[CH:22][C:21]=1[O:24][CH3:25])([CH3:29])[CH3:28]
Reactant: CCOC(=O)c1c(CCl)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC(C)C)c1
Reactant: C1COCCN1
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)c1c(CN2CCOCC2)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC(C)C)c1

Procedure:
A mixture of ethyl 2-chloromethyl-4-(3-isopropoxy-4-methoxyphenyl)-6,7-dimethoxyquinoline-3-carboxylate (3.0 g), morpholine (2.76 g) and ethanol (50 ml)--dichloromethane (5 ml) was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and dichloromethane (50 ml) was added to the residue. The dichloromethane layer was washed with water and dried over magnesium sulfate, and the solvent was evaporated. The residue was subjected to column chromatography on silica gel. The fractions eluted with chloroform-ethyl acetate (1:1, v/v) gave ethyl 4-(3-isopropoxy-4-methoxyphenyl)-6,7-dimethoxy-2-morpholinomethylquinoline-3-carboxylate as an oil. This oil was dissolved in ethanol (20 ml), and a solution of hydrogen chloride in ethanol (23%, 1.05 g) was added. The mixture was stirred at room temperature for 10 minutes, and the solvent was evaporated under reduced pressure. The crystals were separated by filtration and recrystallized from ethanol-ether to give ethyl 4-(3-isopropoxy-4-methoxyphenyl)-6,7-dimethoxy-2-morpholinomethylquinoline-3-carboxylate hydrochloride (1.62 g, 45%). Colorless crystals, mp. 185°-188° C.
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:7][NH:8][C:9]([C:11]1[N:18]2[C:14]([S:15][CH:16]=[CH:17]2)=[N:13][C:12]=1[CH3:19])=[O:10].[Br:20][C:21]1[S:22][C:23]([C:29]2[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=2)=[C:24]([C:26](O)=[O:27])[N:25]=1>>[Br:20][C:21]1[S:22][C:23]([C:29]2[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=2)=[C:24]([C:26]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:6]3)[C@H:2]2[CH2:7][NH:8][C:9]([C:11]2[N:18]3[C:14]([S:15][CH:16]=[CH:17]3)=[N:13][C:12]=2[CH3:19])=[O:10])=[O:27])[N:25]=1
Reactant: Cc1cccc(-c2sc(Br)nc2C(=O)O)c1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2C[C@@H]21
Product: Cc1cccc(-c2sc(Br)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)c1

Procedure:
prepared by reaction of 6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid [(1S,2S,5R)-1-(3-aza-bicyclo[3.1.0]hex-2-yl)methyl]-amide with 2-Bromo-5-m-tolyl-thiazole-4-carboxylic acid. LC-MS (basic): tR=1.41 min; [M+H]+=555.9.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:21][CH3:22])=[C:17]([OH:20])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].O[C@@H:24]1[CH2:28][CH2:27][O:26][CH2:25]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:21][CH3:22])=[C:17]([O:20][C@H:24]4[CH2:28][CH2:27][O:26][CH2:25]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O[C@@H]1CCOC1
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1O[C@H]1CCOC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
300 mg of 4-[(3-chloro-4-fluoro-phenyl)amino]-6-hydroxy-7-methoxy-quinazoline in 6 ml acetonitrile are combined with 114 μl (R)-3-hydroxy-tetrahydrofuran and 370 mg triphenylphosphine. Then 234 μl diethyl azodicarboxylate are added and the reaction mixture is stirred overnight at ambient temperature. For working up the reaction mixture is filtered and the filtrate evaporated down in vacuo. The crude product is purified by chromatography over a silica gel column with ethyl acetate/methanol (95:5) as eluant.
Reaction SMILES: [CH:1]([C:4]1[NH:14][C:7]2=[CH:8][N:9]=[C:10]([O:12][CH3:13])[CH:11]=[C:6]2[C:5]=1[CH:15]=[O:16])([CH3:3])[CH3:2].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:17]([N:14]1[C:7]2=[CH:8][N:9]=[C:10]([O:12][CH3:13])[CH:11]=[C:6]2[C:5]([CH:15]=[O:16])=[C:4]1[CH:1]([CH3:3])[CH3:2])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: COc1cc2c(C=O)c(C(C)C)[nH]c2cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(C=O)c(C(C)C)n(Cc3ccccc3)c2cn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 2-isopropyl-5-methoxy-1H-pyrrolo[2,3-c]pyridine-3-carbaldehyde (Compound 6, 110 mg, 0.50 mmol), benzyl bromide (0.18 ml, 1.50 mmol), and K2CO3 (208 mg, 1.50 mmol) in DMF (2.5 ml) was stirred at room temperature for 4 h. The solvent was removed in vacuo and the residue was purified by chromatography on silica gel (50% EtOAc-hexanes) to yield the title compound as yellow solid.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[NH:16][S:15]2(=[O:25])=[O:24])[CH2:10][CH2:9]1)C1C=CC=CC=1>CO.[Pd]>[NH:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[NH:16][S:15]2(=[O:25])=[O:24])[CH2:12][CH2:13]1
Reactant: O=S1(=O)Nc2ccccc2CN1C1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: O=S1(=O)Nc2ccccc2CN1C1CCNCC1
Reaction time: 8 h
Yield: 75.4 %

Procedure:
3-(1-Benzyl-piperidin-4-yl)-3,4-dihydro-1H-benzo[1,2,6]thiadiazine-2,2-dioxide (0.46 g, 1.29 mmol) in methanol (10 mL) was flushed with nitrogen, and treated with palladium on charcoal (10%, 46 mg). The flask was flushed with hydrogen and allowed to stir under an atmosphere of hydrogen overnight. The reaction was flushed with nitrogen, filtered through celite, and concentrated. Column chromatography gave 0.26 g (75%) of the desired material. 1H-NMR (CD3OD) δ 1.53-1.61 (m, 2H), 1.80 (m, 2H), 2.55 (m, 2H), 2.95-3.05 (m, 2H), 3.30 (m, 2H), 3.70 (m, 2H), 4.65 (s, 2H), 6.70 (d, J=7.9, 1H), 7.40 (dd, J=8.2, 6.7, 1H), 7.10 (m, 2H). Mass spec.: 268.10 (MH)+.
Reaction SMILES: [CH:1]([O:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][N:25]2[C:29](=[O:30])[C:28]3=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]3[C:26]2=[O:35])[CH2:19][CH2:18]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:36]1CCCC1>O>[CH:1]([O:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][NH:25][C:26](=[O:35])[C:27]2[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=2[C:29]([OH:36])=[O:30])[CH2:19][CH2:18]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: O=C1c2ccccc2C(=O)N1CCN1CCN(CCOC(c2ccccc2)c2ccccc2)CC1
Solvent: O
Product: O=C(O)c1ccccc1C(=O)NCCN1CCN(CCOC(c2ccccc2)c2ccccc2)CC1

Procedure:
20 g of 1-[2-(benzhydryloxy)ethyl]-4-[2-(phthalimido)ethyl]piperazine and 200 ml of tetrahydrofuran were placed in a reactor. A solution of 20.4 g of Na2S.9H2O in 80 ml of water was added dropwise at 0° C. After decantation, the solvents were evaporated off. The solid was taken up in 50 ml of water and 100 ml of methylene chloride. After the solution had cooled, the pH was adjusted to 3.7 and extraction was carried out with 2 times 50 ml of methylene chloride. After drying, the solvents were evaporated off to give 17 g of a solid (m.p.=45° C.) of the empirical formula: C29H33N3O4.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][C:10](Cl)=[O:11].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:17][Si:18]([C:21]#[CH:22])([CH3:20])[CH3:19].Cl>ClCCl>[F:8][C:7]1[C:2]([F:1])=[C:3]2[C:4]([CH:22]=[C:21]([Si:18]([CH3:20])([CH3:19])[CH3:17])[C:10]([OH:11])=[CH:9]2)=[CH:5][CH:6]=1
Reactant: O=C(Cl)Cc1cccc(F)c1F
Reactant: C#C[Si](C)(C)C
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: C[Si](C)(C)c1cc2ccc(F)c(F)c2cc1O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 50.0 g (0.26 mol) of 2,3-difluorophenylacetyl chloride in 100 ml of dichloromethane is slowly added to a suspension of 71.5 g (0.53 mol) of aluminium(III) chloride in 300 ml of dichloromethane at −20° C. After 30 min at this temperature, trimethylsilylacetylene is metered in, and the mixture is stirred for 30 min. The batch is added to ice-water and acidified using hydrochloric acid. The organic phase is separated off, and the aqueous phase is extracted with ethyl acetate. The combined organic phases are washed successively with sat. sodium hydrogencarbonate soln. and sat. sodium chloride soln. The solution is dried using sodium sulfate and evaporated to dryness. The residue is purified by column chromatography (SiO2, n-heptane:ethyl acetate=9:1), giving 7,8-difluoro-3-trimethylsilanylnaphthalen-2-ol as a brown oil.
Reaction SMILES: [CH:1]1([O:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15](=[O:20])[CH2:16][CH2:17][CH2:18][CH3:19])=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:28][O:29][C:30](=[O:37])[C:31](=O)[C:32]([F:35])([F:34])[F:33]>C1COCC1>[CH3:28][O:29][C:30](=[O:37])[C:31]([C:32]([F:35])([F:34])[F:33])=[C:14]([C:11]1[CH:10]=[CH:9][C:8]([O:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:13][CH:12]=1)[C:15](=[O:20])[CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: COC(=O)C(=O)C(F)(F)F
Reactant: CCCCC(=O)Cc1ccc(OC2CCCCC2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCC(=O)C(=C(C(=O)OC)C(F)(F)F)c1ccc(OC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 76.1 %

Procedure:
To a stirred solution of 1-(4-cyclohexyloxy-phenyl)-hexan-2-one (Example 14, 4.46 mmol, 1.22 g) and triethylamine (4.46 mmol, 0.62 mL) in THF (5 mL) was added a solution of 3,3,3-trifluoro-2-oxo-propionic acid methyl ester (13.4 mmol, 2.09 g) and continued stirring for 12 h at room temperature. After removal of volatiles in vacuo, the crude product was purified on a 40 g SiO2 cartridge with ethyl acetate/hexanes gradient to afford 3-(4-cyclohexyloxy-phenyl)-4-oxo-2-trifluoromethyl-oct-2-enoic acid methyl ester (1.4 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[C:14]2[C:13](=[O:15])[N:12]([CH3:16])[C:11](=[O:17])[N:10]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:9]=2[S:8][C:7]=1[CH2:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1.Cl[C:34]([O:36][CH3:37])=[O:35]>>[CH3:16][N:12]1[C:13](=[O:15])[C:14]2[C:6]([S:5][CH2:4][CH2:3][CH2:2][NH:1][C:34](=[O:35])[O:36][CH3:37])=[C:7]([CH2:22][C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25][CH:24]=3)[S:8][C:9]=2[N:10]([CH2:18][CH:19]([CH3:20])[CH3:21])[C:11]1=[O:17]
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(SCCCN)c(Cc3cccc4ccccc34)sc21
Reactant: COC(=O)Cl
Product: COC(=O)NCCCSc1c(Cc2cccc3ccccc23)sc2c1c(=O)n(C)c(=O)n2CC(C)C
Yield: 35.6 %

Procedure:
Prepared from 5-[(3-aminopropyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (10 mg) and methyl chloroformate (34 mg) following the method of Example 41 to give the title compound (4 mg).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH2:11][CH2:12][OH:13].[N+:14]([O-])([OH:16])=[O:15].CCO>C(O)(=O)C>[OH:1][C:2]1[C:9]([N+:14]([O-:16])=[O:15])=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH2:11][CH2:12][OH:13]
Reactant: O=[N+]([O-])O
Reactant: O=Cc1ccc(O)c(OCCO)c1
Solvent: CCO
Solvent: CC(=O)O
Product: O=Cc1cc(OCCO)c(O)c([N+](=O)[O-])c1
Temperature: 0 °C
Yield: 88.7 %

Procedure:
To the solution of 4-hydroxy-3-(2-hydroxyethoxy)benzaldehyde in acetic acid (5 mL) was added 65% nitric acid (34.6 mg, 0.55 mmol) at 0° C., and the mixture was stirred at 0° C. 4 hours. The reaction mixture was poured into ice water followed by a standard aqueous/EtOH workup. Isolated 110 mg, yield 88.7% of Intermediate 10.
Reaction SMILES: Br[CH2:2][C:3](=O)[CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1.[Br:19][C:20]1[CH:21]=[C:22]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:23]([NH:26][C:27]([NH2:29])=[S:28])=[N:24][CH:25]=1.C(N(CC)CC)C>C(O)C>[Br:19][C:20]1[CH:21]=[C:22]([O:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:23]([NH:26][C:27]2[S:28][CH:2]=[C:3]([CH2:4][CH:5]3[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]3)[N:29]=2)=[N:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)CBr)CC1
Reactant: NC(=S)Nc1ncc(Br)cc1Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(Cc2csc(Nc3ncc(Br)cc3Oc3ccccc3)n2)CC1
Temperature: 25 °C
Yield: 91.7 %

Procedure:
Heated a mixture tert-butyl 4-(3-bromo-2-oxopropyl)piperidine-1-carboxylate (1.38 g, 4.32 mmol), 1-(5-bromo-3-phenoxypyridin-2-yl)thiourea (1.0 g, 3.08 mmol), triethylamine (0.731 mL, 5.24 mmol), and ethanol (50 mL) at reflux overnight. Cooled to ambient temperature and partitioned between into water and ethyl acetate. Washed the organic layer with water, brine, dried and concentrated. Purified by MPLC (Biotage) eluting with 3:1 hexane:ethyl acetate to afford the title compound (1.54 g, 92%) as a white powder: 1H NMR (CDCl3) δ 8.66 (s, 1H), 8.13 (s, 1H), 7.43 (t, 2H), 7.25 (t, 1H), 7.12 (s, 1H), 7.06 (d, 2H), 6.45 (s, 1H), 4.08 (m, 2H), 2.67 (m, 2H), 2.56 (d, 2H), 1.85 (m, 1H), 1.66 (m, 2H), 1.44 (s, 9H), 1.15 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[C:11]1([CH2:17][CH:18]2[CH2:23][CH2:22][N:21]([CH:24]3[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]3)[CH2:20][CH2:19]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:27]1[CH2:28][CH2:29][CH:24]([N:21]2[CH2:22][CH2:23][CH:18]([CH2:17][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:19][CH2:20]2)[CH2:25][CH:26]=1
Reactant: O=C1CCC(N2CCC(Cc3ccccc3)CC2)CC1
Reactant: Fc1ccc2[nH]ccc2c1
Product: Fc1ccc2[nH]cc(C3=CCC(N4CCC(Cc5ccccc5)CC4)CC3)c2c1
Yield: 87.1 %

Procedure:
This compound was prepared from 5-fluoroindole and 4-[4-(phenylmethyl)-1-piperidinyl]cyclohexanone by the method described in Example 48 to give the product (87.1%, mp:72-74° C.). Calc'd for C26H29FN2.0.15C2H5OH: C, 79.83%; H, 7.72%; N, 7.04%. Found: C, 79.89%; H, 7.63%; N, 7.09%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][C:11]([CH3:20])([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:10][C:9]2=[O:21])[CH:5]=[CH:6][CH:7]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24](B(O)O)[CH:23]=1>>[CH3:20][C:11]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:10][C:9](=[O:21])[N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([C:24]3[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=3)[CH:3]=2)[CH2:13][CH2:12]1
Reactant: OB(O)c1cccnc1
Reactant: CC1(c2ccccc2)CCN(c2cccc(Br)c2)C(=O)O1
Product: CC1(c2ccccc2)CCN(c2cccc(-c3cccnc3)c2)C(=O)O1

Procedure:
The title compound was prepared from 3-(3-bromophenyl)-6-methyl-6-phenyl-1,3-oxazinan-2-one and 3-pyridylboronic acid following procedures analogous to those in Example 1 Step 2. LC-MS Method 2, tR=1.819 min, m/z=345.1. 1H NMR (CDCl3) 1.80 (s, 3H), 2.45-2.65 (m, 2H), 3.40 (m, 1H), 3.62 (m, 1H), 7.30-7.60 (m, 8H), 7.85 (m, 1H), 8.40 (m, 1H), 8.75 (m, 1H), 9.00 (m, 1H), 9.30-9.50 (b, 2H).
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][C:5]2[C:10](=O)[NH:9][CH:8]=[N:7][C:6]=2[N:12]=1.P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:10]1[C:5]2[S:4][C:3]([S:2][CH3:1])=[N:12][C:6]=2[N:7]=[CH:8][N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CSc1nc2nc[nH]c(=O)c2s1
Product: CSc1nc2ncnc(Cl)c2s1
Yield: 86 %

Procedure:
A mixture of 2-(methylthio)thiazolo[4,5-d]pyrimdin-7-(6H)-one (800 mg) and phosphorous oxychloride (8 mL) was refluxed for 2 h. Solvents were removed under vacuum and the mixture was diluted with chloroform. Again the solvents were removed under vacuum and this procedure repeated twice (yellow color solid). The residue was diluted with ice cold water and basified with 10% aqueous sodium bicarbonate. The solution was extracted with chloroform (3×100 mL) and the combined chloroform layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel column using hexane-ethyl acetate (95:5) as eluents to give the product as a white color solid (750 mg, 86%), mp 148-150° C. 1H NMR (400 MHz, CDCl3): δ 8.95 (1H, s), 2.90 (3H, s); LC-MS (positive ion mode): m/z 218, 220 (M+H)+.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.[N:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([C:38](O)=[O:39])=[CH:30][CH:29]=1>>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:38]([C:31]5[C:32]6[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=6)[N:28]=[CH:29][CH:30]=5)=[O:39])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Reactant: O=C(O)c1ccnc2ccccc12
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1)c1ccnc2ccccc12

Procedure:
The title compound, white solid (14.2 mg, 35.8%), MS (ISP) m/z=487.4 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (x mg, x mmol) and quinoline-4-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]1[C@H:7]([C:8]([O:10]C(C)(C)C)=[O:9])[N:6]2[C:15](=[O:27])[C@@H:16]([NH:17][C:18](=[O:26])[CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C@H:5]2[S:4][CH:3]=1.Cl>ClCCl.O.[Ti](Cl)(Cl)(Cl)Cl>[CH3:1][C:2]1[C@H:7]([C:8]([OH:10])=[O:9])[N:6]2[C:15](=[O:27])[C@@H:16]([NH:17][C:18](=[O:26])[CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C@H:5]2[S:4][CH:3]=1
Reactant: CC1=CS[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)OC(C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CC1=CS[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)O
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 82.7 %

Procedure:
A stirred solution of tert-butyl (4R,6R,7R)-3-methyl-7-phenylacetamido-ceph-2-em-4-carboxylate (0.776 g, 2.0 mmol) in dichloromethane (30 ml) was cooled to 0° C. Titanium tetrachloride (0.6 ml, 5.5 mmol) was added in 1 min. After stirring for 2.5 h at 0° C., the suspension was mixed with a chilled 2 M solution of hydrochloric acid in water (40 ml). The organic phase was separated and washed with a 1 M solution of hydrochloric acid in water (20 ml), water (20 ml), and brine (20 ml). The organic phase was concentrated to give 0.55 g of (4R,6R,7R)-3-methyl-7-phenylacetamido-ceph-2-em-4-carboxylic acid (yield 82.7%).
Reaction SMILES: [C:1]([O:4][CH2:5][C@@:6]1([C:21]#[CH:22])[O:10][C@@H:9]([N:11]2[CH:19]=[C:17]([CH3:18])[C:15](=[O:16])[NH:14][C:12]2=[O:13])[CH2:8][C@H:7]1[OH:20])(=[O:3])[CH3:2].[CH3:23][S:24](Cl)(=[O:26])=[O:25]>N1C=CC=CC=1>[C:1]([O:4][CH2:5][C@@:6]1([C:21]#[CH:22])[O:10][C@@H:9]([N:11]2[CH:19]=[C:17]([CH3:18])[C:15](=[O:16])[NH:14][C:12]2=[O:13])[CH2:8][C@H:7]1[O:20][S:24]([CH3:23])(=[O:26])=[O:25])(=[O:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: C#C[C@]1(COC(C)=O)O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@H]1O
Solvent: c1ccncc1
Product: C#C[C@]1(COC(C)=O)O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@H]1OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.5 %

Procedure:
To a pyridine (4 mL) solution of 12 (76 mg, 0.247 mmol) was added methanesulfonyl chloride (57 μL, 0.74 mmol) at 0° C., and the mixture was stirred at room temperature for 16 h. The reaction mixture was partitioned between CHCl3/saturated aqueous NaHCO3 (60 mL×3/20 mL). Silica gel column chromatography (CHCl3/MeOH=100/0-100/1) of the organic layer gave 13 (95.0 mg, 100%) as a foam: 1H NMR (CDCl3)δ1.96 (3H, d, J6,Me=1.2 Hz, Me), 2.16 (3H, s, Ac), 2.38 (1H, ddd, Jgem=16.0 Hz, J1′,2′a=3.5 Hz and J2′a,3′=0.7 Hz, H-2′a), 2.70 (1H, s, ethynyl), 3.11 (1H, s, Ms), 3.19 (1H, ddd, Jgem=16.0 Hz, J1′,2′b=8.4 Hz and J2′b,3′=5.5 Hz, H-2′b), 4.48 (1H, d, Jgem=11.3 Hz, H-5′a), 4.53 (1H, d, Jgem=11.3 Hz, H-5′b), 5.27-5.28 (1H, m, H-3′), 6.52 (1H, dd, J1′,2′a=3.5 Hz and J1′,2′b=8.4 Hz, H-1′), 7.33 (1H, d, J6,Me=1.2 Hz, H-6), 8.86 (1H, brs, NH); FAB-MS m/z 387(M++H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:21])[C:6]([Cl:20])=[CH:7][C:8]=1[C:9]([NH:11][CH:12]1[CH:17]([O:18][CH3:19])[CH2:16][NH:15][CH2:14][CH2:13]1)=[O:10].C(=O)([O-])[O-].[K+].[K+].[CH3:28][O:29][C:30](=[O:33])[CH2:31]Br>CN(C=O)C>[CH3:28][O:29][C:30](=[O:33])[CH2:31][N:15]1[CH2:14][CH2:13][CH:12]([NH:11][C:9](=[O:10])[C:8]2[CH:7]=[C:6]([Cl:20])[C:5]([NH2:21])=[CH:4][C:3]=2[O:2][CH3:1])[CH:17]([O:18][CH3:19])[CH2:16]1
Reactant: COC(=O)CBr
Reactant: COc1cc(N)c(Cl)cc1C(=O)NC1CCNCC1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CN1CCC(NC(=O)c2cc(Cl)c(N)cc2OC)C(OC)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 118.2 %

Procedure:
A mixture containing 313 mg norcisapride and 276 mg potassium carbonate in 10 ml DMF was treated with 153 mg of bromo-acetic acid methyl ester. The reaction was stirred at ambient temperature for 8 hr. Extractive workup with waterdichloromethane followed by flash chromatography afforded 455 mg of product.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]1(=[O:18])[O:17][CH2:16][CH2:15][CH2:14]1.[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1>[CH2:19]([CH:14]1[CH2:15][CH2:16][O:17][C:13]1=[O:18])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: O=C1CCCO1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C1OCCC1Cc1ccccc1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 34 %

Procedure:
A solution of diisopropylamine (63.0 mL) in THF was treated dropwise with butyl lithium (268 mL of 1.6M solution in hexanes) at −10° C. Upon completion of the addition, the reaction mixture was cooled to −70° C. and then treated dropwise with γ-butyrolactone (33.0 mL) keeping the speed of the addition at such a rate that the temperature of the mixture remained below −60° C. After stirring for additional 30 min at −70° C., the mixture was treated dropwise with benzyl bromide (51.0 mL) again keeping the speed of the addition at such a rate that the temperature of the mixture remained below −60° C. After completion of the addition, the stirring of the reaction mixture was continued at −70° C. for 2 h. Then the mixture was warmed-up to 0° C. and quenched by addition of a small amount of water. The solvents were removed in vacuum and the residue was redissolved in dichloromethane, washed with 10% aqueous hydrochloric acid, then with water, dried over magnesium sulfate, filtered, concentrated on a rotary evaporator and distilled in vacuum to give 26.0 g (34%) of the title compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH:16][CH2:17][CH2:18][C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)Cl.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[CH:22]=[CH:21][S:20][C:19]=3[CH2:18][CH2:17][N:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NCCc1cccs1)C1CCN(Cc2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: c1ccc(CN2CCC(C3=NCCc4sccc43)CC2)cc1
Reaction time: 4 h

Procedure:
A solution of 2 g of the product obtained in Step C in 8 ml of toluene, and 12 mmol of POCl3, are heated at reflux. After 4 hours, the reaction mixture is poured onto ice, rendered basic by the addition of a 20% sodium hydroxide solution and then extracted with dichloromethane. The organic phase is dried and filtered and then evaporated, enabling the expected product to be isolated.