Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[CH:8]2)#[N:4].[CH2:14]([N:21]1[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CO>[C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[C:24]1[CH2:25][CH2:26][N:21]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:22][CH:23]=1)#[N:4]
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: N#Cc1ccc2[nH]ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: N#Cc1ccc2[nH]cc(C3=CCN(Cc4ccccc4)CC3)c2c1
Reaction time: 16 h
Yield: 99.8 %

Procedure:
To a solution of 5.02 gm (89.0 mMol) potassium hydroxide in 50 mL methanol were added 5.00 gm (35.17 mMol) 5-cyano-1H-indole and 7.8 mL (42.08 mMol) 1-benzyl-4-piperidone. The reaction mixture was stirred for 16 hours at reflux and then was allowed to cool. The reaction mixture was then concentrated under reduced pressure. The resultant residue was subjected to flash chromatography, eluting with dichloromethane containing 5% methanol. Fractions shown to contain product were combined and concentrated under reduced pressure to give 11.0 gm of the title compound of sufficient purity to be used in subsequent reactions.
Reaction SMILES: C(OC(=O)C[N:6]1[N:10]=[N:9][C:8]([C:11]2[S:15][C:14]([Br:16])=[N:13][CH:12]=2)=[N:7]1)C.Br[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>>[C:23]([O:22][C:20](=[O:21])[CH2:19][N:10]1[N:6]=[N:7][C:8]([C:11]2[S:15][C:14]([Br:16])=[N:13][CH:12]=2)=[N:9]1)([CH3:26])([CH3:25])[CH3:24]
Reactant: CCOC(=O)Cn1nnc(-c2cnc(Br)s2)n1
Reactant: CC(C)(C)OC(=O)CBr
Product: CC(C)(C)OC(=O)Cn1nnc(-c2cnc(Br)s2)n1

Procedure:
This compound was synthesized in a similar manner as described for ethyl[5-(2-bromo-1,3-thiazol-5-yl)-2H-tetrazol-2-yl]acetate (INTERMEDIATE 2) using tert-butyl bromoacetate in place of ethyl bromoacetate in step 4. 1H NMR (CDCl3, 400 MHz) 8.22 (1H, s), 5.32 (2H, s), 1.47 (9H, s). MS (ESI, Q+) m/z 346, 348 (M+1, 79Br, 81Br).
Reaction SMILES: I[CH:2]([CH3:4])[CH3:3].[NH2:5][C:6]1[C:16]([NH2:17])=[CH:15][CH:14]=[CH:13][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]>CN(C)C=O>[NH2:5][C:6]1[C:16]([NH:17][CH:2]([CH3:4])[CH3:3])=[CH:15][CH:14]=[CH:13][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)c1cccc(N)c1N
Reactant: CC(C)I
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc(NC(C)C)c1N
Temperature: 50 °C
Reaction time: 3 h

Procedure:
2-Iodopropane (2.0 mL, 20 mmol) was added to a solution of ethyl 2,3-diaminobenzoate (prepared according to the method of WO 97/10219, page 81, Example 51(1)) (3 g, 16.67 mmol) in N,N-dimethylformamide (20 mL), and the solution stirred at 50° C. for 3 hours. The mixture was concentrated under reduced pressure and the residue partitioned between ethyl acetate (200 mL) and water (50 mL), and the layers separated. The organic layer was washed with water (5×50 mL), dried over magnesium sulphate and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using ethyl acetate:pentane (5:95 to 90:10) to afford the title compound as a yellow oil, 1.4 g.
Reaction SMILES: [Br:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([F:11])=[CH:4][C:3]=1[CH3:12].Cl>CCO.[Fe]>[Br:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([F:11])=[CH:6][C:7]=1[NH2:8]
Reactant: Cc1cc(F)cc([N+](=O)[O-])c1Br
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: Cc1cc(F)cc(N)c1Br
Yield: 79.8 %

Procedure:
A suspension of 2-bromo-5-fluoro-1-methyl-3-nitrobenzene (2.0 g, 8.6 mmol), iron powder (2.4 g) in EtOH (20 mL), and concentrated hydrochloric acid (0.3 mL) was refluxed for 5 hours and then filtered and concentrated. Water (10 mL) was added to the residue and the resulting mixture was extracted with ethyl acetate (2×20 mL). The organic phase was washed with brine and concentrated to give the title compound as a solid (1.4 g, 80%). 1H NMR (400 MHz, CDCl3) δ ppm 6.32-6.26 (2H, m), 4.15 (2H, s), 2.27 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[C:7](/[C:8](/O)=[CH:9]\[C:10]2[CH:15]=[CH:14][N:13]=[C:12]([Cl:16])[N:11]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:18][S:19]([C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[F:29])(=[O:21])=[O:20].C1C(=O)N(Br)C(=O)C1.[CH3:38][C:39]([CH3:44])([CH3:43])[C:40](=[S:42])[NH2:41]>CC(N(C)C)=O.CCOC(C)=O>[Cl:1][C:2]1[C:7]([C:8]2[N:41]=[C:40]([C:39]([CH3:44])([CH3:43])[CH3:38])[S:42][C:9]=2[C:10]2[CH:15]=[CH:14][N:13]=[C:12]([Cl:16])[N:11]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:18][S:19]([C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[F:29])(=[O:21])=[O:20]
Reactant: O=S(=O)(Nc1cccc(/C(O)=C\c2ccnc(Cl)n2)c1Cl)c1cc(F)ccc1F
Reactant: CC(C)(C)C(N)=S
Agent: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2Cl)c(-c2ccnc(Cl)n2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36 %

Procedure:
To a solution of N-{2-chloro-3-[(E)-2-(2-chloro-4-pyrimidinyl)-1-hydroxyethenyl]phenyl}-2,5-difluorobenzenesulfonamide (3.0 g, 6.55 mmol) in DMA (25 mL) was added NBS (1.165 g, 6.55 mmol). After stirring for 1 h at rt, 2,2-dimethylpropanethioamide (0.767 g, 6.55 mmol) was added and the reaction mixture was stirred at 80° C. for 2 h. The reaction mixture was diluted with EtOAc (100 mL) and extracted five times with water. The organic layer was dried over anhydrous NaSO4, adsorbed onto silica gel, and purified via column chromatography, eluting with 0-50% EtOAc/DCM. The desired fractions were combined and concentrated to generate 1.31 g (2.36 mmol, 36.0% yield) of the title compound as a yellow powder. 1H NMR (400 MHz, DMSO-d6): δ 10.74 (s, 1H), 8.56 (d, J=5.4 Hz, 1H), 7.41-7.58 (m, 6H), 6.57 (d, J=5.4 Hz, 1H), 1.42 (s, 9H). MS (ESI): 555.0 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][C:12]2([CH2:16]CC[CH2:13]2)[NH:11][CH2:10][C:9]1([CH3:19])[CH3:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:20]1(C(N)(C)CN)C[CH2:21]1.CC(C)(O)C#N>>[C:1]([O:5][C:6]([N:8]1[CH2:17][C:12]([CH3:13])([CH3:16])[NH:11][CH2:10][C:9]1([CH:18]1[CH2:21][CH2:20]1)[CH3:19])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CC2(CCCC2)NCC1(C)C
Reactant: CC(N)(CN)C1CC1
Agent: CC(C)(O)C#N
Product: CC1(C)CN(C(=O)OC(C)(C)C)C(C)(C2CC2)CN1

Procedure:
2-Cyclopropyl-2,5,5-trimethyl-piperazine-1-carboxylic acid tert-butyl ester was synthesized in analogy to 8,8-dimethyl-6,9-diaza-spiro[4.5]decane-9-carboxylic acid tert-butyl ester starting from 2-cyclopropyl-propane-1,2-diamine and acetone cyanohydrin.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][NH:13][S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]2[C:32]3[C:27](=[C:28]([Cl:34])[CH:29]=[C:30]([Cl:33])[CH:31]=3)[CH2:26][N:25]([CH3:35])[CH2:24]2)[CH:18]=1)(=[O:16])=[O:15].C(O[N:44]1[C:48](=[O:49])[CH2:47][CH2:46][C:45]1=[O:50])(=O)CCC([O-])=O>>[Cl:33][C:30]1[CH:31]=[C:32]2[C:27](=[C:28]([Cl:34])[CH:29]=1)[CH2:26][N:25]([CH3:35])[CH2:24][CH:23]2[C:19]1[CH:18]=[C:17]([S:14]([NH:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][C:45](=[O:50])[CH2:46][CH2:47][C:48]([NH:44][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][NH:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]3[C:32]4[C:27](=[C:28]([Cl:34])[CH:29]=[C:30]([Cl:33])[CH:31]=4)[CH2:26][N:25]([CH3:35])[CH2:24]3)[CH:18]=2)(=[O:16])=[O:15])=[O:49])(=[O:16])=[O:15])[CH:22]=[CH:21][CH:20]=1
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCOCCOCCOCCN)c2)C1
Reactant: O=C([O-])CCC(=O)ON1C(=O)CCC1=O
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCOCCOCCOCCNC(=O)CCC(=O)NCCOCCOCCOCCNS(=O)(=O)c3cccc(C4CN(C)Cc5c(Cl)cc(Cl)cc54)c3)c2)C1
Reaction time: 0.32 h

Procedure:
Compound 181 was prepared from compound 28 and (2,5-dioxopyrrolidin-1-yl) succinate following the procedure outlined in example 175. The crude product (200 mg) was purified by Flash-Prep-HPLC with the following conditions: Column, C18 silica gel; mobile phase, CH3CN/H2O/CF3COOH=0.05/100/0.05 increasing to CH3CN/H2O/CF3COOH=90/100/0.05 within 19 min; Detector, UV 254 nm. This resulted in 201 mg (78%) of a TFA salt of N1,N4-bis(2-(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)succinamide as a white solid. 1H-NMR (300 MHz, DMSO+DCl, ppm): δ 7.76 (d, J=7.5 Hz, 2H), 7.68 (s, 2H), 7.63-7.52 (m, 6H), 6.64 (s, 1H), 4.88-4.82 (m, 2H), 4.62-4.42 (m, 4H), 3.76-3.60 (m, 4H), 3.43-3.30 (m, 25H), 3.14-3.10 (m, 4H), 2.97 (s, 6H), 2.86-2.82 (m, 4H), 2.27 (s, 4H). MS (m/z): 589 [M/2+1]+.
Reaction SMILES: Cl[C:2]1[C:3]([O:5][C:6](=[O:8])[CH:7]=1)=[O:4].[Cl:9][C:10]1=[C:11](Cl)[C:12](O[C:15]1=O)=O.C1C2NC3C(=CC=CC=3)SC=2C=CC=1.C=CC(Cl)=C.Cl>O>[Cl:9][C:10]1[CH:15]=[C:7]2[C:6](=[O:8])[O:5][C:3](=[O:4])[C:2]2=[CH:12][CH:11]=1
Reactant: O=C1C=C(Cl)C(=O)O1
Reactant: O=C1OC(=O)C(Cl)=C1Cl
Agent: C=CC(=C)Cl
Agent: Cl
Agent: c1ccc2c(c1)Nc1ccccc1S2
Solvent: O
Product: O=C1OC(=O)c2cc(Cl)ccc21
Temperature: 105 °C
Yield: 80 %

Procedure:
A 3-necked 50 mL flask was equipped with a pressure equalizing addition funnel, a thermocouple well with thermocouple, a water cooled condensor and a magnetic stir bar. The flask was charged with 13.2 g (0.10 mol) of a 90/10 GC area % mixture of monochloromaleic anhydride and dichloromaleic anhydride and 100 mg of phenothiazine and 0.5 g of activated carbon. The contents of the flask were heated to 80 to 130° C. and 8.8 g (0.1 mol) of chloroprene was added over 15 to 30 minutes. HCl gas was observed evolving from the reactor. After 6 hours at 130° C. the contents of the flask were sparged with oxygen for 2 hours between 130° and 150° C., filtered hot, and multiple distilled into two fractions resulting in the isolation of 13.2 g (80% of theoretical) of 4-chlorophthalic anhydride.
Reaction SMILES: O1C2C=CC=CC=2C=C1C1CCCOC1[N:16]1[C:24]2[C:19](=[CH:20][C:21]([C:25]3[NH:29][N:28]=[C:27]([CH2:30][N:31]([CH3:33])[CH3:32])[N:26]=3)=[CH:22][CH:23]=2)[CH:18]=[N:17]1.O1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>Cl.C(OCC)(=O)C>[O:37]1[C:38]2[CH:39]=[CH:18][CH:19]=[CH:20][C:21]=2[CH:35]=[C:36]1[C:18]1[C:19]2[C:24](=[CH:23][CH:22]=[C:21]([C:25]3[NH:29][N:28]=[C:27]([CH2:30][N:31]([CH3:32])[CH3:33])[N:26]=3)[CH:20]=2)[NH:16][N:17]=1
Reactant: C1COCCO1
Reactant: CN(C)Cc1n[nH]c(-c2ccc3c(cnn3C3OCCCC3c3cc4ccccc4o3)c2)n1
Agent: Cl
Solvent: CCOC(C)=O
Product: CN(C)Cc1n[nH]c(-c2ccc3[nH]nc(-c4cc5ccccc5o4)c3c2)n1

Procedure:
([5-(3-Benzo[d]furan-2-yl-1-perhydro-2H-pyran-2-yl(1H-indazol-5-yl))(1H-1,2,4-triazol-3-yl)]methyl)dimethylamine (15 mg, 0.034 mmol) in anhydrous HCl (5.0 mL of a 4 N solution in 1,4-dioxane) was vigorously stirred at ambient temperature for 18 h. The reaction mixture was neutralized with the slow addition of satd. NaHCO3 and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo to give a solid which was redissolved in a minimum amount of ethyl acetate and precipitated with hexanes to give the desired product as an off-white powder. The product was further purified by preparatory HPLC using a 30–80% acetonitrile/water gradient with 0.1% CF3CO2H. Fractions containing the desired product were pooled and evaporated to give a pale yellow solid which was partitioned between ethyl acetate and satd. NaHCO3. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo to give a solid which was dissolved in a minimum amount of methanol/ethyl acetate and precipitated with hexanes. The solid was collected, washed with ethyl ether/hexanes and dried under vacuum to afford the desired product as a pale solid (5.0 mg, 41% yield) 1H NMR (DMSO-d6) δ 8.9 (s, 1H), 8.14 (dd, 1H), 7.8–7.6 (m, 3H), 7.46 (s, 1H), 7.4–7.26 (m, 2H), 4.65 (s, 2H), 1.85 (s, 6H); ES-MS (m/z) 359 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:22])[CH2:4][C@@H:5]1[C:9]2=[CH:10][C:11]3[C:12]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:13][C:14]([F:17])=[CH:15][C:16]=3[N:8]2[CH2:7][CH2:6]1.[Cl:23][C:24]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:25]=1[CH:26]=O>>[Cl:23][C:24]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:25]=1[CH2:26][C:10]1[C:11]2[C:12]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:13][C:14]([F:17])=[CH:15][C:16]=2[N:8]2[CH2:7][CH2:6][C@H:5]([CH2:4][C:3]([OH:2])=[O:22])[C:9]=12
Reactant: O=Cc1ccc(Cl)cc1Cl
Reactant: COC(=O)C[C@H]1CCn2c1cc1c(S(C)(=O)=O)cc(F)cc12
Product: CS(=O)(=O)c1cc(F)cc2c1c(Cc1ccc(Cl)cc1Cl)c1n2CC[C@@H]1CC(=O)O

Procedure:
Starting from methyl[(1R)-6-fluoro-8-(methylsulfonyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate (Example 62A, Step 2, 120 mg, 0.37 mmol) and 2,4-dichlorobenzaldehyde (71 mg, 0.51 mmol), the title compound was synthesized following the procedures as described in Step 1 of Example 60 and Step 10 of Example 7.
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH:3]([CH3:5])[CH3:4].[Cl-].[Al+3].[Cl-].[Cl-].[C:12]1([O:18][CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClCCl>[CH3:19][O:18][C:12]1[CH:17]=[CH:16][C:15]([C:1](=[O:6])[CH2:2][CH:3]([CH3:5])[CH3:4])=[CH:14][CH:13]=1
Reactant: CC(C)CC(=O)Cl
Reactant: COc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)CC(C)C)cc1
Reaction time: 0.67 h
Yield: 98.6 %

Procedure:
While 40 g of isovaleryl chloride and 44 g of aluminum chloride were added to 140 ml of dichloromethane and stirred, 32.6 ml of anisole were slowly added in droplets at −10° C. or lower, and stirring was continued at room temperature for 40 min. Subsequently, 36.6 ml of isovaleryl chloride were slowly added in droplets, and stirring was further continued at room temperature for 18 hr. After the reaction was completed, the resultant reaction mixture was added with 200 ml of dichloromethane, and then washed with a saturated aqueous solution of sodium bicarbonate and water, in that order, after which the dichloromethane layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure, thus obtaining 56.9 g (yield: 98.6%) of a title compound as light yellow liquid.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].N1C=CN=C1.[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].O>CN(C)C=O>[Si:13]([O:7][CH2:1][CH2:2][CH2:3][CH2:4][C:5]#[CH:6])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C#CCCCCO
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: C#CCCCCO[Si](C)(C)C(C)(C)C
Reaction time: 3 h
Yield: 96.1 %

Procedure:
To a solution of 5-hexyne-1-ol (4.81 g, 49.0 mmol) in N,N-dimethylformamide (100 ml) were added imidazole (4.0 g, 59.0 mmol) and t-butyldimethylsilylchloride (8.12 g, 54.0 mmol) at 0° C., which was then stirred at the same temperature for 3 hour After the reaction was completed, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography (n-hexane:ethyl acetate=10:1) to give the title compound (10.0 g, yield: 99%) as a colorless oil.
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([O:31][CH:32]([F:34])[F:33])=[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][C:21]=1[Cl:30])[C:10]([CH2:17][CH3:18])=[N:11]2.CO.[OH-].[Li+].O>C(O)(=O)C>[Cl:30][C:21]1[CH:22]=[C:23]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:24]=[CH:25][C:20]=1[CH2:19][C:9]1[C:10]([CH2:17][CH3:18])=[N:11][C:12]2[C:7]([C:8]=1[O:31][CH:32]([F:34])[F:33])=[C:6]([O:5][CH2:4][C:3]([OH:35])=[O:2])[CH:15]=[CH:14][C:13]=2[F:16]
Reactant: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(S(C)(=O)=O)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: CCc1nc2c(F)ccc(OCC(=O)O)c2c(OC(F)F)c1Cc1ccc(S(C)(=O)=O)cc1Cl
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
A mixture of [3-(2-chloro-4-methanesulfonylbenzyl)-4-difluoromethoxy-2-ethyl-8-fluoroquinolin-5-yloxy]acetic acid methyl ester (1.0 g), methanol (38 mL), 5.0 M aqueous lithium hydroxide solution (0.8 mL) and water (1.6 mL) was stirred at room temperature for 35 minutes. The pH of the mixture was adjusted to 4 by the addition of glacial acetic acid and the solvent removed under reduced pressure. The residue was diluted with water (4.0 mL) and the solid collected by filtration, washed with water and dried to afford to title compound as a cream solid, 0.66 g.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([CH:11]=O)[S:9][CH:10]=2)=[CH:2]1.[Cl-].[Cl:14][CH2:15][C:16]1[CH:17]=[C:18]([CH:39]=[CH:40][CH:41]=1)[CH2:19][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.ClCC1C=CC=C(CCl)C=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[H-].[Na+]>O1CCCC1.C1(C)C(C)=CC=CC=1>[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8](/[CH:11]=[CH:19]/[C:18]3[CH:17]=[C:16]([CH:41]=[CH:40][CH:39]=3)[CH2:15][Cl:14])[S:9][CH:10]=2)=[CH:2]1
Reactant: ClCc1cccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: O=Cc1cc(-c2ccsc2)cs1
Agent: ClCc1cccc(CCl)c1
Agent: [Cl-]
Agent: [H-]
Solvent: Cc1ccccc1C
Solvent: C1CCOC1
Product: ClCc1cccc(/C=C/c2cc(-c3ccsc3)cs2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 49 %

Procedure:
100 mg of 4-(3-thienyl)-2-thiophenecarboxaldehyde and 250 mg of 3-chloromethylbenzyltriphenylphosphonium chloride [prepared by refluxing a xylene solution of α,α'-dichloro-m-xylene and triphenylphosphine] were suspended in 1 ml of tetrahydrofuran, and 31 mg of 60% oily sodium hydride was added under ice cooling. The mixture was stirred for 1.5 hours at room temperature, and the solvent was evaporated. The residue was neutralized with 1 N HCl, and extracted with ethyl acetate. The extract was worked up in a customary manner, purified by silica gel column chromatography [Wakogel C-300, 5 g; eluting solvent: hexane/ethyl acetate=10/1], and recrystallized from chloroform-hexane to give 80 mg (yield 49%) of the captioned compound as a pale yellow crystalline powder, m.p. 137°-138° C.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[O:10][C:9]([CH:11]=[O:12])=[CH:8][CH:7]=1.[Br-].[CH3:14][S+](C)C.[OH-].[K+].O>C(#N)C>[O:12]1[CH2:14][CH:11]1[C:9]1[O:10][C:6]([CH:2]2[O:3][CH2:4][CH2:5][O:1]2)=[CH:7][CH:8]=1
Reactant: C[S+](C)C
Reactant: O=Cc1ccc(C2OCCO2)o1
Agent: [Br-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: c1cc(C2OCCO2)oc1C1CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.1 %

Procedure:
5-[1,3]Dioxolan-2-yl-furan-2-carbaldehyde (2.03 g, 12.1 mmol), trimethylsulfonium bromide (1.90 g, 12.1 mmol) and potassium hydroxide (779 mg, 13.9 mmol) were suspended in acetonitrile (75 mL), and the solution was stirred overnight at room temperature. Water was added to the reaction solution, which was then extracted with ethyl acetate, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, 2-(5-oxiranyl-furan-2-yl)-[1,3]dioxolane (2.25 g) was obtained as a pale yellow oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2(O)[C:21]3[CH:20]=[C:19]([S:22][C:23]([F:26])([F:25])[F:24])[CH:18]=[CH:17][C:16]=3[S:15][C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:4][CH2:3]1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.FC(F)(F)C(O)=O>>[CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[C:8]2[C:21]3[CH:20]=[C:19]([S:22][C:23]([F:25])([F:24])[F:26])[CH:18]=[CH:17][C:16]=3[S:15][C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:4][CH2:3]1
Reactant: CN1CCC(C2(O)c3ccccc3Sc3ccc(SC(F)(F)F)cc32)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CN1CCC(=C2c3ccccc3Sc3ccc(SC(F)(F)F)cc32)CC1

Procedure:
A solution of 3.29 g. of 1-methyl-4-(2-trifluoromethylthio-9-hydroxy-thioxanthen-9-yl)piperidine in 15 ml. of trifluoroacetic anhydride and 30 ml. of trifluoroacetic acid is stirred and refluxed for 2.5 hours. The solution is evaporated to dryness. The residue is dissolved in benzene and is washed with 10% sodium hydroxide to make the free base form. The benzene is washed with water, dried over magnesium sulfate, filtered and the benzene is removed on a rotary evaporator. The residue is recrystallized from acetonitrile to give 1-methyl-4-[2-(trifluoromethylthio)thioxanthen-9-ylidene]piperidine, m.p. 104°-106° C.
Reaction SMILES: [NH:1]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:2]1[C:3]([O:5][CH3:6])=[O:4].Cl[CH2:12][CH2:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)=[O:15]>>[CH3:6][O:5][C:3](=[O:4])[CH:2]1[CH2:7][CH2:8][CH2:9][CH2:10][N:1]1[CH2:12][CH2:13][C:14]([C:16]1[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=1)=[O:15]
Reactant: O=C(CCCl)c1ccc(F)cc1
Reactant: COC(=O)C1CCCCN1
Product: COC(=O)C1CCCCN1CCC(=O)c1ccc(F)cc1
Yield: 92 %

Procedure:
N-[3-(4-Fluorophenyl)-3-oxopropyl]pipecolic acid methyl ester was prepared in 92% yield by alkylation of methyl pipecolinate with 3-chloro-4′-fluoropropiophenone (Aldrich) as described in Example 20A (Step 1).
Reaction SMILES: [NH:1]([CH2:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][C:20]1[CH:21]=[C:22]([NH:26][C:27](=[O:33])[NH:28][CH2:29][C:30](O)=[O:31])[CH:23]=[CH:24][CH:25]=1.S(Cl)(Cl)=O>>[CH3:19][C:20]1[CH:21]=[C:22]([NH:26][C:27](=[O:33])[NH:28][CH2:29][C:30]([N:1]([CH2:8][C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:31])[CH:23]=[CH:24][CH:25]=1
Reactant: O=C(CNc1ccccc1)OCc1ccccc1
Reactant: Cc1cccc(NC(=O)NCC(=O)O)c1
Solvent: O=S(Cl)Cl
Product: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)OCc2ccccc2)c2ccccc2)c1
Yield: 21.8 %

Procedure:
The procedure is similar to that described in Example 28, but starting with benzyl 2-anilinoacetate (3.6 g), 2-[3-(3-methylphenyl)ureido]acetic acid (3.1 g) and thionyl chloride (1.65 g). The product obtained is purified by chromatography on silica gel (0.063-0.200 mm; 60 g) contained in a column 2 cm in diameter [eluant: cyclohexane/ethyl acetate (50:50 by volume)], collecting 20-cc fractions. Fractions 5 to 9 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallization in acetonitrile, benzyl 2-{2-[3-(3-methylphenyl)ureido]-N-phenylacetamido}acetate (1.4 g), m.p. 140° C., is obtained.
Reaction SMILES: [OH-].[Na+].[O:3]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C@@H:4]1[O:10][C@@H:9]([C@@H:11]([C:13]([O:15]CCCCCCCCCC)=[O:14])[OH:12])[C@H:7]([OH:8])[C@H:5]1[OH:6].C(OCC)C>C1COCC1>[O:3]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C@@H:4]1[O:10][C@@H:9]([C@@H:11]([C:13]([OH:15])=[O:14])[OH:12])[C@H:7]([OH:8])[C@H:5]1[OH:6]
Reactant: CCCCCCCCCCOC(=O)[C@@H](O)[C@@H]1O[C@@H](OCCCCCCCCCC)[C@H](O)[C@H]1O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCCCCCCO[C@@H]1O[C@@H]([C@H](O)C(=O)O)[C@H](O)[C@H]1O
Reaction time: 3 h
Yield: 82.1 %

Procedure:
20 ml of 2.5N sodium hydroxide are added to 240 mg (0.51 mmol) of n-decyl n-decyl β-D-galactofuranoside uronate solubilized in 5 ml of THF and the mixture is allowed to stand at room temperature for 3 hours. 30 ml of ethyl ether are added and then after decanting, the aqueous phase is washed with 30 ml of ethyl ether. The aqueous phase is acidified with 50% HCl at 0° C. to pH=2 and then extracted three times with 30 ml of ethyl acetate. The organic phases are pooled, washed with 30 ml of water, dried over magnesium sulphate (2 g) and evaporated. 140 mg of n-decyl β-D-galactofuranoside uronic acid are then obtained (82% yield) in the form of a gum. *Rf=0.67 (dichloromethane/methanol-1/1-v/v) *13C NMR in CD3OD