Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH:13]=O)[CH2:11][O:10][C:9]1([CH3:16])[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17]([CH:22]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:19][CH2:20][CH3:21])=[O:18]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[C@@H:12](/[CH:13]=[CH:22]/[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:11][O:10][C:9]1([CH3:16])[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1[C@@H](C=O)COC1(C)C
Solvent: Cc1ccccc1
Product: CCOC(=O)/C=C/[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 18 h
Yield: 111.3 %

Procedure:
A mixed solution comprising (4R)-4-formyl-2,2-dimethyl-1,3-oxazolidine-3-carboxylic acid tert-butyl ester (11.7 g), (carboethoxymethylene)triphenylphosphorane (20.7 g) and toluene (100 ml) was heated with stirring at 100° C. for 18 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (hexane:acetic acid ethyl ester=8:1), to obtain the title compound (17 g).
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([NH2:7])=[O:6])[CH2:3][CH2:2]1.I[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(=O)([O-])[O-].[K+].[K+]>>[CH2:11]([N:1]1[CH2:9][CH2:8][CH:4]([C:5]([NH2:7])=[O:6])[CH2:3][CH2:2]1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCI
Reactant: NC(=O)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCCCCCN1CCC(C(N)=O)CC1
Yield: 110.9 %

Procedure:
Prepared from isonipecotamide (2.7 g, 21.0 mmol), 1-iodooctane (5.05 g, 21.0 mmol) and potassium carbonate (2.9 g, 21.0 mmol) of according to procedure used for Example 8 (Step A) to give 5.6 g of the title compound as a white solid.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[S:5][C:6]=1[C:7]1[N:11]2[N:12]=[C:13]([CH3:21])[CH:14]=[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:10]2=[N:9][C:8]=1[CH3:22].[F:29][C:30]([F:35])([F:34])C([O-])=O.[Na+].CCOC(C)=O>CN(C=O)C.C1(C)C=CC=CC=1.[Cu]I.CCCCCC.C(Cl)Cl.CC#N>[CH2:17]([CH:16]([C:15]1[C:10]2[N:11]([C:7]([C:6]3[S:5][C:4]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[N:3][C:2]=3[C:30]([F:35])([F:34])[F:29])=[C:8]([CH3:22])[N:9]=2)[N:12]=[C:13]([CH3:21])[CH:14]=1)[CH2:19][CH3:20])[CH3:18]
Reactant: O=C([O-])C(F)(F)F
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(N4CCOCC4)nc3Br)c(C)nc12
Agent: [Cu]I
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCC(CC)c1cc(C)nn2c(-c3sc(N4CCOCC4)nc3C(F)(F)F)c(C)nc12
Temperature: 210 °C
Yield: 38.3 %

Procedure:
170 mg of 3-(4-Bromo-2-morpholin-4-yl-thiazol-5-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.37 mmol) and 100 mg of sodium trifluoroacetate (0.74 mmol) are dissolved in 3 ml of DMF/toluene=2/1. N2 gas is bubbled into the mixture for 20 min and 141 mg of CuI (0.74 mmol) is added. The vial is sealed and heated in the microwave at 210° C. for 30 min. The reaction mixture is applied onto a silica-gel chromatography column (Hexane:AcOEt=3:1 and CH3CN:CH2Cl2:Hexane=5:45:50) to give 64.3 mg of the title compound. Yield 38%. mass spectrum (m/e): 454 (M+1). 1H NMR (CDCl3): δ 6.72 (s, 1H), 3.88 (m, 4H), 3.60 (m, 4H), 3.32 (m, 1H), 2.54 (s, 3H), 2.47 (s, 3H), 1.85 (m, 4H), 0.89 (t, J=7.0 Hz, 6H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.[Cl-].[Al+3].[Cl-].[Cl-].[C:14]1(=[O:20])[O:19][C:17](=[O:18])[CH2:16][CH2:15]1.Cl>ClC(Cl)C.O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:14](=[O:20])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: O=C1CCC(=O)O1
Reactant: c1ccc2c(c1)CCO2
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: CC(Cl)Cl
Product: O=C(O)CCC(=O)c1ccc2c(c1)CCO2
Temperature: 5 °C

Procedure:
A susension, cooled to 0° C., of 120 g of 2,3-dihydrobenzofuran and 128 g of aluminum chloride in 260 ml of dichloroethane is added to a mixture of 96 g of succinic anhydride and 260 g of aluminum chloride in 512 ml of dichloroethane. The temperature is maintained at approximately 5° C. The reaction medium, maintained for 2 hours at this temperature, is then poured into a solution of 3 liters of water containing 400 ml of concentrated hydrochloric acid. After separation following settling, and extraction with methylene chloride, the organic phase is exhaustively extracted with 1N sodium hydroxide. The combined basic phases are acidified in the cold with 6N hydrochloric acid and the oil formed is extracted with methylene chloride. The organic phase is washed to neutrality and then dried.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:9]1([CH:15]=O)[CH2:14][CH2:13][CH:12]=[CH:11][CH2:10]1>>[CH:2]1(/[CH:1]=[N:8]/[CH2:15][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH:5]=[CH:4][CH2:3]1
Reactant: O=CC1CC=CCC1
Reactant: NCc1ccccc1
Product: C1=CCC(/C=N/Cc2ccccc2)CC1

Procedure:
In another aspect, a process is described for preparing a compound, or a salt of a compound, or a solvate thereof, of Formula (III). The process comprises steps of: (a) condensing benzylamine with cyclohex-3-enecarbaldehyde to form (E)-N-(cyclohex-3-en-1-ylmethylene)-1-phenylmethanamine; (b) contacting (E)-N-(cyclohex-3-en-1-ylmethylene)-1-phenylmethanamine with potassium tert-butoxide present in an amount ranging from about 0.05 molar equivalents to about 0.2 molar equivalents of potassium tert-butoxide to (E)-N-(cyclohex-3-en-1-ylmethylene)-1-phenylmethanamine to form (E)-N-benzylidene-1-(cyclohex-3-en-1-yl)methanamine; (c) contacting (E)-N-benzylidene-1-(cyclohex-3-en-1-yl)methanamine with paraformaldehyde present in an amount ranging from about 2.0 molar equivalents to about 5.0 molar equivalents of paraformaldehyde to (E)-N-benzylidene-1-(cyclohex-3-en-1-yl)methanamine, in presence of formic acid and a reaction medium comprising water present in an amount ranging from about 0.1% to about 6.5% of the reaction medium to form a compound of Formula (I); (d) contacting a compound of Formula (I) with a hydrogen bromide aqueous solution comprising about 43% to about 53% w/w of hydrogen bromide present in an amount ranging from about 1.0 molar equivalent to about 2.0 molar equivalents of the about 43% to about 53% w/w aqueous solution of hydrogen bromide to a compound of Formula (I), the acid addition salt is an HBr salt, and the salt of a compound of Formula (II) is
Reaction SMILES: [CH2:1]([Si:3]([C:8]#[C:9][C@:10]1([CH2:32][O:33]CC2C=CC=CC=2)[O:14][C@@H:13]([N:15]2[CH:22]=[CH:21][C:19](=[O:20])[NH:18][C:16]2=[O:17])[C@H:12]([OH:23])[C@@H:11]1[O:24]CC1C=CC=CC=1)([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].B(Cl)(Cl)Cl.N1C=CC=CC=1.CO>ClCCl>[CH2:1]([Si:3]([C:8]#[C:9][C@:10]1([CH2:32][OH:33])[O:14][C@@H:13]([N:15]2[CH:22]=[CH:21][C:19](=[O:20])[NH:18][C:16]2=[O:17])[C@H:12]([OH:23])[C@@H:11]1[OH:24])([CH2:4][CH3:5])[CH2:6][CH3:7])[CH3:2]
Reactant: CC[Si](C#C[C@]1(COCc2ccccc2)O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](O)[C@@H]1OCc1ccccc1)(CC)CC
Agent: ClB(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CO
Product: CC[Si](C#C[C@]1(CO)O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](O)[C@@H]1O)(CC)CC
Reaction time: 3 h

Procedure:
Compound 8 (1.50 g, 2.67 mmol) was dissolved in dichloromethane (75.0 ml), and a 1.0 M boron trichloride (26.7 ml, 26.7 mmol) in dichloromethane was added to the solution at −78° C. in an argon atmosphere, followed by stirring for three hours at the same temperature. A mixture of pyridine (10.0 ml) and methanol (20.0 ml) was added thereto at −78° C., followed by stirring for ten minutes. The reaction mixture was concentrated through distillation under reduced pressure, and the residue was partitioned with ethyl acetate and water. The organic layer was dried over anhydrous magnesium sulfate and concentrated through distillation under reduced pressure. The residue was purified by means of silica gel column chromatography (silica gel 200 ml, eluent; chloroform:methanol=9:1), to thereby yield a white powdery compound (Compound 9; 0.95 g, 2.48 mmol, 92.9%).
Reaction SMILES: [CH:1]([C:3]1[S:11][C:10]2[C:9](=[O:12])[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][NH:6][C:5]=2[C:4]=1[CH3:18])=[O:2].[C:19](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C.O>[CH:1]([C:3]1[S:11][C:10]2[C:9](=[O:12])[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][N:6]([CH3:19])[C:5]=2[C:4]=1[CH3:18])=[O:2]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1c[nH]c2c(C)c(C=O)sc2c1=O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cn(C)c2c(C)c(C=O)sc2c1=O
Temperature: 50 °C
Reaction time: 24 h
Yield: 68.6 %

Procedure:
A mixture of ethyl 2-formyl-3-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxylate (1.06 g, 3.99 mmol), potassium carbonate (826 mg, 5.98 mmol) and methyl iodide (1.24 mL, 19.9 mmol) in DMF (30 mL) was stirred at 50° C. for 24 hours. The mixture was diluted with water (60 mL), stirred with ice bath cooling for 5 minutes, and then filtered. The collected solid was washed with water and dried in vacuo, leaving a pale tan solid (764 mg, 69%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10][CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:17].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.O>CN(C=O)C>[CH3:1][C:2]1[C:3]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:17])=[O:15])=[CH:10][CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccnc1-c1ccc(CO)cc1
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cccnc1-c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 23.4 %

Procedure:
To a solution of [4-(3-methyl-2-pyridinyl)phenyl]methanol (12 g, 0.06 mol) in dry DMF (150 mL) was added pyridiniumdichromate (91 g, 0.24 mol) and stirred at RT for 3 days. The reaction mixture was poured into water and extracted with ethyl acetate (250 mL). The organic layer was washed with water, brine, dried and concentrated. The crude was purified by column chromatography over silica gel to give 4-(3-methyl-2-pyridinyl)benzoic acid (3 g, 25%) as white solid.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@@H:16]2[C@@H:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:19][NH:18][CH2:17]2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C1C=CC2N(O)N=NC=2C=1.[C:39]([O:43][C:44]([N:46]1[CH:50]([C:51](O)=[O:52])[CH2:49][O:48][C:47]1([CH3:55])[CH3:54])=[O:45])([CH3:42])([CH3:41])[CH3:40].C(N(CC)CC)C.C(Cl)CCl>C(Cl)Cl>[F:11][C:9]([F:12])([F:10])[C:7]1[CH:6]=[C:5]([C@H:13]([O:15][C@@H:16]2[C@@H:20]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:19][N:18]([C:51]([CH:50]3[CH2:49][O:48][C:47]([CH3:55])([CH3:54])[N:46]3[C:44]([O:43][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:45])=[O:52])[CH2:17]2)[CH3:14])[CH:4]=[C:3]([C:2]([F:27])([F:1])[F:28])[CH:8]=1
Reactant: CC(C)(C)OC(=O)N1C(C(=O)O)COC1(C)C
Reactant: C[C@@H](O[C@H]1CNC[C@@H]1c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: C[C@@H](O[C@H]1CN(C(=O)C2COC(C)(C)N2C(=O)OC(C)(C)C)C[C@@H]1c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 38 mg (0.094 mmol) (3R,4S)-3-({(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}oxy)-4-phenylpyrrolidine (Example 1. Step E) in 7.5 mL methylene chloride was added 12.7 mg (0.094 mmol) HOBT, 34.7 mg (0.14 mmol) 3-(tert-butoxycarbonyl)-2,2-dimethyl-1,3-oxazolidine-4-carboxylic acid, 0.04 mL (0.28 mmol) triethylamine and 54 mg (0.28 mmol) EDC. The resulting mixture was stirred at RT for 16 hr. The reaction mixture was partitioned between 5 mL brine and extracted with EtOAc (3×5 mL). The combined organic layers were dried over sodium sulfate, filtered and the solvent removed under vacuum. The yellow oil was purified by prep TLC eluting with methylene chloride/methanol (95/5) to give the title compound. 1H-NMR (CDCl3) rotamers: δ: 1.4-1.8 (m, 18H), 3.20-3.70 (m, 2H), 3.88-4.3 (m, 3H), 4.43-4.70 (m, 1H), 6.97-7.10 (m, 2H), 7.20-7.35 (m, 3H), 7.53. 7.55, 7.62 (3s, 2H), 7.75, 7.78 (2s, 1H)ppm. MS: 631.3 (MH+) observed.
Reaction SMILES: CC([NH2:9])C1C=CC=CC=1.C(OS(C(C1C=CC=CC=1)C1C=CC=CC=1)=O)(=O)C.[CH:29]([S:42]([CH2:44][C:45]([OH:47])=[O:46])=[O:43])([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.S(OC)(OC)(=O)=O.N>>[CH:33]1[CH:32]=[CH:31][C:30]([CH:29]([S+:42]([O-:43])[CH2:44][C:45]([NH2:9])=[O:47])[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:35][CH:34]=1.[CH:39]1[CH:40]=[CH:41][C:36]([CH:29]([S:42]([CH2:44][C:45]([OH:47])=[O:46])=[O:43])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:37][CH:38]=1
Reactant: CC(N)c1ccccc1
Agent: CC(=O)OS(=O)C(c1ccccc1)c1ccccc1
Agent: N
Agent: O=C(O)CS(=O)C(c1ccccc1)c1ccccc1
Solvent: COS(=O)(=O)OC
Product: NC(=O)C[S+]([O-])C(c1ccccc1)c1ccccc1

Procedure:
The (−)-α-methylbenzylamine-(−)-benzhydrylsulphinyl acetate is then converted to (−)-benzhydrylsulphinylacetic acid by acid hydrolysis. The latter is esterified in the presence of dimethyl sulphate and then converted to amide in the presence of ammonia (gas). The (−) or l (laevorotatory) enantiomer of modafinil is obtained through this process with an overall yield of 5.7% in relation to the (±) modafinil acid, calculated on the basis of the yields corresponding to each stage.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:16][CH:15]=1)(=[O:12])=[O:11])([O-:3])=[O:2].[CH2:26]([O:28][CH2:29][CH2:30][O:31][C:32]1[CH:37]=[C:36]([CH3:38])[C:35]([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45]O)[CH:40]=2)=[C:34]([CH3:47])[CH:33]=1)[CH3:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[CH2:26]([O:28][CH2:29][CH2:30][O:31][C:32]1[CH:37]=[C:36]([CH3:38])[C:35]([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][N:13]([S:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11])[C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:16][CH:15]=3)[CH:40]=2)=[C:34]([CH3:47])[CH:33]=1)[CH3:27]
Reactant: COC(=O)CCc1ccc(NS(=O)(=O)c2ccccc2[N+](=O)[O-])cc1
Reactant: CCOCCOc1cc(C)c(-c2cccc(CO)c2)c(C)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOCCOc1cc(C)c(-c2cccc(CN(c3ccc(CCC(=O)OC)cc3)S(=O)(=O)c3ccccc3[N+](=O)[O-])c2)c(C)c1
Temperature: 25 °C
Reaction time: 43 h

Procedure:
A solution of methyl 3-(4-{[(2-nitrophenyl)sulfonyl]amino}phenyl)propanoate (0.802 g, 2.20 mmol), [4′-(2-ethoxyethoxy)-2′,6′-dimethylbiphenyl-3-yl]methanol (0.601 g, 2.00 mmol) and triphenylphosphine (1.05 g, 4.00 mmol) in toluene (40 mL) was stirred under ice-cooling, and diethyl azodicarboxylate (40% toluene solution, 1.81 mL, 4.00 mmol) was added. The mixture was allowed to warm to room temperature and stirred for 43 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (20%-60% ethyl acetate/hexane) to give the title compound as an orange oil.
Reaction SMILES: [CH3:1][CH:2]([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9].ClS(O)(=O)=O.Cl.C[O-].[Na+]>C(Cl)(Cl)Cl>[CH3:1][CH:2]([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH:8][OH:9]
Reactant: CCCCC(C)CCCCCCO
Agent: C[O-]
Agent: Cl
Agent: O=S(=O)(O)Cl
Solvent: ClC(Cl)Cl
Product: CCCCC(C)CCCCC=CO
Temperature: 27.5 °C

Procedure:
Into a dried 1 L 3 neck round bottom flask fitted with a nitrogen inlet, dropping funnel, thermometer, mechanical stirring and nitrogen outlet is added chloroform (300 ml) and 7-methylundecanol (93 g, 0.5 mol). Chlorosulfonic acid (60 g, 0.509 mol) is slowly added to the stirred mixture while maintaining 25-30° C. temperature with a ice bath. Once HCl evolution has stopped (1 hr.) slowly add sodium methoxide (25% in methanol) while keeping temperature at 25-30° C. until an aliquot at 5% concentration in water maintains a pH of 10.5. To the mixture is added hot ethanol (55° C., 2 L). The mixture is vacuum filtered immediately. The filtrate is concentrated to a slurry on a rotary evaporator, cooled and then poured into 2 L of ethyl ether. The mixture is chilled to 5° C., at which point crystallization occurs, and vacuum filtered. The crystals are dried in a vacuum oven at 50C for 3 hrs. to obtain a white solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:19][C:9]2=[CH:10][N:11]=[C:12]([O:14][CH2:15][CH2:16][O:17][CH3:18])[CH:13]=[C:8]2[CH:7]=1)=[O:5])C.[Li+].[OH-]>C1COCC1.CO>[CH3:18][O:17][CH2:16][CH2:15][O:14][C:12]1[CH:13]=[C:8]2[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[NH:19][C:9]2=[CH:10][N:11]=1
Reactant: CCOC(=O)c1cc2cc(OCCOC)ncc2[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COCCOc1cc2cc(C(=O)O)[nH]c2cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1 g (3.784 mmol) 5-(2-Methoxy-ethoxy)-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid ethyl ester (example 10 (iii)) in 50 mL THF and 25 mL MeOH 15.14 mL of a 1M LiOH solution were added. The mixture was stirred for 2 h at room temperature. The organic solvents were removed in vacuo, the solution acidified and concentrated in vacuo. The residue was purified by flash chromatography over silica gel using H2Cl2/MeOH/HOAc/H2O=90/10/1/1 as eluent. The product fractions were combined, concentrated in vacuo and lyophilized.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH2:5][C:6]1[S:10][C:9]([C:11]2[CH:12]=[CH:13][C:14]([N+:28]([O-])=O)=[C:15]([NH:17][C:18](=[O:27])[C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[CH:16]=2)=[CH:8][CH:7]=1.CO.C(N(CC)CC)C>C(Cl)Cl>[NH2:28][C:14]1[CH:13]=[CH:12][C:11]([C:9]2[S:10][C:6]([CH2:5][NH:4][CH2:3][CH2:2][OH:1])=[CH:7][CH:8]=2)=[CH:16][C:15]=1[NH:17][C:18](=[O:27])[C:19]1[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=1
Reactant: COc1ccc(C(=O)Nc2cc(-c3ccc(CNCCO)s3)ccc2[N+](=O)[O-])cc1
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2cc(-c3ccc(CNCCO)s3)ccc2N)cc1
Yield: 46 %

Procedure:
Following the same procedure as described in Example 14, step 4 (scheme 14) but substituting compound 146 for compound 192, the title compound 193 was obtained after column chromatography (46% yield, eluent: 50% MeOH in DCM with 1% triethylamine).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:15])[CH2:13][CH3:14])[CH2:7][CH2:6][C:5]2=[O:16].[Cl:17]N1C(=O)CCC1=O.O>CN(C)C=O>[Cl:17][C:3]1[C:2]([OH:1])=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5](=[O:16])[CH2:6][CH2:7][N:8]2[C:12](=[O:15])[CH2:13][CH3:14]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCC(=O)N1CCC(=O)c2cc(O)ccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCC(=O)N1CCC(=O)c2c1ccc(O)c2Cl
Yield: 91.5 %

Procedure:
A solution of 6-hydroxy-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline (1.643 g) and N-chlorosuccinimide (1.068 g) in N,N-dimethylformamide (10 ml) was stirred at room temperature for 18 hours, poured into water, and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and evaporated in vacuo. The residual solid was recrystallized from chloroform to give 5-chloro-6-hydroxy-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline (1.74 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16]Cl)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:18]=[N+:19]=[N-:20].[Na+]>CS(C)=O>[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:18]=[N+:19]=[N-:20])[CH2:10][CH2:9]1)([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: CC(C)(C)OC(=O)N1CCN(CCCCl)CC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCN(CCCN=[N+]=[N-])CC1
Temperature: 90 °C

Procedure:
Tert-Butyl-4-(3-Chloropropyl)-1-piperazine carboxylate and sodium-azide were dissolved (suspended) in 8 ml DMSO dry and heated to 90° C. for 15 h. The reaction mixture was allowed to cool to room temperature and pored into 50 ml of water. The product was extracted with DCM and the combined organic phases dried over MgSO4. The product was purified by flash column chromatography (n-heptane/ethylacetate 1:1, RF=0.34). Yield: 3.5 g.
Reaction SMILES: [C:1]1([C:7](=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=2)[Cl:12])[CH:8]=[N:9]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].CC1C=CC=CC=1.S(Cl)(O)(=O)=O>C1COCC1>[C:1]1([C:7](=[C:11]([C:13]2[CH:14]=[CH:15][C:16]([Br:19])=[CH:17][CH:18]=2)[Cl:12])[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ON=CC(=C(Cl)c1ccc(Br)cc1)c1ccccc1
Agent: O=S(=O)(O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: N#CC(=C(Cl)c1ccc(Br)cc1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2g of 2-phenyl-3-(4-bromophenyl)-3-chloro-acrylaldoxime (5.9 m moles) were suspended in 50 ml of THF. The mixture was cooled to 0° C and, successively, 5 ml of sodium hydroxide solution and 1.14 g of p-toluene-sulfochloride were added. The mixture was stirred for 1 hour at 10° C and evaporated at room temperature. The solid residue was taken up with a small amount of methylene chloride and applied onto a column with basic aluminum oxide in n-hexane. Elution was effected with petroleum ether and then with methylene chloride. In this way pure 2-phenyl-3-(4-bromophenyl)-3-chloro-acrylonitrile (melting point: 128° -130° C) was obtained.
Reaction SMILES: [NH2:1][C:2]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]2[C:5](=[CH:6][C:7]([Cl:12])=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:13].[CH2:20]([N:22]([CH2:36][CH3:37])[C:23](=[O:35])[NH:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1)[CH3:21]>C(Cl)Cl.CCOC(C)=O>[NH2:1][C:2]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]2[C:5](=[CH:6][C:7]([Cl:12])=[C:8]([Cl:11])[CH:9]=2)[N:4]([S:31]([C:28]2[CH:27]=[CH:26][C:25]([NH:24][C:23]([N:22]([CH2:36][CH3:37])[CH2:20][CH3:21])=[O:35])=[CH:30][CH:29]=2)(=[O:33])=[O:32])[C:3]1=[O:13]
Reactant: CCN(CC)C(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: NC1(c2ccccc2)C(=O)Nc2cc(Cl)c(Cl)cc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCN(CC)C(=O)Nc1ccc(S(=O)(=O)N2C(=O)C(N)(c3ccccc3)c3cc(Cl)c(Cl)cc32)cc1

Procedure:
This compound is prepared according to the procedure described in EXAMPLE 1 from 0.293 g of 3-amino-5,6-dichloro-1,3-dihydro-3-phenylindol-2-one and 0.290 g of 4-(N',N'-diethylureido)benzenesulfonyl chloride. Chromatography on silica using a DCM/AcOEt mixture (85/15; v/v) as the eluent gives the expected product after crystallization from a DCM/iso ether mixture. m=0.26 g. M.p.=119°-121° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:4]=1[C:5]([N:7]1[CH2:21][CH2:20][C:10]2([NH:14][C:13](=[O:15])[C@H:12]([CH2:16][CH2:17][S:18][CH3:19])[NH:11]2)[CH2:9][CH2:8]1)=[O:6].[H-].[Na+].F[C:31]1[CH:38]=[CH:37][C:34]([CH2:35]Cl)=[CH:33][CH:32]=1.[NH4+].[Cl-]>CN(C=O)C>[CH2:35]([N:14]1[C:10]2([CH2:20][CH2:21][N:7]([C:5](=[O:6])[C:4]3[CH:22]=[CH:23][C:24]([O:26][CH3:27])=[CH:25][C:3]=3[O:2][CH3:1])[CH2:8][CH2:9]2)[NH:11][C@@H:12]([CH2:16][CH2:17][S:18][CH3:19])[C:13]1=[O:15])[C:34]1[CH:37]=[CH:38][CH:31]=[CH:32][CH:33]=1
Reactant: COc1ccc(C(=O)N2CCC3(CC2)NC(=O)[C@H](CCSC)N3)c(OC)c1
Reactant: Fc1ccc(CCl)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)N2CCC3(CC2)N[C@@H](CCSC)C(=O)N3Cc2ccccc2)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 8-(2,4-dimethoxybenzoyl)-3-(S)-(2-methylsulfanylethyl)-1,4,8-triazaspiro[4,5]decan-2-one (400 mg, 1.0 mmol) in 10 mL of DMF there was added sodium hydride (40 mg, 1.5 mmol) at RT and under a blanket of nitrogen. Following stirring over a period of 1 h at RT, 4-fluorobenzyl chloride (160 mg, 1.1 mmol) was slowly added dropwise and the mixture was then heated for 30 min in a microwave oven at 100° C. Following the addition of an aqueous saturated NH4Cl solution (15 mL), the mixture was extracted with ether (3×10 mL), the ethereal phase washed with aqueous saturated NaHCO3 solution (2×10 mL) and the combined organic phases were dried over Na2SO4. Following removal, by distillation, of the solvent, there was obtained the crude product as a yellow oil. Further purification was carried out by column chromatography. The product 1-benzyl-8-(2,4-dimethoxybenzoyl)-3-(S)-(2-methylsulfanylethyl)-1,4,8-triazaspiro[4,5]decan-2-one was obtained in a yield of 296 mg (58%).