Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[NH:6][CH2:5][CH2:4][N:3]2[CH2:7][C@H:8]([OH:10])[CH2:9][C@@H:2]12.C(N(CC)CC)C.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](Cl)=[O:24]>ClCCl>[OH:10][C@H:8]1[CH2:7][N:3]2[CH2:4][CH2:5][N:6]([C:23]([C:22]3[CH:26]=[CH:27][CH:28]=[C:20]([C:19]([F:18])([F:29])[F:30])[CH:21]=3)=[O:24])[CH2:1][C@@H:2]2[CH2:9]1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: O[C@@H]1C[C@H]2CNCCN2C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1cccc(C(F)(F)F)c1)N1CCN2C[C@H](O)C[C@H]2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (7R,8aS)-2-benzyloctahydropyrrolo[1,2-a]pyrazin-7-ol (Example 54D, 1 g, 4.30 mmol) and ethanol (10 mL) were added to 20% palladium hydroxide on carbon, wet (0.100 g) in a pressure bottle. The mixture was stirred at 50° C. for 16 hours under 30 psi of hydrogen. The mixture was filtered through a nylon membrane to give a crude intermediate (7R,8aS)-octahydropyrrolo[1,2-a]pyrazin-7-ol. To a solution of crude (7R,8aS)-octahydropyrrolo[1,2-a]pyrazin-7-ol (1.422 g, 10 mmol) and triethylamine (1.62 g, 16 mmol) in dichloromethane (50 mL) was slowly added a solution of 3-(trifluoromethyl)benzoyl chloride (2.09 g, 10 mmol) in dichloromethane (3 mL). The mixture was stirred at room temperature for 2 hours. The mixture was concentrated, diluted with ethyl acetate (100 mL), washed with water (20 mL), dried over sodium sulfate, and filtered. The organic solution was concentrated, and the residue was purified by chromatography on silica gel (dichloromethane/methanol=10:1) to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.43-1.63 (m, 2H), 2.10-2.27 (m, 3H), 2.50 (m, 1H), 2.80-3.00 (m, 2H), 3.20-3.50 (m, 2H), 4.22 (m, 1H), 4.42-4.60 (m, 1H), 4.80 (m, 1H), 7.70 (m, 3H), 7.82 (m, 1H); MS (ESI) m/z 315 (M+H)+.
Reaction SMILES: C(O[C:4](=O)[CH:5]([O:7][C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:15])[CH3:6])C.N.ClC1C=CC=C(Cl)C=1OC(C)C(N)=O.CN1CCOCC1.Cl.[NH2:40][CH2:41][CH2:42][NH2:43]>C(O)C.C(Cl)(Cl)Cl>[Cl:14][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:15])[C:8]=1[O:7][CH:5]([C:4]1[NH:40][CH2:41][CH2:42][N:43]=1)[CH3:6]
Reactant: CCOC(=O)C(C)Oc1c(Cl)cccc1Cl
Reactant: NCCN
Agent: CC(Oc1c(Cl)cccc1Cl)C(N)=O
Agent: Cl
Agent: N
Solvent: CN1CCOCC1
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CC(Oc1c(Cl)cccc1Cl)C1=NCCN1

Procedure:
In a variation of the present process, the (-)-2-(2,6-dichlorophenoxy)-propionic acid ethylester obtained as above described, is reacted with an ethanolic solution of ammonia at room temperature and is converted into (+)-2-(2,6-dichlorophenoxy)-propionic acid amide which is difficultly soluble in ethanol. This amide is dehydrated at from 0° to 30° C. with a titanium tetrachloride/tetrahydrofurane complex and 4-methyl-morpholine in chloroform into (-)-2-(2,6-dichlorophenoxy)-propionic acid nitrile. By introducing hydrogen chloride at 0° C., the nitrile is then converted with ethanol in chloroform into (-)-2-(2,6-dichlorophenoxy)-propionimido acid ethylester hydrochloride. This compound is dissolved in ethanol and is cyclized by adding 1,2-diaminoethane to produce (-)-2-[1-(2,6-dichlorophenoxy)-ethyl]-1,3-diazacyclopent-2-ene. Analogously to the previous process, (-)-2-[1-(2,6-dichlorophenoxy)-ethyl]-1,3-diazacyclopent-2-ene hydrochloride is produced from the (-)-base thus obtained.
Reaction SMILES: [C:1]1([CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@H:8]([OH:11])[CH2:9]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1C=CC=CC=1>[CH:7]([C@H:8]1[CH2:9][O:11]1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OC[C@@H](O)C(c1ccccc1)c1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: c1ccc(C(c2ccccc2)[C@H]2CO2)cc1
Yield: 77.5 %

Procedure:
A solution of (2S)-3,3-diphenyl-propane-1,2-diol (3.5 g, 15.35 mmol), Ph3P (8.05 g, 30.7 mmol), and DEAD (5.4 g, 30.7 mmol) in benzene (50 ml) was refluxed for 24 h. Solvent was removed and the residue was diluted with ethyl ether (200 ml) to precipitate Ph2PO. The filtrate was concentrated and the residue was chromatographed on silica gel (hexane/ether=9:1) to give (25)-2-benzhydryl-oxirane 23b 2.5 g (78%, ([α]D=(−)9.6, c=1, MeOH). The 1HNMR and 13CNMR were identical with (R)-isomer.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][S:12]([C:15]2[S:19][C:18]([C:20]([O:22]C)=[O:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:7][CH:6]=1)=[O:4]>CO.[OH-].[Na+]>[CH3:1][N:2]([CH3:24])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][S:12]([C:15]2[S:19][C:18]([C:20]([OH:22])=[O:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(S(=O)(=O)Nc2ccc(C(=O)N(C)C)cc2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(C)C(=O)c1ccc(NS(=O)(=O)c2ccc(C(=O)O)s2)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 56.2 %

Procedure:
To a solution of methyl 5-(N-(4-(dimethylcarbamoyl)phenyl)-sulfamoyl)-thiophene-2-carboxylate (Int. 75) (100 mg, 0.271 mmol) in methanol (10 ml), sodium hydroxide 1M (1 ml) was added, and the mixture stirred at RT for 4 days with monitoring the progress of reaction and adding further amounts of NaOH 1M until completion. MeOH was evaporated under reduced pressure and the crude taken up with HCl 1N and AcOEt. The organic phase was dried over Na2SO4 and concentrated under vacuum to give 54 mg of 5-(N-(4-(dimethylcarbamoyl)phenyl)sulfamoyl)thiophene-2-carboxylic acid (Int. 76).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:26][OH:27].C(=O)([O-])O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[N:26][OH:27])=[CH:4][CH:3]=1
Reactant: NO
Reactant: Cc1ccccc1C(CC(=O)c1ccncc1)c1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1C(CC(=NO)c1ccncc1)c1ccc(Br)cc1

Procedure:
In analogy to example 132, step 6, from 3-(4-bromo-phenyl)-1-pyridin-4-yl-3-o-tolyl-propan-1-one and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as a white foam, MS (ESI+): m/z=395.1 ([M+H]+, 1Br).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]2([CH2:23][OH:24])[CH2:21][O:20][C:19]([CH3:22])=[N:18]2)=[CH:11][CH:10]=1)C1C=CC=CC=1>CO.[Pd]>[OH:24][CH2:23][C:17]1([CH2:16][CH2:15][C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=2)[CH2:21][O:20][C:19]([CH3:22])=[N:18]1
Reactant: CC1=NC(CO)(CCc2ccc(OCc3ccccc3)cc2)CO1
Agent: [Pd]
Solvent: CO
Product: CC1=NC(CO)(CCc2ccc(O)cc2)CO1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of {4-[2-(4-benzyloxy-phenyl)-ethyl]-2-methyl-4,5-dihydro-oxazol-4-yl}-methanol (26.1 g, 0.08 mol) in methanol (800 ml) is added palladium on charcoal (2.6 g, 10% wt), and the reaction mixture is stirred under hydrogen atmosphere at room temperature for 5 hours. The reaction mixture is then filtered through celite and concentrated under vacuum. 4-[2-(4-Hydroxymethyl-2-methyl-4,5-dihydro-oxazol-4-yl)-ethyl]-phenol is isolated after crystallization with AcOEt and hexanes.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]([O:20][C:21]([N:23]1[CH:27]([C:28]([OH:30])=O)[CH2:26][S:25][CH:24]1[C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1)=[O:22])([CH3:19])([CH3:18])[CH3:17].[CH3:37][CH:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1.ON1C2C=CC=CC=2N=N1>O1CCCC1.C(OCC)(=O)C>[CH3:37][CH:38]1[CH2:43][CH2:42][N:41]([C:28]([CH:27]2[CH2:26][S:25][CH:24]([C:31]3[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=3)[N:23]2[C:21]([O:20][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:22])=[O:30])[CH2:40][CH2:39]1
Reactant: CC(C)(C)OC(=O)N1C(C(=O)O)CSC1c1cccnc1
Reactant: CC1CCNCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1CCN(C(=O)C2CSC(c3cccnc3)N2C(=O)OC(C)(C)C)CC1
Reaction time: 1 h

Procedure:
A solution of 540 mg of dicyclohexylcarbodiimide in 5 ml of tetrahydrofuran was added dropwise to a mixture of 810 mg of N-tert-butoxycarbonyl-2-(3-pyridyl)thiazolidine-4-carboxylic acid, 260 mg of 4-methylpiperidine, 530 mg of 1-hydroxybenzotriazole and 10 ml of tetrahydrofuran with ice cooling, and the mixture was stirred with ice cooling for 1 hour and then at room temperature for 12 hours. The reaction mixture was diluted with 30 ml of ethyl acetate, and the insoluble matter was filtered off. The filtrate was washed in sequence with saturated aqueous solution of sodium hydrogen carbonate and saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 4-methyl-1-[3-tert-butoxycarbonyl-2-(3-pyridyl)thiazolidin-4-ylcarbonyl]piperidine. Trifluoroacetic acid (5 ml) was added to the thus-obtained compound, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, and the solution was washed in sequence with saturated aqueous solution of sodium hydrogen carbonate and saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure The residue thus obtained was purified by silica gel column chromatography (eluent: ethyl acetate) to give 4-methyl-1-[2-(3-pyridyl)thiazolidin-4-ylcarbonyl]piperidine. This compound was dissolved in ethyl acetate, and 3 ml of 2N hydrogen chloride solution in dioxane was added The resultant solid was collected by filtration, washed with ethyl acetate and dried to give 530 mg of 4-methyl-1-(3-pyridyl)thiazolidin-3-ylcarbonyl]piperidine dihydrochloride. Melting point 130° C.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>[OH-].[Na+]>[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([C:2]2[NH:3][C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=2)[CH2:14][CH2:13]1
Reactant: CN1CCNCC1
Reactant: Clc1nc2ccccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Product: CN1CCN(c2nc3ccccc3[nH]2)CC1
Temperature: 125 °C
Reaction time: 5 h
Yield: 49.5 %

Procedure:
A mixture of 2-chlorobenzimidazole (10.00 g) and N-mehylpiperazine (20.00 g) is stirred at 125° C. for 5 hours. A 10% aqueous sodium hydroxide (100 ml) is added to the reaction mixture, and the precipitated crystals are separated by filtration. The filtrate is extracted with chloroform, and the chloroform extract is evaporated to dryness to give the same crystals. The crystals are combined and recrystallized from water-methanol to give 2-(4-methyl-1-piperazinyl)benzimidazole (7.02 g) as colorless needles, m.p. 225°-226° C.
Reaction SMILES: [NH2:1][C@H:2]([C:12]([OH:14])=[O:13])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]#[N:11])[CH:5]=1.[OH-].[Na+].C(OC([O-])=O)(=O)[O:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=O>O1CCOCC1>[NH:1]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:18])[C@H:2]([C:12]([OH:14])=[O:13])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]#[N:11])[CH:5]=1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(=O)[O-]
Reactant: N#Cc1cccc(C[C@H](N)C(=O)O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cccc(C#N)c1)C(=O)O
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
2.5 g (13.1 mmol) of H-Phe(3-CN)—OH were dissolved in 100 ml of dioxane and, at 0° C., 13 ml (13 mmol) of 1N NaOH and 3.16 g (14.5 mmol) of Boc pyrocarbonate were added. The mixture was stirred at 0° C. for 20 min and then at room temperature for 4 h, during which a total of 7 ml (7 mmol) of 1N NaOH was added in portions, thus keeping the pH constant at 8-8.5. The solvent was removed in vacuo, and the residue was taken up in ethyl acetate, washed in each case 3× with 5% KHSO4 and 3× with NaCl-saturated water and then dried over Na2SO4. The solvent was removed in vacuo. A white solid was obtained as residue.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]([CH3:16])[CH:14]=[O:15])[CH:7]=[CH:6]2.[Cr](O)(O)(=O)=[O:18]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]([CH3:16])[C:14]([OH:18])=[O:15])[CH:7]=[CH:6]2
Reactant: O=[Cr](=O)(O)O
Reactant: COc1ccc2cc(C(C)C=O)ccc2c1
Product: COc1ccc2cc(C(C)C(=O)O)ccc2c1

Procedure:
oxidizing said 2-(6-methoxy-2-naphthyl)propionaldehyde in the presence of a chromic acid solution to form 2-(6-methoxy-2-naphthyl)propionic acid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[NH2:7].[H-].[Na+].[CH2:11]1[O:33][C:32]2[CH:31]=[CH:30][C:15]([CH2:16][C:17]3[S:21][C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[C:18]=3[S:26](Cl)(=[O:28])=[O:27])=[CH:14][C:13]=2[O:12]1>C1COCC1>[Cl:1][C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[NH:7][S:26]([C:18]1[C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[S:21][C:17]=1[CH2:16][C:15]1[CH:30]=[CH:31][C:32]2[O:33][CH2:11][O:12][C:13]=2[CH:14]=1)(=[O:28])=[O:27]
Reactant: Cc1noc(N)c1Cl
Reactant: O=S(=O)(Cl)c1c(Cc2ccc3c(c2)OCO3)sc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1noc(NS(=O)(=O)c2c(Cc3ccc4c(c3)OCO4)sc3ccccc23)c1Cl

Procedure:
N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)benzyl]benzo[b]thiophene-3-sulfonamide was prepared in the same manner as described in Example 41. Reaction of 4-chloro-3-methyl-5-aminoisoxazole (0.61 mmoles, 81 mg), NaH (1.5 mmoles), 61 mg), and 2-[3,4-(methylenedioxy)benzyl]benzo[b]thiophene-3-sulfonyl chloride (0.74 mmoles, 0.27 g) in THF (4ml) yielded, after flash chromatography using 50% ethyl acetate/hexanes followed by recrystallization from ethyl acetate and hexanes, 0.23 g (81%) of a light brown solid, m.p. 178°-181° C.
Reaction SMILES: [N:1]([CH2:4][CH:5]1[O:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH2:6]1)=[C:2]=[S:3].[NH2:17][NH2:18]>C(O)C>[Cl:16][C:13]1[CH:12]=[CH:11][C:10]([C:7]2[CH2:6][CH:5]([CH2:4][NH:1][C:2](=[S:3])[NH:17][NH2:18])[O:9][N:8]=2)=[CH:15][CH:14]=1
Reactant: NN
Reactant: S=C=NCC1CC(c2ccc(Cl)cc2)=NO1
Solvent: CCO
Product: NNC(=S)NCC1CC(c2ccc(Cl)cc2)=NO1

Procedure:
A 25 g. portion of the product of Example 1 was reacted with excess hydrazine in 200 ml. of ethanol for 2 hours, allowing the reaction to heat to reflux temperature. The solids which precipitated upon cooling were separated by filtration and identified as 27 g. of product, m.p. 115°-117°, NMR singlets at 4.48, 7.4, 7.63, 7.97 and 8.73 ppm., and multiplets at 3.05-4.12 and 4.67-5.28 ppm.
Reaction SMILES: [NH2:1][C:2]1([C:11]([OH:13])=[O:12])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1.[OH-].[Na+].Cl[C:17]([O:19][CH3:20])=[O:18]>C(Cl)Cl.Cl>[CH3:20][O:19][C:17]([NH:1][C:2]1([C:11]([OH:13])=[O:12])[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:10]1)=[O:18]
Reactant: COC(=O)Cl
Reactant: NC1(C(=O)O)Cc2ccccc2C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COC(=O)NC1(C(=O)O)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.3 %

Procedure:
To a solution of 2-Amino-indan-2-carboxylic acid (0.45 g, 1.63 mmol) in CH2Cl2 (16 mL) was added HCl (in dioxanes, 4 M, 0.41 mL, 1.63 mmol). The solution was stirred at room temperature for 2 h and concentrated to dryness. The crude oil was dissolved in THF (6.5 mL). Aqueous NaOH (6 M, 0.92 mL, 5.5 mmol) and Methyl Chloroformate (0.15 mL, 1.95 mmol) were added and the resulting slurry was stirred at room temperature for 18 h. The reaction was diluted with HCl (1N) and extracted with Et2O (3 times). The combined organic layers were extracted with NaOH (2N, 3 times). The aqueous layers were acidified with HCl (6 N) and extracted with Et2O (3 times). The combined organic layers were dried over MgSO4 and concentrated. The crude oil was diluted in hexanes and concentrated again to provide 2-Methoxycarbonylamino-indan-2-carboxylic acid (0.35 g, 92%). LCMS-ESI+: calc'd for C12H13NO4: 235.08 (M+); Found: 235.94 (M+H+).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[N:11]3[N:12]=[C:13]([CH3:21])[CH:14]=[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:10]3=[N:9][C:8]=2[CH3:22])=[C:4]([C:23]#[N:24])[CH:3]=1.[Br-].[CH3:26][C:27]1[N:32]=[C:31]([Zn+])[CH:30]=[CH:29][CH:28]=1.C1COCC1>CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:17]([CH:16]([C:15]1[C:10]2[N:11]([C:7]([C:5]3[S:6][C:2]([C:31]4[CH:30]=[CH:29][CH:28]=[C:27]([CH3:26])[N:32]=4)=[CH:3][C:4]=3[C:23]#[N:24])=[C:8]([CH3:22])[N:9]=2)[N:12]=[C:13]([CH3:21])[CH:14]=1)[CH2:19][CH3:20])[CH3:18]
Reactant: Cc1cccc([Zn+])n1
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(Br)cc3C#N)c(C)nc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(CC)c1cc(C)nn2c(-c3sc(-c4cccc(C)n4)cc3C#N)c(C)nc12
Temperature: 65 °C
Yield: 39 %

Procedure:
To a flask containing 5-bromo-2-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-thiophene-3-carbonitrile (0.25 g, 0.62 mmol) and PdCl2(dppf) (0.024 g, 0.033 mmol) is added a solution of 0.5 M 6-methyl-2-pyridylzinc bromide in THF (2.50 mL, 1.24 mmol). The solution is heated at 65° C. overnight, diluted with EtOAc (30 mL), washed with sat. NH4Cl (2×30 mL), dried over MgSO4, filtered and concentrated. The residue is purified by ISCO column chromatography (15%-25% EtOAc/hexane gradient), furnish the title compound (0.11 g, 0.26 mmol, 39%). 1H NMR (CDCl3) δ 0.87 (t, J=7.5 Hz, 6H), 1.76-1.92 (m, 4H), 2.57 (s, 3H), 2.58 (s, 3H), 2.65 (s, 3H), 3.26-3.35 (m, 1H), 6.75 (s, 1H), 7.09 (d, J=7.5 Hz, 1H), 7.49 (d, J=7.9 Hz, 1H), 7.63 (dd, J=7.9, 7.5 Hz, 1H), 7.74 (s, 1H). LC/MS (m/z): calcd. for C24H25N5S (M+H)+: 416.6; found: 416.2.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([N:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[C@H:24]([N:31]([C:39](=[O:41])[CH3:40])[C:32]4[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=4)[CH2:23][C@@H:22]3[CH3:42])=[O:20])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C.C(O)C.[OH-].[Na+]>O1CCCC1>[C:39]([N:31]([C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)[C@H:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:21]([C:19]([C:16]2[CH:17]=[CH:18][C:13]([O:12][CH:9]3[CH2:10][CH2:11][CH:6]([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]3)=[CH:14][CH:15]=2)=[O:20])[C@@H:22]([CH3:42])[CH2:23]1)(=[O:41])[CH3:40]
Reactant: CCOC(=O)C1CCC(Oc2ccc(C(=O)N3c4ccccc4[C@H](N(C(C)=O)c4ccc(Cl)cc4)C[C@@H]3C)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OC3CCC(C(=O)O)CC3)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 10 h
Yield: 62 %

Procedure:
(2S,4R)-4-(4-{4-[Acetyl-(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenoxy)-cyclohexanecarboxylic acid ethyl ester (0.060, 0.10 mmol) was hydrolyzed to the acid by dissolving in tetrahydrofuran and ethanol and sodium hydroxide (1N) was added. The mixture was stirred at room temperature 10 hours. The mixture was cooled to room temperature, acidified to form a white precipitate. The solid was filtered to give (2S,4R)-4-(4-{4-[acetyl(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenoxy)-cyclohexanecarboxylic acid as a white powder in 62% yield.
Reaction SMILES: Br[CH:2]([C:4]1[S:8][C:7]([S:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])=[C:6]([N+:18]([O-:20])=[O:19])[CH:5]=1)[CH3:3].[CH3:21][NH:22][CH3:23]>>[Cl:17][C:11]1[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:10]=1[S:9][C:7]1[S:8][C:4]([CH:2]([N:22]([CH3:23])[CH3:21])[CH3:3])=[CH:5][C:6]=1[N+:18]([O-:20])=[O:19]
Reactant: CNC
Reactant: CC(Br)c1cc([N+](=O)[O-])c(Sc2ccc(Cl)cc2Cl)s1
Product: CC(c1cc([N+](=O)[O-])c(Sc2ccc(Cl)cc2Cl)s1)N(C)C

Procedure:
Prepared according to the procedure described for example 28 from 5-(1-bromoethyl)-2-(2,4-dichlorophenyl)sulfanyl-3-nitro-thiophene (0.1 g, 0.25 mmol) and dimethylamine (0.19 mL, 0.8 mmol). The title compound was obtained as a solid (15 mg, 16% yield). 1H NMR (400 MHz, MeOD) δ: 7.92 (1H, m), 7.88 (1H, m), 7.85 (1H, m) 7.58 (1H, m), 4.74 (1H, q), 2.81 (3H, m), 2.78 (3H, m), 1.67 (3H, d). MS m/z: 376.9 [M+H]+.
Reaction SMILES: [BH4-].[Na+].[C:3]([NH:6][CH:7]1[CH:14]2[C:15](=O)[C:16]3[CH:21]=[CH:20][C:19]([O:22]C(=O)C)=[CH:18][C:17]=3[C:8]1([CH3:27])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]2)(=[O:5])[CH3:4].C(O)(=O)C>C(OCC)C.O.[Cl-].[Zn+2].[Cl-].[BH4-].[Zn+2].[BH4-]>[C:3]([NH:6][CH:7]1[C:14]2=[CH:15][C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]=3[C:8]1([CH3:27])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]2)(=[O:5])[CH3:4]
Reactant: CC(=O)NC1C2CCCCCC1(C)c1cc(OC(C)=O)ccc1C2=O
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: O
Product: CC(=O)NC1C2=Cc3ccc(O)cc3C1(C)CCCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.9 %

Procedure:
Zinc chloride (5 g., 0.03 mole) was dissolved in 60 mL of diethyl ether and the insoluble material was filtered. The ethereal solution was added dropwise to sodium borohydride (3.5 g., 0.009 mole) in 150 mL of ether. The reaction mixture was stirred overnight at room temperature. The separated solid was allowed to settle and the supernatent liquid was removed by decantation. This ethereal solution of zinc borohydride was added to a solution of 4 g. (0.01 mole) of 13-acetylamino-6,7,8,9,10,11-hexahydro-3-acetyloxy-5-methyl-5,11-methanobenzocyclodecen-12(5H)-one in 50 mL of diethyl ether and the reaction mixture was stirred at room temperature for 48 hours. Excess zinc borohydride was decomposed by adding 3 mL of glacial acetic acid in 15 mL of water. The reaction mixture was filtered and the layer was washed with water, dried (anhydrous Na2SO4) and evaporated under reduced pressure. The separated solid was slurred in methanol and was heated while adding a few drops of dilute hydrochloric acid. The solvent was evaporated under vacuo and the solid was chromatographed on silica gel using ethyl acetate as eluent which afforded 2.3 g. (80.9% yield) of the title compound, mp 246°-249° C.
Reaction SMILES: [O-:1][C:2]#[N:3].[K+].[NH2:5][C:6]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:7]=1[CH2:8][OH:9].C(O)(=O)C>O>[CH3:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:6]([NH:5][C:2]([NH2:3])=[O:1])[C:7]=1[CH2:8][OH:9]
Reactant: Cc1cccc(N)c1CO
Reactant: N#C[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cccc(NC(N)=O)c1CO
Reaction time: 2.5 h
Yield: 73.9 %

Procedure:
A solution of potassium cyanate (1.62 g) in water (5 ml) was added dropwise to a mixture of 2-amino-6-methylbenzyl alcohol (1.37 g), water (5 ml), and acetic acid (6 ml) at room temperature. After being stirred for 2.5 hours, the resulting precipitates were collected by filtration, washed with water, and dried to give 2-methyl-6-ureidobenzyl alcohol (1.33 g).
Reaction SMILES: [Na].[CH3:2][N:3]1[CH2:7][CH2:6][CH:5]([O:8][C:9]2[C:14]([C:15]([O-])=[O:16])=[CH:13][C:12]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:11][N:10]=2)[CH2:4]1.S(Cl)([Cl:26])=O>>[CH3:2][N:3]1[CH2:7][CH2:6][CH:5]([O:8][C:9]2[C:14]([C:15]([Cl:26])=[O:16])=[CH:13][C:12]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:11][N:10]=2)[CH2:4]1
Reactant: O=S(Cl)Cl
Reactant: CN1CCC(Oc2ncc(-c3ccccc3)cc2C(=O)[O-])C1
Agent: [Na]
Product: CN1CCC(Oc2ncc(-c3ccccc3)cc2C(=O)Cl)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
The crude salt: sodium-2-[(1-methyl-3-pyrrolidinyl)oxy]-5-phenyl-3-pyridinecarboxylate (96 g) prepared in Preparation 55 was mixed with about 400 ml of thionyl chloride and stirred at room temperature for 10 minutes. The unreacted thionyl chloride was evaporated off at 70° C. and the residue was azeotroped with toluene to give the title compound which was used to prepare 2-(2-chloroethyl)-2,3-dihydro-4-methyl-7-phenylpyrido[3,2-f]-1,4-oxazepin-5-(4H)-one midway in preparation of Intermediate 79.