Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1.[BrH:18].C(N(CC)C1C=CC=CC=1)C.[N:30]1([C:35]#[N:36])[CH2:34][CH2:33][CH2:32][CH2:31]1>ClC1C=CC=CC=1.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[BrH:18].[N:12]1([C:10]([CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:35]([N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)=[NH:36])=[CH:3][CH:4]=2)=[O:11])[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1
Reactant: Nc1ccc(CCC(=O)N2CCOCC2)cc1
Reactant: N#CN1CCCC1
Agent: Br
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)c1ccccc1
Solvent: Clc1ccccc1
Product: N=C(Nc1ccc(CCC(=O)N2CCOCC2)cc1)N1CCCC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The product of step (b) (2.22 g, 0.00948 moles) was dissolved in 15 ml chlorobenzene. N,N-diethylaniline hydrobromide (2.18 g, 0.00948 moles) was added followed by 1-pyrrolidinecarbonitrile (1.37 g, 0.01422 moles). A catalytic amount of 4-dimethylaminopyridine was added and the reaction heated to reflux for 6 hours. The reaction was then cooled to room temperature and diluted with 100 ml ethyl acetate. A sticky oil precipitated from solution and was stirred for 24 hours. The resulting solids were filtered and recrystallized from hot isopropanol to give the N-(4(2-((4-morpholinyl)carbonyl)ethyl)phenyl)-1-pyrrolidinecarboximidamide hydrobromide, M.P. 207-209° C.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][CH:10]([OH:14])[CH2:11][O:12][CH3:13].[CH2:15]([O:22][C:23](Cl)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1.C(OCC)(=O)C>[CH2:15]([O:22][C:23]([NH:8][CH2:9][CH:10]([OH:14])[CH2:11][O:12][CH3:13])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COCC(O)CN
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCC(O)CNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.7 %

Procedure:
19.69 g of triethylamine are added to a solution of 10.23 g of 1-amino-3-methoxy-2-propanol in 100 ml of tetrahydrofuran. After the mixture is cooled, a solution of 16.60 g of benzyloxycarbonyl chloride in 50 ml of tetrahydrofuran is added dropwise thereto for 30 minutes. The mixture is stirred at room temperature for one hour. The reaction mixture is diluted with ethyl acetate, washed with water and dried. The residue is purified by silica gel column chromatography [solvent: ethyl acetate-hexane (2:1)]. 13.2 g of 1-benzyloxycarbonylamino-3-methoxy-2-propanol are obtained as colorless oil. ##STR24##
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1O[N:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[CH:10]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:24].N>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[S:24][N:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[CH:10]=1
Reactant: O=[N+]([O-])c1ccc(-c2cc(-c3c(Cl)cccc3Cl)on2)cc1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: N
Product: O=[N+]([O-])c1ccc(-c2cc(-c3c(Cl)cccc3Cl)sn2)cc1

Procedure:
By the method of Tetrahedron, 1992, 48, 8127-8142 the substance 5-(2,6-dichlorophenyl)-3-(4-nitrophenyl)isoxazole can be treated with diphosphorus pentasulfide followed by aqueous or ethanolic ammonia quench to produce 5-(2,6-dichlorophenyl)-3-(4-nitrophenyl)isothiazole. The nitrophenyl group can be reduced to the corresponding aniline with tin (II) dichloride or iron powder and ammonium chloride. This aniline can then be treated with 2,2-dichloroacetyl chloride and triethylamine to yield 2,2-dichloro-N-[4-[5-(2,6-dichlorophenyl)-3-isothiazolyl]phenyl]acetamide.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([CH2:9]P(=O)(OCC)OCC)#[N:8].[Cl:18][C:19]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:20]=1[CH:21]=O>O.O1CCCC1>[Cl:18][C:19]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:20]=1/[CH:21]=[CH:9]/[C:7]#[N:8]
Reactant: O=Cc1ccc(Cl)cc1Cl
Reactant: CCOP(=O)(CC#N)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: N#C/C=C/c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 65.4 %

Procedure:
To a solution of 8 g of potassium carbonate in 10 cm3 of water, 6 g (0.034 mol) of diethyl cyanomethylphosphonate are added followed by 5 g of 2,4-dichlorobenzaldehyde solubilized in 10 cm3 of anhydrous tetrahydrofuran. The mixture is left stirred for 10 minutes at room temperature and 20 cm3 of water are added. The precipitate formed is washed with water to neutrality (8 times with 20 cm3 of water), and then washed with an ether/hexane mixture. 3.7 g (74%) of trans-2,4-dichlorocinnamonitrile are obtained in the form of white crystals, m.p. 156° C.
Reaction SMILES: [C:1]([O:5]O)(C)([CH3:3])[CH3:2].[CH2:7]=[CH:8][CH2:9][CH2:10][CH2:11][CH3:12]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.ClC(Cl)C>[CH3:2][C:1](=[O:5])[CH2:3][CH2:7][CH2:8][CH3:9].[CH2:7]=[CH:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CC(C)(C)OO
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C=CCCCC
Solvent: CC(Cl)Cl
Product: CCCCC(C)=O
Reaction time: 4 h

Procedure:
30 cm3 of 80% tert-butyl hydroperoxide (0.225 mole), 10 cc of 1-hexene (0.064 mole), 20 cc of dichloroethane and 220 mg of palladium acetate (0.001 mole) are introduced into a heat-insulated glass reactor. An argon atmosphere is applied and stirring is performed at a temperature of 60° C. After 4 hours, it is found that 66% of 1-hexene were converted and that 2-hexanone was formed with a molar selectivity of 83% with respect to the converted 1-hexene.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([OH:9])=[O:8].O.[C:11](=[O:14])([OH:13])[O-].[Na+].[CH2:16]([O:23][C:24](Cl)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CC(C)=O.[Pd]>[CH2:16]([O:13][C:11]([N:1]1[CH2:6][CH2:5][N:4]([C:24]([O:23][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:25])[CH2:3][CH:2]1[C:7]([OH:9])=[O:8])=[O:14])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[NH3:1]
Reactant: O=C([O-])O
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)c1cnccn1
Agent: [Pd]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: N
Product: O=C(O)C1CN(C(=O)OCc2ccccc2)CCN1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 60 h

Procedure:
2-Pyrazinecarboxylic acid (2.15 g, 17.32 mmol) is placed in a hydrogenation bottle containing water (100 mL), sodium bicarbonate (1.45 g, 17.32 mmol) and palladium black (500 mg). The bottle is placed under hydrogen (40 p.s.i.) for 60 hours, filtered through celite and lyophilized. The residue is dissolved in water (25 mL), cooled to 0° C., and treated with sodium bicarbonate (3.78 g, 45.00 mmol) and benzyloxycarbonylchloride (6.25 mL, 41.60 mmol) in acetone (25 mL). After stirring 20 hours at ambient temperature, the acetone is removed in vacuo and the mixture is partitioned between methylene chloride (200 mL) and water (50 mL). The pH of the aqueous phase is adjusted to 2 with 1N HCl. The organic phase is washed with saline, dried over MgSO4, and concentrated in vacuo to give the title compound, MS (CI, NH3) m/z 416 [M+NH4 ]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([C:19]1([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:23][CH:22]=[CH:21][CH2:20]1)[N:13]=2)[CH:5]=O.Cl.[NH:31]1[CH2:34][CH:33]([C:35]([O:37][CH3:38])=[O:36])[CH2:32]1>>[F:1][C:2]1[CH:3]=[C:4]([CH2:5][N:31]2[CH2:34][CH:33]([C:35]([O:37][CH3:38])=[O:36])[CH2:32]2)[CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([C:19]1([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:20][CH:21]=[CH:22][CH2:23]1)[N:13]=2
Reactant: O=Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CC=CC4)nc3s2)c(F)c1
Reactant: COC(=O)C1CNC1
Agent: Cl
Product: COC(=O)C1CN(Cc2ccc(-c3nc4ccc(C5(c6ccccc6)CC=CC5)nc4s3)c(F)c2)C1

Procedure:
Reaction of 3-fluoro-4-(5-(1-phenylcyclopent-3-enyl)thiazolo[5,4-b]pyridine-2-yl)-benzaldehyde (0.48 g, 1.2 mmol), methyl azetidine-3-carboxylate hydrochloride (0.365 g, 2.41 mmol) according to Reference R and the general procedure for reductive amination gave methyl 1-((3-fluoro-4-(5-(1-phenylcyclopent-3-enyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)-methyl)azetidine-3-carboxylate as an oil which partially solidified to a white solid. MS (ESI) m/z: Calculated: 499.0; Observed: 500.1 (M++1).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[NH:4][N:3]=1.Cl.Cl[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]([CH3:25])[CH3:24])[N:18]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[N:4]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]([CH3:25])[CH3:24])[N:18]=2)[N:3]=1
Reactant: CC(C)c1cccc(CCl)n1
Reactant: O=[N+]([O-])c1cccc2[nH]nc(Br)c12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1cccc(Cn2nc(Br)c3c([N+](=O)[O-])cccc32)n1
Temperature: 35 °C
Reaction time: 0.33 h
Yield: 91.9 %

Procedure:
A flask was charged with 3-bromo-4-nitro-1H-indazole (64 g, 0.264 mol), 2-(chloromethyl)-6-isopropylpyridine hydrochloride (55 g, 0.264 mol), powdered potassium carbonate (91 g, 0.661 mol), and 500 mL of DMF. This mixture was warmed to 35° C. for 72 hours, then poured into 2 liters of cold water, upon which a tan solid precipitated. After stirring for 20 minutes, the solids were collected by filtration and dried under vacuum to give 91 g (92%) of 3-bromo-1-((6-isopropylpyridin-2-yl)methyl)-4-nitro-1H-indazole.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[C:11]([Cl:13])[N:10]=[C:9](Cl)[N:8]=2)[CH2:3][CH2:2]1.C([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=O.[O:23]1CCOC[CH2:24]1>>[CH:24]([CH:19]1[CH2:18][NH:17][CH2:22][CH2:21][N:20]1[C:9]1[N:8]=[C:7]([N:4]2[CH2:5][CH2:6][S:1][CH2:2][CH2:3]2)[CH:12]=[C:11]([Cl:13])[N:10]=1)=[O:23]
Reactant: C1COCCO1
Reactant: Clc1cc(N2CCSCC2)nc(Cl)n1
Reactant: O=CN1CCNCC1
Product: O=CC1CNCCN1c1nc(Cl)cc(N2CCSCC2)n1

Procedure:
125.1 gm of 4thiomorpholino-2,6-dichloro-pyrimidine (m.p. 118.5°-121.5°C) were dissolved in 1.2 liters of dioxane, a solution of 125.6 gm of N-formyl-piperazine in 0.1 liter of dioxane was added, and the mixture was refluxed for 2.5 hours. The precipitated N-formyl-piperazine hydrochloride was suction-filtered off, and the filtrate was diluted with 2 liters of water and cooled in the ice bath. The precipitated white crystals were washed with a small quantity of 50% dioxane and dried at 100°C. Yield: 146 gm (90% of theory); m.p. 195°-198°C (decomp.).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].[CH2:5]([O:7][C:8]1[CH:9]=[C:10]([CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[C:15]=1[OH:16])[CH:11]=O)[CH3:6].B(F)(F)F.CCOCC.[CH:29]1([CH2:35][C:36]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=O)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>C1COCC1.Cl[Cu].CC(O)=O>[CH:38]1([C:36]2[CH:11]([C:10]3[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[C:15]([OH:16])=[C:8]([O:7][CH2:5][CH3:6])[CH:9]=3)[NH:1][C:2](=[O:3])[NH:4][C:35]=2[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: CCOc1cc(C=O)cc([N+](=O)[O-])c1O
Reactant: NC(N)=O
Reactant: O=C(CC1CCCCC1)c1ccccc1
Agent: Cl[Cu]
Agent: FB(F)F
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCOc1cc(C2NC(=O)NC(c3ccccc3)=C2C2CCCCC2)cc([N+](=O)[O-])c1O
Yield: 9.3 %

Procedure:
A mixture of urea (150 mg, 2.5 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (104 mg, 0.49 mmol), CuCl (99 mg, 1.0 mmol), BF3-Et2O (142 mg, 1.0 mmol) and AcOH (0.2 mL) in anhydrous THF (10 mL) was stirred under refluxing under N2 atmosphere for 0.5 hour. Then 2-cyclohexyl-1-phenylethanone (Intermediate 96) (100 mg, 0.49 mmol) in anhydrous THF (0.5 mL) was added and the reaction mixture was refluxed overnight. Followed a standard aqueous/EtOAc workup and purified by prep-HPLC (0.1% TFA as additive) to give Compound 177 (20 mg, yield 9%). 1H NMR (CD3OD 400 MHz): δ 7.74 (d, J=2.0 Hz, 1H), 7.53-7.38 (m, 6H), 7.39 (d, J=2.0 Hz, 1H), 4.99 (s, 1H), 4.21 (q, J=7.2 Hz, 1H), 2.35-2.28 (m, 1H), 1.69 (m, 1H), 1.64 (m, 1H), 1.55-1.47 (m, 7H), 1.05-0.92 (m, 3H), 0.85-0.79 (m, 1H). MS (ESI): m/z 438.3 [M+1]+.
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][N:9]([CH3:11])[CH3:10])(=[O:5])[C:2]([CH3:4])=[CH2:3].[Br:12][CH:13]([OH:15])C.[C:16](OCC)(=O)C>>[Br-:12].[C:1]([O:6][CH2:7][CH2:8][N+:9]([CH3:16])([CH3:11])[CH2:10][CH2:13][OH:15])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: CC(O)Br
Reactant: C=C(C)C(=O)OCCN(C)C
Reactant: CCOC(C)=O
Product: C=C(C)C(=O)OCC[N+](C)(C)CCO
Product: [Br-]
Yield: 96 %

Procedure:
31.4 g (0.2 mole) of (dimethylamino)ethyl methacrylate was introduced into a 250 ml three-neck flask equipped with ice-bath, thermometer, refluxing condenser, dropping funnel and magnetic stirring bar. The compound was stirred and then the temperature thereof was lowered to -10° C. 25 g (0.2 mole) of bromoethanol was added dropwise thereto over 30 minutes while maintaining the temperature of the contents at 0° C. or less. After the addition was complete the reaction mixture was stirred for 24 hours at room temperature. 100 ml of ethyl acetate was added to the mixture and the whole was stirred, filtered and dried to obtain 54 g (Yield: 96%) of the title compound as a white powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:14][N:15]([CH3:17])[CH3:16])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: COC(OC)N(C)C
Reactant: Cc1ccc(Br)cc1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: CN(C)C=Cc1ccc(Br)cc1[N+](=O)[O-]
Yield: 106229.7 %

Procedure:
A solution of 27 grams (0.125 mmoles) of 4-bromo-1-methyl-2-nitrobenzene and 1 ml (0.31 moles of N,N-dimethylformamide dimethyl acetal in 120 ml of DMF was heated at 80° C. for 2 hours. After cooling, the reaction was poured onto water and extracted with ethylacetate. Then was dried over sodium sulfate and evaporated to give 36 grams of the titled compound as a purple solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[N:15]1[C:19](CC(N)=O)=[CH:18][C:17]([O:24][CH2:25][C:26]([F:32])([F:31])[C:27]([F:30])([F:29])[F:28])=[N:16]1.[CH2:33]([N:35](CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>O1CCCC1>[C:33]([C:19]1[N:15]([C:3]2[CH:4]=[C:5]([S:9][CH2:10][C:11]([F:12])([F:13])[F:14])[C:6]([CH3:8])=[CH:7][C:2]=2[F:1])[N:16]=[C:17]([O:24][CH2:25][C:26]([F:31])([F:32])[C:27]([F:28])([F:30])[F:29])[CH:18]=1)#[N:35]
Reactant: Cc1cc(F)c(-n2nc(OCC(F)(F)C(F)(F)F)cc2CC(N)=O)cc1SCC(F)(F)F
Reactant: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Product: Cc1cc(F)c(-n2nc(OCC(F)(F)C(F)(F)F)cc2C#N)cc1SCC(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.2 %

Procedure:
0.80 g of 1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-(2,2,3,3,3-pentafluoropropoxy)pyrazole-5-carboxyamide was dissolved in 20 mL of tetrahydrofuran, 0.42 g of triethylamine was added, and 0.52 g of trifluoroacetic anhydride was slowly dropwise added under cooling with ice. After stirring at room temperature for 2 hours, the solvent was distilled off under reduced pressure, and extraction with ethyl acetate was carried out. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:4) to obtain 0.60 g of 5-cyano-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-(2,2,3,3,3-pentafluoropropoxy)pyrazole.
Reaction SMILES: [Cl-].Cl[C:3]1[NH:4]S[SH+:6][C:7]=1Cl.[CH3:9][O:10][C:11](=[O:16])/[CH:12]=[C:13](\[NH2:15])/[CH3:14].N1C=CC=CC=1>ClCCl>[C:3]([C:7]1[S:6][N:15]=[C:13]([CH3:14])[C:12]=1[C:11]([O:10][CH3:9])=[O:16])#[N:4]
Reactant: COC(=O)/C=C(/C)N
Reactant: ClC1=C(Cl)[SH+]SN1
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1c(C)nsc1C#N
Yield: 15.6 %

Procedure:
4,5-Dichloro-[1,2,3]-dithiazol-1-ylium chloride (prepared according to Chem. Ber. (1985) 118, 1632) (8.34 g, 40 mmol) was dissolved in dichloromethane (30 ml) and methyl-3-aminocrotonate (4.6 g, 40 mmol) was added dropwise at room temperature. After stirring the solution for 1 hour at room temperature pyridine (6.47 ml, 80 mmol) was added slowly. The mixture was concentrated and purified by chromatography on silica gel (eluent: ethyl acetate/hexane) to give the product as an orange solid (1.14 g, 15.6% yield). 1H-NMR (400 MHz, CDCl3): 2.88 (3H, s, Me), 4.0 (3H, s, Me).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[O:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[NH2:12].[CH2:18]([CH:20]1[C:24](=[O:25])[CH2:23][CH2:22][C:21]1=O)[CH3:19]>>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[O:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[NH:12][C:21]1[CH2:22][CH2:23][C:24](=[O:25])[C:20]=1[CH2:18][CH3:19]
Reactant: CCC1C(=O)CCC1=O
Reactant: COc1ccc(N)cc1OC1CC2CCC1C2
Product: CCC1=C(Nc2ccc(OC)c(OC3CC4CCC3C4)c2)CCC1=O
Yield: 100 %

Procedure:
According to the same procedure as in Example 1(3), using 3-[(1RS,2RS,4SR)-bicyclo[2.2.1]hept-2-yloxy]-4-methoxyaniline produced in Example 8(2) instead of 3-cyclopentyloxy-4-methoxyaniline, and using 2-ethyl-1,3-cyclopentanedione instead of 1,3-cyclopentanedione, the title compound (yield 100%) was obtained as a dark brown oil.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=[O:8])[S:4][N:3]=1.[CH:10]([NH2:13])([CH3:12])[CH3:11]>O1CCCC1>[CH3:1][C:2]1[CH:6]=[C:5]([C:7]([O-:9])=[O:8])[S:4][N:3]=1.[CH:10]([NH3+:13])([CH3:12])[CH3:11]
Reactant: Cc1cc(C(=O)O)sn1
Reactant: CC(C)N
Solvent: C1CCOC1
Product: CC(C)[NH3+]
Product: Cc1cc(C(=O)[O-])sn1
Yield: 85.5 %

Procedure:
3-Methyl-5-isothiazolecarboxylic acid (1.0 g) was dissolved in 10 ml of dry tetrahydrofuran, in which a solution of 0.41 g of isopropylamine in 5 ml of dry tetrahydrofuran were added dropwise at room temperature under stirring. White crystals were formed concurrently with the dropwise addition. After the reaction mixture was stirred further at room temperature for 30 minutes, crystals were collected by filtration and washed with a small amount of dry tetrahydrofuran. The crystals were dried at 40° C. for 3 hours under reduced pressure, whereby 1.20 g of the title compound were obtained (yield: 85%).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9](=[O:21])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(C)(C)C.[ClH:23]>O1CCOCC1>[Cl-:23].[NH2:7][CH2:8][C:9]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:21]
Reactant: CC(C)(C)OC(=O)NCC(=O)NCCCCc1ccccc1
Reactant: Cl
Solvent: C1COCCO1
Product: NCC(=O)NCCCCc1ccccc1
Product: [Cl-]

Procedure:
The crude [(4-phenyl-butylcarbamoyl)-methyl]-carbamic acid tert-butyl ester is stirred in a solution of dioxane (150 mL) and HCl (4 M dioxane, 42 mL, 168 mmol) for 17 h. The volatiles are removed in vacuo to provide 2-amino-N-(4-phenyl-butyl)-acetamide, hydrogen chloride salt which is used as is without further purification.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[C:15]([F:18])([F:17])[F:16])[CH2:3][CH2:2]1.[CH3:19][C:20]([CH3:27])([C:22]1[S:23][CH:24]=[CH:25][N:26]=1)[NH2:21]>>[CH3:19][C:20]([NH:21][C:12]([C:10]1[CH:9]=[CH:8][C:7]([C:15]([F:18])([F:17])[F:16])=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])([C:22]1[S:23][CH:24]=[CH:25][N:26]=1)[CH3:27]
Reactant: CC(C)(N)c1nccs1
Reactant: O=C(O)c1ccc(C(F)(F)F)c(OCC2CC2)n1
Product: CC(C)(NC(=O)c1ccc(C(F)(F)F)c(OCC2CC2)n1)c1nccs1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (Example 113 d) and α,α-dimethyl-2-thiazolemethanamine (CAN 1082393-38-1) as starting materials, MS (EI): m/e=386.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:21])[CH:9]([CH3:20])[CH2:10][N:11](C)[C:12](=O)OC(C)(C)C)[CH:5]=[CH:6][CH:7]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:21])[CH:9]([CH3:20])[CH2:10][NH:11][CH3:12])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(CN(C)C(=O)OC(C)(C)C)C(=O)c1cccc(Cl)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNCC(C)C(O)c1cccc(Cl)c1
Temperature: 50 °C
Reaction time: 4 h
Yield: 46.3 %

Procedure:
A solution of tert-butyl 3-(3-chlorophenyl)-2-methyl-3-oxopropyl(methyl)carbamate (2.8 g, 9.4 mmol) in THF (20 mL) was added slowly to a suspension of LAH (537 mg, 14.1 mmol) in THF (10 mL). The mixture was then stirred at 50° C. for 4 h. The mixture was cooled to 0° C. and 4 g of ice was added into the reaction. The mixture was stirred for 30 min at room temperature, diluted with ethyl acetate, dried over Na2SO4, filtered and concentrated to give the crude product. The residue was purified by chromatography to obtain pure 1-(3-chlorophenyl)-2-methyl-3-(methylamino)propan-1-ol (930 mg, 32%).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].[C:6]([O:21][CH2:22][CH:23]1[O:25][CH2:24]1)(=[O:20])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>C(O)C>[C:6]([O:21][CH2:22][CH:23]([OH:25])[CH2:24][N:2]([CH2:3][CH2:4][OH:5])[CH3:1])(=[O:20])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CNCCO
Reactant: CCCCCCCCCCCCCC(=O)OCC1CO1
Solvent: CCO
Product: CCCCCCCCCCCCCC(=O)OCC(O)CN(C)CCO
Temperature: 80 °C
Reaction time: 2 h
Yield: 60.8 %

Procedure:
A 100-ml flask equipped with a stirrer and dropping funnel was charged with 6.01 g (80 mmol) of N-methylethanolamine, 50 ml of ethanol and 22.8 g (80 mmol) of glycidyl tetradecanate, and the contents were stirred at 80° C. for 2 hours. The resultant reaction mixture was concentrated under reduced pressure, and the residue was purified by chromatography on silica gel, thereby obtaining 17.5 g (yield: 60.8%) of the title compound (IIe-2).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:23])[CH:6]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:7][C:8]1[CH:13]=[CH:12][C:11](O)=[CH:10][CH:9]=1.F[C:25]1[CH:32]=[CH:31][C:28]([CH:29]=[O:30])=[CH:27][CH:26]=1.CN(C=[O:37])C>>[CH3:3][O:4][C:5](=[O:23])[CH:6]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:37][C:25]1[CH:32]=[CH:31][C:28]([CH:29]=[O:30])=[CH:27][CH:26]=1
Reactant: COC(=O)C(Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Reactant: O=Cc1ccc(F)cc1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: COC(=O)C(Cc1ccccc1Oc1ccc(C=O)cc1)NC(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 85 %

Procedure:
To a suspension of fresh sodium hydride (0.813 g, 33.9 mmol) in dry DMF (20 ml) under nitrogen atmosphere was added the solution of methyl-2-[(t-butoxycarbonyl)amino]-3-(4-hydroxyphenyl)propanoate (10 g, 33.9 mmol) in DMF (20 ml) slowly. The mixture was stirred for 15 minutes. 4-Fluorobenzaldehyde (4.20 g, 33.9 mmol) was added and the mixture was heated to 80° C. After completion of the reaction, the solvent was removed by high vacuum and the mixture was quenched with addition of saturated aqueous ammonium chloride. The mixture was extracted with ethyl acetate (3×50 ml). After washing with brine and dried on anhydrous sodium sulfate, the solvent was evaporated and the product was purified with flash column from eluent of hexanes: ethyl ether; 12/30 to 12/22 to afford the title compound as an oil (yield 11.5 g, 85.0%).
Reaction SMILES: [CH3:1][NH2:2].[C:3]([O:8][CH2:9][CH3:10])(=[O:7])/[CH:4]=[CH:5]/[CH3:6]>>[CH3:1][NH:2][CH:5]([CH3:6])[CH2:4][C:3]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CN
Reactant: C/C=C/C(=O)OCC
Product: CCOC(=O)CC(C)NC
Yield: 72.1 %

Procedure:
A solution of 479.2 mL (0.958 mole) methylamine (2M in tetrahydrofuran) was added dropwise to 99.44 gm ethyl crotonate with stirring. After stirring 5 days at room temperature the reaction mixture was concentrated under reduced pressure to remove tetrahydrofuran. The residue was distilled to provide 91.25 gm (72%) of the desired product in 2 fractions.