Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:43]=[CH:42][C:6]([CH2:7][C@@:8]2([CH3:41])[N:12]3[C:13]([S:16]([N:19]4[CH2:23][CH2:22][CH2:21][C@H:20]4[C:24]([NH:26][C@H](C)C(O)=O)=[O:25])(=[O:18])=[O:17])=[CH:14][N:15]=[C:11]3[N:10]([C:32]3[CH:37]=[C:36]([Cl:38])[CH:35]=[C:34]([Cl:39])[CH:33]=3)[C:9]2=[O:40])=[CH:5][CH:4]=1)#[N:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN([CH:72]([CH3:74])[CH3:73])C(C)C.F[C:76](F)(F)[C:77]([OH:79])=[O:78]>CN(C=O)C.CCOC(C)=O>[O:78]=[C:77]1[O:79][C@@H:72]([CH2:73][NH:26][C:24]([C@@H:20]2[CH2:21][CH2:22][CH2:23][N:19]2[S:16]([C:13]2[N:12]3[C@@:8]([CH2:7][C:6]4[CH:42]=[CH:43][C:3]([C:1]#[N:2])=[CH:4][CH:5]=4)([CH3:41])[C:9](=[O:40])[N:10]([C:32]4[CH:37]=[C:36]([Cl:38])[CH:35]=[C:34]([Cl:39])[CH:33]=4)[C:11]3=[N:15][CH:14]=2)(=[O:18])=[O:17])=[O:25])[CH2:74][CH2:76]1
Reactant: C[C@@H](NC(=O)[C@@H]1CCCN1S(=O)(=O)c1cnc2n1[C@](C)(Cc1ccc(C#N)cc1)C(=O)N2c1cc(Cl)cc(Cl)c1)C(=O)O
Reactant: O=C(O)C(F)(F)F
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(S(=O)(=O)N3CCC[C@H]3C(=O)NC[C@H]3CCC(=O)O3)n21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (S)-1-[(R)-5-(4-cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-sulfonyl]-pyrrolidine-2-carboxylic acid (see Example 5) (0.1 g, 0.174 mmol) in anhydrous DMF was added the above mixture of amines (0.030 g), followed by TBTU (0.084 g, 0.261 mmol) followed by DIPEA (0.075 mL, 0.435 mmol). The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was then diluted with EtOAc and washed with water (×3), 1N HCl, and saturated NaHCO3. The organic phase was dried over Na2SO4 and concentrated. The resulting residue was dissolved in CH2Cl2 and trifluoroacetic acid (1 eq) was added to the solution. The reaction mixture was stirred at room temperature for 3 h and washed with saturated NaHCO3 and water. The organic phase was dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel preparative thin layer chromatography using CH2Cl2-MeOH (95:5) as an eluent to afford 0.063 g of the title compound as a white foam (M+1, 671.1).
Reaction SMILES: CN([CH:4]=[O:5])C.P(Cl)(Cl)(Cl)=O.[CH2:11]([C:13]1[C:14]([NH:20][CH2:21][CH2:22][NH:23][C:24](=[O:26])[CH3:25])=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=1)[CH3:12].[OH-].[Na+]>O>[OH:19][C:15]1[C:14]([NH:20][CH2:21][CH2:22][NH:23][C:24](=[O:26])[CH3:25])=[C:13]([CH2:11][CH3:12])[CH:18]=[CH:17][C:16]=1[CH:4]=[O:5]
Reactant: CCc1cccc(O)c1NCCNC(C)=O
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CCc1ccc(C=O)c(O)c1NCCNC(C)=O
Temperature: 40 °C
Reaction time: 8 h

Procedure:
A scrupulously dry flask was charged with anhydrous DMF (15 ml) and cooled in ice under argon. Phosphorus oxychloride, POCl3, 1.5 ml (1.15 eq) was added slowly dropwise to the stirred solution. After the addition was complete, the flask was removed from the ice bath and allowed to reach ambient temperature. This was accompanied by a color change to yellow. The flask was heated in a 40° C. bath for one hour. It was removed from the heat, and once at ambient temperature, a DMF solution of 3-(ethyl)(2-acetylaminoethyl)aminophenol (8; 3.2 g, 14 mmol) was added via addition funnel. After the addition was complete, the flask was returned to the 40° C. bath and stirred overnight. The reaction was cooled to 0° C. and 25 ml 10% NaOH was added, the mixture was allowed to warm to ambient temperature and was then placed in a 40° C. bath. Additional NaOH was added to achieve pH>10. Water (50 ml) was added. After 15 minutes the flask was removed from the bath and the pH adjusted to 5–5.5 with 1N HCl. The mixture was transferred to a separatory funnel and extracted with 4×100 ml ethyl acetate. The pooled organic fractions were washed with water (1×75 ml), predried with Na2SO4, and then dried with MgSO4 overnight. The solution was collected by filtration and the volatiles removed by rotary evaporation to yield the crude product (2.9 g). The material was purified by flash chromatography on silica, 45×150 mm column, eluting with 200 ml each of 2.5%, 5%, and 10% methanol/chloroform. Purified yield of (2-hydroxy-4-(ethyl)(2-acetylaminoethyl)aminobenzaldehyde) (9) was 1.52 g (45%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:17][NH:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(O)(=O)C.C([BH3-])#N.[Na+].[C:35]([O-:42])(=[O:41])/[CH:36]=[CH:37]/[C:38]([O-:40])=[O:39].C(O)(=O)/C=C/C(O)=O>>[C:35]([OH:42])(=[O:41])/[CH:36]=[CH:37]/[C:38]([OH:40])=[O:39].[CH3:17][N:18]([CH:13]1[CH2:14][CH2:15][N:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:11][CH2:12]1)[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Reactant: CNCCc1ccccc1
Reactant: O=C([O-])/C=C/C(=O)[O-]
Agent: O=C(O)/C=C/C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CN(CCc1ccccc1)C1CCN(c2ccc([N+](=O)[O-])cc2)CC1

Procedure:
2.5 g (11.4 mmol) of 1-(4-nitrophenyl)-4-piperidone, 1.5 g (11.4 mmol) of N-methyl-N-(2-phenylethyl)amine, 0.7 g (11.4 mmol) of acetic acid and 0.7 g (11.4 mmol) of sodium cyanoborohydride were reacted in a similar manner to Example 1. The product was converted into the fumarate with fumaric acid in a conventional manner. 2.8 g of 4-(N-methyl-N-(2-phenylethyl)amino)-1-(4-nitrophenyl)piperidine fumarate were obtained. Melting point 201°-202° C.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[O:11])=[CH:5][CH:4]=1.[N+:14]([C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][CH2:26][CH:25]([NH:29][C@@H:30]3[CH2:35][CH2:34][CH2:33][CH2:32][C@H:31]3[NH2:36])[CH2:24]2)=[CH:19][CH:18]=1)([O-:16])=[O:15]>>[N+:14]([C:17]1[CH:18]=[CH:19][C:20]([N:23]2[CH2:28][CH2:27][CH2:26][C@H:25]([NH:29][C@@H:30]3[CH2:35][CH2:34][CH2:33][CH2:32][C@H:31]3[NH:36][C:10]([NH:9][C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:12])([F:13])[F:1])=[CH:8][CH:7]=3)=[O:11])[CH2:24]2)=[CH:21][CH:22]=1)([O-:16])=[O:15]
Reactant: N[C@@H]1CCCC[C@H]1NC1CCCN(c2ccc([N+](=O)[O-])cc2)C1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Product: O=C(Nc1ccc(C(F)(F)F)cc1)N[C@@H]1CCCC[C@H]1N[C@H]1CCCN(c2ccc([N+](=O)[O-])cc2)C1
Yield: 5.7 %

Procedure:
1-((1R,2R)-2-((S)-1-(4-Nitrophenyl)piperidin-3-ylamino)cyclohexyl)-3-(4-(trifluoromethyl)phenyl)urea was synthesized as described in General Procedure F using 4-trifluoromethyl-phenyl isocyanate (13 mg, 0.069 mmol) and (1R,2R)—N1-(1-(4-nitrophenyl)piperidin-3-yl)cyclohexane-1,2-diamine (30 mg, 0.069 mmol) to give 1-((1R,2R)-2-((S)-1-(4-nitrophenyl)piperidin-3-ylamino)cyclohexyl)-3-(4-(trifluoromethyl)phenyl)urea as a yellow solid (2.0 mg, 54% yield). Anal. Calcd. for C25H30F3N5O3 m/z 505.5, found: 506.3 (M+H)+; 1H NMR (500 MHz, CDCl3) δ ppm 9.61-8.86 (m, 1H), 8.76 (br. s., 1H), 7.72 (d, J=8.80 Hz, 2H), 7.42-7.33 (m, 2H), 7.30 (d, J=8.25 Hz, 2H), 7.06 (br. s., 1H), 6.66 (d, J=8.80 Hz, 2H), 3.75-3.56 (m, 2H), 3.48 (d, J=12.65 Hz, 1H), 3.44-3.29 (m, 2H), 3.25 (d, J=7.70 Hz, 1H), 3.11 (br. s., 1H), 2.24-2.00 (m, 4H), 1.86 (d, J=13.20 Hz, 3H), 1.84-1.75 (m, 1H), 1.71 (d, J=11.00 Hz, 1H), 1.49 (br. s., 1H) 1.37-1.17 (m, 2H); 13C NMR (126 MHz, CDCl3) δ ppm 154.35, 144.05, 125.87, 125.55, 123.02, 120.76, 117.83, 114.19, 66.81, 63.17, 52.86, 52.53, 48.20, 31.08, 28.87, 26.95, 23.72, 22.69, 21.03.
Reaction SMILES: Br[CH2:2][C:3]1[NH:7][C:6](=[O:8])[NH:5][C:4]=1[C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2([OH:31])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CC(O)C.O.C(O)C>[ClH:18].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2([OH:31])[CH2:26][CH2:27][N:28]([CH2:2][C:3]3[NH:7][C:6](=[O:8])[NH:5][C:4]=3[C:9](=[O:17])[C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[CH2:29][CH2:30]2)=[CH:21][CH:20]=1
Reactant: O=C(c1ccc(F)cc1)c1[nH]c(=O)[nH]c1CBr
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Solvent: CCO
Product: O=C(c1ccc(F)cc1)c1[nH]c(=O)[nH]c1CN1CCC(O)(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 4.3 g (14.2 mmole) of 5-(bromomethyl)-1,3-dihydro-4-(4-fluorobenzoyl)-2H-imidazol-2-one, 3.0 g (14.2 mmole) of 4-(4-chlorophenyl)-4-hydroxypiperidine, 2.0 g (14.2 mmole) of potassium carbonate and 75 ml of ethanol is stirred under argon for 16 hours at 25° C. Water (100 ml) is added and the precipitate which forms is collected and washed with water. It is then suspended in 2-propanol and 1 equivalent of hydrogen chloride in 2-propanol is added. The resulting solid is separated and recrystallized twice from a mixture of 2-propanol and water to give 4-[[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl]methyl]-5-(4-fluorobenzoyl)-1,3-dihydro-2H-imidazol-2-one hydrochloride melting at about 235°-236° C. with decomposition.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][C:9]#[N:10])[CH2:3][CH2:2]1.C[O-].[Na+].[CH2:14]1[O:18][C:17]2[CH:19]=[C:20]([CH:23]=O)[CH:21]=[CH:22][C:16]=2[O:15]1>CS(C)=O>[O:1]1[CH2:6][CH2:5][N:4]([CH:7]=[C:8]([CH2:23][C:20]2[CH:21]=[CH:22][C:16]3[O:15][CH2:14][O:18][C:17]=3[CH:19]=2)[C:9]#[N:10])[CH2:3][CH2:2]1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: N#CCCN1CCOCC1
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CC(=CN1CCOCC1)Cc1ccc2c(c1)OCO2

Procedure:
β-Morpholinopropionitrile (20 g.), dimethylsulphoxide (30 ml.), and sodium methoxide (1 g.) were heated together at 80°C and a solution of piperonaldehyde (19 g.) in dimethylsulphoxide was added. The mixture was reacted at 80°C for 15 min., and on work-up gave β-morpholino-α-piperonylacrylonitrile. Wt.=21 g. (61%) m.p. 85°-85.5°C (recrystallized from methanol).
Reaction SMILES: C([N:8]1[C:12]([C:13]2[O:14][C:15]3[CH:21]=[C:20]([O:22][CH2:23][CH:24]4[CH2:26][CH2:25]4)[CH:19]=[CH:18][C:16]=3[N:17]=2)=[CH:11][C:10]([O:27][CH2:28][C@@H:29]([NH:31][C:32](=[O:34])[CH3:33])[CH3:30])=[N:9]1)C1C=CC=CC=1.C(O)C>[OH-].[OH-].[Pd+2].C1COCC1>[CH:24]1([CH2:23][O:22][C:20]2[CH:19]=[CH:18][C:16]3[N:17]=[C:13]([C:12]4[NH:8][N:9]=[C:10]([O:27][CH2:28][C@@H:29]([NH:31][C:32](=[O:34])[CH3:33])[CH3:30])[CH:11]=4)[O:14][C:15]=3[CH:21]=2)[CH2:25][CH2:26]1
Reactant: CC(=O)N[C@@H](C)COc1cc(-c2nc3ccc(OCC4CC4)cc3o2)n(Cc2ccccc2)n1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(=O)N[C@@H](C)COc1cc(-c2nc3ccc(OCC4CC4)cc3o2)[nH]n1
Temperature: 50 °C
Reaction time: 4 h
Yield: 24.2 %

Procedure:
Under a hydrogen atmosphere, a mixture of N-[(1S)-2-({1-benzyl-5-[6-(cyclopropylmethoxy)-1,3-benzoxazol-2-yl]-1H-pyrazol-3-yl}oxy)-1-methylethyl]acetamide (120 mg), 20% palladium hydroxide/carbon (containing water (50%), 60 mg), ethanol (5 mL) and THF (3 mL) was stirred at 50° C. for 4 hr. The catalyst was removed by filtration, and the obtained filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (23.4 mg).
Reaction SMILES: [Cl:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([NH:16][CH3:17])=[C:7]2[N:14]=[O:15].C[O:19][C:20]1C=CC(C=O)=C[CH:21]=1.CN.[Cl:30][C:31]1[C:40]([O:41][CH3:42])=[CH:39][CH:38]=[C:37]2[C:32]=1[CH:33]=[CH:34][C:35](O)=[C:36]2N=O.ClC1C(OC)=CC=C2C=1C=CC(O)=C2>C(O)C>[Cl:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([NH:16][CH3:17])=[C:7]2[N:14]=[O:15].[Cl:30][C:31]1[C:40]([O:41][CH3:42])=[CH:39][CH:38]=[C:37]2[C:32]=1[CH:33]=[CH:34][C:35]([C:20](=[O:19])[CH3:21])=[CH:36]2
Reactant: COc1ccc(C=O)cc1
Reactant: COc1ccc2c(N=O)c(O)ccc2c1Cl
Agent: CN
Agent: CNc1ccc2c(Cl)c(OC)ccc2c1N=O
Agent: COc1ccc2cc(O)ccc2c1Cl
Solvent: CCO
Product: COc1ccc2cc(C(C)=O)ccc2c1Cl

Procedure:
The compound of the title is prepared by following essentially the same procedure described in example 2 but starting from 5-chloro-6-methoxy-2-methylamino-1-nitrosonaphthalene instead of 2-methylamino-1-nitrosonaphthalene and employing 4-methoxybenzaldehyde instead of 4-ethoxybenzaldehyde. Yield 48%. M.p. 247°-48° C. (from ethanol). The starting 5-chloro-6-methoxy-2-methylamino-1-nitrosonaphthalene is prepared through reaction of methylamine with 5-chloro-6-methoxy-1-nitroso-2-naphthol following the procedure described in the second portion of the foregoing example. In its turn this last compound is prepared by nitrosation of 5-chloro-6-methoxy-2-naphthol obtained from (5-chloro-6-methoxy-2-naphthalenyl)-ethanone which is a commercial product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:19]=[C:18]([C:20]([O:22]CC)=[O:21])[CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+]>O1CCCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[N:19]=[C:18]([C:20]([OH:22])=[O:21])[CH:17]=[CH:16][CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cccc(C2CCN(C(=O)OC(C)(C)C)CC2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2cccc(C(=O)O)n2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 6-[1-(tert-butoxycarbonyl)piperidin-4-yl]pyridine-2-carboxylate (500 mg) in tetrahydrofuran (5 ml) and water (1.3 ml) is added, at room temperature, lithium hydroxide monohydrate (125 mg). The mixture is stirred at room temperature for 2 h and then admixed with ice-cold 1N HCl solution. The aqueous phase is extracted with ethyl acetate and then the combined organic phases are dried over sodium sulphate. The solids are filtered off and the solvent is distilled off. This gives 6-[1-(tert-butoxycarbonyl)piperidin-4-yl]pyridine-2-carboxylic acid (310 mg).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:23][C:24]1[C:32]([OH:33])=[CH:31][CH:30]=[C:29]2[C:25]=1[CH:26]=[C:27]([CH3:34])[NH:28]2.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.C(OCC)(=O)C>[F:23][C:24]1[C:32]([O:33][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][N:3]=2)=[CH:31][CH:30]=[C:29]2[C:25]=1[CH:26]=[C:27]([CH3:34])[NH:28]2
Reactant: Cc1cc2c(F)c(O)ccc2[nH]1
Reactant: CCOC(=O)CCCOc1cc2ncnc(Cl)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCOc1cc2ncnc(Oc3ccc4[nH]c(C)cc4c3F)c2cc1OC
Temperature: 50 °C
Reaction time: 2 h
Yield: 84.5 %

Procedure:
To a solution of Compound 6 (5.0 g, 15.39 mmol) and 4-fluoro-2-methyl-1H-indol-5-ol (3.56 g, 21.55 mmol) in acetonitrile (50 mL) was added cesium carbonate (15.05 g, 46.18 mmol). The reaction mixture was stirred at 50° C. for 2 h. TLC showed that no starting material remained. The inorganic material was removed by filtration and the filtrate was concentrated to give a brown solid. The solid was dissolved in ethyl acetate (100 mL) and washed with water (100 mL×2). The organic phase was concentrated and the residue was purified by silica column (gradient of hexane:ethyl acetate 5:1 to 1:2) to give Compound 7 (5.90 g) as a purple solid.
Reaction SMILES: [Cl:1][CH:2]=[C:3](Cl)[Cl:4].[Cl:6][C:7]1[CH:8]=[C:9]([CH3:14])[CH:10]=[CH:11][C:12]=1[Cl:13].[Cl-].[Al+3].[Cl-].[Cl-]>>[CH3:14][C:9]1[CH:8]=[C:7]([Cl:6])[C:12]([Cl:13])=[CH:11][C:10]=1[C:3]([Cl:4])=[CH:2][Cl:1]
Reactant: ClC=C(Cl)Cl
Reactant: Cc1ccc(Cl)c(Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1cc(Cl)c(Cl)cc1C(Cl)=CCl

Procedure:
A mixture containing 131.5 g (1.0 mole), of trichloroethylene, 80.5 (0.5 mole) of 3,4-dichlorotoluene and 5 g. of aluminum chloride was stirred and heated at reflux for 2 hours. The reaction mixture was then washed with concentrated HCl, then with water until neutral, dried and distilled. 42.7 grams of product was collected, having a boiling point of 97°-102°C at 0.5 mm Hg pressure.
Reaction SMILES: CI.[Mg].[Cl:4][C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([Cl:13])[CH:12]=1)C#N.Cl.CC[O:17][CH2:18][CH3:19]>C1C=CC=CC=1.O>[Cl:4][C:5]1[CH:6]=[C:7]([C:18](=[O:17])[CH3:19])[CH:10]=[C:11]([Cl:13])[CH:12]=1
Reactant: CCOCC
Reactant: N#Cc1cc(Cl)cc(Cl)c1
Agent: Cl
Agent: [Mg]
Solvent: c1ccccc1
Solvent: CI
Solvent: O
Product: CC(=O)c1cc(Cl)cc(Cl)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of methyl iodide (4 mL) in anhydrous Et2O (40 mL) was dropped into a suspension of magnesium (1.6 g) in anhydrous Et2O (16 mL) under a Nitrogen atmosphere. At the end of the dropping, benzene (120 mL) was added and the Et2O eliminated with a Nitrogen flux. Then, a solution of 3,5-dichlorobenzonitrile (4 g) in benzene (48 mL) was added and the mixture was heated to reflux for 3 hours. The solution was cooled to 0° C. and a 6N hydrochloric acid solution was added and the mixture was stirred overnight at r.t. Water and Et2O were added and the layers were separated. The organic phase was washed with a saturated sodium hydrogen carbonate solution and brine, dried and concentrated in vacuo. The residue was purified by flash chromatography (CH/AcOEt 95:5) to give the title compound (2.55 g) as an orange oil.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH2:3][NH:4][CH2:5][CH:6]1[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]1.[ClH:21].O1CCOCC1>C(Cl)Cl>[ClH:21].[ClH:21].[F:20][C:2]([F:1])([F:19])[CH2:3][NH:4][CH2:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCC(CNCC(F)(F)F)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: FC(F)(F)CNCC1CCNCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 79 %

Procedure:
To a solution of tert-butyl 4-((2,2,2-trifluoroethylamino)methyl)piperidine-1-carboxylate (1.49 g, 5.03 mmol) in DCM (25 mL) was added 4 N HCl in dioxane (5.03 mL, 20.11 mmol). The reaction was stirred at RT. After 16 hours, the white precipitate was collected by vacuum filtration, washed with diethyl ether, and dried in vacuo, to generate 2,2,2-trifluoro-N-(piperidin-4-ylmethyl)ethanamine dihydrochloride as a white powder (1.07 g, 3.98 mmol, 79% yield).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:30])=[C:16]([NH:21][C:22](=O)[O:23]CC(Cl)(Cl)Cl)[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][CH2:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:31][O:32][CH2:33][CH2:34][NH2:35]>CCCCCC.C(OCC)(=O)C>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:30])=[C:16]([NH:21][C:22]([NH:35][CH2:34][CH2:33][O:32][CH3:31])=[O:23])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][CH2:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: COCCN
Reactant: Cc1c(C)c2c(c(C)c1NC(=O)OCC(Cl)(Cl)Cl)C(c1ccc(C(C)C)cc1)CO2
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COCCNC(=O)Nc1c(C)c(C)c2c(c1C)C(c1ccc(C(C)C)cc1)CO2
Yield: 58 %

Procedure:
Using 2,2,2-trichloroethyl (3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)carbamate obtained in Example 138 and 2-methoxyethylamine, the title compound was synthesized in the same manner as in Example 143. Yield: 58%. Melting point: 172-173° C. (hexane-ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:65][C:66]1[CH:74]=[CH:73][C:69]([C:70]([NH2:72])=[O:71])=[CH:68][CH:67]=1>C(Cl)Cl>[C:70]([C:69]1[CH:73]=[CH:74][C:66]([NH:65][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:26])([CH3:25])[CH3:27])[NH:10]2)=[O:30])=[CH:67][CH:68]=1)(=[O:71])[NH2:72]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: NC(=O)c1ccc(N)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(C(N)=O)cc2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (100 mg, 0.17 mmol) in methylene chloride (10 mL), HATU (Aldrich, 98 mg, 0.26 mmol) was added followed by the addition of DIPEA (90 uL, 0.52 mmol) and 4-amino benzamide (Aldrich, 35 mg, 0.26 mmol). The mixture was stirred at rt overnight. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (40 g column, eluent, 20% EtOAc/hexanes) to give a white solid. 30 mg.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:16]([CH3:23])=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=4)[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([OH:27])[CH2:25][CH3:26])=[CH:4][CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C.[CH:47]1([C:50](O)=[O:51])[CH2:49][CH2:48]1>O1CCCC1.CN(C)C1C=CN=CC=1>[CH:47]1([C:50]([O:27][CH:24]([C:5]2[C:6]3[N:7]4[CH2:14][CH2:13][CH2:12][N:11]([C:15]5[C:16]([CH3:23])=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=5)[C:8]4=[N:9][C:10]=3[C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:25][CH3:26])=[O:51])[CH2:49][CH2:48]1
Reactant: O=C(O)C1CC1
Reactant: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(OC)nc1C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC(OC(=O)C1CC1)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(OC)nc1C
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 73.1 %

Procedure:
To a solution of 1-[9-chloro-1-(6-methoxy-2-methylpyridin-3-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-ol (122.3 mg, 0.316 mmol) in tetrahydrofuran (0.5 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (121.2 mg, 0.632 mmol), triethylamine (88 μL, 0.632 mmol), cyclopropanecarboxylic acid (37.8 μL, 0.474 mmol) and 4-dimethylaminopyridine (57.9 mg, 0.474 mmol). The reaction mixture was stirred at room temperature for 3.5 hrs. The mixture was quenched with aqueous saturated ammonium chloride and extracted with ethyl acetate (×3). The combined organic layer was washed with brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-40% ethyl acetate/n-hexane gradient mixture. The residue was recrystallized from diisopropyl ether/n-hexane to give the title compound as a colorless powder (105.2 mg, 0.231 mmol, 73%).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([OH:16])=O)[CH2:6][CH2:5]2.C1N=CN(C(N2C=NC=C2)=O)C=1.C[NH:32][CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=1>C1COCC1>[OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([NH:32][CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=1)=[O:16])[CH2:6][CH2:5]2
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)O)O2
Reactant: CNCCc1ccccn1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)NCCc1ccccn1)O2
Reaction time: 1 h

Procedure:
A solution of 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (500 mg, 2.0 mmol) in 10 mL THF was treated with 356 mg CDI (2.2 mmol). After 1 h, 366 mg 2-(2-methylaminoethyl)pyridine (3.0 mmol) in 10 mL THF was added over 1 h and stirred overnight. The solution was concentrated, dissolved into 70 mL CH2Cl2, extracted once with 1.0 M NaHCO3. The aqueous phase was then back extracted 2×25 mL CH2Cl2 and the combined organics washed with 2×25 mL saturated NaCl and dried over Na2SO4. The solution was concentrated and purified by flash chromatography to give 6-hydroxy-2,5,7,8-tetramethyl-N-(2-(pyridin-2-yl)ethyl)chroman-2-carboxamide.