Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[CH:28][C:27]=1[CH3:38].[Cl:39][C:40]1[C:41]([C:50]([F:53])([F:52])[F:51])=[N:42][N:43]([CH2:46][C:47](O)=[O:48])[C:44]=1[CH3:45]>>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:37][CH2:36][N:35]([C:47](=[O:48])[CH2:46][N:43]3[C:44]([CH3:45])=[C:40]([Cl:39])[C:41]([C:50]([F:53])([F:52])[F:51])=[N:42]3)[CH2:34][CH2:33]2)=[CH:28][C:27]=1[CH3:38]
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Reactant: Cc1cc(N2CCNCC2)ccc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1cc(N2CCN(C(=O)Cn3nc(C(F)(F)F)c(Cl)c3C)CC2)ccc1Cl

Procedure:
Title compound was prepared following the HATU mediated coupling protocol P, wherein 1-(4-Chloro-3-methylphenyl)-piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a solid: 1H NMR (DMSO-d6, 400 MHz) 7.25 (d, 1H), 7.05 (s, 1H), 6.90 (d, 1H), 5.38 (s, 2H), 3.64 (m, 4H), 3.27 (m, 2H), 3.17 (m, 2H), 2.26 (s, 3H), 2.19 (s, 3H) ppm; MS (ES) M+H expected=435.1, found=435.0.
Reaction SMILES: O[Li].O.C[O:5][C:6](=[O:45])[C@@H:7]([NH:35][S:36]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)(=[O:38])=[O:37])[CH2:8][NH:9][C:10]([C:12]1[O:16][N:15]=[C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]2)[CH:13]=1)=[O:11].OS([O-])(=O)=O.[Na+]>C1COCC1>[C:28]([N:25]1[CH2:26][CH2:27][CH:22]([CH2:21][CH2:20][CH2:19][CH2:18][O:17][C:14]2[CH:13]=[C:12]([C:10]([NH:9][CH2:8][C@H:7]([NH:35][S:36]([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)(=[O:38])=[O:37])[C:6]([OH:45])=[O:5])=[O:11])[O:16][N:15]=2)[CH2:23][CH2:24]1)([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]
Reactant: COC(=O)[C@H](CNC(=O)c1cc(OCCCCC2CCN(C(=O)OC(C)(C)C)CC2)no1)NS(=O)(=O)c1ccccc1
Agent: O=S(=O)([O-])O
Agent: [Li]O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(CCCCOc2cc(C(=O)NC[C@H](NS(=O)(=O)c3ccccc3)C(=O)O)on2)CC1
Yield: 99.2 %

Procedure:
A solution of LiOH.H2O (35 mg, 0.87 mmol, 4-6 (176 mg, 0.29 mmol), and 20% aq. THF (10 mL) was stirred at ambient temperature for 1 h. The reaction mixture was acidified with 1M NaHSO4 and extracted with EtOAc (3×). The combined extracts were dried (MgSO4) and concentrated to give 4-7 (171 mg) as a foam. Rf 0.73 (silica, 9:0.5:0.5 CH2Cl2 /CH3OH/AcOH). ##STR49## 3-[4-(Piperidin-4-yl)butyloxy]isoxazole-5-carbonyl-2(S)-phenylsulfonylamino-β-alanine (4-8)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:30][CH3:31])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[O:27][CH2:28][CH3:29])=[N:13][C:14]=1[CH2:15][CH3:16].ClC1C=[C:37]([O:39]C)C=CC=1C1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=NC=1CC>>[Cl:1][C:2]1[CH:7]=[C:6]([O:39][CH3:37])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:30][CH3:31])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[O:27][CH2:28][CH3:29])=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Reactant: CCc1nc(-c2ccc(OC)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Product: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(OC)cc2Cl)nc1CC

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but substituting (1R,2S)-1-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol and making non-critical variations provided the title compound as a pale yellow semi-solid. IR (liq.) 2971, 2935, 2875, 1606, 1565, 1480, 1440, 1391, 1287, 1230, 1206, 1183, 1091, 1079, 1044 cm−1; OAMS supporting ions at: ESI+ 452.1; MS (EI) m/z 451 (M+); MS (FAB) calcd for C26H30CLN3O2+H1 452.2104, found 452.2100. [α]25D=−91 (c 0.39, methylene chloride); Anal. Calcd for C26H30ClN3O2: C, 69.09; H, 6.69; N, 9.30. Found: C, 69.04; H, 6.74; N, 9.30.
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4][CH3:5].CCCCCC.BrC1[CH:33]=[C:32](C)[C:16]([O:17][C:18]2[C:23]([CH3:24])=[C:22]([O:25][CH:26]([CH2:29][CH3:30])[CH2:27][CH3:28])[CH:21]=[C:20]([CH3:31])[N:19]=2)=[C:15]([CH3:35])[CH:14]=1.C(I)C>C1COCC1>[CH2:4]([C:3]1[CH:2]=[C:32]([CH3:33])[C:16]([O:17][C:18]2[C:23]([CH3:24])=[C:22]([O:25][CH:26]([CH2:29][CH3:30])[CH2:27][CH3:28])[CH:21]=[C:20]([CH3:31])[N:19]=2)=[C:15]([CH3:35])[CH:14]=1)[CH3:5]
Reactant: [Li]CCCC
Reactant: CCC(CC)Oc1cc(C)nc(Oc2c(C)cc(Br)cc2C)c1C
Solvent: C1CCOC1
Solvent: CCI
Solvent: CCCCCC
Product: CCc1cc(C)c(Oc2nc(C)cc(OC(CC)CC)c2C)c(C)c1
Reaction time: 0.08 h

Procedure:
To a solution of 2.5 N n-BuLi in hexane (0.47 ml, 1.18 mmol) in 5 ml of dry THF was added a solution of 2-(4-bromo-2,6-dimethyl-phenoxy)-4-(1-ethyl-propoxy)-3,6-dimethyl-pyridine (465 mg, 1.18 mmol) in 5 ml of dry THF at −78° C. After stirring at that temperature for 5 min, an excess of ethyl iodide (0.4 ml) was added and the resulting mixture was stirred at −78° C. for 30 min, then at 0° C. for 15 min. The mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic layer was dried and concentrated to give a light brown oil. The oil was purified through silica gel column chromatography using chloroform as eluent to give 260 mg of the title compound as white solid. 1H NMR (CDCl3) δ 6.90 (s, 2H), 6.38 (s, 1H), 4.20 (m, 1H), 2.61 (q, 2H), 2.24 (s, 3H), 2.21 (s, 3H), 2.10 (s, 6H), 1.70 (m, 4H), 1.30 (t, 3H), 0.98 (t, 6H) ppm.
Reaction SMILES: [C:1]([C:3]1([CH2:6][OH:7])[CH2:5][CH2:4]1)#[N:2].C(N(CC)CC)C.C(Cl)Cl.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>O>[CH3:18][S:19]([O:7][CH2:6][C:3]1([C:1]#[N:2])[CH2:5][CH2:4]1)(=[O:21])=[O:20]
Reactant: N#CC1(CO)CC1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC1(C#N)CC1

Procedure:
A mixture of 1-cyanocycloprop-1-ylmethanol (4.31 g, 44.4 mmol), obtained as in the proceeding paragraph, triethylamine (9.04 mL, 64.8 mmol) and methylene chloride (78 mL) was cooled under argon to between 0° and 5° C. and methanesulfonyl chloride (4.67 mL, 59.9 mmol) was added slowly. The mixture was cooled 3 hours with stirring at 0° to 5° C., then diluted with water and extracted with methylene chloride. The extract was washed with 5% sodium bicarbonate, dried (MgSO4) and concentrated to dryness to give 1-cyano-cycloprop-1-ylmethyl methanesulfonate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N:3]=1.[F:10][CH:11]([F:14])[CH2:12][NH2:13].C(N(CC)CC)C>C(#N)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][NH:13][CH2:12][CH:11]([F:14])[F:10])=[CH:6][CH:7]=1
Reactant: NCC(F)F
Reactant: ClCc1ccc(Cl)nc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: FC(F)CNCc1ccc(Cl)nc1
Yield: 53.9 %

Procedure:
41.57 g (256.6 mmol) of 2-chloro-5-chloromethylpyridine, 20.80 g (256.6 mmol) of 2,2-difluoroethane-1-amine and 35.8 ml (256.6 mmol) of triethylamine in 500 ml of acetonitrile are stirred at 45° C. for 21 hours. The reaction mixture is concentrated under reduced pressure and the residue is then taken up in 1 N aqueous hydrochloric acid and the mixture is washed with ethyl acetate. The aqueous phase is made alkaline using 2.5 N aqueous sodium hydroxide solution and extracted repeatedly with ethyl acetate. Concentration of the organic phase under reduced pressure gives 28.6 g (53% of theory) of N-[(6-chloropyridin-3-yl)methyl]-2,2-difluoroethane-1-amine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9](O)[C:10]1[S:11][CH:12]=[CH:13][N:14]=1.CN(C)C=O.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([SH:28])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>S(Cl)(Cl)=O.C(OCC)(=O)C>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28][CH:9]([C:3]2[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=2[F:1])[C:10]2[S:11][CH:12]=[CH:13][N:14]=2)=[CH:24][CH:23]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: OC(c1nccs1)c1cc(F)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Fc1ccc(F)c(C(Sc2ccc(Cl)cc2)c2nccs2)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 24 %

Procedure:
The 2-[(2,5-difluorophenyl)-hydroxymethyl]thiazole (348 mg, 1.53 mmol) obtained in Referential Example 15 was dissolved in thionyl chloride (1.5 ml). To the resulting solution was added a drop of dimethylformamide. The resulting mixture was stirred at room temperature for 14 hours. The reaction mixture was concentrated under reduced pressure. Dioxane was added to the residue, followed by further concentration under reduced pressure. The residue was dissolved in dimethylformamide (10.0 ml). To the resulting solution were added 4-chlorobenzenethiol (332 mg, 2.3 mmol) and potassium carbonate (845 mg, 6.12 mmol). The resulting mixture was stirred at 50° C. for 2 hours. After the reaction mixture was allowed to stand until it became room temperature, ethyl acetate (60 ml) was added thereto. The resulting mixture was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate=10:1 to 6:1) to give the title compound (130 mg, 24%) as a colorless oil.
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][CH:11]=[CH:10]3)[CH:2]=1.[H-].[Na+].Br[C:20]1[CH:21]=[C:22]2[C:26](=CC=1)N(CCCCCCCC)C=[C:23]2CC(O)=O>O>[CH3:23][C:22]([CH3:26])=[CH:21][CH2:20][N:12]1[C:13]2[C:9](=[CH:8][C:7]([C:3]3[CH:2]=[C:1]([CH3:16])[CH:6]=[CH:5][CH:4]=3)=[CH:15][CH:14]=2)[CH:10]=[CH:11]1
Reactant: CCCCCCCCn1cc(CC(=O)O)c2cc(Br)ccc21
Reactant: Cc1cccc(-c2ccc3[nH]ccc3c2)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CC(C)=CCn1ccc2cc(-c3cccc(C)c3)ccc21
Reaction time: 1 h
Yield: 87.1 %

Procedure:
To the solution of 5-m-tolyl-1H-indole (3, 4 mmol, 1 equiv.) in anhydrous dimethylsulfoxide(DMSO) was added NaH (60% in mineral oil dispersion, 4.8 mmol, 1.2 equiv.) at room temperature. The mixture was stirred for about 1 h at the same temperature, then 1-chloro-3-methylbut-2-ene (4, 4.8 mmol, 1.2 equiv.) was added and the mixture was stirred for 4 h. Water was added to stop the reaction. The mixture was extracted by dichloromethane and the organic layer was washed with brine, dried (Na2SO4), filtered, and evaporated. The residue was purified by column chromatography of silica gel to get off-yellow oil. Yield: 87.1%. 1H NMR (300 MHz, CDCl3): δ 1.82 (s, 3 H), 1.88 (s, 3 H), 2.48 (s, 3 H), 4.74 (d, J=6.6 Hz, 2 H), 5.45 (t, J=6.9 Hz, 1 H), 6.57 (d, J=2.4 Hz, 1 H), 7.17 (t, J=3.3 Hz, 2 H), 7.34-7.43 (m, 2H), 7.49-7.52 (m, 3H), 7.89 (s, 1H). 13C NMR (75 MHz, CDCl3) δ 18.0, 21.6, 25.6, 44.2, 101.3, 109.6, 119.4, 119.9, 121.2, 124.4, 126.9, 128.0, 128.2, 128.5, 129.2, 132.9, 135.5, 136.3, 138.1, 142.6.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C@H:7]([CH2:8][C:9](=[O:32])[C@@H:10]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:31])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:22])[CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH2:6]1)(=[O:3])[CH3:2].[Br:33]Br.Br.O>C(O)(=O)C>[C:1]([O:4][C@@H:5]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C@H:7]([CH:8]([Br:33])[C:9](=[O:32])[C@@H:10]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:31])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:22])[CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: BrBr
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C(=O)C[C@@H]4C[C@H](OC(C)=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C(=O)C(Br)[C@@H]4C[C@H](OC(C)=O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
A solution of methyl 3α-acetoxy-7-keto-5β-cholanoate. (5.6 g, 12.54 mmoles) in acetic acid (100 ml) was added with a bromine solution (2.8g) in acetic acid (10 ml) and immediately after with 48% hydrobromic acid (0.74 ml). The resulting reaction mixture was left to react overnight under strong magnetic stirring, then it was poured into water (300 ml) and filtered under vacuum to obtain a solid (8,03 g) which was subjected to flash chromatography on silica, eluting with methylene chloride/methanol 99.5:0.5, to yield 6.0 g of a pure product (91%).
Reaction SMILES: [CH3:1][N:2]([CH3:4])[CH3:3].[CH3:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][Cl:12])=[CH:9][C:8]=1[N+:15]([O-:17])=[O:16].C(O)(=O)C>O>[Cl-:12].[N+:15]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:7]=1[O:6][CH3:5])[CH2:11][N+:2]([CH3:4])([CH3:3])[CH3:1])([O-:17])=[O:16]
Reactant: COc1ccc(CCl)cc1[N+](=O)[O-]
Reactant: CN(C)C
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(C[N+](C)(C)C)cc1[N+](=O)[O-]
Product: [Cl-]
Temperature: 50 °C

Procedure:
) To a stirred solution of 35.0 parts of trimethylamine in 105 parts of water there was added over a one and one-half hour period 100.8 parts of 4-methoxy-3-nitrobenzyl chloride. The reaction mixture was heated at approximately 50° C. for three and a half hours and was then diluted with an additional 50 parts of water. The solution was allowed to cool to about 25° C. and the pH was adjusted to 4.9 by the addition of dilute acetic acid. The solution was clarified by filtration and used directly for reduction of the thus obtained N-(3-nitro-4-methoxybenzyl)-N,N,N-trimethylammonium chloride dissolved therein. b. The aqueous solution of N-(3-nitro-4-methoxybenzyl)-N,N,N-trimethylammonium chloride obtained in a.) was heated to approximately 85° C. Then 110 parts of iron powder was added at a rate sufficient to maintain a temperature in the range 85°-90° C. without further external heating. At the end of the addition, heating was resumed at 85°-90° C. for one hour and then the reaction was set aside at room temperature overnight. The reaction mixture was heated to 80° C. and the pH adjusted to approximately 8.0 by the addition of a dilute aqueous solution of sodium carbonate. The mixture was allowed to cool to approximately 45° C. and was then filtered with the aid of 3 parts of decolorizing charcoal. A sample of the clear solution was analyzed for free amine content by diazotization using a standardized sodium nitrite solution. The analytical results showed that N-(3-amino-4-methoxybenzyl)-N,N,N-trimethylammonium chloride was obtained in nearly quantitative yield. The product was used directly in the form of its aqueous solution without isolation.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][Br:8].[Cl:9][C:10]1[CH:11]=[C:12]([CH2:16][CH2:17][OH:18])[CH:13]=[CH:14][CH:15]=1>>[Br:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:18][CH2:17][CH2:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([Cl:9])[CH:11]=1
Reactant: OCCc1cccc(Cl)c1
Reactant: BrCCCCCCBr
Product: Clc1cccc(CCOCCCCCCBr)c1

Procedure:
(4.12 g), T.l.c. (ER- HX 1:79) Rf 0.16, from 1,6-dibromohexane (11.71 g) and 3-chlorobenzeneethanol (2.5 g).
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].P(Cl)(Cl)(Cl)(Cl)[Cl:18]>>[Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([Cl:18])=[O:7])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Product: O=C(Cl)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 71.5 %

Procedure:
A mixture of 75.75 gm. (0.307 mole) of 4-chloro-3,5-dinitrobenzoic acid and 64.0 gm. (0.307 mole) of phosphorus pentachloride is heated at reflux for ninety minutes and cooled to room temperature. The phosphorus oxychloride is removed by distillation in vacuo. The residue is washed with Skellysolve "B" and the solvent removed by decantation. The oily residue is recrystallized from benzene-cyclohexane. There is obtained 58.2 gm (72%) of tan needles melting at 55°-57°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:11][C:12]2[CH:17]=[C:16](F)[CH:15]=[CH:14][C:13]=2[S:19]([CH3:22])(=[O:21])=[O:20])[CH3:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[N:23]1(C(OC(C)(C)C)=O)[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:11][C:12]2[CH:17]=[C:16]([N:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[CH:15]=[CH:14][C:13]=2[S:19]([CH3:22])(=[O:21])=[O:20])[CH3:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(Nc1cc(F)ccc1S(C)(=O)=O)c1cc(Cl)cc(Cl)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1cc(N2CCNCC2)ccc1S(C)(=O)=O)c1cc(Cl)cc(Cl)c1
Yield: 49 %

Procedure:
N-(1-(3,5-Dichlorophenyl)ethyl)-5-fluoro-2-(methylsulfonyl)benzenamine (600 mg, 1.62 mmol), t-butyl piperazine-1-carboxylate (0.29 mmol), N,N-diisopropylethylamine (0.58 mmol) were stirred at 60° C. in dry acetonitrile (20 mL) for 3 days. The solvent was evaporated and the residue was dissolved in dichloromethane and washed with water. The dichloromethane was evaporated and the crude compound was purified by silica chromatography using 20% ethyl acetate in hexanes to afford the title compound (49% yield). 1H NMR (400 MHz, CDCl3): δ 9.31 (d, 1H), 7.63 (d, 1H), 7.25 (s, 1H), 7.22 (s, 2H), 6.18 (d, 1H), 5.53 (s, 1H), 4.48 (m, 1H), 3.48 (m, 4H), 3.25 (m, 4H), 1.60 (d, 3H), 1.47 (s, 9H); MS (ESI) m/z: Calculated for C19H23Cl2N3O2S: 428.3; Observed: 429.4 (M++1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=O)=[CH:3][CH:2]=1.[C:16]([NH:24][NH2:25])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)(=O)C>[C:10]1([CH2:9][C:7](=[N:25][NH:24][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cc1ccccc1)c1ccncc1
Reactant: NNC(=O)c1ccccc1
Solvent: CC(=O)O
Product: O=C(NN=C(Cc1ccccc1)c1ccncc1)c1ccccc1

Procedure:
Following the general method of procedure 9 and making non-critical variations, except 12 drops of glacial acetic acid was used, 6.00 gm (0.0304 mole) of benzyl 4-pyridyl ketone and 4.14 gm (0.0304 mole) of benzhydrazide yield 8.90 gm (93%) of the title compound in two crops melting at 84.4° and 90.9°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:16]([NH:18][C@H:19]4[CH2:24][CH2:23][CH2:22][C@H:21]([NH2:25])[CH2:20]4)=[N:15][CH:14]=[N:13][C:12]=3[O:11][C:10]=2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:5][CH:4]=1.C(O)(=O)C.[CH3:36][O:37][C:38](=[O:41])[CH:39]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.O>[CH3:36][O:37][C:38](=[O:41])[CH2:39][NH:25][C@H:21]1[CH2:22][CH2:23][CH2:24][C@H:19]([NH:18][C:16]2[C:17]3[C:9]([C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)=[C:10]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[O:11][C:12]=3[N:13]=[CH:14][N:15]=2)[CH2:20]1
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(N[C@H]4CCC[C@H](N)C4)c23)cc1
Reactant: COC(=O)C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)CN[C@H]1CCC[C@H](Nc2ncnc3oc(-c4ccccc4)c(-c4ccc(OC)cc4)c23)C1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Dissolve 132 mg (0.318 mmol) of −(+/−)-cis/trans-N-[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]-cyclohexane-1,3-diamine (Example 36A) in 1.5 ml of dichloromethane and add 18.7 μl of acetic acid at RT. Add 28 mg (0.318 mmol) of oxoacetic acid methyl ester and, after 5 min, 101 mg (0.478 mmol) of sodium triacetoxyborohydride. Stir the mixture at RT for 2 h and then dilute with water and dichloromethane. Wash the organic phase with saturated sodium carbonate solution, dry over sodium sulphate and concentrate under reduced pressure. Purify the crude product by preparative RP-HPLC (eluent: acetonitrile/water gradient) and separate the cis/trans isomers:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][NH2:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][NH:15][C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC(CN)C1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC(CNC(=O)OCc2ccccc2)C1

Procedure:
A solution of 3-aminomethylpiperidine-1-carboxylic acid tert-butyl ester (2.20 g, 10.3 mmol) in dichloromethane (40 mL) was treated with triethylamine (1.90 mL, 13.3 mmol) and stirred on an ice bath. A solution of benzyl chloroformate (1.90 mL, 13.3 mmol) in dichloromethane (10 mL) was added over 5 minutes. The mixture was stirred at room temperature for 70 hours. It was washed with 0.1 N aqueous hydrochloric acid, dried over sodium sulfate, and concentrated under vacuum to provide a colorless gum (3.58 g, quantitative) which was used without further purification. 1H NMR (300 MHz, CDCl3) δ7.37 (m, 5H), 5.11 (s, 2H), 3.75 (m, 2H), 3.18 (m, 1H), 3.05 (m, 2H), 2.83 (m, 1H), 1.9-1.6 (m, 4H), 1.46 (s, 9H), 1.27 (m, 1H).
Reaction SMILES: [Na].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[O-]CC.[Na+:16].Br[CH:18]([CH2:20][CH2:21][CH3:22])[CH3:19]>C(O)C>[O-:5][CH2:4][CH3:3].[Na+:16].[CH3:19][CH:18]([CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]([O:10][CH2:11][CH3:12])=[O:9])[CH2:20][CH2:21][CH3:22]
Reactant: CCCC(C)Br
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCCC(C)C(C(=O)OCC)C(=O)OCC
Temperature: 80 °C
Reaction time: 24 h

Procedure:
Sodium ethoxide was prepared from sodium metal (7.61 g) and absolute ethanol (200 ml). Diethyl malonate (50.3 ml) was added dropwise to the ethanol containing sodium ethoxide. After heating to 80° C., 2-bromopentane (50 g) was added and the mixture was reflued for 24 h. Diethyl (2-pentyl)malonate (62.7 g) was obtained after the usual work-up. Diethyl (2-pentyl)malonate was added to a 50% potassium hydroxide solution and the mixture was heated for 3 h while water/ethanol being distilled off. After cooling, the solution was acidified with concentrated hydrochloric acid. Then, the solution was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the resulting product was heated to 180° C. until bubbling ceased. After distillation, colorless 3R,S-methy-caproic acid was obtained. Yield : 27.7 g (35%), b.p. 200° C./760 mmHg.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH2:4][N:3]=1.C([N:19](C(C)C)CC)(C)C.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1.O>C(#N)C>[Cl:8][C:6]1[N:19]=[C:4]([NH:5][C:9]2[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=2)[N:3]=[C:2]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)[N:7]=1
Reactant: Fc1ccc(N2CN=C(Cl)N=C2Cl)cc1
Reactant: Cc1ccc(N)cc1
Reactant: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CC#N
Product: Cc1ccc(Nc2nc(Cl)nc(Nc3ccc(F)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 2.59 g portion of 4,6-dichloro-N-(4-fluorophenyl)-1,3,5-triazine was dissolved in 20 ml of acetonitrile, and 2.09 ml of diisopropylethylamine and 1.18 g of p-toluidine were added thereto and stirred overnight at room temperature. The reaction solution was mixed with water and extracted with ethyl acetate, and the organic layer was washed with 1 M hydrochloric acid and saturated brine and then dried using anhydrous magnesium sulfate. The solvent was evaporated under a reduced pressure, the thus obtained residue was applied to a silica gel column chromatography and eluted with ethyl acetate:n-hexane (1:9), and then the thus obtained crude product was crystallized from benzene, thereby obtaining 2.74 g of 6-chloro-N-(4-fluorophenyl)-N′-(4-methylphenyl)-1,3,5-triazine-2,4-diamine as a white solid.