Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na+].CS([CH2-])=O.[Br-].[C:7]([CH2:10][CH2:11][CH2:12][CH2:13][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:9])=[O:8].[CH:33](=O)[C:34]1[O:38][CH:37]=[CH:36][CH:35]=1>CS(C)=O>[O:38]1[CH:37]=[CH:36][CH:35]=[C:34]1[CH:33]=[CH:13][CH2:12][CH2:11][CH2:10][C:7]([OH:9])=[O:8]
Reactant: O=C(O)CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccco1
Agent: [Br-]
Agent: [CH2-]S(C)=O
Agent: [Na+]
Solvent: CS(C)=O
Product: O=C(O)CCCC=Cc1ccco1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cooled solution of dimsyl sodium (prepared by heating 4.35 g. of 50% oil dispersion of sodium hydride in 50 ml. dimethylsulfoxide at 60° for 2 hours under argon) is added dropwise 20.0 g. of (4-carboxybutyl)triphenylphosphonium bromide in 90 ml. dimethylsulfoxide. After the solution has stirred at room temperature for one hour, a solution of 4.34 g. furfural in 20 ml. dimethylsulfoxide is added dropwise to the cool (15°) solution over 20 minutes. After 2 hours the dimethylsulfoxide is evaporated, the residue is dissolved in 100 ml. water, filtered and extracted four times with 150 ml. portions of ethyl acetate. The aqueous solution is acidified to pH 1 with 1 N hydrochloric acid, saturated with sodium chloride and extracted twice with 150 ml. portions of ethyl ether. The ether is dried and evaporated to yield the title compound as a yellow oil.
Reaction SMILES: [C:1]1([C@@H:7]([CH3:11])[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:12][C:13]1[CH:14]=[CH:15][C:16]2[O:20][C:19]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[N:18][C:17]=2[CH:27]=1>>[C:1]1([C@@H:7]([CH3:11])[C:8]([NH:12][C:13]2[CH:14]=[CH:15][C:16]3[O:20][C:19]([C:21]4[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=4)=[N:18][C:17]=3[CH:27]=2)=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[C@@H](C(=O)O)c1ccccc1
Reactant: Nc1ccc2oc(-c3ccncc3)nc2c1
Product: C[C@@H](C(=O)Nc1ccc2oc(-c3ccncc3)nc2c1)c1ccccc1

Procedure:
Similarly prepared as per compound 8 procedure, using starting materials (R)-2-phenylpropanoic acid and compound 4 (4-pyridine) to obtain title compound Q49 as white solid (78%). 1H NMR (CDCl3, 400 MHz) δ 1.59 (d, J=7.2 Hz, 3H), 3.76 (q, J=6.8 Hz, 1H), 7.21-7.29 (m, 1H), 7.32-7.41 (m, 6H), 7.90 (s, 1H), 7.97 (d, J=4.8 Hz, 3H), 8.74 (s, 2H); 13C NMR (CDCl3, 100 MHz) δ 18.9, 48.0, 110.8, 112.3, 119.8, 121.2, 127.7, 127.8, 129.2, 134.3, 135.6, 141.1, 142.1, 147.7, 150.7, 161.4, 172.9; ESI-HRMS for C21H18N3O2 (M+H)+ calcd. 344.1399. found 344.1393 (% ee 99, tR=11.29 min).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:11]=[C:12]([N:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][N:24]=4)[C:19](=[O:26])[C:18]([C:27](O)=[O:28])=[CH:17]3)[CH:13]=[CH:14][CH:15]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:2].S(Cl)(Cl)=O.[CH:34]([NH2:37])([CH3:36])[CH3:35]>O1CCCC1>[CH:34]([NH:37][C:27]([C:18]1[C:19](=[O:26])[C:20]2[C:25](=[N:24][CH:23]=[CH:22][CH:21]=2)[N:16]([C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=3)[CH:11]=2)[CH:17]=1)=[O:28])([CH3:36])[CH3:35]
Reactant: CCOc1cccc(-c2cccc(-n3cc(C(=O)O)c(=O)c4cccnc43)c2)c1
Reactant: CC(C)N
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CCOc1cccc(-c2cccc(-n3cc(C(=O)NC(C)C)c(=O)c4cccnc43)c2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 1-[3-(3-ethoxyphenyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxylic acid from Step 2 and thionyl chloride (4 eq) in tetrahydrofuran (10 ml/mmol) was refluxed for 45 minutes, then evaporated. The residue was dissolved in the same volume of tetrahydrofuran, isopropylamine (5 eq) was added and the mixture was stirred at room temperature for 18 hours. After quenching with saturated aqueous ammonium chloride solution, the resulting mixture was partitioned between ethyl acetate and water, and the product from the organic phase was chromatographed on silica gel eluting with 10% ether in methylene chloride to afford the N-Isopropyl-1-[3-(3-ethoxyphenyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide compound as a solid.
Reaction SMILES: C([O:4][C@@H:5]1[C@H:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[C@@H:10]([CH2:22][O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])[O:9][C@@H:6]1[O:7][CH3:8])(=O)C>C([O-])([O-])=O.[K+].[K+]>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[CH2:13][O:12][C@@H:11]1[C@@H:10]([CH2:22][O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])[O:9][C@H:6]([O:7][CH3:8])[C@@H:5]1[OH:4]
Reactant: CO[C@H]1O[C@H](COCc2ccc(Cl)cc2Cl)[C@@H](OCc2ccc(Cl)cc2Cl)[C@H]1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CO[C@H]1O[C@H](COCc2ccc(Cl)cc2Cl)[C@@H](OCc2ccc(Cl)cc2Cl)[C@H]1O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 101.6 %

Procedure:
A mixture of 2-O-acetyl-3,5-bis-O-(2,4-dichlorobenzyl)-1-O-methyl-α-D-ribofuranose (2-1) [for preparation, see: Helv. Chim. Acta 78: 486 (1995)](52.4 g, 0.10 mol) in methanolic K2CO3 (500 mL, saturated at room temperature) was stirred at room temperature for 45 min. and then concentrated under reduced pressure. The oily residue was suspended in CH2Cl2 (500 mL), washed with water (300 mL+5×200 mL) and brine (200 mL), dried (Na2SO4), filtered, and concentrated to give the title compound (49.0 g) as colorless oil, which was used without further purification in Step B below.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH:8][CH3:9])=[N:6][CH:7]=1.F[C:12](F)(F)[C:13](O)=O.[C:18](O[BH-](O[C:28](=O)[CH3:29])OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C(OC(C)C)(=O)C.O.CC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][CH:12]([CH3:13])[CH3:18])[C:5]([NH:8][CH3:9])=[N:6][CH:7]=1.[Br:1][C:2]1[CH:3]=[C:4]2[NH:10][C:28]([CH3:29])([CH3:12])[N:8]([CH3:9])[C:5]2=[N:6][CH:7]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CNc1ncc(Br)cc1N
Reactant: O=C(O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Solvent: CC(=O)OC(C)C
Product: CN1c2ncc(Br)cc2NC1(C)C
Product: CNc1ncc(Br)cc1NC(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 1225.3 %

Procedure:
5-bromo-N2-methylpyridine-2,3-diamine (54.4 mg, 0.269 mmol) was dissolved in isopropyl acetate (1.5 ml) and acetone (23 μl, 0.31 mmol), trifluoroacetic acid (0.045 ml, 0.58 mmol), and sodium triacetoxyborohydride (64 mg, 0.30 mmol) were added. The reaction was stirred under nitrogen at room temperature for 4 hours, and then more acetone was added (0.040 ml) along with TFA (0.090 ml) and isopropyl acetate (0.5 ml). The reaction was then stirred overnight. This reaction was repeated on a larger scale using 5-bromo-N2-methylpyridine-2,3-diamine (288 mg, 1.43 mmol), 2,2,2-trifluoroacetic acid (0.30 ml, 3.9 mmol), acetone (0.13 ml, 1.8 mmol), and sodium triacetoxyborohydride (352 mg, 1.66 mmol). Then, both reactions were poured into water (25 ml), and solid sodium hydroxide was added to raise the pH to about 10. The layers were separated, and the aqueous phase was extracted with EtOAc. The organic extracts were combined, dried over sodium sulfate, filtered, concentrated, and dried under high vacuum. To afford 5-bromo-N3-isopropyl-N2-methylpyridine-2,3-diamine and 6-bromo-2,2,3-trimethyl-2,3-dihydro-1H-imidazo[4,5-b]pyridine (399 mg, 97% combined yield).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([C:13]3([CH2:26][C:27]#[N:28])[CH2:18][CH2:17][N:16]([C:19]([O:21]C(C)(C)C)=O)[CH2:15][CH2:14]3)[CH:12]=2)[CH:5]=[CH:4][N:3]=1.Cl.C(N(CC)CC)C.[O:37]1[C:41](C(Cl)=O)=[CH:40][CH:39]=[N:38]1>O1CCOCC1.C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([C:13]3([CH2:26][C:27]#[N:28])[CH2:18][CH2:17][N:16]([C:19]([C:41]4[O:37][N:38]=[CH:39][CH:40]=4)=[O:21])[CH2:15][CH2:14]3)[CH:12]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CC#N)(n2cc(-c3ccnc(Cl)n3)cn2)CC1
Reactant: O=C(Cl)c1ccno1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#CCC1(n2cc(-c3ccnc(Cl)n3)cn2)CCN(C(=O)c2ccno2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of tert-butyl 4-(4-(2-chloropyrimidin-4-yl)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate (0.259 g, 0.643 mmol) in 2 mL of dioxane was added 4 M HCl in dioxane (4.0 mL). The reaction was stirred at room temperature for 30 min, then evaporated to dryness. To the resulting crude HCl salt in methylene chloride (5.0 mL) was added triethylamine (0.269 mL, 1.93 mmol) followed by isoxazole-5-carbonyl chloride (0.0744 mL, 0.771 mmol). The mixture was stirred at room temperature for 30 min, washed with saturated sodium bicarbonate, dried, and evaporated to dryness. The residue was used directly in next step (233 mg, 91%). LCMS (M+H) 398.0.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=O.[NH2:18][C:19]1[CH:31]=[C:30]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:29]=[CH:28][C:20]=1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C(=O)([O-])O.[Na+]>C(N(CC)CC)C.C(Cl)Cl.CN(C)C=O>[CH3:7][O:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([NH:18][C:19]1[CH:31]=[C:30]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:29]=[CH:28][C:20]=1[C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])=[O:13]
Reactant: CC(C)(C)OC(=O)c1ccc(Oc2ccccc2)cc1N
Reactant: COc1ccccc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccccc1C(=O)Nc1cc(Oc2ccccc2)ccc1C(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
1.0 mL of methylene chloride, 2.7 pit of N,N-dimethylformamide and 0.061 mL of oxalyl chloride were added to 0.11 g of 2-methoxybenzoic acid at room temperature sequentially and stirred at the same temperature for 1 hour. The reaction mixture was added to a mixed solution of 4.0 mL of methylene chloride and 0.45 mL triethylamine containing 57 mg of tert-butyl 2-amino-4-phenoxybenzoate and stirred at room temperature for 1 hour. A saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, and the organic layer was separated, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane:ethyl acetate=4:1] to obtain tert-butyl 2-(2-methoxybenzamido)-4-phenoxybenzoate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[N:7]([CH2:15][CH2:16][CH2:17][OH:18])[C@H:8]1[CH2:13][CH2:12][C@H:11]([CH3:14])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:20]1(O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:1]([O:5][C:6](=[O:19])[N:7]([CH:8]1[CH2:9][CH2:10][CH:11]([CH3:14])[CH2:12][CH2:13]1)[CH2:15][CH2:16][CH2:17][O:18][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N(CCCO)[C@H]1CC[C@H](C)CC1
Reactant: Oc1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1CCC(N(CCCOc2ccccc2)C(=O)OC(C)(C)C)CC1
Reaction time: 18 h
Yield: 51.5 %

Procedure:
(3-Hydroxy-propyl)-(trans-4-methyl-cyclohexyl)-carbamic acid tert-butyl ester (1.5 g, 5.53 mmol) and phenol (0.52 g, 5.53 mmol) in dry THF (15 mL) was added DEAD (1.06 g, 6.08 mmol) and resin bound triphenyl phosphine (polystyrene, 2% cross linking, loading=3 mmol/g, 2.76 g). The reaction mixture was gently stirred for 18 h before the resin was filtered off and washed with THF (2×15 mL). The fitrate was concentrated in vacuo and the resulting residue was purified (SiO2, 0-20% EtOAc in heptane) to give 0.99 g of (4-methyl-cyclohexyl) -(3-phenoxy-propyl)-carbamic acid tert-butyl ester. This was dissolved in DCM-TFA ((3:1), 16 mL) and the mixture was stirred for 18 h before the solvent was removed in vacuo to give 0.75 g of the TFA salt of (4-methyl-cyclohexyl)-(3-phenoxy-propyl)-amine.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([CH3:29])=[C:7]([NH:15][CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)=[O:4].[CH:30](=O)[CH3:31].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl.CC(O)=O>[C:25]([O:24][C:22]([N:19]1[CH2:18][CH2:17][CH:16]([N:15]([CH2:30][CH3:31])[C:7]2[CH:8]=[C:9]([C:11]([F:13])([F:14])[F:12])[CH:10]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[C:6]=2[CH3:29])[CH2:21][CH2:20]1)=[O:23])([CH3:26])([CH3:28])[CH3:27]
Reactant: COC(=O)c1cc(C(F)(F)F)cc(NC2CCN(C(=O)OC(C)(C)C)CC2)c1C
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCN(c1cc(C(F)(F)F)cc(C(=O)OC)c1C)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 23 °C
Reaction time: 24 h
Yield: 39.9 %

Procedure:
To a stirred solution of tert-butyl 4-{[3-(methoxycarbonyl)-2-methyl-5-(trifluoromethyl)phenyl]amino}piperidine-1-carboxylate (10.6 g, 25.4 mmol) in CH2Cl2 (200 mL) and AcOH (10 mL) was added acetaldehyde (2.80 g, 63.5 mmol) and sodium triacetoxyborohydride (13.4 g, 63.5 mmol). The reaction mixture was stirred at 23° C. for 24 hours. Then saturated NaHCO3 was added and the mixture was separated. The aqueous layer was extracted with CH2Cl2 (3×50 mL) and the combined organic layer was concentrated in vacuo. The residue was purified by silica gel column chromatography (SiO2 Heptane/EtOAc=5/1) to give the titled compound as oil (4.50 g, 40% yield). 1H-NMR (400 MHz, CDCl3) δppm; 7.82 (br. s., 1H), 7.45 (d, J=1.6 Hz, 1H), 3.96-4.18 (m, 2H), 3.92 (s, 3H), 3.08 (q, J=7.0 Hz, 2H), 2.89 (tt, J=11.0, 3.7 Hz, 1H), 2.69 (m, 2H), 2.55 (s, 3H), 1.73 (m, 2H), 1.49-1.56 (m, 2H), 1.45 (s, 9H), 0.86 (t, J=7.0 Hz, 3H); MS (ES) [M+Na] 467.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[C:18]([CH3:20])([CH3:19])[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:21](O)=[O:22])[CH:15]=3)[NH:10]2)[CH:6]=[CH:7][CH:8]=1.C[NH3+].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[CH3:64][C:65]1([OH:70])[CH2:69][CH2:68][NH:67][CH2:66]1>ClCCl>[OH:70][C:65]1([CH3:64])[CH2:69][CH2:68][N:67]([C:21]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[NH:10][CH:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:18]([CH3:20])([CH3:19])[CH2:17]3)=[O:22])[CH2:66]1
Reactant: CC1(O)CCNC1
Reactant: COc1cccc(C2Nc3ccc(C(=O)O)cc3CC2(C)C)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C[NH3+]
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(C2Nc3ccc(C(=O)N4CCC(C)(O)C4)cc3CC2(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.9 %

Procedure:
To a stirred solution of 2-(3-methoxy-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (100 mg, 0.32 mmol), 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (HATU) (243 mg, 0.64 mmol) and triethyl amine (0.36 mL, 1.28 mmol) in dichloromethane was added 3-methyl-pyrrolidin-3-ol (66 mg, 0.38 mmol) at room temperature and stirred at room temperature for overnight. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded (3-hydroxy-3-methyl-pyrrolidin-1-yl)-[2-(3-methoxy-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinolin-6-yl]-methanone (63 mg, 50%) as a white foam: LC/MS m/e calcd for C24H30N2O3 (M+H)+: 395.52, observed: 395.2.
Reaction SMILES: [Br:1]N1C(=O)NC(=O)N(Br)C1=O.[CH2:12]([O:14][C:15]1[CH:16]=[C:17]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH:18]=[CH:19][C:20]=1[C:21]([O:23][CH3:24])=[O:22])[CH3:13].CN(C=O)C>O>[Br:1][C:18]1[CH:19]=[C:20]([C:21]([O:23][CH3:24])=[O:22])[C:15]([O:14][CH2:12][CH3:13])=[CH:16][C:17]=1[C:25]1[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=1
Reactant: CCOc1cc(-c2ccc(F)cc2)ccc1C(=O)OC
Reactant: O=c1[nH]c(=O)n(Br)c(=O)n1Br
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc(-c2ccc(F)cc2)c(Br)cc1C(=O)OC
Yield: 188.7 %

Procedure:
Dibromoisocyanuric acid (3.28 g) was added to a mixture of methyl 3-ethoxy-4′-fluorobiphenyl-4-carboxylate (5.92 g) and DMF (40 mL), and the resultant mixture was stirred overnight at room temperature. Water was added to the reaction mixture at room temperature, followed by extraction with ethyl acetate. The obtained organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (7.62 g).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:12][C:13]([O:15]C)=O)[CH:9]=2)[CH2:4]1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.Cl.[CH3:29][NH:30][CH2:31][C:32]([O:34]C)=[O:33]>>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH:2][CH:3]2[CH2:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([CH2:12][C:13]([N:30]([CH2:31][C:32]([OH:34])=[O:33])[CH3:29])=[O:15])[CH:9]=3)[CH2:4]2)(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: COC(=O)Cc1ccc2c(c1)CC(N)C2
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CNCC(=O)OC
Agent: Cl
Product: CN(CC(=O)O)C(=O)Cc1ccc2c(c1)CC(NS(=O)(=O)c1ccc(Cl)cc1)C2

Procedure:
In the same manner as described in Examples 24 and 33, methyl (2-aminoindan-5-yl)acetate hydrochloride, 4-chlorophenylsulfonyl chloride and methyl N-methyl-glycinate hydrochloride are treated to give 2-[N-[2-[(4-chlorophenyl)sulfonylamino]indan-5-yl]acetyl-N-methylamino]-acetic acid
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][CH:8]([CH2:11][CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.Br[C:19]1[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][CH:24]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.CC(C)([O-])C.[Na+]>O1CCOCC1>[CH:1]1([N:5]2[CH2:6][CH2:7][CH:8]([CH2:11][CH:12]3[CH2:17][CH2:16][N:15]([C:19]4[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][CH:24]=4)[CH2:14][CH2:13]3)[CH2:9][CH2:10]2)[CH2:4][CH2:3][CH2:2]1
Reactant: C1CC(N2CCC(CC3CCNCC3)CC2)C1
Reactant: FC(F)(F)c1ncc(Br)cn1
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Na+]
Solvent: C1COCCO1
Product: FC(F)(F)c1ncc(N2CCC(CC3CCN(C4CCC4)CC3)CC2)cn1
Temperature: 120 °C
Yield: 36.8 %

Procedure:
1-Cyclobutyl-4-(4-piperidinylmethyl)piperidine (may be prepared as described in Description 6) (0.15 g), 5-bromo-2-trifluoromethylpyrimidine (may be prepared as described in F. Cottet and M. Schlosser, Eur. J. Org. Chem., 2002, 327) (0.129 g), tris(dibenzylidineacetone)dipalladium(0) (0.053 g), 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (0.088 g) and sodium tert-butoxide (0.092 g) were added to dioxane (2 ml) and heated at 120° C. for 14 min in the microwave reactor. The crude reaction mixture was passed through an SCX column (10 g, eluting with methanol [80 ml ] then 2 N NH3 in methanol [80 ml]). Chromatography (silica gel, eluting with methanol/dichloromethane, 0-20%) afforded the title compound (E35) (0.08 g). MS electrospray (+ion) 383 (MH+).
Reaction SMILES: Br[CH2:2][C:3](OC(=O)CBr)=[O:4].[NH2:10][C:11]1[CH:12]=[C:13]([CH2:27][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[CH:14]=[C:15]2[C:20]=1[N:19]=[CH:18][C:17]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:16]2[OH:26].C(N(CC)CC)C>CN(C=O)C>[N:28]1([CH2:27][C:13]2[CH:14]=[C:15]3[C:16](=[O:26])[C:17]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:18][N:19]4[CH2:2][C:3](=[O:4])[NH:10][C:11]([CH:12]=2)=[C:20]34)[CH2:29][CH2:30][O:31][CH2:32][CH2:33]1
Reactant: O=C(CBr)OC(=O)CBr
Reactant: CCOC(=O)c1cnc2c(N)cc(CN3CCOCC3)cc2c1O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn2c3c(cc(CN4CCOCC4)cc3c1=O)NC(=O)C2
Temperature: 60 °C
Reaction time: 1 h
Yield: 83.8 %

Procedure:
Bromoacetic anhydride (280 mg) is added to ethyl 8-amino-4-hydroxy-6-(4-morpholinylmethyl)-3-quinolinecarboxylate (Preparation 2, 330 mg) in DMF (4.0 mL). Triethylamine (400 mg) is added and the reaction is heated for 10 min at 60° C. After 1 h, the DMF is removed and the product is chromatographed on silica gel with 10% methanol as the eluant to give 310 mg of the title compound as a mixture with triethylamine hydrobromide. Physical characteristics: 1H NMR (DMSO-d6) δ1.40, 2.45, 3.56, 3.69, 4.39, 4.88, 7.49, 7.97, 8.34.
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[CH:13]1([NH2:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.CO.[H][H]>[Ni].O>[CH:13]1([NH:19][CH2:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: NC1CCCCC1
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Solvent: O
Product: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CNC1CCCCC1
Reaction time: 8 h

Procedure:
18 G. of D-glucose, 9.9 g. of cyclohexylamine and 1 g. of Raney Nickel in 140 ml. of methanol and 40 ml. of water are treated with hydrogen at 160 psi for 2 hours at 60° C. The solution is filtered to remove the catalyst, and stored overnight at -10° C. to give a precipitate which is recovered by filtration. 2.35 G. of N-cyclohexyl-D-glucamine [m.p. 144°-146° C.; [α]D -20.4° (dimethylsulfoxide)] is obtained.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:25])[C:11]2[CH:16]=[C:15]([NH2:17])[C:14]([NH:18][CH3:19])=[CH:13][C:12]=2[O:20][CH2:21][CH:22]([F:24])[F:23])[CH2:5][CH2:4]1.[C:28]([O:32][C:33](=[O:47])[NH:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[C:38]([N:43]=[C:44]=S)[C:37]=1[Cl:46])([CH3:31])([CH3:30])[CH3:29].CC(C)N=C=NC(C)C>>[F:1][C:2]([F:26])([F:27])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:11]2[C:12]([O:20][CH2:21][CH:22]([F:23])[F:24])=[CH:13][C:14]3[N:18]([CH3:19])[C:44]([NH:43][C:38]4[C:39]([Cl:42])=[CH:40][CH:41]=[C:36]([CH2:35][NH:34][C:33]([O:32][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:47])[C:37]=4[Cl:46])=[N:17][C:15]=3[CH:16]=2)=[O:25])[CH2:5][CH2:4]1
Reactant: CNc1cc(OCC(F)F)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1N
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)c(N=C=S)c1Cl
Agent: CC(C)N=C=NC(C)C
Product: Cn1c(Nc2c(Cl)ccc(CNC(=O)OC(C)(C)C)c2Cl)nc2cc(C(=O)N[C@H]3CC[C@H](C(F)(F)F)CC3)c(OCC(F)F)cc21

Procedure:
The title compound is prepared from N-(trans-4-trifluoromethyl-cyclohex-1-yl)-2-(2,2-difluoro-ethoxy)-4-methylamino-5-amino-benzoic acid amide and (2,4-dichloro-3-isothiocyanato-benzyl)-carbamic acid tert-butyl ester with DIC in analogy to examples 7b/7c.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10](=[O:17])[NH:9][C:8]2[CH:18]=[CH:19][CH:20]=[N:21][C:7]1=2)=[O:5].[CH3:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][NH:24]1>C(O)(C)C>[CH3:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][N:24]1[CH2:2][CH2:3][C:4]([N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10](=[O:17])[NH:9][C:8]2[CH:18]=[CH:19][CH:20]=[N:21][C:7]1=2)=[O:5]
Reactant: O=C1Nc2cccnc2N(C(=O)CCCl)c2ccccc21
Reactant: CC1CCCCN1
Solvent: CC(C)O
Product: CC1CCCCN1CCC(=O)N1c2ccccc2C(=O)Nc2cccnc21

Procedure:
16 gm of 11-(3-chloropropionyl)-5,11-dihydro-6H-pyrido [2,3-b]-[1,4]benzodiazepin-6-one were, after addition of 20 ml of 2-methylpiperidine, refluxed for 1 hour in 200 ml of isopropanol, and the reaction mixture was then evaporated in vacuo to dryness. The residue was admixed with water, the mixture was made alkaline by addition of ammonia and extracted with chloroform. The evaporation residue of the chloroform extract was purified on a silica gel column. The eluate was then evaporated in vacuo to dryness, and the residue was recrystallized from isopropanol.