Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[CH:27]([N:30]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=[C:31]1[N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)([CH3:29])[CH3:28]>>[F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:42]2[CH2:43][CH2:44][N:39]([C:31]3[N:30]([CH:27]([CH3:29])[CH3:28])[C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=4[N:32]=3)[CH2:40][CH2:41]2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: CC(C)n1c(N2CCNCC2)nc2ccccc21
Product: CC(C)n1c(N2CCN(CCCCC3(C(=O)NCC(F)(F)F)c4ccccc4-c4ccccc43)CC2)nc2ccccc21

Procedure:
Prepared analogously to Example 10 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 1-isopropyl-2-(piperazin-1-yl)-1H-benzimidazole.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].C1(NC(C)(C)C)C=CC=CC=1.NC(N)=O.C(NN[CH2:25][C:26]([C:28]1[CH:29]=[CH:30][C:31]([OH:37])=[C:32]([CH2:34][C:35]#[N:36])[CH:33]=1)=[O:27])(C)C>>[OH:37][C:31]1[CH:30]=[CH:29][C:28]([CH:26]([OH:27])[CH2:25][NH:4][CH:1]([CH3:3])[CH3:2])=[CH:33][C:32]=1[CH2:34][C:35]#[N:36]
Reactant: CC(C)NNCC(=O)c1ccc(O)c(CC#N)c1
Reactant: CC(C)N
Agent: CC(C)(C)Nc1ccccc1
Agent: NC(N)=O
Product: CC(C)NCC(O)c1ccc(O)c(CC#N)c1

Procedure:
The procedure of Example 1(c) is repeated with substitution of an equimolar amount of isopropylamine for phenyl-t-butylamine in that example. The resulting aminoketone, 5-[N-(isopropylamino)glycyl]-2-hydroxyphenylacetonitrile, is reduced according to the procedure of Example 1(d) to yield 2-hydroxy-5-[1-hydroxy-2-(isopropylamino)ethyl]-benzeneacetonitrile.
Reaction SMILES: C([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:48])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:47])[CH2:12][CH2:13][C@@:14]3([C:30](=[O:46])[NH:31][C@@H:32]4[CH2:35][C@H:34]([C:36]([N:38]5[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]5)=[O:37])[C:33]4([CH3:45])[CH3:44])[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:50])[CH3:49])(=O)C.[OH-].[Na+]>CO.C1COCC1>[CH3:44][C:33]1([CH3:45])[C@@H:34]([C:36]([N:38]2[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]2)=[O:37])[CH2:35][C@H:32]1[NH:31][C:30]([C@:14]12[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]1[C@@H:16]1[C@@:11]([CH3:47])([CH2:12][CH2:13]2)[C@@:10]2([CH3:48])[C@@H:19]([C@:20]3([CH3:23])[C@@H:7]([CH2:8][CH2:9]2)[C:6]([CH3:49])([CH3:50])[C@@H:5]([OH:4])[CH2:22][CH2:21]3)[CH2:18][CH2:17]1)=[O:46]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@@H]3C[C@H](C(=O)N4CCCCC4)C3(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(C)=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@@H]3C[C@H](C(=O)N4CCCCC4)C3(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.6 %

Procedure:
To a stirred solution of (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((1R,3S)-2,2-dimethyl-3-(piperidine-1-carbonyl)cyclobutylcarbamoyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl acetate (Example 46, 0.400 g, 0.579 mmol) in MeOH:THF (2:1) (30 ml) 2N NaOH (10 ml) was added at 0° C. and allowed to stir at room temperature for about 16 hours. After completion of the reaction (monitored by TLC), the volatile was evaporated and the aqueous layer was extracted with ethyl acetate and the organic layer was washed with water, brine and dried over Na2SO4 then the solvent was evaporated and the resulting crude stirred in hexane and the resulting solid was obtained which was filtered and dried under vacuum to afford the title compound. Wt: 0.280 g; Yield: 74.6%; 1H NMR (300 MHz, CDCl3): δ 5.86 (d, 1H, J=8.1 Hz), 4.72 (s, 1H), 4.57 (s, 1H), 4.18-4.06 (m, 1H), 3.78-3.68 (m, 1H), 3.52-3.30 (m, 3H), 3.23-3.08 (m, 2H), 2.92-2.86 (m, 1H), 2.52-2.20 (m, 3H), 2.01-1.88 (m, 2H), 1.80-1.12 (m, 33H), 0.96, 0.93, 0.87, 0.81, 0.74 (s, 18H); Mass: [M+1]+ 649 (5%), [M+Na]+ 671 (100%); IR (KBr, cm−1): 3353, 2937, 2858, 1635, 1618, 1533, 1459, 1390, 1262, 1250, 1148, 1048, 1033, 1020, 983, 883; M.R: 177° C.-188.7° C.; HPLC: 95.72%.
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[CH3:9][O:10][C:11](=[O:17])[CH2:12][C:13](=[O:16])[CH2:14][CH3:15]>>[CH3:6][N:4](/[CH:3]=[C:12](/[C:13](=[O:16])[CH2:14][CH3:15])\[C:11]([O:10][CH3:9])=[O:17])[CH3:5]
Reactant: CCC(=O)CC(=O)OC
Reactant: COC(OC)N(C)C
Product: CCC(=O)/C(=C/N(C)C)C(=O)OC
Temperature: 110 °C

Procedure:
To N,N-dimethylformamide dimethyl acetal (0.384 ml, 2.88 mmol) was added methyl-3-oxo-pentanoate (250 mg, 1.92 mmol) and the mixture was heated to 110° C. in a sealed vessel. After 30 minutes the reaction mixture was cooled and concentrated to afford methyl (2Z)-2-[(dimethylamino)methylene]-3-oxopentanoate which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Br:11])=[CH:9][C:8]([Cl:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:13](Cl)(Cl)=[O:14]>O1CCOCC1>[Br:11][C:10]1[C:2]2[NH:1][C:13](=[O:14])[O:5][C:4](=[O:6])[C:3]=2[CH:7]=[C:8]([Cl:12])[CH:9]=1
Reactant: Nc1c(Br)cc(Cl)cc1C(=O)O
Reactant: O=C(Cl)Cl
Solvent: C1COCCO1
Product: O=c1[nH]c2c(Br)cc(Cl)cc2c(=O)o1
Temperature: 25 °C
Reaction time: 48 h
Yield: 114.2 %

Procedure:
To a solution of 2-amino-3-bromo-5-chlorobenzoic acid (10.0 g, 39.9 mmol) in dioxane (170 mL) was added phosgene (20% in toluene, 42.0 mL, 79.9 mmol) over a period of 15 mins. The reaction was stirred at ambient temperature for 48 h and then concentrated in vacuo. The resulting solid was crushed and further dried in vacuo to yield the desired product (12.6 g, 114%) which was used in the subsequent step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:5]([N+:18]([O-])=O)=[C:4]([C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][CH:22]=2)[N:3]=1.Cl>C(O)C>[NH2:18][C:5]1[C:4]([C:21]2[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=2)=[N:3][C:2]([Cl:1])=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:6]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)c1c(Cl)nc(-c2ccc([N+](=O)[O-])cc2)c([N+](=O)[O-])c1C(=O)OCC
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1c(Cl)nc(-c2ccc(N)cc2)c(N)c1C(=O)OCC
Temperature: 60 °C
Yield: 74.2 %

Procedure:
In 20ml of ethanol were suspended 0.91 g of 2-chloro-3,4-diethoxycarbonyl-5-nitro-6-(4-nitrophenyl)pyridine and 1.11 g of reduced iron, and the suspension was heated to 60° C. After 4.7 ml of conc. hydrochloric acid was added, the mixture was heated under reflux for 20 minutes. After the reaction mixture was concentrated, extraction with ethyl acetate was conducted. The extract was washed with an aqueous solution of sodium hydrogencarbonate and an aqueous solution of sodium chloride consecutively, and dried over magnesium sulfate. After concentration, the residue was subjected to silica gel column chromatography (eluent:chloroform/methanol 40:1), to give 0.58 g of the title compound as yellow prisms.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:19][C:20]3[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=3[Cl:28])=[N:14][CH:15]=[N:16]2)=[C:11]([O:29][CH:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[CH:10]=1)C1C=CC=CC=1.FC(F)(F)C(O)=O.N>C(Cl)Cl>[Cl:28][C:21]1[CH:22]=[CH:23][C:24]([O:26][CH3:27])=[CH:25][C:20]=1[NH:19][C:13]1[C:12]2[C:17](=[CH:18][C:9]([OH:8])=[CH:10][C:11]=2[O:29][CH:30]2[CH2:31][CH2:32][O:33][CH2:34][CH2:35]2)[N:16]=[CH:15][N:14]=1
Reactant: COc1ccc(Cl)c(Nc2ncnc3cc(OCc4ccccc4)cc(OC4CCOCC4)c23)c1
Agent: N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(Cl)c(Nc2ncnc3cc(O)cc(OC4CCOCC4)c23)c1
Yield: 73.8 %

Procedure:
Using an analogous procedure to that described in Example 20, 7-benzyloxy-4-(2-chloro-5-methoxyanilino)-5-tetrahydropyran-4-yloxyquinazoline (0.78 g) was, reacted with trifluoroacetic acid (5 ml). The reaction mixture was evaporated and the residue was triturated under diethyl ether. The precipitate was isolated and the solid was dissolved in a mixture of methylene chloride and a saturated methanolic ammonia solution. The mixture was evaporated and the residue was purified by column chromatography on silica using a 97:3 mixture of methylene chloride and methanol as eluent. There was thus obtained the title compound (0.47 g); NMR Spectrum: (DMSOd6) 1.8–1.9 (m, 2H), 2.2 (d, 2H), 3.52 (t, 2H), 3.8 (s, 3H), 3.92 (m, 2H), 4.95 (m, 1H), 6.7 (s, 1H), 6.75–6.85 (m, 2H), 7.5 (d, 1H), 8.12 (d, 1H), 8.4 (s, 1H), 9.85 (s, 1H); Mass Spectrum: M+H+ 402 and 404.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([F:10])([F:9])[F:8])=[N:5][NH:4][C:3]1=S.OO.[S:14]([O-:17])([OH:16])=[O:15].[Na+:18].Cl>[OH-].[Na+]>[CH3:1][N:2]1[C:6]([C:7]([F:10])([F:9])[F:8])=[N:5][N:4]=[C:3]1[S:14]([O-:17])(=[O:16])=[O:15].[Na+:18]
Reactant: Cn1c(C(F)(F)F)n[nH]c1=S
Reactant: O=S([O-])O
Agent: Cl
Agent: OO
Agent: [Na+]
Product: Cn1c(C(F)(F)F)nnc1S(=O)(=O)[O-]
Temperature: 40 °C
Reaction time: 6 h
Yield: 73 %

Procedure:
25 g (0.14 mol) of 4-methyl-5-trifluoromethyl-2,4-dihydro-3H-1,2,4-triazole-3-thione are dissolved in 250 ml of 2.5-molar sodium hydroxide solution, and 46.5 g of a 35% strength hydrogen peroxide solution (0.48 mol of H2O2) are added in the course of 60 minutes at a reaction temperature of 40° C. to 45° C. (external cooling). The mixture is stirred for 6 hours at 40° C.; excess oxidant is then decomposed using sodium hydrogen sulphite, and the solution is acidified with 18-molar hydrochloric acid to a pH of 2. It is subsequently washed with ethyl acetate, and the aqueous solution is then concentrated under a water pump vacuum to approximately 200 ml. The solid obtained during cooling is isolated by filtration. 25 g (73% of theory) of sodium 4-methyl-5-trifluoromethyl-4H-1,2,4-triazole-3-sulphonate are obtained.
Reaction SMILES: N1C=CC=CC=1.[N+:7]([C:10]1[CH:30]=[CH:29][CH:28]=[CH:27][C:11]=1[CH2:12][O:13][C:14]([O:16][C:17]1[C:24]([CH3:25])=[CH:23][C:20]([CH2:21]O)=[CH:19][C:18]=1[CH3:26])=[O:15])([O-:9])=[O:8].[Cl:31]C(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[N+:7]([C:10]1[CH:30]=[CH:29][CH:28]=[CH:27][C:11]=1[CH2:12][O:13][C:14]([O:16][C:17]1[C:24]([CH3:25])=[CH:23][C:20]([CH2:21][Cl:31])=[CH:19][C:18]=1[CH3:26])=[O:15])([O-:9])=[O:8]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1cc(CO)cc(C)c1OC(=O)OCc1ccccc1[N+](=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc(CCl)cc(C)c1OC(=O)OCc1ccccc1[N+](=O)[O-]
Reaction time: 0.75 h
Yield: 89.1 %

Procedure:
Pyridine (34 mL, 0.42 mmol) was added to a stirring mixture of 8h (56 mg, 0.17 mmol) and triphosgene (60 mg, 0.20 mmol) in a mixture of CDCl3 (1 mL) and CH2Cl2 (2.5 mL) at r.t. After 45 minutes, the reaction mixture was filtered through a pad of silica gel (5 g, 3 cm) washing with CH2Cl2 (20 mL) and concentrated in vacuo to yield pure 9h (53 mg, 90%) as a clear oil which became an off-white solid on addition of hexane: 1H NMR (270 MHz, CDCl3) d 2.20 (s, 6H), 4.50 (s, 2H), 5.70 (s, 2H), 7.09 (s, 2H), 7.50-7.56 (m, 1H), 7.69-7.72 (m, 2H), 8.16 (d, J=7.9 Hz, LH); 13C NMR (68 MHz, CDCl3) d 16.1, 64.7, 66.9, 125.4, 127.5, 128.8, 129.3, 130.3, 131.6, 134.1, 138.9, 147.3, 147.69, 152.7.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][C@@H:13]3[CH2:15][C@H:10]2[CH2:11][O:12]3)=[CH:5][C:4]=1[N+:16]([O-])=O>CO.ClCCl.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][C@@H:13]3[CH2:15][C@H:10]2[CH2:11][O:12]3)=[CH:5][C:4]=1[NH2:16]
Reactant: COc1ccc(N2C[C@@H]3C[C@H]2CO3)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(N2C[C@@H]3C[C@H]2CO3)cc1N
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 97.6 %

Procedure:
To a stirred solution of 5.01 g (20.0 mmol) (1S,4S)-5-(4-methoxy-3-nitro-phenyl)-2-oxa-5-aza-bicyclo[2.2.1]heptane in 375 ml methanol and 62.5 ml dichloromethane was added 500 mg 10% palladium on charcoal and the mixture was then stirred for 3.5 hours at room temperature under an atmosphere of hydrogen. The mixture was then filtered and the filtrate concentrated in vacuo to afford 4.30 g (98%) 2-methoxy-5-{(1S,4S)-(2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl)}-phenylamine as a brown crystalline solid. ES-MS m/e (%): 221 (M+H+, 100).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[Cl:11].[CH2:12](Br)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[OH-].[Na+]>>[CH2:23]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[Cl:11])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12]
Reactant: CCCCCCCCCCCCBr
Reactant: O=C(O)c1ccc(O)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCCCCCOc1ccc(C(=O)O)cc1Cl

Procedure:
In the same manner as described in Referential Example 15, 4-hydroxy-3-chlorobenzoic acid was reacted with n-dodecyl bromide in an aqueous solution of sodium hydroxide to obtain 4-dodecyloxy-3-chlorobenzoic acid. Then, thionyl chloride was added to 2 g of the so-obtained compound, reaction was carried out under reflux for 3 hours, and unreacted thionyl chloride was removed by distillation, whereby 4-dodecyloxy-3-chlorobenzoic acid chloride was quantitatively obtained. The so-obtained compound was diluted with 50 ml of tetrahydrofuran, and 1.7 g of p-benzyloxyphenol and 1.0 g of triethylamine were added to the dilution and reaction was carried out at room temperature with stirring overnight. Precipitated triethylamine hydrochloride was removed by filtration, and the filtrate was concentrated and purified by the silica gel column chromatography to obtain 2.1 g of 4-benzyloxyphenyl 4-dodecyloxy-3-chlorobenzoate. The so-obtained compound was catalytically reduced under a hydrogen pressure of 1 kg/cm2 in the pressure of Pd/C as the catalyst according to customary procedures to obtain 1.8 g of (4-hydroxyphenyl) 4 -dodecyloxy-3-chlorobenzoate.
Reaction SMILES: [NH2:1][C:2]1[C:22]([CH2:23][N:24]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[CH2:25][CH3:26])=[CH:21][C:5]([C:6]([O:8][CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][OH:20])[CH2:14][CH2:13]2)=[O:7])=[CH:4][C:3]=1[Br:33].[Cl:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[C:36]=1[NH:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[CH2:49][C:50](O)=[O:51].C1(N=C=NC2CCCCC2)CCCCC1>>[NH2:1][C:2]1[C:22]([CH2:23][N:24]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[CH2:25][CH3:26])=[CH:21][C:5]([C:6]([O:8][CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][O:20][C:50](=[O:51])[CH2:49][C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=3[NH:42][C:36]3[C:35]([Cl:34])=[CH:40][CH:39]=[CH:38][C:37]=3[Cl:41])[CH2:14][CH2:13]2)=[O:7])=[CH:4][C:3]=1[Br:33]
Reactant: O=C(O)Cc1ccccc1Nc1c(Cl)cccc1Cl
Reactant: CCN(Cc1cc(C(=O)OCCCN2CCN(CCO)CC2)cc(Br)c1N)C1CCCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CCN(Cc1cc(C(=O)OCCCN2CCN(CCOC(=O)Cc3ccccc3Nc3c(Cl)cccc3Cl)CC2)cc(Br)c1N)C1CCCCC1

Procedure:
This compound was prepared from N-{3-[4-amino-3-bromo-5-(N-ethyl-cyclohexylaminomethyl)-benzoyloxy]-propyl}-N'-(2-hydroxyethyl)-piperazine and 2-[(2,6-dichlorophenyl)amino]-phenyl-acetic acid with dicyclohexyl-carbodiimide, analogous to Example 4.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:31]([CH3:33])[CH3:32])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:10]([CH:34]=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][C@@H:10]([CH2:34][NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C@H:11]([CH2:13][N:14]([CH:31]([CH3:32])[CH3:33])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[CH2:12]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2C=O)C(C)C)ccc1OC
Reactant: Nc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CNc2ccccc2)C(C)C)ccc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (3S*,4R*)-3-formyl-4-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (100 mg, 0.20 mmol) and aniline (26 μL, 0.28 mmol) in 1,2-dichloroethane (5 mL) is stirred 25 min, before the addition of NaBH(OAc)3 (60 mg, 0.28 mmol) follows. The solution is stirred overnight at RT, then diluted with CH2Cl2 and washed with an aqueous saturated solution of NaHCO3. The combined organic extracts are dried over Na2SO4 and concentrated. The crude material is purified by flash chromatography on silica gel (eluent: CH2Cl2/MeOH 100:0 to 97:3) to give the title product. TLC, Rf (CH2Cl2/MeOH 95:5)=0.25. MS (LC-MS): 570.0 [M+H]+; tR (HPLC, nucleosil C18 column, 10-100% CH3CN/H2O/ 5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 ml/min): 5.31 min.
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][N:9]2[C:14]([O:16]C(C)(C)C)=O)=[CH:6][CH:5]=[CH:4][N:3]=1.[C:21](O)(C(F)(F)F)=O.C(OC(=O)C)(=O)C>C(Cl)Cl>[F:1][C:2]1[C:7]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][N:9]2[C:14](=[O:16])[CH3:21])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCCCC1c1cccnc1F
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N1CCCCC1c1cccnc1F
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 2-(2-fluoropyridin-3-yl)piperidine-1-carboxylate (70 mg, 0.250 mmol) and DCM (5 mL) was added TFA (0.50 mL, 6.49 mmol). After 1 hour, the reaction was washed with 10% Na2CO3. The organic layer was treated with TEA (0.070 mL, 0.499 mmol), then acetic anhydride (0.024 mL, 0.250 mmol). After 15 minutes, LC-MS shows conversion to the desired product [M+1=223]. The reaction was washed with water and concentrated in vacuo to give 1-(2-(2-fluoropyridin-3-yl)piperidin-1-yl)ethanone as a yellow oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([CH2:18]Cl)=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:11]=2)[CH:8]=1.[F:20][C:21]1[CH:26]=[C:25]([F:27])[N:24]=[C:23]([NH2:28])[N:22]=1>>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([CH2:18][NH:28][C:23]3[N:24]=[C:25]([F:27])[CH:26]=[C:21]([F:20])[N:22]=3)=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:11]=2)[CH:8]=1
Reactant: ClCc1c(-c2ccccc2)nc2ccc(Cl)cn12
Reactant: Nc1nc(F)cc(F)n1
Agent: Cl
Product: Fc1cc(F)nc(NCc2c(-c3ccccc3)nc3ccc(Cl)cn23)n1
Yield: 43 %

Procedure:
The title compound was prepared according to Method A and the experimentals described for compound 139 from 6-chloro-3-(chloromethyl)-2-phenylimidazo[1,2-a]pyridine hydrochloride and 4,6-difluoropyrimidin-2-amine. ((0.26 g, 43% yield), M/e+ 372.2 for C18H12ClF2N5 (M+H)+.
Reaction SMILES: Cl.[CH2:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2[CH:34]=[CH:33][C:17]([CH2:18][NH:19][C:20]3[CH:32]=[CH:31][C:23]4[O:24][C:25]([CH3:30])([CH3:29])[O:26][C:27](=[O:28])[C:22]=4[CH:21]=3)=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH3:5].[CH:35]1([C:41](Cl)=[O:42])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>>[CH2:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]#[C:13][C:14]2[CH:34]=[CH:33][C:17]([CH2:18][N:19]([C:20]3[CH:32]=[CH:31][C:23]4[O:24][C:25]([CH3:30])([CH3:29])[O:26][C:27](=[O:28])[C:22]=4[CH:21]=3)[C:41]([CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)=[O:42])=[CH:16][CH:15]=2)=[CH:10][CH:11]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCc1ccc(C#Cc2ccc(CNc3ccc4c(c3)C(=O)OC(C)(C)O4)cc2)cc1
Reactant: O=C(Cl)C1CCCCC1
Agent: Cl
Product: CCCCc1ccc(C#Cc2ccc(CN(C(=O)C3CCCCC3)c3ccc4c(c3)C(=O)OC(C)(C)O4)cc2)cc1

Procedure:
The titled compound was prepared following the procedure J using 6-({4-[(4-butylphenyl)ethynyl]benzyl}amino)-2,2-dimethyl-4H-1,3-benzodioxin-4-one hydrochloride and cyclohexanecarbonyl chloride as a colorless oil (86%). 1H NMR (CDCl3, 300 MHz) δ 7.70 (d, J=2.3 Hz, 1H), 7.43 (m, 4H), 7.15 (m, 4H), 7.04 (dd, J=8.7, 2.3 Hz, 1H), 6.91 (d, J=8.7 Hz, 1H), 4.86 (s, 2H), 2.63 (t, J=7.7 Hz, 2H), 2.10 (m, 1H), 1.76 (s, 6H), 1.75-1.56 (m, 10H), 1.42-0.97 (m, 4H), 0.94 (t, J=7.4 Hz, 3H). M+ (ESI): 550.8. HPLC, Rt: 6.45 min (Purity: 100%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[S:13]([CH3:16])(=[O:15])=[O:14])[C:7]([OH:9])=[O:8])([O-])=O.[H][H]>[Ni].CO>[NH2:1][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[S:13]([CH3:16])(=[O:15])=[O:14])[C:7]([OH:9])=[O:8]
Reactant: [H][H]
Reactant: CS(=O)(=O)c1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Product: CS(=O)(=O)c1ccc(C(=O)O)cc1N

Procedure:
0.447 mol of 3-nitro-4-methylsulfonylbenzoic acid was reduced with hydrogen by employing 100 g of Raney nickel in 2.5 l of methanol. The mixture was then heated to reflux and filtered off hot with suction. The filtrate was concentrated.
Reaction SMILES: CC([NH:5][S:6]([C:9]1[C:14]([S:15]([CH2:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=[CH:11][N:10]=1)(=[O:8])=[O:7])(C)C.ClC1C=CC=C(C(OO)=[O:28])C=1.O>C(Cl)Cl.FC(F)(F)C(O)=O>[CH2:17]([S:15]([C:14]1[C:9]([S:6]([NH2:5])(=[O:7])=[O:8])=[N:10][CH:11]=[CH:12][CH:13]=1)(=[O:16])=[O:28])[CH2:18][CH3:19]
Reactant: CCCS(=O)c1cccnc1S(=O)(=O)NC(C)(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCCS(=O)(=O)c1cccnc1S(N)(=O)=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 69.1 %

Procedure:
To a stirred solution of 8.8 g (0.029 mol) of the product from Example 3 in 400 mls methylene chloride cooled to -5°, under nitrogen, was added 6.6 g (0.038 mol) of 3-chloroperbenzoic acid and stirred at room temperature for 20 hours. The reaction mixture was poured into water and extracted with methylene chloride. The organic layers were combined and washed with saturated sodium bisulfite and brine, dried over magnesium sulfate, and evaporated to a solid mixture which was washed with hexanes to afford a white solid. The solid was dissolved and stirred in 150 mls trifluoroacetic acid for 72 hours. The solution was evaporated and triturated with ether to afford 5.3 g (46%) white solid: m.p. 153°-157°; NMR (CDCl3, 200 MHz) 1.06 (3H, t, J=7 Hz), 1.8 (2H, m), 3.7 (2H, m) 5.8 (NH2), 7.8 (1H, m), 8.6 (1H, m), 8.95 (1H, m); IR (nujol) 3390, 3180, 1360, 1310, 1175, 1150 cm-1.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][NH:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][NH:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc(NCC2CCCN2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(NCC2CCCN2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.1 %

Procedure:
To a stirred solution of methyl 4-[1-(tert-butoxycarbonyl)-2-pyrrolidinylmethylamino]benzoate (2.17 g, 6.490 mmol) in CH2Cl2 (44 mL) was added TFA (8.7 mL) at 0° C., and the resulting mixture was stirred overnight at room temp. The solvent was removed under a reduced pressure and the residue was treated with 1N NaOH. The mixture was extracted with CH2Cl2. The extract was washed with brine, dried over Na2SO4, and the solvent was concentrated under a reduced pressure to afford 1.34 g (88%) methyl 4-(2-pyrrolidinylmethylamino)benzoate as a brown oil, which is used to the subsequent reaction without further purification.