Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.Cl.[Cl:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([NH:14][C:15]3[C:16]4[CH:23]=[C:22]([C:24]5[CH2:25][CH2:26][NH:27][CH2:28][CH:29]=5)[NH:21][C:17]=4[N:18]=[CH:19][N:20]=3)[CH:12]=2)[NH:7][N:6]=1.[N:30]1([CH2:36][CH2:37][C:38](O)=[O:39])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([NH:14][C:15]3[C:16]4[CH:23]=[C:22]([C:24]5[CH2:25][CH2:26][N:27]([C:38](=[O:39])[CH2:37][CH2:36][N:30]6[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]6)[CH2:28][CH:29]=5)[NH:21][C:17]=4[N:18]=[CH:19][N:20]=3)[CH:12]=2)[NH:7][N:6]=1
Reactant: Clc1n[nH]c2ccc(Nc3ncnc4[nH]c(C5=CCNCC5)cc34)cc12
Reactant: O=C(O)CCN1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCN1CCCCC1)N1CC=C(c2cc3c(Nc4ccc5[nH]nc(Cl)c5c4)ncnc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of (3-chloro-1H-indazol-5-yl)-[6-(1,2,3,6-tetrahydropyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine tris-hydrochloride (46.9 mg, 0.0967 mmol, 1 eq), 1-piperidinepropanoic acid (40.5 mg, 0.255 mmol, 2.6 eq), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC) (56.2 mg, 0.293 mmol, 3 eq), and 1-hydroxybenzotriazole (HOBt) (13.9 mg, 0.103 mmol, 1 eq) in anhydrous DMF (5 mL), DiPEA (85 μL, 0.48 mmol, 5 eq) was added under an atmosphere of N2 The reaction was stirred at rt for 18 h, after which all solvent was evaporated under reduced pressure. The crude material was adsorbed onto Hydromatrix, dry loaded, and purified by chromatography on silica gel [Jones Flashmaster, 5 g/25 mL cartridge, eluting with MeOH:DCM 5%→7N NH3/MeOH:DCM 2%→5%→8%→15%]. Fractions 25-39 were combined and concentrated in vacuo, yielding the desired amide, but which contained a considerable amount of 1-(3-dimethylaminopropyl)-3-ethylurea. The yellow solid was triturated in hot MeOH/sonication, giving the title compound as an off-white solid. 1H NMR (400 MHz, CDCl3): δ=1.26 (s, br, 2H), 1.63 (m, 4H), 2.37-2.56 (m, 6H), 2.56-2.68 (m, 2H), 2.68-2.80 (m, 2H), 3.68 & 3.76 (t, J=5.6 Hz, rotamers, 2H), 4.22 & 4.25 (s, br, rotamers, 2H), 5.92 & 5.98 (s, rotamers, 1H), 6.18 & 6.22 (s, br, rotamers, 1H), 7.49 (d, J=8.8 Hz, 1H), 7.79 (dd, J=8.8, 1.6 Hz, 1H), 8.13 (s, 1H), 8.26 (s, 1H). MS (ES+): m/z 505.00/506.99 (27/10) [MH+]; m/z 407.96/409.98 (100/36) [MH+—C6H14N]. HPLC: tR=1.75 min (ZQ2000, polar—5 min).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[NH2:30])=[CH:18][CH:17]=1.[C:31](N1C=CN=C1)(N1C=CN=C1)=[O:32]>CN(C)C=O.O1CCCC1.O>[NH:30]1[C:25]2[C:24](=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:23][N:22]([C:19]2[CH:18]=[CH:17][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:21][CH:20]=2)[C:31]1=[O:32]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1cc2nccc(Oc3ccc(NCc4ccccc4N)cc3)c2cc1OC
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc(N4Cc5ccccc5NC4=O)cc3)c2cc1OC
Temperature: 70 °C
Reaction time: 8 h
Yield: 7 %

Procedure:
6,7-Dimethoxy-4-(4-(2-aminophenyl)methylaminophenyloxy)quinoline (40 mg, 0.0996 mmol) was dissolved in dimethylformamide (0.5 ml), 1,1′-carbonyldiimidazole (19 mg, 0.1196 mmol) was added, and the mixture was stirred at 70° C. for 8 hours. After cooling to room temperature, the reaction solution was diluted with tetrahydrofuran, water was added, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was distilled off under reduced pressure. The residue was purified with a silica gel column (ethyl acetate-methanol system) and recrystallized with hexane-diethyl ether to obtain the title compound (3 mg, 0.0070 mmol, 7.05%) as colorless crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][N:6]([CH2:8][CH2:9][CH:10]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1)[CH3:7])[CH3:2].[I:29][CH3:30]>C1C=CC=CC=1>[I-:29].[CH3:7][N+:6]([CH3:30])([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:28])[CH2:8][CH2:9][CH:10]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][CH:13]=1
Reactant: CCOC(=O)CN(C)CCC(Oc1ccc(C(F)(F)F)cc1)c1ccccc1
Reactant: CI
Solvent: c1ccccc1
Product: CCOC(=O)C[N+](C)(C)CCC(Oc1ccc(C(F)(F)F)cc1)c1ccccc1
Product: [I-]
Yield: 85.7 %

Procedure:
A solution of 0.152 g (0.38 mmol) N-[3-phenyl-3-(4-trifluoromethylphenoxy)propyl]sarcosine ethyl ester (Compound A2 ) and 0.273 g (1.93 mmol) iodomethane in 2 ml benzene was heated under reflux for 2 hours and the solvent evaporated. The residue was washed three times with anhydrous diethyl ether and dried under vacuum to give 0.175 g (yield 85%) dimethyl(ethoxycarbonylmethyl)[3-phenyl-3-(4trifluoromethylphenoxy)propyl]ammonium iodide (Compound A148) as a pale yellow hygroscopic powder.
Reaction SMILES: S(=NS(C)(=O)=O)=O.[S:8](=[N:10][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][C:20]=1[CH3:21])[C:14]([O:16][CH3:17])=[O:15])=O.N1C=CC=CC=1>C1C=CC=CC=1>[N:10]1[S:8][CH:21]=[C:20]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:11]=12
Reactant: COC(=O)c1ccc(C)c(N=S=O)c1
Agent: CS(=O)(=O)N=S=O
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: COC(=O)c1ccc2csnc2c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
51.6 g (0.365 mole) of N-sulphinylmethanesulphonamide in 50 ml of benzene are added to a solution of 60 g (0.298 mole) of methyl 3-sulphinylamino-4-methylbenzoate in 200 ml of benzene at room temperature under argon. Thereafter, 24.9 g (0.315 mole) of pyridine, dissolved in 75 ml of benzene, are added in portions to the reaction mixture, while cooling with ice. The mixture is subsequently stirred at 0° C. for 10 minutes and then heated under reflux for 45 hours. After cooling, the benzene and pyridine are distilled off in vacuo, the oil which remains is poured into 150 ml of water and the mixture is acidified to pH 4 with 2N HCl. A brown solid thereby forms from the oil, and is extracted with chloroform. The chloroform extracts are washed with water, dried over MgSO4 and concentrated to dryness. The oil which remains crystallizes to a brown-yellow material by adding n-hexane, and the material is filtered off with suction and washed with n-hexane.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:11][C:12](=[S:20])OC2C=CC=CC=2)[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8].[OH:21][C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1>>[CH3:1][C:2]1[CH:3]=[C:4]([NH:11][C:12]([N:31]2[CH2:30][CH2:29][N:28]([C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([OH:21])[CH:23]=3)[CH2:33][CH2:32]2)=[S:20])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8]
Reactant: COc1nc(C)c(C)cc1NC(=S)Oc1ccccc1
Reactant: Oc1cccc(N2CCNCC2)c1
Product: COc1nc(C)c(C)cc1NC(=S)N1CCN(c2cccc(O)c2)CC1
Yield: 43 %

Procedure:
Phenyl N-(5,6-dimethyl-2-methoxypyridin-3-yl)thiocarbamate and 1-(3-hydroxyphenyl)piperazine were reacted by the same way with the example 22 to obtain the titled compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([NH2:10])[C:7]([NH2:11])=[N:6][CH:5]=1.C1(C)C=C(C)C=C(C)C=1S(O[NH2:25])(=O)=O.[CH:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]([NH2:10])[C:7]2[N:6]([N:25]=[C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:11]=2)[CH:5]=1)=[O:12]
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Reactant: COC(=O)c1cnc(N)c(N)c1
Reactant: O=Cc1ccccc1
Product: COC(=O)c1cc(N)c2nc(-c3ccccc3)nn2c1

Procedure:
The title compound, MS m/e (%): 269 (M+, 100), was prepared in accordance with the general method of example 1 from 5,6-diamino-nicotinic acid methyl ester, O-mesitylene-sulfonylhydroxylamine, and benzaldehyde. The purification was performed by flash column chromatography on silica eluting with a mixture of ethyl acetate and n-hexane.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C:13](O)([C:25]([F:28])([F:27])[F:26])[CH2:14][C:15]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([Cl:24])[CH:18]=2)=[O:16])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C1(C)C=CC=CC=1.C(OC(=O)C)(=O)C>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[F:30][C:2]([F:1])([F:31])[C:3]1[CH:4]=[C:5]([C:13]([C:25]([F:28])([F:27])[F:26])=[CH:14][C:15]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([Cl:24])[CH:18]=2)=[O:16])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: Cc1ccc(C(=O)CC(O)(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(F)(F)F)cc1Cl
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: Cc1ccc(C(=O)C=C(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(F)(F)F)cc1Cl
Temperature: 70 °C
Reaction time: 9 h
Yield: 98.5 %

Procedure:
1.15 g of 3-(3,5-bis(trifluoromethyl)phenyl)-1-(3-chloro-4-methylphenyl)-4,4,4-trifluoro-3-hydroxybutan-1-one, 2.3 g of toluene, 0.49 g of acetic anhydride, 29 mg of 4-dimethylaminopyridine and 0.38 g of pyridine were fed, and stirred for 9 hours at 70° C. The mixture was cooled to room temperature, and separated by adding 5 ml of toluene, iced water and 0.6 ml of concentrated hydrochloric acid. The organic phase was washed with water, and the solvent was distilled off under reduced pressure. The obtained residue was roughly purified by using a small amount of silica gel to obtain 1.09 g of 3-(3,5-bis(trifluoromethyl)phenyl)-1-(3-chloro-4-methylphenyl)-4,4,4-trifluoro-2-buten-1-one as yellow liquid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:16])[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.C([O:21][C:22]([N:24]1[CH:29]2CC[CH:25]1[CH2:26]C(=O)[CH2:28]2)=O)(C)(C)C.[Br:33][C:34]1[CH:35]=[CH:36][C:37]2[C:38](=[C:48]3[CH2:54][CH:53]4[NH:55][CH:50]([CH2:51][CH2:52]4)[CH2:49]3)[C:39]3[C:44]([O:45][C:46]=2[CH:47]=1)=[CH:43][CH:42]=[CH:41][CH:40]=3>>[CH2:25]([N:24]([CH2:29][CH3:28])[C:22]([C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:16])[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3)=[O:21])[CH3:26].[Br:33][C:34]1[CH:35]=[CH:36][C:37]2[C:38](=[C:48]3[CH2:54][CH:53]4[NH:55][CH:50]([CH2:51][CH2:52]4)[CH2:49]3)[C:39]3[C:44]([O:45][C:46]=2[CH:47]=1)=[CH:43][CH:42]=[CH:41][CH:40]=3
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(=O)C2
Reactant: O=c1c2ccccc2oc2cc(Br)ccc12
Agent: Brc1ccc2c(c1)Oc1ccccc1C2=C1CC2CCC(C1)N2
Product: CCN(CC)C(=O)c1ccc2c(=O)c3ccccc3oc2c1

Procedure:
Using an adaptation of the method described in Procedure 7, substituting 3-bromo-xanthen-9-one, 3a, for 9-oxo-9H-xanthene-3-carboxylic acid diethylamide, 6a (13.69, 46 mmol) and 3-oxo-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester for N-carbethoxynortropinone, the title compound 3-(3-bromo-xanthen-9-ylidene)-8-aza-bicyclo[3.2.1]octane, 1b was obtained. MS m/z (MH+) 368.0/370.0
Reaction SMILES: C([N:3]([CH2:6]C)CC)C.[Br:8][C:9]1[CH:20]=[C:13]2[C:14]([O:16]C(=O)[NH:18][C:12]2=[CH:11][CH:10]=1)=O.[CH2:21]([OH:23])C>O>[NH2:18][C:12]1[CH:11]=[CH:10][C:9]([Br:8])=[CH:20][C:13]=1[C:14]([N:3]([O:23][CH3:21])[CH3:6])=[O:16]
Reactant: CCO
Reactant: CCN(CC)CC
Reactant: O=c1[nH]c2ccc(Br)cc2c(=O)o1
Solvent: O
Product: CON(C)C(=O)c1cc(Br)ccc1N
Yield: 68 %

Procedure:
To a mixture of N, O-dimethylhydroxylamine hydrochloride (9.42 g, 96 mmol) and triethyl amine (13.5 mL, 96 mmol) in ethanol and water (100 mL/10 mL) was added a solution of 5-bromoisatoic anhydride (20 g, 74 mmol) in ethanol and water (100 mL/10 mL) at ambient temperature under nitrogen. The reaction mixture was heated at reflux for 3 hours. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate (100 mL), washed with 1N aqueous sodium hydroxide solution (2×20 mL), brine (30 mL), and dried with MgSO4. After removal of solvent, the residue was purified by a silica gel flash chromatography (hexane:ethyl acetate/3:2) to give 2-amino-5-bromo-N-methoxy-N-methylbenzamide as an off-white solid (13 g, 68%): mp 80-81° C.; 1H-NMR (CDCl3) δ7.49 (d, 1H, J=2.1 Hz), 7.26 (dd, 1H, J=8.3, 2.0 Hz), 6.59 (d, 1H, J=8.4 Hz), 4.69 (br, 2H), 3.58 (s, 3H), 3.34 (s, 3H), Anal. Calc. For C9H11BrN2O2: C, 41.72, H, 4.28, N, 10.81. Found: C, 41.99, H, 4.16, N, 10.82.
Reaction SMILES: [NH2:1][CH:2]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:3]([NH:5][CH:6]1[C:24](=[O:25])[N:8]2[C:9]([C:21]([OH:23])=[O:22])=[C:10]([CH:13]([S:15][C:16]3[NH:20][N:19]=[N:18][N:17]=3)[CH3:14])[CH2:11][S:12][C@H:7]12)=[O:4].[O:32]=[C:33]1[N:37]([C:38](Cl)=[O:39])[C:36]2[CH:41]=[CH:42][CH:43]=[CH:44][C:35]=2[NH:34]1.Cl>C(#N)C>[O:32]=[C:33]1[N:37]([C:38]([NH:1][CH:2]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:3]([NH:5][CH:6]2[C:24](=[O:25])[N:8]3[C:9]([C:21]([OH:23])=[O:22])=[C:10]([CH:13]([S:15][C:16]4[NH:20][N:19]=[N:18][N:17]=4)[CH3:14])[CH2:11][S:12][C@H:7]23)=[O:4])=[O:39])[C:36]2[CH:41]=[CH:42][CH:43]=[CH:44][C:35]=2[NH:34]1
Reactant: O=C(Cl)n1c(=O)[nH]c2ccccc21
Reactant: CC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(NC(=O)C(N)c3ccccc3)[C@H]2SC1
Agent: Cl
Solvent: CC#N
Product: CC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(NC(=O)C(NC(=O)n3c(=O)[nH]c4ccccc43)c3ccccc3)[C@H]2SC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 93.3 %

Procedure:
To 15 ml. of dry acetonitrile were added 923 mg. (2 mmoles of 7-(α-aminophenylacetamido)-3-(1-methyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid and 1.62 grams (8 mmoles) of N,O-bis-trimethylsilylacetamide. Solution was complete within 5 minutes. To the mixture then were added 452 mg. (2.3 mmoles) of 2,3-dihydro-2-oxo-1H-benzimidazol-1-ylcarbonyl chloride. The temperature of the mixture rose about 4°and solution was complete within 5 minutes. After 20 minutes, a sample of the reaction mixture, analyzed by TLC, indicated that the reaction was complete. After two hours, the mixture (containing some solid) was slowly dropped into rapidly stirred ice water. A gummy solid deposited and was changed to particulate solid upon further stirring of the mixture. The suspension (pH 1.9) was adjusted to pH 1.7 by addition of concentrated hydrochloric acid. The mixture was filtered, and the solid was washed with dilute hydrochloric acid and air-dried to give 1.16 grams of the title compound as a buff-colored powder.
Reaction SMILES: CC([CH2:5][N:6]([CH2:10][CH2:11][N:12]1[CH:16]=[C:15]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[N:23]([C:27](=[O:29])[CH3:28])[C@@H:22]([CH3:30])[CH2:21][C@H:20]3[NH:31][C:32]2[C:37]([CH3:38])=[CH:36][CH:35]=[CH:34][N:33]=2)[CH:14]=[N:13]1)C(=O)[O-])(C)C.FC(F)(F)C(O)=O.[ClH:46].CCOCC>ClCCl>[ClH:46].[C:27]([N:23]1[C:24]2[C:19](=[CH:18][C:17]([C:15]3[CH:14]=[N:13][N:12]([CH2:11][CH2:10][NH:6][CH3:5])[CH:16]=3)=[CH:26][CH:25]=2)[C@H:20]([NH:31][C:32]2[C:37]([CH3:38])=[CH:36][CH:35]=[CH:34][N:33]=2)[CH2:21][C@@H:22]1[CH3:30])(=[O:29])[CH3:28]
Reactant: CC(=O)N1c2ccc(-c3cnn(CCN(CC(C)(C)C)C(=O)[O-])c3)cc2[C@H](Nc2ncccc2C)C[C@@H]1C
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CNCCn1cc(-c2ccc3c(c2)[C@H](Nc2ncccc2C)C[C@H](C)N3C(C)=O)cn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 68.9 %

Procedure:
A solution of 1,1-dimethylethyl[2-(4-{(2S,4R)-1-acetyl-2-methyl-4-[(3-methyl-2-pyridinyl)amino]-1,2,3,4-tetrahydro-6-quinolinyl}-1H-pyrazol-1-yl)ethyl]methylcarbamate (for a preparation see intermediate 70) (161 mg, 0.310 mmol) in dichloromethane (DCM) (4 mL) was treated with trifluoroacetic acid (TFA) (1 mL, 12.98 mmol) and the resulting mixture was stirred at room temperature for 1.5 h then concentrated in vacuo. The residue was loaded on a 5 g SCX cartridge then eluted with MeOH (20 mL) followed by 2M NH3 in MeOH (20 mL). The ammonia fractions were combined and concentrated in vacuo to give a residue which was dissolved in DCM (5 mL). The resulting solution was treated with HCl (1M in Et2O, 0.22 mL, 0.220 mmol) then concentrated in vacuo. Trituration of the residue with Et2O gave (2S,4R)-1-acetyl-2-methyl-6-{1-[2-(methylamino)ethyl]-1H-pyrazol-4-yl}-N-(3-methyl-2-pyridinyl)-1,2,3,4-tetrahydro-4-quinolinamine hydrochloride (103.3 mg, 0.214 mmol, 68.9% yield) as a light brown solid.
Reaction SMILES: [B].[NH2:2][C:3](=[N:25][OH:26])[C:4]1[CH:9]=[C:8]([Cl:10])[N:7]=[C:6]([N:11]2[CH2:16][CH2:15][CH:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:13][CH2:12]2)[CH:5]=1.[CH2:27](OC(OCC)(OCC)C)C>>[Cl:10][C:8]1[N:7]=[C:6]([N:11]2[CH2:12][CH2:13][CH:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])[CH2:15][CH2:16]2)[CH:5]=[C:4]([C:3]2[N:2]=[CH:27][O:26][N:25]=2)[CH:9]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2cc(C(N)=NO)cc(Cl)n2)CC1
Reactant: CCOC(C)(OCC)OCC
Agent: [B]
Product: CC(C)(C)OC(=O)NC1CCN(c2cc(-c3ncon3)cc(Cl)n2)CC1

Procedure:
Boron trifluoroetherate (0.1 ml) was added to a solution of tert-butyl 1-{4-[amino (hydroxyimino)methyl]-6-chloropyridin-2-yl}piperidin-4-ylcarbamate (Intermediate 54) (0.254 g, 0.69 mmol) in 1,1,1-triethoxyethane (1.5 ml) at room temperature. The mixture was refluxed for 10 minutes. The mixture was purified by flash chromatography on silica gel eluting with (n-hexanes:EtOAc; 70:30) to afford the title compound (50 mg).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1.[N:34]1[CH:35]=[CH:36][N:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=12>C(#N)C>[Br-:1].[CH2:19]([O:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][C:10]([NH:9][C:5]2[CH:4]=[C:3]([CH2:2][N+:34]3[CH:35]=[C:36]4[CH:39]=[CH:40][CH:41]=[CH:42][N:37]4[CH:38]=3)[CH:8]=[CH:7][CH:6]=2)=[O:33])=[CH:13][CH:14]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: c1ccn2ccnc2c1
Reactant: CCCCCCCCCCCCCCOc1ccc(CC(=O)Nc2cccc(CBr)c2)cc1
Solvent: CC#N
Product: CCCCCCCCCCCCCCOc1ccc(CC(=O)Nc2cccc(C[n+]3cc4ccccn4c3)c2)cc1
Product: [Br-]
Yield: 81.4 %

Procedure:
A mixture of 1.5 g of N-[3-(bromomethyl)phenyl]-4-(tetradecyloxy)benzeneacetamide and 1.03 g of imidazo[1,2-a]pyridine in 25 ml of acetonitrile is refluxed under argon for 3.5 hours. The solvent is evaporated and the residue stirred with ether and collected by centrifugation. The solid is washed several times with ether and vacuum dried to give 1.5 g of the desired product as a white powder, m.p 133°-135° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=O.[C:13]1([CH2:19][CH2:20][NH2:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[Cl:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH2:4][NH:21][CH2:20][CH2:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: NCCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=[N+]([O-])c1ccc(Cl)c(CNCCc2ccccc2)c1
Temperature: 0 °C
Yield: 82 %

Procedure:
2-Chloro-5-nitro-benzaldehyde (5 g, 27 mmol) and 2-phenylethylamine (4.1 g, 33.75 mmol) were dissolved in methanol, cooled to 0° C., and sodium cyanoborohydride (2.1 g, 33.75 mmol) was added. The reaction was adjusted to pH 6 with acetic acid and warmed to room temperature for 6 h. The reaction mixture was quenched with ice and diluted with water. The pH was adjusted to 11 with sodium hydroxide and the mixture was extracted with methylene chloride. The organic extracts were washed with water and brine and dried briefly over sodium sulfate. Filtration of the mixture and concentration of the filtrate in vacua yielded the title compound (82%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:33])[N:10]([CH2:23][C:24]2[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=2)[C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.[CH2:56]([O:58][C:59](=[O:64])[C@H:60]([OH:63])[CH2:61][NH2:62])[CH3:57].C(N(CC)C(C)C)(C)C>CN(C=O)C.C(OCC)(=O)C>[CH2:56]([O:58][C:59](=[O:64])[C@H:60]([OH:63])[CH2:61][NH:62][C:28](=[O:29])[C:27]1[CH:31]=[CH:32][C:24]([CH2:23][N:10]([C:11]2[CH:12]=[CH:13][C:14]([CH:17]3[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]3)=[CH:15][CH:16]=2)[C:9]([NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=2)=[O:33])=[CH:25][CH:26]=1)[CH3:57]
Reactant: O=C(O)c1ccc(CN(C(=O)Nc2cccc(Br)c2)c2ccc(C3CCCCC3)cc2)cc1
Reactant: CCOC(=O)[C@H](O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](O)CNC(=O)c1ccc(CN(C(=O)Nc2cccc(Br)c2)c2ccc(C3CCCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-[3-(3-Bromophenyl)-1-(4-cyclohexylphenyl)ureidomethyl]benzoic acid (0.20 g, 0.39 mmol) was dissolved in DMF (2.5 mL) and EDAC (0.12 g, 0.6 mmol) and HOBt (0.089 mg, 0.6 mmol) were added and the mixture was stirred at room temperature for 10 min. (R)-Isoserine ethyl ester hydrochloride (0.10 g, 0.6 mmol) and N,N-diisopropylethylamine (130 μL) dissolved in DMF (2.5 mL) were added and the resulting mixture was stirred at room temperature for 16 hours. The mixture was added ethyl acetate (70 mL) and washed with water (2×100 mL), the organic phase was dried with sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with a mixture of ethyl acetate:n-heptane (1:2) containing 10% acetic acid. This afforded 100 mg of (R)-3-{4-[3-(3-bromophenyl)-1-(4-cyclohexylphenyl)ureidomethyl]benzoylamino}-2-hydroxypropionic acid ethyl ester. HPLC-MS (Method B): m/z=624 (M+1); Rt=5.33 min.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:5]=[N:6][CH:7]=[N:8][CH:9]=1.[C:11]([C:13]1[CH:14]=[C:15]([F:21])[C:16]([F:20])=[C:17]([F:19])[CH:18]=1)#[CH:12].N>>[N:6]1[CH:5]=[C:4]([C:3]2[CH:12]=[C:11]([C:13]3[CH:14]=[C:15]([F:21])[C:16]([F:20])=[C:17]([F:19])[CH:18]=3)[O:1][N:2]=2)[CH:9]=[N:8][CH:7]=1
Reactant: C#Cc1cc(F)c(F)c(F)c1
Reactant: ON=C(Cl)c1cncnc1
Agent: N
Product: Fc1cc(-c2cc(-c3cncnc3)no2)cc(F)c1F

Procedure:
The titled compound was prepared as the hydrochloride salt according to Method CB using the product of Example 44B (79 mg, 0.5 mmol) and 5-ethynyl-1,2,3-trifluorobenzene (Apollo, 78 mg, 0.5 mmol). 1H NMR (300 MHz, DMSO-d6) δ 7.88 (s, 1H), 7.95 (dd, J=8.6, 6.6 Hz, 2H), 9.29 (s, 2H), 9.36 (s, 1H) ppm; MS (DCI/NH3) m/z 278 (M+H)+.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH:7]=[C:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1>[Pt].C.O1CCOCC1.C(N(CC)CC)C>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:15]=[CH:16][C:17]([C:18]([NH2:20])=[O:19])=[CH:21][CH:22]=2)[CH2:10][CH2:9]1
Reactant: NC(=O)c1ccc(C2CCC(=CCC3OCCO3)CC2)cc1
Agent: [Pt]
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: NC(=O)c1ccc([C@H]2CC[C@H](CCC3OCCO3)CC2)cc1

Procedure:
A mixture of 500 mg of 4-[4-[2-(1,3-dioxolan-2-yl)ethylidene]cyclohexyl]benzamide and 20 ml of dioxan/triethylamine (vol. 9:1) was hydrogenated by means of 500 mg of 10 percent platinum-charcoal for 2 hours. The reaction mixture was then filtered and the filtrate was evaporated. Recrystallization of the evaporation residue from 40 ml of dioxan gave 230 mg of 4-[trans-4-[2-(1,3-dioxolan-2-yl)ethyl]cyclohexyl]benzamide as colorless crystals.