Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7](=[O:15])[CH2:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2([C:27](O)=O)[CH2:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1.C(N(C(C)C)CC)(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(Cl)Cl.O.CCOCC.C1COCC1.CCOC(C)=O.CCCCCC>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2([CH2:27][N:11]3[CH2:12][CH2:13][CH2:14][CH:9]([CH2:8][C@@H:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[OH:15])[CH2:10]3)[CH2:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CCC1
Reactant: O=C(C[C@@H]1CCCNC1)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O[C@@H](CC1CCCN(CC2(c3ccc(Cl)cc3)CCC2)C1)c1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 76.3 %

Procedure:
(S)-[1-Phenyl-2-piperidin-3-yl-ethanone] (142 mg, 0.70 mmol) and 1-(4-Chloro-phenyl)-cyclobutanecarboxylic acid (148 mg, 0.70 mmol) were dissolved in 5 mL of methylene chloride and treated with the amide coupling agent BrOP (1.05 mmol), and diisopropylethylamine (2.1 mmol). The mixture was kept at room temperature overnight, diluted with 20 mL of water, and 50 mL of ether. Extractive workup gave, after concentration of the organic layers in vacuo and chromatography on silica gel using a EtOAc-hexane gradient column, the desired amide intermediate 2-{1-[1-(4-Chloro-phenyl)-cyclobutanecarbonyl]-piperidin-3-yl}-1-phenyl-ethanone (254 mg, 92%). This amide was dissolved in 10 mL of THF at 0° C. and excess lithium aluminum hydride (245 mg) was added. The solution was heated to reflux for 5 minutes, cooled to 0° C., and quenched by dropwise addition of 1.5 mL 1M NaOH. Additional THF (10 mL) was added, and the suspension was stirred at room temperature for 30 minutes and then filtered though a plug of sodium sulfate. The solution thus obtained was concentrated in vacuo and the residue was purified by flash chromatography on silica gel using as eluent a gradient of ethyl acetate in hexane containing 1% ammonium hydroxide. 205 mg of (S)-[2-{1-[1-(4-Chloro-phenyl)-cyclobutylmethyl]-piperidin-3-yl}-1-phenyl-ethanol], 182, was obtained (83%). 1H and 13C NMR data was consistent with the assigned structure. Data for this compound as a mixture of diastereomers: MS 384 (M++1).
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[N:8]=1)=O.[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH:32][NH2:33]>>[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:16][CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:33]1
Reactant: NNc1ccccc1F
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(C(F)(F)F)cc2)ccc1=O
Product: O=c1ccn(-c2ccc(C(F)(F)F)cc2)nc1-c1ccnn1-c1ccccc1F

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-trifluoromethyl-phenyl)-1H-pyridazin-4-one (A-22) and 2-fluoro-phenylhydrazine according to the method described for example 1. MS: M=401.1 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]([Br:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C[O-].[Na+].O>C1(C)C(C)=CC=CC=1>[NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]([Br:13])=[CH:8][C:3]=1[C:4]([O:6][CH2:7][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:5]
Reactant: OCc1ccccc1
Reactant: COC(=O)c1cc(Br)cc(C)c1N
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1C
Product: Cc1cc(Br)cc(C(=O)OCc2ccccc2)c1N
Yield: 52.1 %

Procedure:
A solution of methyl 2-amino-5-bromo-3-methylbenzoate (5 g, 20.4 mmol) in benzyl alcohol (4.43 g, 40.9 mmol) and sodium methoxide (0.37 g, 2.04 mmol, 30% in methanol) was refluxed in xylene (10 ml) for 5 hours. Then, water was added, the phases were separated and the combined organic solvents were removed in vacuo. The residue was purified by column chromatography to obtain benzyl 2-amino-5-bromo-3-methylbenzoate (3.40 g, 43.3% of theory, 83.6 area % GC) as a pale brown solid.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27].CN(C)P(N(C)C)(N(C)C)=O>O>[C:26]([CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][NH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)([O:28][CH3:29])=[O:27]
Reactant: N#Cc1ccc(N)cc1
Reactant: COC(=O)CCCCCCCCCCCCCCCBr
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: COC(=O)CCCCCCCCCCCCCCCNc1ccc(C#N)cc1

Procedure:
A solution of 12 g. of 4-aminobenzonitrile and 15 g. of methyl 16-bromohexadecanoate in 200 ml. of hexamethylphosphoramide is heated at 120° for 22 hours, allowed to cool, and diluted with water. The mixture is chilled and the precipitate which forms is collected, dried, and recystallized from etherhexane to yield 4-(15-carbomethoxypentadecylamino)benzonitrile as a white solid.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([S:8]([C:11]2[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=2)[C:14](OC)=[O:15])(=[O:10])=[O:9])[CH2:4][CH2:3]1.[NH2:21][NH2:22]>CO>[CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([S:8]([C:11]2[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=2)[C:14]([NH:21][NH2:22])=[O:15])(=[O:10])=[O:9])[CH2:4][CH2:3]1
Reactant: NN
Reactant: COC(=O)c1cccc(S(=O)(=O)N2CCC(C)CC2)c1
Solvent: CO
Product: CC1CCN(S(=O)(=O)c2cccc(C(=O)NN)c2)CC1
Temperature: 65 °C
Yield: 64.6 %

Procedure:
Methyl 3-((4-methylpiperidin-1-yl)sulfonyl)benzoate (100 mg, 0.336 mmol) was added to the hydrazine (21.55 mg, 0.673 mmol) in methanol and refluxed for 8 h at 65° C. Following cooling, reaction was monitored by TLC. After completion of the reaction, the solvent was removed by vacuum and then compound was purified by column chromatography to yield 3-((4-methylpiperidin-1-yl)sulfonyl)benzohydrazide (70 mg, 0.217 mmol, 64.4% yield). 1H NMR (CD3OD, 400 MHz): δ 8.16 (m, 1H), 8.05 (m, 1H), 7.91 (m, 1H), 7.70 (t, 1H, J=7.6 Hz), 3.74 (m, 2H), 2.28 (m, 2H), 1.69 (m, 2H), 1.32-1.16 (m, 3H), 0.90 (d, 3H, J=6.0 Hz). ESI-MS: 298.1[M+H]+
Reaction SMILES: Br.Cl[C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([NH2:12])=[N:10][N:11]=2)[N:8]=1.[CH2:13]([NH:15][CH2:16][CH3:17])[CH3:14]>O>[CH2:13]([N:15]([CH2:16][CH3:17])[C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([NH2:12])=[N:10][N:11]=2)[N:8]=1)[CH3:14]
Reactant: CCNCC
Reactant: Nc1nnc2ccc(Cl)nn12
Agent: Br
Solvent: O
Product: CCN(CC)c1ccc2nnc(N)n2n1

Procedure:
6-Chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine hydrobromide (W2.001; 150 mg) was initially charged in water (5 ml) and admixed with diethylamine (814 μl) while stirring. Thereafter, the mixture was heated to reflux for 16 h and then further diethylamine (407 μl) was added. After refluxing for a further 12 h, the mixture was freed of the solvent, admixed with water and extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate and, after the desiccant had been filtered off, dried under reduced pressure. 67 mg of the title compound were obtained.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]3[CH:13]=[C:14]([NH:19][C:20](=[O:33])[C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([C:30]#[N:31])([CH3:29])[CH3:28])[C:22]=4[Cl:32])[CH:15]=[CH:16][C:17]=3[F:18])[CH:8]=[CH:7][C:5]=2[N:6]=1.[C:34](Cl)(=[O:36])[CH3:35].N1C=CC=CC=1.O>O1CCCC1.C(OCC)(=O)C>[C:34]([NH:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]3[CH:13]=[C:14]([NH:19][C:20](=[O:33])[C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([C:30]#[N:31])([CH3:29])[CH3:28])[C:22]=4[Cl:32])[CH:15]=[CH:16][C:17]=3[F:18])[CH:8]=[CH:7][C:5]=2[N:6]=1)(=[O:36])[CH3:35]
Reactant: CC(=O)Cl
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2ccc(F)c(Oc3ccc4nc(N)sc4c3)c2)c1Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2ccc(Oc3cc(NC(=O)c4cccc(C(C)(C)C#N)c4Cl)ccc3F)cc2s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 27.5 %

Procedure:
To a solution of N-{3-[(2-amino-1,3-benzothiazol-6-yl)oxy]-4-fluorophenyl}-2-chloro-3-(1-cyano-1-methylethyl)benzamide (350 mg, 0.73 mmol) in tetrahydrofuran (20 mL) were added acetyl chloride (63 mg, 0.80 mmol) and pyridine (86 mg, 1.09 mmol), and the mixture was stirred at room temperature for 10 min. To the reaction mixture were added water (100 mL) and ethyl acetate (100 mL). After stirring for 30 min, the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=20/80→0/100), and triturated with ethyl acetate/hexane to give the title compound (105 mg, 28%) as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21](Cl)[S:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[CH:25]([C:28]1[CH:29]=[C:30]([OH:34])[CH:31]=[CH:32][CH:33]=1)([CH3:27])[CH3:26]>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21]([O:34][C:30]3[CH:31]=[CH:32][CH:33]=[C:28]([CH:25]([CH3:27])[CH3:26])[CH:29]=3)[S:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: CC(C)c1cccc(O)c1
Reactant: CC(NC(=O)c1csc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Product: CC(C)c1cccc(Oc2nc(C(=O)NC(C)c3cc(F)c(NS(C)(=O)=O)c(F)c3)cs2)c1
Yield: 65.2 %

Procedure:
2-Chloro-thiazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted with 3-isopropyl phenol (34 mg, 0.25 mmol) to give the title compound (42 mg, 67%) after purification by column chromatography (gradient 12% to 100% EtOAc in n-hexane).
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([C:12](=O)[CH:13]([CH:21]([C:25]2[CH:42]=[CH:41][C:28]([C:29]([NH:31][CH2:32][CH2:33][C:34]([O:36]C(C)(C)C)=[O:35])=[O:30])=[CH:27][CH:26]=2)[CH2:22][CH2:23][CH3:24])[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[C:45]1([NH:51][NH2:52])[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>N1C=CC=CC=1.CCOC(C)=O>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([CH:13]([C:12]2[N:51]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[N:52]=[C:3]3[C:4]=2[CH:5]=[C:6]([C:8]([F:10])([F:9])[F:11])[CH:7]=[C:2]3[Cl:1])[CH:21]([C:25]2[CH:42]=[CH:41][C:28]([C:29]([NH:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:30])=[CH:27][CH:26]=2)[CH2:22][CH2:23][CH3:24])=[CH:19][CH:18]=1
Reactant: NNc1ccccc1
Reactant: CCCC(c1ccc(C(=O)NCCC(=O)OC(C)(C)C)cc1)C(C(=O)c1cc(C(F)(F)F)cc(Cl)c1F)c1ccc(Cl)cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCCC(c1ccc(C(=O)NCCC(=O)O)cc1)C(c1ccc(Cl)cc1)c1c2cc(C(F)(F)F)cc(Cl)c2nn1-c1ccccc1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a solution of the major diastereomer of tert-butyl N-(4-{1-[2-[3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]-1-(4-chlorophenyl)-2-oxoethyl]butyl}benzoyl)-β-alaninate (EXAMPLE 2, Step A, 100 mg, 0.153 mmol) in pyridine (1.5 mL) was added phenylhydrazine (0.083 mL, 0.076 mmol). The mixture was stirred at 80° C. for 18 hours in a sealed tube. The mixture was diluted with EtOAc then washed with 2 N HCl (aq) then saturated NaCl (aq). The organic layer was dried over sodium sulfate, filtered, then concentrated. The resulting residue was purified by silica gel chromatography eluting with 0-50% EtOAc/hexanes to afford the title compound. This diastereomer was resolved to provide enantiopure material by HPLC on a ChiralPak IA column (2 cm×25 cm) eluting with 9 mL/min of 5% EtOH/n-heptane. LC1 2.98 min. (M-tBu+H)+ 668.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[C:14]([C:23](=[O:25])[CH3:24])=[N:15][C:16]4[C:21]([CH:22]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:26][CH3:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC1(C)[O:53][CH2:52][CH:51]([CH2:54]O)[CH2:50][O:49]1.CCOC(/N=N/C(OCC)=O)=O.S(=O)(=O)(O)O.[OH-].[Na+]>O1CCCC1.O>[OH:49][CH2:50][CH:51]([CH2:52][OH:53])[CH2:54][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[C:14]([C:23](=[O:25])[CH3:24])=[N:15][C:16]4[C:21]([CH:22]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:26][CH3:27]
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C(C)=O)ccnc2cc1O
Reactant: CC1(C)OCC(CO)CO1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc2c(Oc3cc4ccccc4nc3C(C)=O)ccnc2cc1OCC(CO)CO
Temperature: 25 °C
Reaction time: 4 h
Yield: 75.5 %

Procedure:
1-[3-(7-Hydroxy-6-methoxy-quinolin-4-yloxy)-quinolin-2-yl]-ethanone (compound 390) (50 mg) was dissolved in tetrahydrofuran (1 ml) to prepare a solution. Triphenylphosphine (73 mg), (2,2-dimethyl-[1,3]dioxan-5-yl)-methanol (24 mg), and diethylazodicarboxylate (0.05 ml) were added to the solution, and the mixture was stirred at room temperature for 4 hr. Further, 1 N sulfuric acid (3 ml) was added thereto, and the mixture was stirred at room temperature overnight. The reaction solution was brought to 0° C. and was stirred. The reaction solution was made alkaline by the addition of a 10% aqueous sodium hydroxide solution. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (47 mg, yield 75%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)([CH2:12][CH2:13]OS(C)(=O)=O)[C:8]1=[O:27].I.[CH2:36]([O:38][CH2:39][CH2:40][N:41]1[C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=2[N:43]=[C:42]1[N:50]1[CH2:56][CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1)[CH3:37].C(N(CC)C(C)C)(C)C.C(N(CC)CC)C>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:12][CH2:13][N:53]2[CH2:54][CH2:55][CH2:56][N:50]([C:42]3[N:41]([CH2:40][CH2:39][O:38][CH2:36][CH3:37])[C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=4[N:43]=3)[CH2:51][CH2:52]2)([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)[C:8]1=[O:27]
Reactant: COc1cc(CN2CCC(CCOS(C)(=O)=O)(Cc3ccc(F)cc3)C2=O)cc(OC)c1OC
Reactant: CCOCCn1c(N2CCCNCC2)nc2ccccc21
Agent: I
Solvent: CCN(C(C)C)C(C)C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOCCn1c(N2CCCN(CCC3(Cc4ccc(F)cc4)CCN(Cc4cc(OC)c(OC)c(OC)c4)C3=O)CC2)nc2ccccc21
Reaction time: 12 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzyl)-3-(4-fluorophenylmethyl)-3-(2-methanesulfonyloxyethyl)-2-oxopyrrolidine (0.34 g, 0.63 mmol) and 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic acid salt (0.35 g, 0.63 mmol), and N,N-diisopropylethylamine (0.33 g, 2.5 mmol) in acetonitrile (10 mL). Heat to reflux. After 12 hours, cool and partition the reaction mixture between dichloromethane and a saturated aqueous ammonium chloride solution. Separate the layers and extract the organic layer with a saturated aqueous sodium bicarbonate solution. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Chromatograph the residue on a short column of silica gel eluting with 2% triethylamine/5% methanol/ethyl acetate to give the title compound: Rf=0.39 (silica gel, 2% triethylamine/10% methanol/ethyl acetate).
Reaction SMILES: [CH2:1]([C:3]1([CH2:18][C:19]2[N:20]=[CH:21][N:22](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:23]=2[CH3:24])[C:16](=[O:17])[N:7]2[C:8]3[C:13]([C:14]([CH3:15])=[C:6]2[CH2:5][CH2:4]1)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH3:2]>C(O)(=O)C.O>[CH2:1]([C:3]1([CH2:18][C:19]2[N:20]=[CH:21][NH:22][C:23]=2[CH3:24])[C:16](=[O:17])[N:7]2[C:8]3[C:13]([C:14]([CH3:15])=[C:6]2[CH2:5][CH2:4]1)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH3:2]
Reactant: CCC1(Cc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2C)CCc2c(C)c3ccccc3n2C1=O
Solvent: CC(=O)O
Solvent: O
Product: CCC1(Cc2nc[nH]c2C)CCc2c(C)c3ccccc3n2C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
A solution of 7-ethyl-8,9-dihydro-10-methyl-7-[(5-methyl-1-trityl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one (0.45 g) in acetic acid (10 ml) and water (2.5 ml) was stirred at 60° C. for 2 hours. After evaporation of the solvent, the residue was diluted with ether (10 ml) and an aqueous solution of sodium hydrogencarbonate (10 ml). The resultant mixture was stirred for 30 minutes at ambient temperature. The insoluble material was collected, washed with water and ether, and dried to give crystalline 7-ethyl-8,9-dihydro-10-methyl-7-[(5-methyl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one (0.20 g).
Reaction SMILES: [CH3:1][N:2]([CH2:28][CH:29]1[CH2:33][CH2:32][NH:31][CH2:30]1)[C:3]1[S:4][C:5]2[CH:11]=[C:10]([NH:12][C:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)=[CH:17][CH:16]=3)=[O:14])[CH:9]=[CH:8][C:6]=2[N:7]=1.I[CH:35]([CH3:37])[CH3:36].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C>[CH:35]([N:31]1[CH2:32][CH2:33][CH:29]([CH2:28][N:2]([CH3:1])[C:3]2[S:4][C:5]3[CH:11]=[C:10]([NH:12][C:13]([C:15]4[CH:16]=[CH:17][C:18]([C:21]5[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=5)=[CH:19][CH:20]=4)=[O:14])[CH:9]=[CH:8][C:6]=3[N:7]=2)[CH2:30]1)([CH3:37])[CH3:36]
Reactant: CN(CC1CCNC1)c1nc2ccc(NC(=O)c3ccc(-c4ccc(F)cc4)cc3)cc2s1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)N1CCC(CN(C)c2nc3ccc(NC(=O)c4ccc(-c5ccc(F)cc5)cc4)cc3s2)C1
Yield: 90.9 %

Procedure:
Place 4′-fluoro-biphenyl-4-carboxylic acid [2-(methyl-pyrrolidin-3-ylmethyl-amino)-benzothiazol-6-yl]-amide (16 mg, 0.035 mmol), 2-iodopropane (0.007 mL, 0.070 mmol), and potassium carbonate (15 mg, 0.108 mmol) in DMF (2 mL) and stir at rt for 3 d. Dilute the reaction with ethyl acetate and wash the organic layer with water (5 times). Chromatograph (silica gel, eluting with 10% 2M NH3 in MeOH:DCM) to yield 16 mg (91%) of the title compound: mass spectrum (ion-spray): (m/z)=503.3 (M+1).
Reaction SMILES: OO.[OH:3][CH:4]([CH2:23][CH:24]([CH3:29])[CH2:25][CH2:26][CH2:27][CH3:28])[CH:5]=[CH:6][CH:7]1[C:11](=[CH:12][CH2:13][CH2:14][CH2:15][CH:16]=[CH:17][C:18]([O:20][CH3:21])=[O:19])[C:10](=[O:22])[CH:9]=[CH:8]1.[OH-].[Na+].[Cl-:32].[NH4+].Cl.C(=O)([O-])O.[Na+]>CO.CC(C)=O>[Cl:32][C:9]1[C:10](=[O:22])[C:11](=[CH:12][CH2:13][CH2:14][CH2:15][CH:16]=[CH:17][C:18]([O:20][CH3:21])=[O:19])[CH:7]([CH:6]=[CH:5][CH:4]([OH:3])[CH2:23][CH:24]([CH3:29])[CH2:25][CH2:26][CH2:27][CH3:28])[CH:8]=1
Reactant: [Cl-]
Reactant: CCCCC(C)CC(O)C=CC1C=CC(=O)C1=CCCCC=CC(=O)OC
Agent: Cl
Agent: O=C([O-])O
Agent: OO
Solvent: CO
Solvent: CC(C)=O
Product: CCCCC(C)CC(O)C=CC1C=C(Cl)C(=O)C1=CCCCC=CC(=O)OC
Yield: 47 %

Procedure:
0.3 ml of 30% aqueous hydrogen peroxide was added to a solution of 160 mg (428 micromol) of 4-(3-hydroxy-5-methyl-1nonenyl)-5-(6-methoxycarbonyl-5-hexenylidene)-2-cyclopentenone in 5 ml of methanol under ice cooling and stirring, and then 60 microliters of 1N sodium hydroxide was added. The mixture was stirred at 0° C. for 20 minutes. A saturated aqueous solution of ammonium chloride was added, and the mixtue was extracted with hexane. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The dried product was filtered and concentrated to give an oily product. The product was dissolved in 3 ml of acetone, and 0.5 ml of concentrated hydrochloric acid was added. The mixture was stirred for 50 minutes. A saturated aqueous solution of sodium hydrogencarbonate was added, and the mixture was extracted with ethylacetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The dried product was filtered, concentrated and subjected to silica gel column chromatography (silica gel, 10 g; eluent, cyclohexane:ethylacetate=4:1) to give 82 mg (yield 47%) of 2-chloro-4-(3-hydroxy-5-methyl-1-nonenyl)-5-(6-methoxycarbonyl-5-hexenylidene)-2-cyclopentenone.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Br:7][C:8]1[C:9]([CH3:19])=[C:10]([C:15]([CH3:18])=[CH:16][CH:17]=1)[C:11](OC)=[O:12].Cl>O1CCCC1.O>[Br:7][C:8]1[C:9]([CH3:19])=[C:10]([CH2:11][OH:12])[C:15]([CH3:18])=[CH:16][CH:17]=1
Reactant: COC(=O)c1c(C)ccc(Br)c1C
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(Br)c(C)c1CO
Temperature: 25 °C
Reaction time: 4 h
Yield: 128.4 %

Procedure:
Using dried glassware, a solution of lithium aluminum hydride (0.79 gram, 0.021 mole) in dry tetrahydrofuran (90 ml) was cooled in a dry ice/acetone bath (78° C.) under a nitrogen atmosphere, and methyl 3-bromo-2,6-dimethylbenzoate (5.0 grams, 0.021 mole) in dry tetrahydrofuran (10 ml) was added. The mixture was stirred at room temperature for four hours, and a mixture of tetrahydrofuran (9 ml) in water (1 ml) was added, followed by water (10 ml) and 3 N hydrochloric acid until the solution was acidic. The reaction mixture was extracted with three 200 ml portions of diethyl ether. The combined extracts were dried over magnesium sulfate, filtered and the solvent evaporated to give (3-bromo-2,6-dimethylphenyl)methanol (5.8 grams). The ir spectrum was consistent with the named compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:10]=1[C:11]([NH:13][CH2:14][C:15]([NH:17][CH2:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:16])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][C:33]=1[N+:40]([O-:42])=[O:41].C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:10]=1[C:11]([NH:13][CH2:14][C:15]([NH:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([CH2:36][C:35]2[CH:38]=[CH:39][C:32]([Cl:31])=[C:33]([N+:40]([O-:42])=[O:41])[CH:34]=2)[CH2:21][CH2:20]1)=[O:16])=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(F)cc1C(=O)NCC(=O)NCC1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1cc(F)c(F)cc1C(=O)NCC(=O)NCC1CCN(Cc2ccc(Cl)c([N+](=O)[O-])c2)CC1
Temperature: 50 °C
Reaction time: 8 h
Yield: 52.7 %

Procedure:
To a mixture of 4-[{N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl}aminomethyl]piperidine (0.14 mmol), 4-chloro-3-nitrobenzaldehyde (0.50 mmol), methanol (1.5 mL), and acetic acid (0.070 mL) was added NaBH3CN (0.63 mmol) in methanol (1.3 mL). The reaction mixture was stirred at 50° C. overnight. The mixture was cooled to room temperature, loaded onto Varian™ SCX column, and washed with CH3OH. Product was eluted off using 2 N NH3 in CH3OH and concentrated. The resulting material was dissolved into ethyl acetate/methanol=5/1, loaded onto Varian™ Si column, eluted off using ethyl acetate/methanol=5/1 (6 mL), and concentrated to give 4-[{N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl}aminomethyl]-1-(4-chloro-3-nitrobenzyl)piperidine (44 mg, 53%): ESI/MS m/e 596.3 (M++H).