Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH:9]1[C:14]2=[N:15][C:16]([CH3:38])=[C:17]([CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH:25]([C:28]4[C:32]5[CH:33]=[CH:34][C:35]([OH:37])=[CH:36][C:31]=5[O:30][N:29]=4)[CH2:24][CH2:23]3)[C:18](=[O:19])[N:13]2[CH2:12][CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CN(C=O)C.C(=O)([O-])[O-].[K+].[K+].[C:50]([N:57](Br)[CH2:58][CH3:59])([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51]>CC(C)=O>[Si:1]([O:8][CH:9]1[C:14]2=[N:15][C:16]([CH3:38])=[C:17]([CH2:20][CH2:21][N:22]3[CH2:23][CH2:24][CH:25]([C:28]4[C:32]5[CH:33]=[CH:34][C:35]([O:37][CH2:59][CH2:58][NH:57][C:50](=[O:51])[O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[CH:36][C:31]=5[O:30][N:29]=4)[CH2:26][CH2:27]3)[C:18](=[O:19])[N:13]2[CH2:12][CH2:11][CH2:10]1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: Cc1nc2n(c(=O)c1CCN1CCC(c3noc4cc(O)ccc34)CC1)CCCC2O[Si](C)(C)C(C)(C)C
Reactant: CCN(Br)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: Cc1nc2n(c(=O)c1CCN1CCC(c3noc4cc(OCCNC(=O)OC(C)(C)C)ccc34)CC1)CCCC2O[Si](C)(C)C(C)(C)C
Temperature: 60 °C
Reaction time: 17 h

Procedure:
A solution of 9-((tert-butyldimethylsilyl)oxy)-3-(2-(4-(6-hydroxybenzo[d]isoxazol-3-yl)piperidin-1-yl)ethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one, prepared as described in the previous step, (50 mg, 0.093 mmol) in acetone (0.5 mL) and DMF (0.5 mL) was treated with potassium carbonate (33.3 mg, 0.24 mmol) and N-Boc-2-bromoaminoethane (27 mg, 0.12 mmol), and the reaction mixture was stirred for 17 h at 60° C. under argon. The reaction mixture was evaporated at 40° C. under reduced pressure and dissolved in water (10 mL) and extracted with dichloromethane (3×10 mL). The organic layers were combined, dried over Na2SO4, filtered, and the solvent was evaporated yield the crude title compound. (ESI-MS (M+1) 682)
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:24]>C(O)C.O1CCOCC1>[ClH:24].[ClH:24].[NH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][N:16]=2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(C(=O)O)cn2)CC1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: O=C(O)c1ccc(NC2CCNCC2)nc1

Procedure:
A solution of 6-(1-tert-butoxycarbonyl-piperidin-4-ylamino)-nicotinic acid (0.46 g, 1.43 mmol) in ethanol (40 mL) and 4 M HCl in dioxane (40 mL) was stirred at rt for 1 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 222.3 [M+H]+.
Reaction SMILES: O=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([C:11]([OH:13])=[O:12])[CH2:3]1>[Pd].CO>[CH:4]1([C:11]([OH:13])=[O:12])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:2][CH2:3]1
Reactant: O=C1CC(C(=O)O)c2ccccc21
Agent: [Pd]
Solvent: CO
Product: O=C(O)C1CCc2ccccc21
Yield: 94.6 %

Procedure:
A MeOH (1 mL) solution of 3-oxo-indancarboxylic acid (85.5 mg, 0.485 mmol) was mixed with Pd/C (16.5 mg) and hydrogenated at room temperature under 55 psi H2 pressure for 18 h. The crude mixture was filtered and concentrated to give 1-indanecarboxylic acid (74.4 mg, 95%). MS Found: (M−H)−=161.
Reaction SMILES: C(=C(O)[C@@H](O)[C@@H](O)C=[O:8])(C)C.[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>C1COCC1>[CH3:22][C:12]1[CH:17]=[CH:16][C:15]([S:18]([OH:8])(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)=C(O)[C@@H](O)[C@@H](O)C=O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)O)cc1
Yield: 50 %

Procedure:
For example, alcohol 4 was prepared with a 50-65 percent yield by coupling 2,3,-isopropylidene-D-erythrose with the known Wittig reagent (4-carbethoxybutyl) triphenylphosphonium bromide and KN(SiMe3)2 in THF at -78 degrees C. to 0 degrees C. The alcohol 4 was then treated with p-toluenesulfonyl chloride to furnish the corresponding p-toluenesulfonate. This p-toluenesulfonate was treated with sodium azide NaN3 in dimethyl formamide (DMF) (CH3)2NCHO at about 70 degrees C. to 100 degrees C. to produce the imino ester having the structure ##STR8## wherein R is (C1 -C8) alkyl;
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]3[N:13]=[CH:14][CH:15]=[CH:16][C:10]3=[N:9][C:8]=2[C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])=O.[NH4+]>CO.[Pd]>[C:1]1([C:7]2[N:12]=[C:11]3[NH:13][CH2:14][CH2:15][CH2:16][C:10]3=[N:9][C:8]=2[C:17]2[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(-c2nc3cccnc3nc2-c2ccccc2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Cc1ccc(-c2nc3c(nc2-c2ccccc2)NCCC3)cc1
Temperature: 25 °C

Procedure:
3-Phenyl-2-p-tolylpyrido[2,3-b]pyrazine (step 4) (179 mg, 0.602 mmol) under nitrogen in dry MeOH (5 ml) was treated with ammonium formate (190 mg, 3.01 mmol) and 10% palladium on carbon (64.1 mg, 0.060 mmol). The resulting mixture was heated at reflux for 16 hours. After cooling to RT, the mixture was filtered through Celite® (filter material) and the catalyst was washed with MeOH and MeOH/DCM (1:1). The filtrate was concentrated in vacuo and dissolved in DCM (50 ml). The solution was washed with water (×2) and brine (×1). The resulting organic portion was passed through a phase separating column and concentrated in vacuo to afford the title compound;
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH:9][C:10](=[O:12])[CH3:11])=[CH:4][C:3]=1[CH3:13].[Li]CCCC.CN([CH:22]=[O:23])C>C1COCC1>[CH:22]([C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH:9][C:10](=[O:12])[CH3:11])=[CH:4][C:3]=1[CH3:13])=[O:23]
Reactant: CN(C)C=O
Reactant: CC(=O)Nc1cc(C)c(Br)c(C)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(=O)Nc1cc(C)c(C=O)c(C)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-(4-bromo-3,5-dimethyl-phenyl)-acetamide (150 mg) in THF (5 mL) was added n-BuLi (1.36 mL, 1.0 M solution in hexane) at −78° C. The mixture was stirred at −78° C. for 30 min, then warmed up to −40° C. for 5 min, then cooled down to at −78° C. again. After 20 min, DMF (0.24 mL) was added. The mixture was stirred at −78° C. for 30 min and then allowed to warm up to room temperature for 1 h. The reaction was quenched with saturated NH4Cl aqueous solution and extracted with EtOAc. The organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give N-(4-formyl-3,5-dimethyl-phenyl)-acetamide: MS (m/z) 192 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[NH2:22][CH:23]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:25][CH2:24]1>CN(C)C=O.C(O)C>[CH2:29]([N:26]1[CH2:27][CH2:28][CH:23]([NH:22][CH2:19][C@@H:17]([OH:18])[CH2:16][O:15][C:12]2[CH:11]=[CH:10][C:9]([C:6]3[C:5]4[CH:20]=[CH:21][C:2]([F:1])=[CH:3][C:4]=4[O:8][N:7]=3)=[CH:14][CH:13]=2)[CH2:24][CH2:25]1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Solvent: CCO
Solvent: CN(C)C=O
Product: O[C@H](CNC1CCN(Cc2ccccc2)CC1)COc1ccc(-c2noc3cc(F)ccc23)cc1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 4-amino-1-benzylpiperidine in ethanol, essentially as described above in Example 70. Purity by LC/MS=100%, [M+H]+=476.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]([C:13]2[N:17]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[C:16](=[S:25])[NH:15][CH:14]=2)([CH3:12])[CH3:11])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C([O-])([O-])=O.[K+].[K+].Br[CH2:33][C:34]1[CH:35]=[CH:36][C:37]([Cl:42])=[C:38]([CH:41]=1)[C:39]#[N:40]>CC(C)=O>[Cl:42][C:37]1[CH:36]=[CH:35][C:34]([CH2:33][S:25][C:16]2[N:17]([C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)[C:13]([C:10]([C:4]3[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Cl:1])[CH:3]=3)([CH3:12])[CH3:11])=[CH:14][N:15]=2)=[CH:41][C:38]=1[C:39]#[N:40]
Reactant: COc1ccc(C(C)(C)c2c[nH]c(=S)n2-c2ccc(F)cc2)cc1Cl
Reactant: N#Cc1cc(CBr)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(C(C)(C)c2cnc(SCc3ccc(Cl)c(C#N)c3)n2-c2ccc(F)cc2)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.4 %

Procedure:
To a solution of 5-(2-(3-chloro-4-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole-2(3H)-thione (125 mg, 0.33 mmol) in acetone (2 mL) were added K2CO3 (70, mg, 0.50 mmol) and 5-(bromomethyl)-2-chlorobenzonitrile (92 mg, 0.40 mmol). The mixture was stirred at room temperature for 2 h and filtered. The mother liquor was concentrated and purified by column chromatography (silica, 0 to 30% EtOAc/Hex) to afford the title compound (105 mg, 60%) as a white solid. MS (EI) m/z 526 (MH+).
Reaction SMILES: [CH2:1]([O:8][C@H:9]([C@@H:11](O)[CH2:12][CH2:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:25]1[CH:29]=[C:28]([C:30]([O:32][CH3:33])=[O:31])[N:27]=[CH:26]1>>[CH2:1]([O:8][C@H:9]([C@H:11]([N:25]1[CH:29]=[C:28]([C:30]([O:32][CH3:33])=[O:31])[N:27]=[CH:26]1)[CH2:12][CH2:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](OCc1ccccc1)[C@@H](O)CCc1cccc2ccccc12
Reactant: COC(=O)c1c[nH]cn1
Product: COC(=O)c1cn([C@H](CCc2cccc3ccccc23)[C@H](C)OCc2ccccc2)cn1

Procedure:
Methyl 1-[(2S,3R)-2-benzyloxy-5-(1-naphthyl)-3-pentyl]-imidazole-4-carboxylate was prepared from (2S,3S)-2-benzyloxy-5-(1-naphthyl)pentan-3-ol (obtained in Preparation 26) and methyl imidazole-4-carboxylate.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[CH2:18][O:17][C:16]3=[O:21])=[CH:8][CH:7]=[CH:6][C:5]=12.[CH:22](=O)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].N1CCCC1>C(O)C>[CH:22](=[C:18]1[O:17][C:16](=[O:21])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][S:10][C:9]2[N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH:6]=[CH:7][CH:8]=2)[C:19]1=[O:20])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: O=C1COC(=O)N1CCCCSc1cccc2nccn12
Reactant: CCCCCCCCCC=O
Solvent: C1CCNC1
Solvent: CCO
Product: CCCCCCCCCC=C1OC(=O)N(CCCCSc2cccc3nccn23)C1=O

Procedure:
To a solution of 1.527 g (5.0 mmol) of 3-[4-(imidazo[1,2-a]pyridin-5-ylthio)butyl]oxazolidine-2,4-dione and 1.11 ml (5.0 mmol) of decanal in 20 ml of ethanol, 0.04 ml (0.5 mmol) of pyrrolidine was added, followed by refluxing for 20 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in dichloromethane, washed with water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, n-hexane/ethyl acetate 3/1→ethyl acetate). The resulting residue was crystallized from n-hexane to yield 0.13 g (5.8%, white crystal) of the desired product.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([N:10]3[CH2:14][CH2:13][C:12]4([CH2:19][CH2:18][C:17](=[CH2:20])[CH2:16][CH2:15]4)[C:11]3=[O:21])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=[O:30])C=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([N:10]3[CH2:14][CH2:13][C:12]4([CH2:15][CH2:16][C:17]5([O:30][CH2:20]5)[CH2:18][CH2:19]4)[C:11]3=[O:21])=[CH:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C1CCC2(CC1)CCN(c1ccc(C3CC3)cc1)C2=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C1N(c2ccc(C3CC3)cc2)CCC12CCC1(CC2)CO1
Temperature: 25 °C

Procedure:
A solution of 0.251 g (0.89 mmol) 2-(4-cyclopropyl-phenyl)-8-methylene-2-aza-spiro[4.5]decan-1-one in 3 mL DCM was added at 0° C. to a solution of 0.157 g (0.91 mmol) m-chloroperbenzoic acid and 0.098 mg (1.1 mmol) NaHCO3 in 3 mL DCM and allowed to stir to room temperature and continued for another hour at room temperature. The mixture was poured onto water and extracted with DCM. The combined organic phases were dried with MgSO4, filtered and evaporated. The title compound (0.312 g) was used in the consecutive step without further purification. MS (m/e): 298.8 [MH+].
Reaction SMILES: [C:1]1([CH:7]2[N:21]3[C:22]4[C:14]([C:15]5[C:16]([O:23][CH2:24][CH2:25][CH2:26]Cl)=[CH:17][CH:18]=[CH:19][C:20]=53)=[CH:13][CH:12]=[CH:11][C:10]=4[O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:28]([NH:30][CH2:31][CH3:32])[CH3:29].[I-].[Na+]>CN(C=O)C>[CH2:28]([N:30]([CH2:31][CH3:32])[CH2:26][CH2:25][CH2:24][O:23][C:16]1[C:15]2[C:14]3[C:22]4=[C:10]([O:9][CH2:8][CH:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[N:21]4[C:20]=2[CH:19]=[CH:18][CH:17]=1)[CH:11]=[CH:12][CH:13]=3)[CH3:29]
Reactant: ClCCCOc1cccc2c1c1cccc3c1n2C(c1ccccc1)CO3
Reactant: CCNCC
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CC)CCCOc1cccc2c1c1cccc3c1n2C(c1ccccc1)CO3
Temperature: 50 °C
Yield: 43.4 %

Procedure:
To a mixture of 3-chloropropyl 1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-yl ether (0.45 g, 1.2 mmol) in dry DMF (10 mL) is added diethylamine (1.2 mL, 12 mmol) and sodium iodide (0.18 g, 1.2 mmol). The mixture is heated at 50° C. overnight. The mixture is partitioned between water and CH2Cl2. The layers are separated and the organic layer washed with brine (50 mL) followed by water (100 mL). The organic layer is dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography with silica gel (60 mL) using CH3OH/CH2Cl2 (3/97) as eluent gave 0.216 g (43%) of the title compound.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5][CH2:4]1)#[N:2].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:29]=[O:30]>C1COCC1>[C:1]([C:3]1([CH2:29][OH:30])[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:10])[CH2:5][CH2:4]1)#[N:2]
Reactant: C=O
Reactant: N#CC1CCN(C(=O)OCc2ccccc2)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#CC1(CO)CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 1 h
Yield: 41 %

Procedure:
To a mixture of benzyl 4-cyanopiperidine-1-carboxylate (1.0 g, 4.0 mmol, Oakwood) in THF (50 mL) at about −78° C. was added LiHMDS (1.0 M solution in THF, 6.14 mL, 6.14 mmol) dropwise via syringe. The mixture was stirred for about 1 h. Paraformaldehyde (0.25 g, 8.2 mmol) was added in one portion and the mixture was stirred overnight at rt. The mixture was concentrated in vacuo and the residue was purified by preparative TLC (1:1 EtOAc/pet ether) to give benzyl 4-cyano-4-(hydroxymethyl)piperidine-1-carboxylate (0.45 g, 35%): LC/MS (Table 2, Method k) Rt=0.60 min; MS m/z: 274 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:10])[C:7]=1[CH:8]=[O:9].Cl.[F:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][NH2:20])=[CH:15][CH:14]=1.CN1C(=O)CCC1.[OH-].[K+:29]>O>[OH-:9].[K+:29].[Br:10][C:6]1[CH:5]=[N:4][CH:3]=[C:2]2[N:19]([C:16]3[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=3)[N:20]=[CH:8][C:7]=12
Reactant: NNc1ccc(F)cc1
Reactant: O=Cc1c(Br)cncc1Br
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: Fc1ccc(-n2ncc3c(Br)cncc32)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 1 L flask was charged 3,5-dibromopyridine-4-carboxaldehyde (50.0 g, 188.7 mmol, 1.0 eq) and 4-fluorophenylhydrazine hydrochloride (31.0 g, 190.7 mmol, 1.01 eq). NMP (250 mL) was charged, and the resulting slurry was stirred at ambient temperature for 2 hours. A solution of aqueous KOH was prepared from 85% KOH pellets (27.4 g, 415.2 mmol, 2.2 eq) and water (27.4 mL), and this KOH solution was charged to the reaction mixture. The batch was heated to 80° C. and held at this temperature for 30-60 minutes. Water (250 mL) was then charged at 80° C., and the resulting slurry was cooled to ambient temperature over 4-16 hours. The slurry was filtered, the solid was washed with water, and oven dried under vacuum to afford 4-bromo-1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine as a tan colored solid, 51.5 g, 99.3 area % purity by HPLC, 93% yield.
Reaction SMILES: [CH:1]1([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:29])[CH2:23][S:24][CH2:25][C:26](O)=[O:27])=[C:17]([C:30]([O:32]C)=[O:31])[CH:16]=1>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:29])[CH2:23][S:24][CH2:25][C:26]([NH:11][C:10]2[CH:9]=[CH:8][C:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[CH:13][CH:12]=2)=[O:27])=[C:17]([CH:16]=1)[C:30]([OH:32])=[O:31]
Reactant: Nc1ccc(C2CCCCC2)cc1
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)CSCC(=O)O
Product: O=C(CSCC(=O)Nc1ccc(Cl)cc1C(=O)O)Nc1ccc(C2CCCCC2)cc1

Procedure:
Using the same method as in Example 1-(ii), 4-cyclohexylaniline was reacted with the [(2-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-2-oxoethyl)sulfanyl]acetic acid obtained in Example 12-(i) to give 5-chloro-2-([((2-[(4-cyclohexylphenyl)amino]-2-oxoethyl)sulfanyl)acetyl]amino)benzoic acid.methyl ester (yield: 68%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:25]=[CH:24][C:10]2[C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)=[N:12][S:13][C:9]=2[CH:8]=1.[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[N:26]1([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:25]=[CH:24][C:10]3[C:11]([C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=4)=[N:12][S:13][C:9]=3[CH:8]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: FC(F)(F)c1ccc(-c2nsc3cc(OCCCCBr)ccc23)cc1
Reactant: C1CCNCC1
Product: FC(F)(F)c1ccc(-c2nsc3cc(OCCCCN4CCCCC4)ccc23)cc1

Procedure:
According to the method in example 7, 6-(4-Bromo-butoxy)-3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazole and Piperidine were converted to yield 6-(4-Piperidin-1-yl-butoxy)-3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazole, MS: 435 (MH+).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15]3=[N:17][C@H:18]([CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:19][N:14]3[C:13](Cl)=[N:12][C:11]=2[N:10]=[C:9]1[CH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:33].[Na+]>O1CCOCC1>[CH2:1]([N:8]1[C:16]2[C:15]3=[N:17][C@H:18]([CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:19][N:14]3[C:13](=[O:33])[NH:12][C:11]=2[N:10]=[C:9]1[CH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: ClC1=Nc2nc(C3CCCC3)n(Cc3ccccc3)c2C2=N[C@H](Cc3ccccc3)CN12
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C1Nc2nc(C3CCCC3)n(Cc3ccccc3)c2C2=N[C@H](Cc3ccccc3)CN12
Temperature: 70 °C
Yield: 90 %

Procedure:
Compound 66 (1.87 g, 4.21 mmol) obtained in Example 66 was dissolved in 1,4-dioxane (30 mL), to the solution was added 2 mol/L aqueous sodium hydroxide (15 mL), and the mixture was stirred with heating at 70° C. for 3 hours. The reaction solution was concentrated under reduced pressure, and then the residue was neutralized by addition of concentrated hydrochloric acid. The deposited crystals were collected by filtration, washed with water and dried to obtain (R)-1,8-dibenzyl-2-cyclopentyl-7,8-dihydro-1H-imidazo[2,1-i]purin-5(4H)-one (Compound 77a, 1.61 g, 90%). Compound 77a (500 mg, 1.08 mmol) was dissolved in N,N-dimethylformamide (5 mL), to the solution were added potassium carbonate (192 mg, 1.41 mmol, 1.2 equivalents) and bromoacetic acid methyl ester (140 μL, 1.41 mmol, 1.2 equivalents), and the mixture was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, water was added to the concentrate, the mixture was extracted with chloroform, and the extract was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=90:10) to obtain (R)-1,8-dibenzyl-2-cyclopentyl-7,8-dihydro-4-methoxycarbonylmethyl-1H-imidazo[2,1-i]purin-5(4H)-one (Compound 77b, 400 mg, 69%). From Compound 77b (850 mg, 1.71 mmol), (R)-8-benzyl-2-cyclopentyl-7,8-dihydro-4-methoxycarbonylmethyl-1H-imidazo[2,1-i]purin-5(4H)-one (Compound 77c, 220 mg, 29%) was obtained in a manner similar to the method by which Compound 40 was obtained from Adduct 40a in Example 40. Compound 77c (200 mg, 0.49 mmol) was dissolved in a mixed solvent of tetrahydrofuran (1 mL) and water (1 mL), to the solution was added lithium hydroxide hydrate (0.04 g, 0.98 mmol), and the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was adjusted to pH 3 with 1 mol/L hydrochloric acid, and the resulting solid was washed with ethanol and collected by filtration to obtain the title compound (180 mg, 93%).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:10])[C@H:7]([CH3:9])[NH2:8])([CH3:4])[CH3:3].[C:11](#[N:13])[CH3:12]>>[O:5]=[C:2]([NH:8][C@H:7]([C:6]([O:5][C:2]([CH3:4])([CH3:3])[CH3:1])=[O:10])[CH3:9])[CH2:1][CH2:12][CH:11]1[CH2:9][CH2:7][C:6](=[O:10])[NH:13]1
Reactant: C[C@H](N)C(=O)OC(C)(C)C
Reactant: CC#N
Product: C[C@H](NC(=O)CCC1CCC(=O)N1)C(=O)OC(C)(C)C
Temperature: 80 °C

Procedure:
A solution of 7.0 g (0.05 mol) of dihydro-1H-3,5(2H,6H) dioxopyrrolizidine in 150 ml of acetonitrile is treated with 14.5 g (0.1 mol) L-alanine 1,1-dimethylethyl ester. The mixture is refluxed 24 hours. The solution is concentrated at reduced pressure and the resulting oil is chromatographed over silica gel using elution with 2.5% methanol in dichloromethane. After concentration at reduced pressure the oil is rechromatographed over silica gel using 19:1 dichloromethane:methanol. The eluate is concentrated at reduced pressure and heated at 80° C. to yield N-[1-oxo-3-(5-oxo-2-pyrrolidinyl)propyl]-L-alanine, 1,1-dimethylethyl ester as an analytically pure oil with the following characteristic proton NMR spectrum: 1H-NMR(CDCL3) 1.35 (d, 3H), 1.5 (s, 9H), 1.5-2.4 (m, 9H), 3.5-3.8 (m, 1H), 4.4 (m, 1H), 6.6-6.8 (m, 1H), 7.4-7.6 (m, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]([F:21])[CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17][CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OCC)(=O)C.[Pd]>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@H:15]2[CH2:16][CH2:17][N:18]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[CH2:19][C@H:20]2[F:21])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(OCc3ccccc3)cc2)C(F)C1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC[C@H](c2ccc(OCc3ccccc3)cc2)[C@H](F)C1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 77.1 %

Procedure:
To 10% Pd/C (220 mg) under nitrogen was added a soln of tert-butyl 4-(4-(benzyloxy)-phenyl)-5-fluoro-5,6-dihydropyridine-1(2H)-carboxylate (1.35 g, 3.5 mmol) in ethyl acetate (20 mL). The mixture was stirred at rt under a hydrogen atmosphere at balloon pressure for 45 min. The Pd/C was removed by filtration, and the filtrate was concentrated. The residue was purified via silica gel chromatography (40 g of silica gel) eluting with a gradient of 0-100% ethyl acetate in hexanes to give the product cis-tert-butyl 4-(4-(benzyloxy)phenyl)-3-fluoropiperidine-1-carboxylate (1.05 g, 2.7 mmol, 77% yield). LC/MS (Conditions CZ-1) (M−t-butyl, AcCN+H)+=371.25. RT=1.504 min; 1H NMR (500 MHz, chloroform-d) δ 7.45 (d, J=7.6 Hz, 2H), 7.40 (t, J=7.5 Hz, 2H), 7.34 (t, J=7.0 Hz, 1H), 7.22 (d, J=8.4 Hz, 2H), 6.96 (ddd, J=8.9, 2.7, 2.0 Hz, 2H), 5.07 (s, 2H), 4.79-4.60 (m, 1H), 4.55-4.23 (m, 2H), 3.08-2.81 (m, 2H), 2.75 (ddd, J=36.0, 13.4, 3.1 Hz, 1H), 2.21 (qd, J=12.9, 4.3 Hz, 1H), 1.69 (d, J=11.7 Hz, 1H), 1.59 (s, 3H), 1.51 (s, 9H). The structure of this compound was verified by single-crystal X-ray analysis.