Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16](Cl)=[O:17].[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1>>[N:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[NH:19][C:16]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[OH:1])=[CH:10][CH:9]=[CH:8][C:7]=2[C:12]([F:15])([F:14])[F:13])=[O:17]
Reactant: Nc1ccccn1
Reactant: O=C(Cl)c1cnc2c(C(F)(F)F)cccc2c1O
Product: O=C(Nc1ccccn1)c1cnc2c(C(F)(F)F)cccc2c1O

Procedure:
Using the procedure of Step B of Example 1, 4-hydroxy- 8-trifluoromethyl-3-quinoline carboxylic acid chloride and 2-amino-pyridine were reacted to obtain N-[2-pyridinyl]-4 -hydroxy-8-trifluoromethyl-3-quinoline-carboxamide melting at 335°-336° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH:4]([NH:13][C:14]([O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24]OCCOC)=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[CH2:31](OCCOCCO)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]CC.C(N(CC)CC)C>C(#N)C>[CH3:1][O:2][C:3](=[O:30])[CH:4]([NH:13][C:14]([O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[O:15])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([OH:12])=[CH:10][CH:11]=1
Reactant: CCCCCCCCCCCCOCCOCCO
Reactant: COCCOCCOCCOCCOC(=O)NC(Cc1ccc(O)cc1)C(=O)OC
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCCCCCCCCCOCCOCCOC(=O)NC(Cc1ccc(O)cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Oligomer XXIV was prepared in an analogous manner to that described above for Oligomer XXII. Diethylene glycol monododecyl ether (2.712 g, 9.88 mmol) was dissolved in 100 mL dry acetonitrile. Triethylamine (2.06 mL, 14.8 mmol) and DSC (3.80 g, 14.8 mmol) were added. After stirring for 18 hours at room temperature under an inert atmosphere, the reaction mixture was concentrated in vacuo. The residual oil was taken up in concentrated sodium bicarbonate solution and extracted with EtOAc (2×200 mL). The combined EtOAc layers were washed with water (2×100 mL) and brine (2×100 mL). The organics were dried over Na2SO4, filtered and evaporated to dryness to give 3.58 g (87%) of XXIII.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[N:5]=[C:4]([F:10])[C:3]=1Cl.C(N(CC)CC)C>C(O)C.[Pd]>[NH2:1][C:2]1[CH:3]=[C:4]([F:10])[N:5]=[C:6]([F:9])[C:7]=1[F:8]
Reactant: Nc1c(F)c(F)nc(F)c1Cl
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: Nc1cc(F)nc(F)c1F
Reaction time: 1 h
Yield: 87.5 %

Procedure:
A suspension of 4-amino-3-chloro-2,5,6-trifluoropyridine (2, 19.7 g, 108 mmol), 10% Pd/C (1.8 g) and triethylamine (20 mL, 140 mmol) in 150 mL of anhydrous ethanol was hydrogenated at 50 psi in a Parr hydrogenation apparatus until TLC showed the reaction was completed (about 18 hours). The catalyst was removed by filtration and carefully washed with ethanol. The combined filtrate and washings were evaporated to dryness in vacuo. The residue was stirred with 80 mL of water for 1 h, filtered, and washed with water to give 3 (14 g) as a white solid. The filtrate and washings were combined and extracted with ether. The combined ether layers were then dried (MgSO4) and concentrated to give an additional 1.3 g of 3 (total yield: 15.3 g, 96%). A small analytical sample was purified by silica gel column chromatography (Rf0.47, CH2Cl2): mp 94-96° C.; 1H NMR (CDCl3) δ4.78 (br s, 2 H, 4-NH2, D2O exchangeable), 6.20 (d, 1 H, 5-H). Analysis calculated for C5H3F3N2: C, 40.55; H, 2.04; N, 18.92. Found: C, 40.60; H, 2.16; N, 18.67.
Reaction SMILES: C[CH:2]1[S:8][CH:7]([C:9]([OH:11])=[O:10])[CH2:6][C:5]2[CH:12]=C3OCOC3=C[C:4]=2[C:3]1=O.N[C@@H](CO)[C@H:22](C1C=CC=CC=1)[OH:23].[CH2:32]1[CH2:36][O:35][CH2:34][CH2:33]1>>[CH3:12][C@@H:5]1[CH2:6][C@H:7]([C:9]([OH:11])=[O:10])[S:8][C:2]2[CH:3]=[C:22]3[O:23][CH2:34][O:35][C:36]3=[CH:32][C:33]=2[CH2:4]1
Reactant: C1CCOC1
Reactant: CC1SC(C(=O)O)Cc2cc3c(cc2C1=O)OCO3
Reactant: N[C@@H](CO)[C@@H](O)c1ccccc1
Product: C[C@H]1Cc2cc3c(cc2S[C@@H](C(=O)O)C1)OCO3
Reaction time: 0.5 h

Procedure:
In 15 mL of THF was suspended 0.5 g of a racemic mixture, 1,2,4,5-tetrahydro-4-methyl-7,8-methylenedioxy-5-oxo-3-benzothiepin-2-carboxylic acid (content 99.5%; trans compound 88.1%, cis compound 11.4%). To the suspension was added 0.3 g (1 equivalent) of (1S,2S)-2-amino-1-phenyl-1,3-propanediol, which was made into a solution, followed by crystallization. The crystals were then aged for 30 minutes at room temperature (25° C.). The crystals were collected by filtration using, for example, glass filter, washed with 5 mL of THF, followed by drying overnight at room temperature under reduced pressure to afford 0.37 g of substantially pure (2R,4S)-1,2,4,5-tetrahydro-4-methyl-7,8-methylenedioxy-5-benzothiepin-2-carboxylic acid.(1S,2S)-2-amino-1-phenyl-1,3-propanediol salt as colorless crystals [HPLC area percentage; (2R,4R):(2S,4S):(2S,4R):(2R,4S)=0.6%:0.6%:8.3%:85.6%].
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([CH2:10]O)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.S(Cl)([Cl:14])=O>ClCCl>[Cl:14][CH2:10][C:7]1[CH:8]=[CH:9][C:4]2[N:3]=[CH:2][S:1][C:5]=2[CH:6]=1
Reactant: OCc1ccc2ncsc2c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: ClCc1ccc2ncsc2c1

Procedure:
To a dichloromethane solution (1.2 mL) of benzo[d]thiazol-6-yl-methanol (60 mg, 0.36 mmol), thionyl chloride (53 μL) was added at room temperature and the resultant solution was stirred for 1 day. After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude product of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[CH3:9]I>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH3:9]
Reactant: CI
Reactant: Sc1ccccc1Cl
Product: CSc1ccccc1Cl
Yield: 89 %

Procedure:
2-Chlorothioanisole was prepared in 89% yield from commercially available 2-chlorothiophenol (4.0 g, 27.6 mmol) using methyl iodide (4.66 g, 32.81 mmol) according to the procedure described in preparation 1.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([NH2:6])=[O:5].[CH3:7][NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1.C(N(CC)CC)C>C(#N)C>[CH3:20][O:19][C:13]1[CH:12]=[C:11]([CH2:10][CH2:9][N:8]([CH3:7])[CH2:2][CH2:3][C:4]([NH2:6])=[O:5])[CH:16]=[CH:15][C:14]=1[O:17][CH3:18]
Reactant: CNCCc1ccc(OC)c(OC)c1
Reactant: NC(=O)CCCl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(CCN(C)CCC(N)=O)cc1OC
Yield: 64.1 %

Procedure:
6.42 g (60 mmol) 3-Chloropropanamide, 5.85 g (30 mmol) N-methyl-3,4-dimethoxybenzeneethanamine and 7.7 g (75 mmol) triethylamine in 100 ml acetonitrile were stirred under reflux for 18 hours. The reaction mixture was concentrated in vacuo and the residue purified by chromatography on silicagel using methylene chloride/methanol: 92/8 to yield 5.12 g (64.1%) of the desired compound as an orange oil.
Reaction SMILES: [BH4-].[Na+].[C:3]1([CH:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10](=[O:13])[CH2:11][Br:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CCOCC>[OH-].[Na+].CO>[C:3]1([CH:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:10]([OH:13])[CH2:11][Br:12])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(CBr)C(c1ccccc1)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOCC
Product: OC(CBr)C(c1ccccc1)c1ccccc1
Reaction time: 1 h
Yield: 33.1 %

Procedure:
Sodium borohydride (1 52 g.) in sodium hydroxide solution (15 ml. 0.02M) was added to 1,1-diphenyl-3-bromo-propan-2-one (12 g.) in methanol (50 ml.), and the solution was stirred for one hour. Isolation through ether in the usual manner afforded 1,1-diphenyl-3-bromo-propan-2-ol (10 4 g. 86%) as an oil.
Reaction SMILES: [C:1]([Cl:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10]CCl.Cl.Cl.Cl.[CH3:16][NH:17][CH2:18][CH2:19][N:20]([CH2:36][C:37]1[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=1)[CH2:21][CH2:22][CH2:23][O:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[C:31](=[O:35])[NH:30][CH2:29][CH2:28]2.C(OC(=O)C)C.Cl>C(OCC)(=O)C.O.C(N(CC)CC)C>[ClH:9].[ClH:10].[CH3:16][N:17]([CH2:18][CH2:19][N:20]([CH2:21][CH2:22][CH2:23][O:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[C:31](=[O:35])[NH:30][CH2:29][CH2:28]2)[CH2:36][C:37]1[CH:38]=[CH:39][N:40]=[CH:41][CH:42]=1)[C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCCl
Reactant: O=C(Cl)c1ccccc1
Reactant: CNCCN(CCCOc1ccc2c(c1)CCNC2=O)Cc1ccncc1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CN(CCN(CCCOc1ccc2c(c1)CCNC2=O)Cc1ccncc1)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Benzoyl chloride (0.14 ml) was added to a dichloromethane solution (10 ml) of 6-{3-[(2-methylaminoethyl)pyridin-4-ylmethylamino]propoxy}-3,4-dihydro-2H-isoquinolin-1-one trihydrochloride (382 mg), and triethylamine (0.56 ml) under ice cooling. The mixture was stirred at room temperature overnight. Water was added to the reaction mixture, followed by extraction using dichloromethane. The organic layer was dried with anhydrous sodium sulfate, and condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=10:1→4:1). The purified product was condensed under reduced pressure. A 4N-hydrogen chloride ethyl acetate solution (0.28 ml) was added to an ethyl acetate solution (10 ml) of the residue. The precipitated insoluble matter was separated, washed with ethyl acetate, and dried to give the title compound (242 mg) as a white powder.
Reaction SMILES: COC([C:5]1[CH:6]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:7]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH2:8][CH:9]=1)=O.[I-].C[S+](C)(C)=[O:29].[H-].[Na+].O.[CH2:35]1[CH2:39][O:38][CH2:37][CH2:36]1>CS(C)=O>[CH2:39]([O:38][C:37]([C:36]12[CH2:5][CH:9]1[CH2:8][N:7]([S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)(=[O:12])=[O:11])[CH:6]2[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:29])[CH3:35]
Reactant: C1CCOC1
Reactant: COC(=O)C1=CCN(S(=O)(=O)c2ccc(C)cc2)C1c1ccccc1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)C12CC1CN(S(=O)(=O)c1ccc(C)cc1)C2c1ccccc1
Temperature: -20 °C
Reaction time: 16 h
Yield: 58.8 %

Procedure:
Racemic 2-phenyl-1-(toluene-4-sulfonyl)-2,5-dihydro-1H-pyrrole-3-carboxylic acid methyl ester (JOC 1998, 63, 5031-5041), (10.2 g, 27.5 mmol) and trimethylsulfoxoniumiodide (Aldrich), (6.6 9, 30.2 mmol) were dissolved in DMSO (100 mL), diluted with THF (200 mL), and cooled to −20° C. Oil free sodium hydride (0.8 g, 33.0 mmol) was added portionwise over approximately 20 minutes, the reaction was allowed to warm to room temperature and stirred 16 hours. The reaction mixture was poured into approximately 500 mL cold water and extracted with EtOAc. The EtOAc was washed with water two times and the aqueous extracts were combined and extracted with EtOAc. The last EtOAc extract was washed with water two times and the organic extracts were combined and washed with brine, dried over magnesium sulfate, and concentrated to a yellow gum. The gum was diluted with 45-50 mL Et2O and cooled. Scratching induced crystallization and the resultant crystals were collected by filtration to yield 2-phenyl-3-(toluene-4-sulfonyl)-3-aza-bicyclo[3.1.0]hexane-1-carboxylic acid ethyl ester (6.23 g, 58.8% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]C(=O)C(C)(C)C)=[CH:4][CH:3]=1.C([Li])CCC.[F:20][C:21]([F:28])([F:27])[C:22](OCC)=[O:23].C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.CCCCCC.O>[NH2:8][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][C:6]=1[C:22](=[O:23])[C:21]([F:28])([F:27])[F:20]
Reactant: CCOC(=O)C(F)(F)F
Reactant: CC(C)(C)C(=O)Nc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Nc1ccc(F)cc1C(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
To an ice-cooled solution of 4.0 g of N-(4-fluorophenyl)-2,2-dimethylpropanamide in 80 mL of dry THF was added dropwise over 30 min 30.8 mL of a 1.6 M solution of n-butyllithium in hexane. After addition was complete, the reaction mixture was stirred an additional 1 h at 0° after which time 5.63 mL of ethyl trifluoroacetate was added quickly dropwise. The cooling bath was removed and the reaction was allowed to proceed at ambient temperature for 40 min. The reaction was quenched by the addition of aqueous ammonium chloride and the reaction mixture was partitioned between ether and water. The ether layer was washed with brine, dried and evaporated to 6.29 g of the title compound as an orange oil. The bulk of this material (6.0 g) was dissloved in ethylene glycol dimethyl ether, 30 mL of 6N HCl was added nd the mixture was heated at reflux for 1.5 h. The cooled reaction mixture was diluted with water, and made basic by the addition of solid sodium carbonate. This was extracted with ether, and the combined extacts were dried and evaporated. The residue was purified by column chromatography over silica gel (elution with 10-20% ethyl acetate in hexanes) affording 2.10 g of the title compound as an orange solid.
Reaction SMILES: [NH2:1][C:2]1([CH3:23])[CH2:7][CH2:6][N:5]([CH2:8][C@H:9]2[N:19]3[C:20]4[N:11]([C:12](=[O:22])[CH:13]=[CH:14][C:15]=4[CH:16]=[CH:17][C:18]3=[O:21])[CH2:10]2)[CH2:4][CH2:3]1.[S:24]1[C:32]2[CH:31]=[C:30]([CH:33]=O)[N:29]=[CH:28][C:27]=2[O:26][CH2:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+].C(Cl)(Cl)[Cl:55]>CO>[ClH:55].[CH3:23][C:2]1([NH:1][CH2:33][C:30]2[N:29]=[CH:28][C:27]3[O:26][CH2:25][S:24][C:32]=3[CH:31]=2)[CH2:3][CH2:4][N:5]([CH2:8][C@H:9]2[N:19]3[C:20]4[N:11]([C:12](=[O:22])[CH:13]=[CH:14][C:15]=4[CH:16]=[CH:17][C:18]3=[O:21])[CH2:10]2)[CH2:6][CH2:7]1
Reactant: CC1(N)CCN(C[C@@H]2Cn3c(=O)ccc4ccc(=O)n2c43)CC1
Reactant: ClC(Cl)Cl
Reactant: O=Cc1cc2c(cn1)OCS2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CC1(NCc2cc3c(cn2)OCS3)CCN(C[C@@H]2Cn3c(=O)ccc4ccc(=O)n2c43)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
A suspension of (1R)-1-[(4-amino-4-methyl-1-piperidinyl)methyl]-1,2-dihydro-4H,9H-imidazo[1,2,3-ij]-1,8-naphthyridine-4,9-dione (26 mg, 0.083 mmol) (for a preparation see Example 23(i)) in chloroform (2 ml) and methanol (0.1 ml) at rt under argon was treated with [1,3]oxathiolo[5,4-c]pyridine-6-carbaldehyde (13.83 mg, 0.083 mmol) (for a synthesis see WO2004058144 Example 61) and stirred at rt for 2 h. The solution was then treated with sodium triacetoxyborohydride (52.6 mg, 0.248 mmol) and stirred at rt for 0.5 h. The reaction was then treated with saturated aqueous NaHCO3 (10 ml) and extracted with 20% methanol/DCM (3×50 ml). The combined organic fractions were dried (MgSO4), filtered, evaporated and chromatographed (0-20% methanol/DCM, Rf=0.3 in 15% methanol/DCM) to give the free base of the title compound as a yellow solid (29 mg, 75%,).
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3]([C@@H:5]1[CH2:9][C@H:8]([OH:10])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].[C:19]([O:22][CH2:23][CH2:24]Br)(=[O:21])[CH3:20]>>[CH3:1][N:2]([CH3:18])[C:3]([C@@H:5]1[CH2:9][C@@H:8]([O:10][CH2:20][C:19]([O:22][CH2:23][CH3:24])=[O:21])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])=[O:4]
Reactant: CC(=O)OCCBr
Reactant: CN(C)C(=O)[C@@H]1C[C@H](O)CN1C(=O)OC(C)(C)C
Product: CCOC(=O)CO[C@@H]1C[C@@H](C(=O)N(C)C)N(C(=O)OC(C)(C)C)C1
Yield: 46.1 %

Procedure:
With 20.0 g of tert-butyl (2S,4S)-2-[(dimethylamino)carbonyl]-4-hydroxypyrrolidine-1-carboxylate and 25.9 g of bromoethyl acetate as starting material, 12.3 g of the title compound obtained by a similar procedure to Step 139-1.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([CH:23]=O)[CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:13]=[C:8]2[N:7]=[C:6]1[CH3:18].[S:25]1[CH2:29][C:28](=[O:30])[NH:27][C:26]1=[O:31].N1CCCCC1>C(O)C>[Cl:1][C:2]1[CH:22]=[C:21]([CH:23]=[C:29]2[S:25][C:26](=[O:31])[NH:27][C:28]2=[O:30])[CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:13]=[C:8]2[N:7]=[C:6]1[CH3:18]
Reactant: O=C1CSC(=O)N1
Reactant: COC(=O)c1ccc2nc(C)n(Cc3ccc(C=O)cc3Cl)c2n1
Solvent: C1CCNCC1
Solvent: CCO
Product: COC(=O)c1ccc2nc(C)n(Cc3ccc(C=C4SC(=O)NC4=O)cc3Cl)c2n1
Yield: 73.3 %

Procedure:
A suspension of methyl 3-(2-chloro-4-formylbenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (200 mg, 0.582 mmol), thiazolidine-2,4-dione (82 mg, 0.698 mmol) and piperidine (25 mg, 0.291 mmol) in ethanol (4 ml) was refluxed under heating overnight. The reaction mixture was cooled, and the precipitated crystals were filtrated to give the objective compound (189 mg) as pale-yellow crystals.
Reaction SMILES: CS[C:3]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][N+:5]([O-:7])=[O:6].[CH2:13]([O:15][CH2:16][CH2:17][O:18][C:19]1[N:24]=[C:23]([NH:25][NH2:26])[CH:22]=[C:21]([C:27]([F:30])([F:29])[F:28])[CH:20]=1)[CH3:14]>C(O)C>[CH2:13]([O:15][CH2:16][CH2:17][O:18][C:19]1[N:24]=[C:23]([N:25]([C:4]([N+:5]([O-:7])=[O:6])=[CH:3][NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[NH2:26])[CH:22]=[C:21]([C:27]([F:30])([F:28])[F:29])[CH:20]=1)[CH3:14]
Reactant: CSC(=C[N+](=O)[O-])NS(C)(=O)=O
Reactant: CCOCCOc1cc(C(F)(F)F)cc(NN)n1
Solvent: CCO
Product: CCOCCOc1cc(C(F)(F)F)cc(N(N)C(=CNS(C)(=O)=O)[N+](=O)[O-])n1
Temperature: 25 °C
Yield: 34.2 %

Procedure:
1.40 g of N-(1-(methylthio)-2-nitroethenyl)methanesulfonamide (Intermediate No. 57), 1.80 g of 6-(2-ethoxyethoxy)-4-trifluoromethyl-2-pyridylhydrazine and 11 ml of ethanol were stirred for 15 hours under heating and refluxing and then cooled to room temperature, whereupon precipitated crystals were collected by filtration. The crystals obtained by filtration were washed with a small amount of ethanol and then dried to obtain 0.97 g of N-(1-(6-(2-ethoxyethoxy)-4-trifluoromethyl-2-pyridyl)hydrazino-2-nitroethenyl)methanesulfonamide (Compound No. 164) having a melting point of 153° C.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:17]=[C:6]2[C:7]3[CH:13]([CH2:14][CH2:15][NH2:16])[CH2:12][CH2:11][C:8]=3[CH:9]=[CH:10][N:5]2[N:4]=1.C(N(CC)CC)C.[C:25](OC(=O)C)(=[O:27])[CH3:26]>O1CCCC1.C(=O)([O-])O.[Na+]>[CH3:2][C:3]1[CH:17]=[C:6]2[C:7]3[CH:13]([CH2:14][CH2:15][NH:16][C:25](=[O:27])[CH3:26])[CH2:12][CH2:11][C:8]=3[CH:9]=[CH:10][N:5]2[N:4]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc2c3c(ccn2n1)CCC3CCN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)NCCC1CCc2ccn3nc(C)cc3c21
Reaction time: 0.25 h
Yield: 45 %

Procedure:
To a mixture of 2-(2-methyl-8,9-dihydro-7H-cyclopenta[c]pyrazolo[1,5-a]pyridin-9-yl)ethanamine hydrochloride obtained in Reference Example 43 and triethylamine (1.36 mL, 9.76 mmol) in tetrahydrofuran (5 mL) was added acetic anhydride (115 μL, 1.22 mmol) under ice-cooling, and the mixture was stirred for 15 min. The reaction solution was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=50/50→100/0) and recrystallization (ethyl acetate/diisopropyl ether) to give the title compound (56.6 mg, total yield from Reference Example 43, 45%).
Reaction SMILES: [C:1]([N:4]1[CH2:8][CH2:7][N:6]([CH3:9])[CH:5]1[C:10]1[CH:11]=[C:12]([C:20]([O:22]C)=[O:21])[C:13]([C:16](OC)=O)=[N:14][CH:15]=1)(=[O:3])[CH3:2].[NH2:24][C:25]([CH3:32])([CH:29]([CH3:31])[CH3:30])[C:26]([NH2:28])=[O:27].CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1>[NH4+:4].[C:1]([N:4]1[CH2:8][CH2:7][N:6]([CH3:9])[CH:5]1[C:10]1[CH:15]=[N:14][C:13]([C:16]2[NH:28][C:26](=[O:27])[C:25]([CH:29]([CH3:31])[CH3:30])([CH3:32])[N:24]=2)=[C:12]([CH:11]=1)[C:20]([O-:22])=[O:21])(=[O:3])[CH3:2]
Reactant: CC(C)C(C)(N)C(N)=O
Reactant: COC(=O)c1cc(C2N(C)CCN2C(C)=O)cnc1C(=O)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(=O)N1CCN(C)C1c1cnc(C2=NC(C)(C(C)C)C(=O)N2)c(C(=O)[O-])c1
Product: [NH4+]
Temperature: 25 °C
Reaction time: 2 h
Yield: 213.5 %

Procedure:
To a stirred solution of dimethyl 5-(1-acetyl-3-methyl-2-imidazolidinyl)pyridine-2,3-dicarboxylate (0.70 g, 0.0022 mol), and 2-amino-2,3-dimethylbutyramide (0.28 g, 0.0022 mol) in toluene (10 mL) is added potassium tert-butoxide (0.49 g, 0.0044 mol). The resulting mixture is stirred for 2 hours at 80° C. to 90° C. After cooling to room temperature, the reaction is quenched by the addition of water (15 mL) and ammonium chloride (0.25 g). The layers are separated, the aqueous solution concentrated under high vacumn, the product triturated with 33% ethanol in chloroform and filtered. The filtrate is concentrated in vacuo to afford the title compound (0.95 g, 100%) as a gold solid, mp 93°-98° C., identified by IR and NMR spectral analyses.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N:9]2[C:13]3=[N:14][C:15]([CH3:27])=[CH:16][C:17]([N:18]4[CH2:23][CH2:22][CH:21]([CH2:24][CH2:25]I)[CH2:20][CH2:19]4)=[C:12]3[C:11]([CH3:28])=[CH:10]2)=[C:4]([CH3:29])[CH:3]=1.[O-:30][S:31]([O-:33])=[O:32].[Na+].[Na+].C(O)C.O1CCCC1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N:9]2[C:13]3=[N:14][C:15]([CH3:27])=[CH:16][C:17]([N:18]4[CH2:23][CH2:22][CH:21]([CH2:24][CH2:25][S:31]([OH:33])(=[O:32])=[O:30])[CH2:20][CH2:19]4)=[C:12]3[C:11]([CH3:28])=[CH:10]2)=[C:4]([CH3:29])[CH:3]=1
Reactant: Cc1cc(N2CCC(CCI)CC2)c2c(C)cn(-c3c(C)cc(Br)cc3C)c2n1
Reactant: O=S([O-])[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(N2CCC(CCS(=O)(=O)O)CC2)c2c(C)cn(-c3c(C)cc(Br)cc3C)c2n1
Yield: 24.4 %

Procedure:
A mixture of 1-(4-bromo-2,6-dimethyl-phenyl)-4-[4-(2-iodo-ethyl)-piperidin-1-yl]-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridine (0.25 g), Na2SO3 (0.28 g), tetrabutylammonium iodide (16 mg), ethanol (5 mL), tetrahydrofuran (5 mL) and water (3 mL) was heated at reflux for 10 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified with column chromatography (silica gel: Wako gel C200, eluent: ethyl acetate:methanol=5/1) to obtain the title compound (56 mg) as a yellow amorphous.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)([OH:8])[CH2:5][CH:6]=[CH2:7].[NH2:16][C@H:17]1[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[C:26]([O:25][C:23]([N:19]1[CH2:20][CH2:21][CH2:22][C@H:17]([NH:16][CH2:2][CH2:3][C:4]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)([OH:8])[CH2:5][CH:6]=[CH2:7])[CH2:18]1)=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: C=CCC(O)(CCCl)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCC(O)(CCN[C@H]1CCCN(C(=O)OC(C)(C)C)C1)c1ccc(F)cc1
Yield: 38.6 %

Procedure:
A mixture of 1-chloro-3-(4-fluorophenyl)hex-5-en-3-ol (760 mg, 3.3 mmol), (S)-tert-butyl 3-aminopiperidine-1-carboxylate (1.0 g, 5 mmol), KI (1.1 g, 6.7 mmol) and K2CO3 (920 mg, 6.7 mmol) in acetonitrile (33 mL) was heated to reflux overnight. The reaction mixture was filtered. The filtrate was condensed to give the crude product, which was purified by preparative TLC to afford (3S)-tert-butyl-3-(3-(4-fluorophenyl)-3-hydroxyhex-5-enylamino)piperidine-1-carboxylate (500 mg, 38%). 1H NMR: (CDCl3): 1.23 (m, 1H), 1.38 (d, 9H), 1.57 (m, 1H), 1.75 (broad, 1H), 1.94 (m, 2H), 2.37 (m, 1H), 2.43 (m, 2H), 2.56 (m, 1H), 2.80 (broad, 3H), 3.49 (broad, 1H), 3.71 (broad, 3H), 4.95 (d, 2H), 5.56 (m, 1H), 6.95 (t, 2H), 7.32 (m, 2H).