Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)[CH:18]=3)(=[O:16])=[O:15])[C@H:10]([CH3:29])[CH2:9]2)=[C:4]([C:30]([F:33])([F:32])[F:31])[CH:3]=1.[CH3:34][CH:35]=O.CC(O)=O.[BH3-]C#N.[Na+]>CO>[CH2:34]([N:26]1[CH2:27][CH2:28][N:23]([C:19]2[CH:18]=[C:17]([S:14]([N:11]3[CH2:12][CH2:13][N:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=4[C:30]([F:31])([F:33])[F:32])[CH2:9][C@H:10]3[CH3:29])(=[O:16])=[O:15])[CH:22]=[CH:21][CH:20]=2)[CH2:24][CH2:25]1)[CH3:35]
Reactant: CC=O
Reactant: C[C@@H]1CN(c2ccc(F)cc2C(F)(F)F)CCN1S(=O)(=O)c1cccc(N2CCNCC2)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCN1CCN(c2cccc(S(=O)(=O)N3CCN(c4ccc(F)cc4C(F)(F)F)C[C@H]3C)c2)CC1
Yield: 91.3 %

Procedure:
To a solution of (2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methyl-1-[(3-piperazin-1-ylphenyl)sulfonyl]piperazine (120 mg, 0.247 mmol) in MeOH (2 mL) was added CH3CHO (12 mg, 0.27 mmol), HOAc (17.7 μL, 0.3 mmol) and NaBH3CN (8 mg, 0.125 mmol) at room temperature. The resultant mixture was stirred till disappearance of starting material as monitored by LCMS. The solvent was removed. The crude product was purified by SiO2 column eluted with DCM/MeOH to give the desired product as a light yellow solid (116 mg, 100%). HRMS: calcd for C24H30F4N4O2S+H+, 515.20983. found (ESI-FTMS, [M+H]1+), 515.20891.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C@H:12]([NH:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:13][OH:14])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:28]([C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1)#[N:29].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C@H:12]([N:15]([S:36]([C:33]1[CH:32]=[CH:31][C:30]([C:28]#[N:29])=[CH:35][CH:34]=1)(=[O:38])=[O:37])[CH2:16][CH:17]([CH3:18])[CH3:19])[CH2:13][OH:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)CN[C@H](CO)CCCCNC(=O)OC(C)(C)C
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)CN([C@H](CO)CCCCNC(=O)OC(C)(C)C)S(=O)(=O)c1ccc(C#N)cc1
Reaction time: 8 h
Yield: 36 %

Procedure:
(S)-(6-Hydroxy-5-isobutylamino-hexyl)-carbamic acid tert-butyl ester (4) (1.85 g) was dissolved in 50 mL CH2Cl2. Triethylamine (1.05 eq) and 4-cyano benzene sulfonylchloride (1 eq) were added and the mixture was stirred overnight. Saturated NaHCO3 (50 mL) was added, the mixture was well shaken. Organic layer was separated, dried on MgSO4, filtrated and evaporated. The crude compound was purified by column chromatography using EtOAc-heptane (1-3) as the eluent. Fractions containing the product were evaporated yielding (1.06 g, 36%) of a solid.
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:11][C:10]=2[F:24])[C:6]2[S:25][C:26]([CH2:28][C:29]([F:32])([F:31])[F:30])=[CH:27][C:5]=2[C:4](=[O:33])[NH:3]1.Br[CH2:35][C:36]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[O:44][CH3:45])=[O:37].CN(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[F:24][C:10]1[CH:11]=[C:12]([C:16]2[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:13]=[C:14]([F:15])[C:9]=1[CH2:8][N:7]1[C:6]2[S:25][C:26]([CH2:28][C:29]([F:32])([F:31])[F:30])=[CH:27][C:5]=2[C:4](=[O:33])[N:3]([CH2:35][C:36]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[O:44][CH3:45])=[O:37])[C:2]1=[O:1]
Reactant: N#Cc1ccccc1-c1cc(F)c(Cn2c(=O)[nH]c(=O)c3cc(CC(F)(F)F)sc32)c(F)c1
Reactant: COc1ccccc1C(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccccc1C(=O)Cn1c(=O)c2cc(CC(F)(F)F)sc2n(Cc2c(F)cc(-c3ccccc3C#N)cc2F)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.4 %

Procedure:
To a mixture of 4′-{[2,4-dioxo-6-(2,2,2-trifluoroethyl)-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}-3′,5′-difluorobiphenyl-2-carbonitrile (0.65 g), 2-bromo-1-(2-methoxyphenyl)ethanone (0.34 g) and N,N-dimethylformamide (15 mL) was added 60% sodium hydride (0.082 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% potassium hydrogensulfate and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as a colorless solid (0.48 g, 59%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].C(N(C(C)C)C(C)C)C.[Cl:15][C:16]1[N:21]=[C:20](Cl)[C:19]([I:23])=[CH:18][N:17]=1>C(#N)C>[Cl:15][C:16]1[N:21]=[C:20]([NH:1][CH2:2][CH2:3][CH2:4][OH:5])[C:19]([I:23])=[CH:18][N:17]=1
Reactant: NCCCO
Reactant: Clc1ncc(I)c(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: OCCCNc1nc(Cl)ncc1I
Yield: 95 %

Procedure:
In analogy to GP 2 reaction of 3-amino-1-propanol (0.38 ml, 5 mmol) in the presence of N-ethyldiisopropylamine (1.74 ml, 10 mmol) in 150 ml acetonitrile with 2,4-dichloro-5-iodo-pyrimidine (1.51, 5.5 mmol) provided the target compound after column chromatography in 95% yield.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([O:6]/[N:7]=[C:8](/[C:10]2[N:15]=[C:14]3[N:16]([CH2:19][C:20]4[CH:21]=[C:22]5[C:27](=[CH:28][C:29]=4[F:30])[N:26]=[CH:25][CH:24]=[CH:23]5)[N:17]=[N:18][C:13]3=[N:12][CH:11]=2)\[CH3:9])[CH2:2]1.[N:31]([Si](C)(C)C)=[C:32]=[O:33]>CCO>[F:30][C:29]1[CH:28]=[C:27]2[C:22]([CH:23]=[CH:24][CH:25]=[N:26]2)=[CH:21][C:20]=1[CH2:19][N:16]1[C:14]2=[N:15][C:10](/[C:8](=[N:7]/[O:6][C@H:3]3[CH2:4][CH2:5][N:1]([C:32]([NH2:31])=[O:33])[CH2:2]3)/[CH3:9])=[CH:11][N:12]=[C:13]2[N:18]=[N:17]1
Reactant: C/C(=N\O[C@H]1CCNC1)c1cnc2nnn(Cc3cc4cccnc4cc3F)c2n1
Reactant: C[Si](C)(C)N=C=O
Solvent: CCO
Product: C/C(=N\O[C@H]1CCN(C(N)=O)C1)c1cnc2nnn(Cc3cc4cccnc4cc3F)c2n1
Reaction time: 8 h
Yield: 66.7 %

Procedure:
To a solution of (S,E)-1-(1-((7-fluoroquinolin-6-yl)methyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone O-pyrrolidin-3-yl oxime (example 19) (20.0 mg, 0.05 mmol) in EtOH (5 mL) was added isocyanatotrimethylsilane (7.9 mg, 0.07 mmol). The mixture was stirred overnight. The solvent was removed under reduced pressure. The residue was diluted with MeOH (3 mL) and filtered. The filtrate was purified on HPLC (basic with 0.05% NH4OH) to give the title compound as a white solid (15.0 mg, 64%). 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.31 (s, 1H), 8.92 (dd, 1H), 8.40 (d, 1H), 8.17 (d, 1H), 7.82 (d, 1H), 7.53 (dd, 1H), 6.23 (s, 2H), 5.77 (s, 2H), 4.99 (m, 1H), 3.59 (d, 1H), 3.51-3.47 (m, 1H), 3.44-3.38 (m, 1H), 3.28-3.23 (m, 1H), 2.26 (s, 3H), 2.18-2.17 (m, 2H). LCMS (method A): [MH]+=450, tR=4.38 min.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:25]([OH:27])=O)[CH:4]=[N:3]1.Cl.[C@H:29]12[CH2:35][C@H:32]([NH:33][CH2:34]1)[CH2:31][O:30]2.CCCP(=O)=O.C(N(CC)C(C)C)(C)C>O1CCCC1>[N:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:16]2[N:17]=[C:11]3[CH:10]=[C:9]([NH:8][C:7]([C:6]4[N:2]([CH3:1])[N:3]=[CH:4][C:5]=4[C:25]([N:33]4[CH2:34][C@H:29]5[CH2:35][C@@H:32]4[CH2:31][O:30]5)=[O:27])=[O:24])[CH:14]=[CH:13][N:12]3[N:15]=2)[CH:19]=1
Reactant: C1O[C@@H]2CN[C@H]1C2
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(-c3cccnc3)nc2c1
Agent: CCCP(=O)=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cn1ncc(C(=O)N2C[C@H]3C[C@@H]2CO3)c1C(=O)Nc1ccn2nc(-c3cccnc3)nc2c1
Yield: 53.1 %

Procedure:
A mixture of 1-methyl-5-(2-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (150 mg, 335 μmol), (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (136 mg, 1.00 mmol), propylphosphonic anhydride (50% in ethyl acetate, 493 μl, 837 μmol) and N,N-diisopropylethylamine (398 μl, 2.34 mmol) in tetrahydrofuran (7.00 ml) was refluxed for 2.5 days (weekend). The solvent was evaporated, the residue was triturated with sodium hydrogencarbonate solution. The precipitated solid was filtered off, washed with water and dried affording 2-methyl-4-((1R,4R)-2-oxa-5-aza-bicyclo[2.2.1]heptane-5-carbonyl)-2H-pyrazole-3-carboxylic acid (2-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-amide (79 mg, 53.1%) as a white solid. mp: 272-273° C., MS: m/z=445.1 (M+H+)
Reaction SMILES: [CH3:1][N:2]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[C:17]([C:25]2[NH:29][C:28](=[O:30])[NH:27][N:26]=2)[N:16]=1)[C@H:3]1[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][N:2]([C@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1)[C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[C:17]([C:25]2[NH:29][C:28](=[O:30])[NH:27][N:26]=2)[N:16]=1
Reactant: CN(c1nc(-c2n[nH]c(=O)[nH]2)cc2ccccc12)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(c1nc(-c2n[nH]c(=O)[nH]2)cc2ccccc12)[C@H]1CCNC1

Procedure:
To (S)-tert-butyl 3-(methyl(3-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)isoquinolin-1-yl)amino)pyrrolidine-1-carboxylate (91 mg, 0.222 mmol) in DCM was added TFA (1.5 mL). After 2 hours the solvent was removed in vacuo to give the title compound, which was used without further purification.
Reaction SMILES: C(N(CCCC)CCCC)CCC.[F:14][C:15]([F:19])([F:18])[CH2:16][OH:17].[CH2:20]=[C:21]([C:26](OS(F)(=O)=O)([F:28])[F:27])[C:22]([F:25])([F:24])[F:23]>COCCOCCOC>[CH2:20]=[C:21]([C:26]([O:17][CH2:16][C:15]([F:19])([F:18])[F:14])([F:28])[F:27])[C:22]([F:25])([F:24])[F:23]
Reactant: C=C(C(F)(F)F)C(F)(F)OS(=O)(=O)F
Reactant: OCC(F)(F)F
Solvent: COCCOCCOC
Solvent: CCCCN(CCCC)CCCC
Product: C=C(C(F)(F)F)C(F)(F)OCC(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 29.7 %

Procedure:
A 100 ml flask is charged with tributylamine (15 g), diglyme (20 ml) in a dry box. 2,2,2-Trifluoroethanol (8.05 g) is added to the mixture. CH2═C(CF3)CF2OSO2F (19.5 g) is added dropwise while the mixture is cooled in an ice-water bath. The resulting mixture is stirred at room temperature for 3 hours. The mixture is then distilled to give a liquid, which is redistilled (spinning band column) giving 5.8 g CH2═C(CF3)CF2OCH2CF3, b.pt. 85-86° C., a yield of 30%. Less pure fractions are not included in the yield calculation.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12](Br)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7](C3C=CC=CC=3)[C:6]=2[CH:22]=1.[NH:23]1[CH2:28][CH2:27][S:26][CH2:25][CH2:24]1.C(Cl)Cl>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([N:23]4[CH2:28][CH:27]([C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:22]=5)[S:26][CH2:25][CH2:24]4)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[CH:7][C:6]=2[CH:22]=1
Reactant: Clc1ccc2c(c1)C(c1ccccc1)=NCc1nnc(Br)n1-2
Reactant: C1CSCCN1
Solvent: O
Solvent: ClCCl
Product: Clc1ccc2c(c1)C=NCc1nnc(N3CCSC(c4ccccc4)C3)n1-2
Temperature: 120 °C

Procedure:
A mixture of 2.0 gm (5.35 mmol) of 8-chloro-1-bromo-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine and 2.0 ml of thiomorpholine was heated under nitrogen in an oil bath at 120° C. for 18 hr and then allowed to cool. The reaction mixture was treated with methylene chloride and water. The organic layer was separated, washed with dilute brine and concentrated in vacuo. The residue was recrystallized from methanol to yield 1.40 gm (72.7%) with m.p. 241°-243° C. and 0.46 gm (23.9%) with m.p. 239°-241° C. of the title product. Analysis of the title product for carbon, hydrogen, nitrogen, chlorine and sulphur revealed 60.47% C, 4.58% H, 18.03% N, 9.14% Cl, and 8.09% S. Calculated values for such an analysis for the title product are: 60.67% C, 4.58% H, 17.69% N, 8.98% Cl, and 8.10% S.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[C:11]([O:15][C:16]([NH:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22](O)=O)=[O:17])([CH3:14])([CH3:13])[CH3:12].N>>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([C:3]2[N:10]=[C:22]([C:21]3[CH:20]=[C:19]([NH:18][C:16](=[O:17])[O:15][C:11]([CH3:13])([CH3:12])[CH3:14])[CH:27]=[CH:26][CH:25]=3)[O:1][N:2]=2)[CH:5]=1
Reactant: NC(=NO)c1cccnc1
Reactant: CC(C)(C)OC(=O)Nc1cccc(C(=O)O)c1
Agent: N
Product: CC(C)(C)OC(=O)Nc1cccc(-c2nc(-c3cccnc3)no2)c1

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and 3-(tert-butoxycarbonylamino)benzoic acid (Aldrich). 1H NMR (300 MHz, CDCl3) δ 1.56 (s, 9 H), 6.71 (s, 1 H), 7.39-7.58 (m, 2 H), 7.68 (d, J=7.9 Hz, 1 H), 7.89 (d, J=9.1 Hz, 1 H), 8.24 (s, 1 H), 8.45 (d, J=7.9 Hz, 1 H), 8.77 (d, J=4.8 Hz, 1 H), 9.40 (s, 1 H) ppm; MS (DCI/NH3) m/z 339 (M+H)+, 356 (M+NH4)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]>>[C:11]([O:15][C:16]([N:18]1[CH2:19][CH:20]=[C:21]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=2)[CH2:22][CH2:23]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: O=[N+]([O-])c1cccc(Br)c1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Product: CC(C)(C)OC(=O)N1CC=C(c2cccc([N+](=O)[O-])c2)CC1

Procedure:
4-(3-Nitro-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester was prepared from 1-bromo-3-nitro-benzene (3.0 g, 15 mmol) and 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (5.0 g, 16 mmol) in a manner analogous to Example 2c. Product isolated as a yellow oil (3.95 g, 88%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.23 (s, 1H), 8.11 (d, J=8.1 Hz, 1H), 7.69 (d, J=7.7 Hz, 1H), 7.51 (t, J=7.8 Hz, 1H), 6.20 (br s, 1H), 4.12 (s, 2H), 3.70-3.65 (m, 2H), 2.56 (s, 2H), 1.50 (s, 9H).
Reaction SMILES: [CH3:1][C:2]([CH2:13][CH2:14][CH2:15][CH:16]([CH3:28])[CH2:17][CH2:18][CH2:19][CH:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])=[CH:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[C:6]=1[OH:12].Cl.O>CO>[CH3:1][C:2]1([CH2:13][CH2:14][CH2:15][CH:16]([CH3:28])[CH2:17][CH2:18][CH2:19][CH:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:3][CH2:4][C:5]2[C:6](=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=2)[O:12]1
Reactant: CC(=CCc1cccc(O)c1O)CCCC(C)CCCC(C)CCCC(C)C
Agent: Cl
Solvent: CO
Solvent: O
Product: CC(C)CCCC(C)CCCC(C)CCCC1(C)CCc2cccc(O)c2O1
Yield: 79 %

Procedure:
3-(3,7,11,15-Tetramethyl-2-hexadecenyl)-1,2-benzenediol (1.00 g; 2.57 mmole) and conc. hydrochloric acid (2.0 ml) in 10 ml of methanol were heated under reflux for 4 hours, then the reaction solution was poured into 100 ml of water and was extracted twice with 50 ml of isopropyl ether. The extract was washed twice with 100 ml of water and once with 100 ml of saturated aqueous solution of sodium chloride, followed by drying it over anhydrous magnesium sulfate, distilling off the solvent and subjecting the resulting residue to silica gel column chromatography. Thus, 790 mg of the title compound was recovered from the fractions eluted through the column with hexane-ethyl acetate (30:1). Yield=79%.
Reaction SMILES: [CH2:1]1[CH2:15][O:14][C:3]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([CH2:4][CH2:5][CH2:6]O)[O:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.C([Br:31])C=C.O>C(#N)C>[CH2:1]1[CH2:15][O:14][C:3]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([CH2:4][CH2:5][CH2:6][Br:31])[O:2]1
Reactant: C=CCBr
Reactant: OCCCC1(c2ccccc2)OCCO1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Solvent: O
Product: BrCCCC1(c2ccccc2)OCCO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1.2 g of the alcohol compound obtained in 20 ml of acetonitrile were added 1.2 g of 1,1'-carbonyldiimidazole and 2.5 ml of allyl bromide. The mixture was stirred for 2 hours at room temperature and then heated under reflux for 1.5 hours. After cooling, water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The ethereal layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 1.1 g of 4,4-ethylenedioxy-4-phenylbutyl bromide as colorless crystals.
Reaction SMILES: Cl.[NH:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH2:7][OH:8].O[N:10]1[C:14](=[O:15])[C:13]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]2[C:11]1=[O:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[NH:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH2:7][O:8][N:10]1[C:14](=[O:15])[C:13]2[C:12](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:11]1=[O:20]
Reactant: OCc1ncc[nH]1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1OCc1ncc[nH]1
Temperature: 25 °C
Reaction time: 24 h
Yield: 6.6 %

Procedure:
To an ice-cold solution of (1H-imidazol-2-yl)methanol hydrochloride (2.0 g, 15 mmol), N-hydroxyphthalimide (2.4 g, 15 mmol) and triphenylphosphine (4.0 g, 15 mmol) in THF (65 mL) was added a solution of diethyl azodicarboxylate (2.6 mL, 16 mmol) in THF (10 mL) dropwise. The stirred reaction mixture was allowed to warm to ambient temperature. After 1 day, most of the THF was removed under reduced pressure. The residue was partitioned between CH2Cl2 (75 ml) and H2O (30 mL). The organic layer was separated and washed with saturated NaHCO3 (75 mL) and saturated NaCl (20 ml), dried (Na2SO4) and concentrated under reduced pressure. Purification by column chromatography (silica gel, CH2Cl2 to 95:5 CH2Cl2/MeOH) gave 2-(1H-imidazol-2-ylmethoxy)-1,3-dihydro-2H-isoindole-1,3-dione (240 mg, 6.5%) which was used directly in the next reaction.
Reaction SMILES: [CH:1]12[CH2:7][CH:6]1[CH2:5][CH:4]([C:8]([NH:10][C:11]1([C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=3)[CH2:13][CH2:12]1)=[O:9])[NH:3][CH2:2]2.C([O-])([O-])=O.[Cs+].[Cs+].[F:30][C:31]([F:41])([F:40])[C:32]1[CH:39]=[CH:38][C:35]([CH2:36]Br)=[CH:34][CH:33]=1>CC#N>[F:30][C:31]([F:40])([F:41])[C:32]1[CH:39]=[CH:38][C:35]([CH2:36][N:3]2[CH:4]([C:8]([NH:10][C:11]3([C:14]4[CH:15]=[CH:16][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:22][CH:23]=4)[CH2:12][CH2:13]3)=[O:9])[CH2:5][CH:6]3[CH:1]([CH2:7]3)[CH2:2]2)=[CH:34][CH:33]=1
Reactant: COC(=O)c1ccc(C2(NC(=O)C3CC4CC4CN3)CC2)cc1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)c1ccc(C2(NC(=O)C3CC4CC4CN3Cc3ccc(C(F)(F)F)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.9 %

Procedure:
To a solution of methyl 4-(1-(3-azabicyclo[4.1.0]heptane-4-carboxamido)cyclopropyl)benzoate (racemic mixture) (D100) (155 mg, 0.49 mmol) in dry MeCN (4 ml), Cs2CO3 (241 mg, 0.74 mmol) and 4-(trifluoromethyl)-benzylbromide (0.09 ml, 0.59 mmol) were added in sequence and the resulting mixture was stirred at RT for 4 hrs. The residue obtained after solvent evaporation was loaded on Biotage SNAP-Si column (25 g) eluting with a mixture cHex/EtOAc from 65/35 to 40/60. Collected fractions after solvent evaporation afforded the title compound (D139) (racemic mixture) (215 mg).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10]O)[CH2:2][CH2:3][CH3:4].[CH2:12]([O:19][C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[CH2:22][CH2:23][CH2:24][CH:25]2[C:30]([N:32]([C:39]1[CH:40]=[N:41][C:42]([CH:45]([CH3:47])[CH3:46])=[CH:43][CH:44]=1)[CH2:33][C:34]1[CH:35]=[N:36][NH:37][CH:38]=1)=[O:31])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([O:19][C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[CH2:22][CH2:23][CH2:24][CH:25]2[C:30]([N:32]([CH2:33][C:34]1[CH:35]=[N:36][N:37]([CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:1][CH2:2][CH2:3][CH3:4])[CH:38]=1)[C:39]1[CH:40]=[N:41][C:42]([CH:45]([CH3:47])[CH3:46])=[CH:43][CH:44]=1)=[O:31])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCCCOCCOCCO
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Product: CCCCOCCOCCn1cc(CN(C(=O)C2CCCc3c(OCc4ccccc4)cccc32)c2ccc(C(C)C)nc2)cn1

Procedure:
By the reaction and treatment of diethylene glycol monobutyl ether (1.0 mL) and 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.96 g) in the same manner as in Example 394, 5-benzyloxy-N-({1-[2-(2-butoxyethoxy)ethyl]pyrazol-4-yl}methyl)-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.94 g) was obtained.
Reaction SMILES: [CH2:1]([NH:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([NH2:22])[CH:17]=3)=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)=[O:5])[CH3:2].N1C=CC=CC=1.[C:29](Cl)(=[O:37])[O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN(C)C=O>[CH2:1]([NH:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:29](=[O:37])[O:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH:17]=3)=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)=[O:5])[CH3:2]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCNC(=O)n1ccc2cc(Oc3ccnc(N)c3)ccc21
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCNC(=O)n1ccc2cc(Oc3ccnc(NC(=O)Oc4ccccc4)c3)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.3 %

Procedure:
N1-ethyl-5-(2-amino-4-pyridyl)oxy-1H-1-indolecarboxamide (3.168 g, 10.69 mmol) synthesized in Production example 27-1 was dissolved in N,N-dimethylformamide (30 ml) under nitrogen atmosphere. Pyridine (1.25 ml, 15.40 mmol) and phenyl chlorocarbonate (1.61 ml, 12.83 mmol) were sequentially added dropwise while cooled with an ice water bath. The reaction mixture was heated to room temperature while stirred. After 1 hour, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the crystals were precipitated from ethyl acetate, filtered off, and dried under aeration to yield the title compound (1.530 g, 3.67 mmol, 34.4%) as white crystals.
Reaction SMILES: C([O:4][CH:5]1[CH2:9][CH:8]([CH2:10][O:11]C(=O)C)[CH2:7][CH:6]1[N:15]1[C:19]2[CH:20]=[C:21]([Cl:25])[C:22]([Cl:24])=[CH:23][C:18]=2[N:17]=[C:16]1Br)(=O)C.[CH:27]1([NH2:30])[CH2:29][CH2:28]1>>[CH:27]1([NH:30][C:16]2[N:15]([CH:6]3[CH2:7][CH:8]([CH2:10][OH:11])[CH2:9][CH:5]3[OH:4])[C:19]3[CH:20]=[C:21]([Cl:25])[C:22]([Cl:24])=[CH:23][C:18]=3[N:17]=2)[CH2:29][CH2:28]1
Reactant: NC1CC1
Reactant: CC(=O)OCC1CC(OC(C)=O)C(n2c(Br)nc3cc(Cl)c(Cl)cc32)C1
Product: OCC1CC(O)C(n2c(NC3CC3)nc3cc(Cl)c(Cl)cc32)C1

Procedure:
(±)-(1R*, 2R*, 4S*)-4-(Acetoxymethyl)-2-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl)-cyclopentyl acetate (500 mg, 1.50 mmol) was reacted with cyclopropylamine (0.73 mL) in the manner of Example 74. Crude product was chromatographed on silica gel and title compound eluted with 5% methanol-ethyl acetate as a colorless glass which solidified from ethyl acetate-hexanes to white powder (180 mg, 48%), m.p. 251°-253° C.; 1H-NMR(DMSO-d6)δ: 7.54 and 7.45 (both s, 2, aromatic CH), 5.04 (d, J=5.1 Hz, 1, OH), 4.97 (t, J=4.7 Hz, 1, OH), 4.60-4.50 and 4.50-4.30 (both m, 1 each, NCH and OCH), 3.50 (m, 2, OCH2), 2.80 (m, 1, CH), 2.35-2.10 (m, 1, CH), 2.05-1.80 (m, 3, CH2 and CH of cyclopentane), 1.80-1.60 (m, 1, CH), 0.80-0.50 (1 m, 4, 2CH2 of cyclopropyl); mass spectrum (CI): 356 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[C:12]([NH2:16])([CH3:15])([CH3:14])[CH3:13]>CCO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([NH:16][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:3]=1
Reactant: CC(C)(C)N
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Solvent: CCO
Product: CC(C)(C)Nc1cc(Br)ccc1[N+](=O)[O-]
Temperature: 85 °C
Reaction time: 15 h
Yield: 96.6 %

Procedure:
A mixture of 4-bromo-2-fluoro-nitrobenzene (4 g, 18.2 mmol) and tert-butylamine (4.78 mL, 45.5 mmol, 2.5 eq) in EtOH (80 mL) is stirred for 15 h at 85° C., allowed to cool and concentrated. The residue purified by silica gel column chromatography (Hex/EtOAc, 1:0→99:1) to afford 4.8 g of the title compound as an orange solid: ESI-MS: 273.0/275.0 [M+H]+; tR=5.68 min (System 1); TLC: Rf=0.49 (Hex/EtOAc, 9:1).