Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.[OH:28][C:29]1([C:34](O)=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30]1>>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:34]([C:29]5([OH:28])[CH2:33][CH2:32][CH2:31][CH2:30]5)=[O:35])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Reactant: O=C(O)C1(O)CCCC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1)C1(O)CCCC1

Procedure:
The title compound, white solid (17 mg, 53.5%), MS (ISP) m/z=444.3 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine trihydrochloride (Intermediate A) (30 mg, 68.1 mmol) and 1-hydroxycyclopentanecarboxylic acid.
Reaction SMILES: [C:1]1([C:7]2([NH:10][C:11]3[C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=[C:13]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([N:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)[CH:22]=4)[CH:12]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:33][C:34](OC(C)=O)=[O:35].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:34]([N:30]1[CH2:31][CH2:32][N:27]([C:23]2[CH:22]=[C:21]([NH:20][C:13]3[CH:12]=[C:11]([NH:10][C:7]4([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)[CH2:9][CH2:8]4)[C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)[CH:26]=[CH:25][CH:24]=2)[CH2:28][CH2:29]1)(=[O:35])[CH3:33]
Reactant: NC(=O)c1cnc(Nc2cccc(N3CCNCC3)c2)cc1NC1(c2ccccc2)CC1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1CCN(c2cccc(Nc3cc(NC4(c5ccccc5)CC4)c(C(N)=O)cn3)c2)CC1

Procedure:
To a solution of 4-(1-phenylcyclopropylamino)-6-(3-(piperazin-1-yl)phenylamino)nicotinamide (30 mg, 0.07 mmol) in DCM was added Ac2O (0.0066 mL, 0.07 mmol) and DIPEA (0.024 mL, 0.14 mmol), the mixture was concentrated and purified by preparative HPLC to give 6-(3-(4-acetylpiperazin-1-yl)phenylamino)-4-(1-phenylcyclopropylamino)nicotinamide. MS found for C27H30N6O2 as (M+H)+ 471.4. UV: λ=251.8 nm. 1H NMR: (CD3OD) δ 8.14 (s, 1H), 7.27 (m, 4H), 7.12 (dd, J=8.8, 1.2 Hz, 2H), 6.93 (dd, J=8.4, 2.4 Hz, 1H), 6.72 (s, 1H), 6.56 (dd, J=7.6, 1.2 Hz, 1H), 6.11 (s, 1H), 3.68 (m, 4H), 3.17 (m, 2H), 3.09 (m, 2H), 2.15 (s, 3H), 1.38 (m, 4H) ppm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:15]2[CH:11]([N:12](C(OCC3C=CC=CC=3)=O)[CH2:13][CH:14]2[CH2:16][OH:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]2[NH:12][CH2:13][CH:14]([CH2:16][O:17][S:38]([CH3:37])(=[O:40])=[O:39])[CH:15]12)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC2C1C(CO)CN2C(=O)OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2NCC(COS(C)(=O)=O)C21
Reaction time: 1 h

Procedure:
A solution of alcohol 77 (0.78 g, 2.1 mmol) in DCM (12 mL) was cooled to 0° C. and treated with DIPEA (0.55 mL, 3.2 mmol) followed by methanesulfonyl chloride (0.22 mL, 2.8 mmol). After 1 h, the solution was diluted with DCM, washed successively with 1M HCl, and brine, dried over anhydrous Na2SO4, filtered and concentrated to afford mesylate 79 as a light yellow-colored foam which was used without further purification. 1H NMR (CDCl3, 300 MHz): δ7.36-7.31 (m, 5H), 5.19-5.09 (m, 2H), 4.45 (m, 1H), 4.29-4.04 (m, 3H), 3.71-3.44 (m, 4H), 3.22-3.12 (m, 1H), 2.96 (s, 3H), 2.85-2.70 (m, 1H), 2.21-1.99 (m, 2H), 1.49 (s, 9H) ppm.
Reaction SMILES: [CH2:1]([C:4]12[CH2:10][CH:7]([CH:8]=[CH:9]1)[CH:6]1[C:11]([O:13][C:14](=[O:15])[CH:5]21)=[O:12])[CH:2]=[CH2:3].[CH2:16]([NH2:22])[CH2:17][O:18][CH2:19][CH2:20][OH:21]>>[OH:21][CH2:20][CH2:19][O:18][CH2:17][CH2:16][N:22]=[C:14]([CH:5]1[CH:6]([C:11]([OH:13])=[O:12])[CH:7]2[CH2:10][C:4]1([CH2:1][CH:2]=[CH2:3])[CH:9]=[CH:8]2)[OH:15]
Reactant: NCCOCCO
Reactant: C=CCC12C=CC(C1)C1C(=O)OC(=O)C12
Product: C=CCC12C=CC(C1)C(C(=O)O)C2C(O)=NCCOCCO
Temperature: 200 °C

Procedure:
120 g of allylbicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic anhydride (isomeric mixture) are reacted at 140° C. with 67.9 g of diglycolamine; the mixture is heated to 200° C. and the pressure lowerd to 10.6 Pa. The yield is 142.6 g of a yellow oil having a viscosity of 1.55 Pa.s at 25° C. and an n25D of 1.5230.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[C:20]=2[CH2:27][S:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:15][C:14]=1[CH3:35]>>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[C:20]=2[CH2:27][S:28]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[O:9])=[CH:15][C:14]=1[CH3:35]
Reactant: Cc1cc(C)c(CSc2ccccc2)c(-c2ccc(F)c(C)c2)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Product: Cc1cc(C)c(CS(=O)c2ccccc2)c(-c2ccc(F)c(C)c2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
m-Chloroperbenzoic acid (tech. grade, approximately 75% peroxide; 1.19 g, approximately 5 mmoles) was added in small portions to a stirred solution of (4'-fluoro-3,3',5-trimethyl-[1,1'-biphenyl]-2-yl-methyl)phenyl sulfide (1.68 g, 5 mmoles) at -78° C. The reaction mixture was then stirred at -78° C. for 30 minutes and allowed to warm to room temperature. The solution of the product was separated by filtration from the 3-chlorobenzoic acid which was washed with methylene chloride. The combined methylene chloride solutions of the product were diluted with methylene chloride to 100 ml then washed with dilute sodium hydroxide solution (2×50 ml) dried (MgSO4), filtered, and the solvent was evaporated in vacuo to leave 1.7 g of crude product. This was purified by flash chromatography on silica gel using a 40×150 mm column eluting with 3.5% (v:v) acetone in methylene chloride to give 1.55 g of the title compound as a gum. Dry toluene was added and evaporated in vacuo four times to dry the product, which then crystallized, m.p. 75°-85° C.
Reaction SMILES: [C:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][CH2:9][C:10]2[CH:11]=[C:12]([S:16][C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][N:24]=3)[C:20]#[N:21])[CH:13]=[CH:14][CH:15]=2)=[C:6]([CH2:27][CH2:28][CH3:29])[C:5]=1[OH:30])(=[O:3])[CH3:2].[N-:31]=[N+:32]=[N-:33].[Na+].Cl.C(N(CC)CC)C>>[OH:30][C:5]1[C:6]([CH2:27][CH2:28][CH3:29])=[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([S:16][C:17]3[CH:18]=[C:19]([C:20]4[N:31]=[N:32][NH:33][N:21]=4)[CH:22]=[CH:23][N:24]=3)[CH:11]=2)[CH:25]=[CH:26][C:4]=1[C:1](=[O:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCc1c(OCc2cccc(Sc3cc(C#N)ccn3)c2)ccc(C(C)=O)c1O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Product: CCCc1c(OCc2cccc(Sc3cc(-c4nn[nH]n4)ccn3)c2)ccc(C(C)=O)c1O

Procedure:
Employing the procedure essentially as described in Example 1 using 2-[3-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenylsulfanyl]-isonicotinonitrile (380 mg, 0.908 mmol), sodium azide (590 mg, 9.08 mmol), and triethylamine hydrochloride (1.25 g, 9.08 mmol), the title compound is obtained as a white solid (261 mg, 62%): 1H NMR (DMSO-d6) δ 0.760 (t, 3H), 1.39 (sextuplet, 2H), 2.52 (t, 2H), 2.56 (s, 3H), 5.32 (s, 2H), 6.71 (d, 1H), 7.59 (m, 4H), 7.73 (m, 2H), 7.79 (d, 1H), 8.64 (d, 1H), 12.82 (s, 1H); MS (esi negative) m/z 460 (m−1).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH:6](OC(CC)C(O)=O)[C:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)([CH3:13])[C:8]2=[O:12])=[CH:4][CH:3]=1.[C:26]([N:33]1[CH:37]=[CH:36][N:35]=[CH:34]1)(N1C=CN=C1)=[O:27]>O1CCCC1>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH:14]3[CH2:15][CH2:16][CH2:17][CH2:18]3)([CH3:13])[C:8]2=[O:12])=[CH:4][C:3]=1[O:12][CH2:8][CH2:7][CH2:6][C:26]([N:33]1[CH:37]=[CH:36][N:35]=[CH:34]1)=[O:27]
Reactant: CCC(OC1c2ccc(Cl)c(Cl)c2C(=O)C1(C)C1CCCC1)C(=O)O
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC1(C2CCCC2)Cc2cc(OCCCC(=O)n3ccnc3)c(Cl)c(Cl)c2C1=O
Temperature: 0 °C

Procedure:
(+) [(6,7-Dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-yl)oxy]butanoic acid (Example 8, Step B) (0.77 g, 0.002 mole) is suspended in dry tetrahydrofuran (20 ml) and cooled to 0° C. A solution of 1,1'-carbonyldiimidazole (0.32 g, 0.002 mole) in teterahydrofuran (5 ml) is added. The solution of 1-{(+)-4-[(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy]butanoyl}imidazole that is formed is used in the next step without isolation.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14](N3C4C(=CC(OC(F)F)=CC=4)C=N3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[CH:14][N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-n3ncc4cc(OC(F)F)ccc43)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1c[nH]c2nccnc12
Reaction time: 15 h
Yield: 103.4 %

Procedure:
To a stirred solution of N-tert-butyl-2-(5-(difluoromethoxy)-1H-indazol-1-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (130 mg, 245 μmol) in dichloromethane (1 mL) was added trifluoroacetic acid (1 mL). After 15 h, then mixture was concentrated in vacuo and 25 mL of a Jan. 10, 1960 mixture of ammonium hydroxide/methanol/dichloromethane was added. After 1 h the mixture was concentrated in vacuo. Purification by chromatography (silica, 24 g Analogix column, 0-5% of a solution of methanol containing 10% ammonium hydroxide in dichloromethane) gave 245-difluoromethoxy-indazol-1-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (55.3 mg, 56%). MS: (M+H)+=401; 1H NMR (DMSO-d6) δ: 9.09 (s, 1H), 8.57 (s, 1H), 8.51 (s, 1H), 7.78 (d, J=2.3 Hz, 2H), 7.43 (dd, J=9.0, 2.5 Hz, 2H), 7.31 (s, 1H), 1.51 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:13]([F:16])([F:15])[F:14])[C:11]=1F)[N:8]([CH3:17])[CH:7]=[C:6]([C:18]([OH:20])=[O:19])[C:5]2=[O:21].[N:22]1[CH:27]=[CH:26][CH:25]=[N:24][C:23]=1[N:28]1[CH2:34][CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:13]([F:15])([F:16])[F:14])[C:11]=1[N:31]1[CH2:32][CH2:33][CH2:34][N:28]([C:23]3[N:22]=[CH:27][CH:26]=[CH:25][N:24]=3)[CH2:29][CH2:30]1)[N:8]([CH3:17])[CH:7]=[C:6]([C:18]([OH:20])=[O:19])[C:5]2=[O:21]
Reactant: Cn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(C(F)(F)F)c21
Reactant: c1cnc(N2CCCNCC2)nc1
Solvent: c1ccncc1
Product: Cn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCCN(c4ncccn4)CC3)c(C(F)(F)F)c21
Temperature: 105 °C
Reaction time: 3 h
Yield: 37.2 %

Procedure:
In 12 ml of pyridine were dissolved 0.8 g (0.0026 mole) of 6,7-difluoro-8-trifluoromethyl-1,4-dihydro-1-methyl-4-oxoquinoline-3-carboxylic acid and 2.1 g (0.0118 mole) of 1-(2-pyrimidinyl)homopiperazine, the mixture was stirred at 105° C. for 3 hours, and then the solvent was removed by evaporation under reduced pressure. The residue was applied to silica gel column chromatography (eluent; a chloroform:methanol=9.5:0.5 mixed solution) to obtain 0.45 g of 6-fluoro-8-trifluoromethyl-1,4-dihydro-4-oxo-1-methyl-7-[4-(2-pyrimidinyl)homopiperazin-1-yl)quinoline-3-carboxylic acid as yellow powder.
Reaction SMILES: [CH3:1][C@H:2]1[C@H:6]([CH3:7])[CH2:5][C:4](=O)[CH2:3]1.[C:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])#[N:10].C([O-])(=O)C.[NH4+].C(O)(=O)C>C1(C)C=CC=CC=1>[CH2:15]([O:14][C:12](=[O:13])[C:11]([C:9]#[N:10])=[C:4]1[CH2:3][C@@H:2]([CH3:1])[C@H:6]([CH3:7])[CH2:5]1)[CH3:16]
Reactant: C[C@@H]1CC(=O)C[C@H]1C
Reactant: CCOC(=O)CC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C#N)=C1C[C@@H](C)[C@H](C)C1
Yield: 93 %

Procedure:
Trans-3,4-dimethyl cyclopentanone (2.91 g, 25.94 mmol), ethyl cyanoacetate (2.93 g, 25.93 mmol), ammonium acetate (0.20 g, 2.60 mmol), and acetic acid (0.31 g, 5.17 mmol) were heated together in refluxing toluene under a Dean-Stark trap for 24 hours. After cooling and filtration through kieselguhr, evaporation gave the required product as an off-white solid (5.0 g, 93%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[N:5]2[C:6]=1[C:7]([S:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH2:19])=[N:8]3.C(N(CC)CC)C.CC[O:29][C:30]([C:32]([F:35])([F:34])[F:33])=O>C(#N)C>[CH3:1][C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[N:5]2[C:6]=1[C:7]([S:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:30](=[O:29])[C:32]([F:35])([F:34])[F:33])=[N:8]3
Reactant: CCOC(=O)C(F)(F)F
Reactant: Cc1nc2cccc3nc(SCCCCCN)c1n23
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1nc2cccc3nc(SCCCCCNC(=O)C(F)(F)F)c1n23
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 275 mg (1.00 mmol) of 3-methyl-2-[5-(amino)pentan-1-ylthio]-1,4,7b-triazacyclopent[cd]indene in 30 ml of acetonitrile were added 0.19 ml (1.36 mmol) of triethylamine and 171 mg (1.20 mmol) of ethyl ester of trifluoroacetic acid. The mixture was stirred for 15 hours at room temperature. The solvent was distilled off. To the residue was added ethyl acetate, which was washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (eluent: ethyl acetate) to afford 267 mg (72.0%, a pale yellow solid) of the desired compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([F:14])[C:12]=1[CH3:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6].C1C(=O)N([Br:22])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl.O>[Br:22][CH2:13][C:12]1[C:11]([F:14])=[CH:10][C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:3][C:2]=1[Cl:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1cc(F)c(C)c(Cl)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: CCOC(=O)c1cc(F)c(CBr)c(Cl)c1
Temperature: 80 °C
Yield: 48.8 %

Procedure:
To a solution of ethyl 3-chloro-5-fluoro-4-methylbenzoate (5.3 g, 24.46 mmol) in CCl4 (100 mL) was added NBS (4.79 g, 26.91 mmol) followed by AIBN (0.4 g, 2.45 mmol). The reaction mixture was heated at 80° C. overnight. After cooling, the reaction mixture was diluted with H2O and washed with DCM (2×). The combined extracts were dried (Na2SO4), concentrated and purified by flash chromatography (12% EtOAc/Hex) to yield ethyl 4-(bromomethyl)-3-chloro-5-fluorobenzoate (3.53 g, 49%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 7.96-7.85 (m, 1H), 7.83 (dd, J=9.6, 1.5 Hz, 1H), 4.80 (t, J=5.7 Hz, 2H), 4.41 (q, J=7.1 Hz, 2H), 3.47 (s, 1H), 1.47-1.30 (m, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][C:5](Br)=[CH:4][N:3]=1.[C:9]([C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1)#[N:10]>>[C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:2]2[CH:7]=[N:6][C:5]([C:14]3[CH:15]=[CH:16][C:11]([C:9]#[N:10])=[CH:12][CH:13]=3)=[CH:4][N:3]=2)=[CH:13][CH:12]=1)#[N:10]
Reactant: Brc1cnc(Br)cn1
Reactant: N#Cc1ccc(B(O)O)cc1
Product: N#Cc1ccc(-c2cnc(-c3ccc(C#N)cc3)cn2)cc1
Yield: 52 %

Procedure:
The same procedure described for 1,4-Bis-(2′-cyanopyridin-5′-yl)phenylene was used by employing 2,5-dibromopyrazine and 4-cyanophenylboronic acid to furnish 74 in 52% yield; mp >300° C. (DMF). 1H NMR (DMSO-d6): δ 7.99 (d, J=8.4 Hz, 4H), 8.39 (d, J=8.4 Hz, 4H), 9.42 (s, 2H).
Reaction SMILES: [NH2:1]C1C=C(SC(F)(F)F)C=CC=1O.CCN=C=NCCCN(C)C.[C:25]([OH:33])(=O)[C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1.N1C=CC=CC=1>O>[C:25]([NH2:1])(=[O:33])[C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1
Reactant: O=C(O)c1ccncc1
Reactant: Nc1cc(SC(F)(F)F)ccc1O
Agent: CCN=C=NCCCN(C)C
Solvent: O
Solvent: c1ccncc1
Product: NC(=O)c1ccncc1
Temperature: 80 °C

Procedure:
A mixture of 0.70 g of 2-amino-4-(trifluoromethylthio)phenol, 0.83 g of WSC, 0.41 g of isonicotinic acid and 7 ml of pyridine was stirred while heating at 80° C. for three hours. The reaction mixture was cooled to room temperature, and then water was poured into the reaction mixture, followed by extraction with ethyl acetate three times. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.42 g of N-[2-hydroxy-5-trifluoromethylthio)phenyl]isonicotinamide.
Reaction SMILES: [C:1]([C:5]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:6]=1[O:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[N:20]=[CH:19][NH:18][N:17]=2)=[O:15])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:26][S:27](Cl)(=[O:29])=[O:28]>N1C=CC=CC=1>[C:1]([C:5]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:6]=1[O:7][CH:8]1[CH2:9][CH2:10][N:11]([C:14]([C:16]2[N:20]=[CH:19][N:18]([S:27]([CH3:26])(=[O:29])=[O:28])[N:17]=2)=[O:15])[CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(F)ccc1OC1CCN(C(=O)c2nc[nH]n2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CC(C)(C)c1cc(F)ccc1OC1CCN(C(=O)c2ncn(S(C)(=O)=O)n2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.5 %

Procedure:
To a solution of 4-(2-tert-butyl-4-fluorophenoxy)-1-(1H-1,2,4-triazol-3-ylcarbonyl)piperidine (200 mg, 0.58 mmol) obtained in Example 274 in pyridine (3 mL) was added methanesulfonyl chloride (99 mg, 0.87 mmol), and the mixture was stirred at room temperature for 16 hr. The reaction mixture was concentrated, and the residue was partitioned between ethyl acetate-water. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the title compound (245 mg, 99%) as a white solid.
Reaction SMILES: Br[CH2:2][C:3](=[CH2:14])[CH2:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:7])=[O:6].C([N-]C(C)C)(C)C.[Li+].[C:23]([O:27][C:28]([N:30]1[CH:34]([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:33]([CH2:42][CH:43]=[CH:44][C:45]([O:47][CH3:48])=[O:46])[O:32][C:31]1([CH3:50])[CH3:49])=[O:29])([CH3:26])([CH3:25])[CH3:24]>O1CCCC1>[C:23]([O:27][C:28]([N:30]1[CH:34]([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:33]([CH2:42][CH:43]2[CH:44]([C:45]([O:47][CH3:48])=[O:46])[CH2:14][C:3](=[CH2:2])[CH:4]2[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)(=[O:6])=[O:7])[O:32][C:31]1([CH3:50])[CH3:49])=[O:29])([CH3:25])([CH3:26])[CH3:24]
Reactant: C=C(CBr)CS(=O)(=O)c1ccccc1
Reactant: COC(=O)C=CCC1OC(C)(C)N(C(=O)OC(C)(C)C)C1Cc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C1CC(C(=O)OC)C(CC2OC(C)(C)N(C(=O)OC(C)(C)C)C2Cc2ccccc2)C1S(=O)(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
A solution of (2-Bromomethyl-prop-2-ene-1-sulfonyl)-benzene (25.4 g, 92.5 mmol) in dry tetrahydrofuran (500 ml) was stirred at −78° C. under nitrogen during the addition of lithium diisopropyl amide (2M in hexanes, 46.3 ml, 92.5 mmol). The resulting mixture was stirred at −78° C. for 15 minutes and 4-Benzyl-5-(3-methoxycarbonyl-allyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (30 g, 77 mmol) in dry tetrahydrofuran (150 ml) then added via a cannula over 5 minutes. The resulting mixture was stirred at −78° C. for 2 hours, then quenched with saturated aqueous ammonium chloride solution and warmed to room temperature. After addition of brine and ethyl acetate, the phases were separated and the aqueous layer extracted with ethyl acetate. The combined organic layers were washed with brine, dried (anhydrous magnesium sulfate) and concentrated in vacuo to give, after purification by flash chromatography on silica gel (ethylacetate/hexane: 1/9 to 4/6) 5-(2-Benzenesulfonyl-5-methoxycarbonyl-3-methylene-cyclopentylmethyl)-4-benzyl-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester 41 g (89%) as a white foam. Mass spectrum 584 [M+H]+.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1)=[O:6].C(N(CC)CC)C.[C:29](Cl)(=[O:33])[O:30][CH2:31][CH3:32]>C(Cl)Cl>[CH2:31]([O:30][C:29]([NH:3][CH:4]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:12][CH2:11][N:10]([CH2:15][CH2:14]2)[CH2:9]1)=[O:6])=[O:33])[CH3:32]
Reactant: NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 54.7 %

Procedure:
To a suspension of (R)-quinuclidin-3-yl 2-amino-2-phenylacetate dihydrochloride (I25) (110 mg, 0.33 mmol) in DCM (5 ml), were added triethylamine (138 μl, 0.99 mmol) and ethyl carbonochloridate (38 μl, 0.40 mmol). The reaction was stirred at RT for 4 hours, and then solvent was evaporated. EtOAc was added, and the organic phase was washed with water and brine, dried over Na2SO4 and evaporated to obtain (R)-quinuclidin-3-yl 2-(ethoxycarbonylamino)-2-phenylacetate (60 mg; 55% yield). The product was used as such in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].[Br:12]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OCC)C.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:12][CH2:11][C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[C:3]([O:2][CH3:1])[CH:10]=1
Reactant: COc1cc(C)ccc1C#N
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOCC
Product: COc1cc(CBr)ccc1C#N
Temperature: 25 °C
Yield: 68.3 %

Procedure:
To a solution of 2-methoxy-4-methylbenzonitrile (0.438 g, 2.98 mmol) in CCl4 (6 mL) was added recrystallized N-bromosuccinimide (0.544 g, 3.05 mmol) followed by benzoyl peroxide (47 mg, 0.19 mmol). The resultant mixture was heated to reflux for 45 minutes then cooled to room temperature. The mixture was diluted with diethyl ether (30 mL), filtered through filter paper, and the filtrate was concentrated. Purification of the crude material by column chromatography (6:1 hexanes-EtOAc) provided 0.46 g (68%) of 4-(bromomethyl)-2-methoxybenzonitrile as a white solid. 1H NMR (CDCl3) δ3.96 (s, 3H), 4.45 (s, 2H), 6.99 (s, 1H), 7.03 (d, 1H, J=9 Hz), 7.53 (d, 1H, J=9 Hz).
Reaction SMILES: COC(=O)C1C=CC=C(N[C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:14]2=[O:37])C=1.[CH2:40]([O:42]C(=O)CSC1C=CC=C(N)C=1)[CH3:41]>>[CH2:40]([O:42][C:11](=[O:38])[CH2:12][N:13]1[N:19]=[C:18]([CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)[C:17]2[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=2[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:34])([CH3:33])[CH3:35])[C:14]1=[O:37])[CH3:41]
Reactant: COC(=O)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1
Reactant: CCOC(=O)CSc1cccc(N)c1
Product: CCOC(=O)CN1N=C(C2CCCCC2)c2ccccc2N(CC(=O)C(C)(C)C)C1=O

Procedure:
The title compound was obtained by the method used in the preparation of 3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-benzoic acid methyl ester (Example 1) except that (3-amino-phenylsulfanyl)-acetic acid ethyl ester (S. Hagishita et al. Bioorg. Med. Chem. (1997), 5, 1433) was used instead of 3-amino-benzoic acid methyl ester in step e, followed by reaction of the product obtained, in place of [5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid ethyl ester (Example 1, step c), according to the method of Example 1, step d. 1H NMR (DMSO-d6) 12.60 (1H, br s), 9.81 (1H, s), 7.50 (3H, m), 7.27-7.21 (4H, m), 6.97 (1H, m), 4.78 (2H, m), 4.27 (1H, d), 3.96 (1H, d), 3.72 (2H, s), 2.86 (1H, m), 1.83-1.65 (6H, m), 1.29-1.17 (13H, m). The compound was further characterised as the N-methyl-D-glucamine salt. Found C, 54.50; H, 7.36; N, 8.44; C30H36N4O5S.C7H17NO5.3.0H2O requires C, 54.59; H, 7.30; N, 8.60%.