Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH3:14])=[N:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[Cl:15]N1C(=O)CCC1=O>C(O)(=O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH3:14])=[N:10][CH:9]=2)[C:5]([Cl:15])=[CH:4][N:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1ncc(-c2ccnc(N)n2)n1C
Solvent: CC(=O)O
Product: Cc1ncc(-c2nc(N)ncc2Cl)n1C
Temperature: 65 °C
Yield: 233 %

Procedure:
2-Amino-4-(1,2-dimethylimidazol-5-yl)pyrimidine (Method 26; 378 mg, 2 mmol) and N-chlorosuccimide (267 mg, 2 mmol) were dissolved in glacial acetic acid (7 ml) under an atmosphere of nitrogen. The reaction mixture was heated at 65° C. for 18 hours when further N-chlorosuccinimide (89 mg, 0.66 mmol) was added and the reaction heated at 65° C. for an additional 2 hours. The volatiles were removed by evaporation and the residue dissolved in water (10 ml). The solution was adjusted to pH 11-12 by addition of 40% aqueous sodium hydroxide solution. The precipitated solid was collected by filtration and washed sparingly with water, dried under vacuum at 60° C. to give the title compound (344 mg, 77%) as a yellow solid. NMR 2.35 (s, 3H, 3.75 (s, 3H), 4.83 (s, 2H), 7.53 (s, 1H), 8.27 (s, 1H); m/z 224.
Reaction SMILES: [CH2:1]=[CH:2][CH:3]1[CH:8]2[CH2:9][CH:10]([C@H:11]([OH:23])[C:12]3[CH:21]=[CH:20][N:19]=[C:18]4[C:13]=3[CH:14]=[C:15]([OH:22])[CH:16]=[CH:17]4)[N:5]([CH2:6][CH2:7]2)[CH2:4]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][CH2:32][CH2:33][C:34]#[N:35]>CC(C)=O.CN(C)C=O.C1OCCOCCOCCOCCOCCOC1>[OH:23][C@@H:11]([C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[C:15]([O:22][CH2:31][CH2:32][CH2:33][C:34]#[N:35])[CH:14]=2)[N:19]=[CH:20][CH:21]=1)[C@@H:10]1[N:5]2[CH2:6][CH2:7][C@H:8]([C@@H:3]([CH:2]=[CH2:1])[CH2:4]2)[CH2:9]1
Reactant: C=CC1CN2CCC1CC2[C@H](O)c1ccnc2ccc(O)cc12
Reactant: N#CCCCBr
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: C=C[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](O)c1ccnc2ccc(OCCCC#N)cc12
Yield: 94.3 %

Procedure:
To a solution of 400 mg (1.2 mmol) of 6-hydroxycinchonane (1) in 25 ml of anhydrous acetone (dried and distilled over potassium carbonate) and 5 ml of anhydrous dimethylformamide was added 267 mg (1.93 mmol) of anhydrous potassium carbonate followed by 129 ml (0.87 mmol) of 4-bromobutyronitrile and a catalytic amount (3 mg) of 18-crown-6. The reaction mixture was heated to reflux for 18 h, cooled and filtered. The filtrate was concentrated under reduced pressure and redissolved in 200 ml of chloroform. The organic layer was washed with 2×50 ml of 5% aqueous sodium hydroxide, washed with brine, dried using anhydrous magnesium sulfate and yielded 310 mg (0.82 mmol, 66%) of (9S)-4-[(9-hydroxycinchonan-6'-yl)oxy]butanenitrile (2) as pale yellow solids. MS, IR and NMR data confirmed the identity of the compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:11][NH:12][C:13]([C:15]3[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[C:17]([F:25])[CH:16]=3)=[O:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(#N)C.[S:29]1[C:33]([NH2:34])=[N:32][CH:31]=[N:30]1.[OH-].[Na+].O1CCOCC1.O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:11][NH:12][C:13](=[O:14])[C:15]3[CH:20]=[CH:19][C:18]([S:21]([NH:34][C:33]4[S:29][N:30]=[CH:31][N:32]=4)(=[O:23])=[O:22])=[C:17]([F:25])[CH:16]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: Nc1ncns1
Reactant: O=C(NCC1(c2ccc(Cl)cc2)CC1)c1ccc(S(=O)(=O)Cl)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: C1COCCO1
Solvent: O
Product: O=C(NCC1(c2ccc(Cl)cc2)CC1)c1ccc(S(=O)(=O)Nc2ncns2)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 15.5 %

Procedure:
A solution of 4-[({[1-(4-chlorophenyl)cyclopropyl]methyl}amino)carbonyl]-2-fluorobenzenesulfonyl chloride (Preparation 93, 205 mg, 0.510 mmol) in acetonitrile (1.0 mL, 19 mmol) was added dropwise to a solution of 1,2,4-thiadiazol-5-amine (155 mg, 1.53 mmol) and sodium hydroxide (61.1 mg, 1.53 mmol) in 1,4-dioxane (1.6 mL, 2.0E1 mmol) and water (0.32 mL, 18 mmol). After stirring 30 min at ambient temperature, the reaction mixture was quenched with 2 N HCl. The mixture was partitioned with methylene chloride. The aqueous layer was washed with methylene chloride, and the combined organic layers were dried over sodium sulfate, filtered and concentrated onto Celite. The residue was purified via automated flash chromatography (12 g SiO2, chloroform to 20% MeOH in chloroform). The product containing fractions were concentrated in vacuo, and the residue was dissolved in 1 mL of DMSO, filtered, and purified via reverse-phase HPLC (Prep: Phenomenex 250×30.0 mm 15 micron C18 column. 40 mL/min. Gradient 15% B to 100% B over 25 min. Solvent A: 7800 water/200 acetonitrile/8 TFA. Solvent B: 7200 acetonitrile/800 water/8 TFA). The product containing fractions were lyophilized to afford the product as a white powder (37 mg, 15%).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6](=[S:8])[NH2:7])[CH:3]=[N:2]1.Br[CH2:10][C:11](=O)[C:12]([OH:14])=O.[NH2:16][C@H:17]([CH3:33])[CH2:18][N:19]1[CH:23]=[CH:22][C:21]([C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[C:26]([Cl:32])[CH:25]=2)=[N:20]1.C(Cl)Cl>C1COCC1>[Cl:32][C:26]1[CH:25]=[C:24]([C:21]2[CH:22]=[CH:23][N:19]([CH2:18][C@H:17]([NH:16][C:12]([C:11]3[N:7]=[C:6]([C:4]4[CH:5]=[N:1][NH:2][CH:3]=4)[S:8][CH:10]=3)=[O:14])[CH3:33])[N:20]=2)[CH:31]=[CH:30][C:27]=1[C:28]#[N:29]
Reactant: C[C@@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: O=C(O)C(=O)CBr
Reactant: NC(=S)c1cn[nH]c1
Solvent: C1CCOC1
Solvent: ClCCl
Product: C[C@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1csc(-c2cn[nH]c2)n1
Temperature: 60 °C
Yield: 13.7 %

Procedure:
1H-Pyrazole-4-carbothioic acid amide (300 mg, 2.359 mmol) and 3-bromo-2-oxopropanoic acid (433 mg, 2.60 mmol) were dissolved in dry THF under nitrogen atmosphere. The reaction mixture was heated at 60° C. for 3 h. The reaction mixture was cooled to RT and evaporated to dryness. (R)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (300 mg, 1.151 mmol) and DCM were added to the reaction flask and the title compound was prepared using the method of Example 34(d). The product was purified by Flash-chromatography and triturated using methanol. Yield 13.7%. 1H-NMR (400 MHz; DMSO): δ 1.17 (d, 3H), 4.31-4.54 (m, 3H), 6.96 (d, 1H), 7.84 (d, 1H), 7.87 (d, 1H), 7.94 (dd, 1H), 8.00 (bs, 1H), 8.06 (d, 1H), 8.08 (d, 1H), 8.38 (d, 1H), 8.40 (bs, 1H), 13.38 (s, 1H).
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:30]=[CH:29][C:8]([C:9]([O:11][C@H:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([N:21]4[CH2:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)[C:15]=3[C@H:14]([CH3:28])[CH2:13]2)=[O:10])=[CH:7][CH:6]=1)([O-:4])=[O:3].[C:31]([O:35][C:36]([N:38]([CH:51]([CH3:53])[CH3:52])[CH2:39][CH:40]([C:44]1[CH:49]=[CH:48][C:47]([Cl:50])=[CH:46][CH:45]=1)[C:41](O)=[O:42])=[O:37])([CH3:34])([CH3:33])[CH3:32].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[N+:2]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([O:11][C@H:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([N:21]4[CH2:27][CH2:26][CH2:25][N:24]([C:41](=[O:42])[C@@H:40]([C:44]5[CH:45]=[CH:46][C:47]([Cl:50])=[CH:48][CH:49]=5)[CH2:39][N:38]([C:36]([O:35][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:37])[CH:51]([CH3:52])[CH3:53])[CH2:23][CH2:22]4)[C:15]=3[C@H:14]([CH3:28])[CH2:13]2)=[O:10])=[CH:29][CH:30]=1)([O-:4])=[O:3]
Reactant: CC(C)N(CC(C(=O)O)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Reactant: C[C@@H]1C[C@@H](OC(=O)c2ccc([N+](=O)[O-])cc2)c2ncnc(N3CCCNCC3)c21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N(C[C@@H](C(=O)N1CCCN(c2ncnc3c2[C@H](C)C[C@H]3OC(=O)c2ccc([N+](=O)[O-])cc2)CC1)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Yield: 49.5 %

Procedure:
(5R,7R)-4-(1,4-Diazepan-1-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl 4-nitrobenzoate hydrochloride (61 mg, 0.140 mmol) and 3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoic acid (48 mg, 0.140 mmol) were suspended in dichloromethane (5 mL). N,N-Diisopropylethylamine (54 mg, 0.420 mmol) was then added. HBTU (53 mg, 0.140 mmol) was added, and the resultant solution was stirred at ambient for 16 hours. After this time, the reaction mixture was quenched by the addition of saturated sodium carbonate solution and then extracted twice with dichloromethane. The combined organic portions were dried over sodium sulfate, filtered, and concentrated. The residue thus obtained was purified by silica gel chromatography to give (5R,7R)-4-(4-((S)-3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoyl)-1,4-diazepan-1-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl 4-nitrobenzoate (50 mg, 50%). LCMS (APCI+) M+=721.1, Rt=4.51 min.
Reaction SMILES: C(S[N:5]1[CH2:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[S:6]1(=[O:15])=[O:14])CC.[OH2:16].ClCl>C(O)(=O)C>[CH2:9]([N:5]1[CH2:9][C:8]2[CH:10]=[CH:11][CH:12]=[C:13]([S:6]([NH2:5])(=[O:14])=[O:16])[C:7]=2[S:6]1(=[O:14])=[O:15])[CH2:8][CH2:7][CH2:13][CH3:12]
Reactant: CCCSN1Cc2ccccc2S1(=O)=O
Reactant: O
Agent: ClCl
Solvent: CC(=O)O
Product: CCCCCN1Cc2cccc(S(N)(=O)=O)c2S1(=O)=O
Temperature: 25 °C

Procedure:
A solution of 9.5 g of 2-pentyl-7-(propylthio-2,3-dihydro-1,2-benzisothiazole-1,1-dioxide in 40 ml of acetic acid containing 1.3 ml of water was contacted with 7.0 ml of liquified chlorine at 10° to 15° C. and allowed to warm to 25° C. The excess chlorine was removed via a stream of nitrogen gas and the solution was poured onto ice. The resulting solid was filtered, washed with water and hexane, dried, dissolved in CH2Cl2 and contacted with 2.0 ml of liquified ammonia at -78° to 25° C. The mixture was added to 100 ml of 1N HCl and extracted with CH2Cl2. The extract was washed with water and brine, dried over MgSO4, concentrated and slurried in ether to give 6.35 g of the title compound as a white powder, m.p. 156°-160° C.
Reaction SMILES: I[C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH3:14])([CH3:13])[S:7](=[O:12])(=[O:11])[C:8]([CH3:10])([CH3:9])[C:4]=2[CH:3]=1.[SH:17][C:18]1[CH:19]=[C:20]([C:24]2([O:30][CH3:31])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:21]=[CH:22][CH:23]=1>>[CH3:31][O:30][C:24]1([C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([S:17][C:2]3[CH:16]=[CH:15][C:5]4[C:6]([CH3:14])([CH3:13])[S:7](=[O:12])(=[O:11])[C:8]([CH3:10])([CH3:9])[C:4]=4[CH:3]=3)[CH:19]=2)[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1
Reactant: CC1(C)c2ccc(I)cc2C(C)(C)S1(=O)=O
Reactant: COC1(c2cccc(S)c2)CCOCC1
Product: COC1(c2cccc(Sc3ccc4c(c3)C(C)(C)S(=O)(=O)C4(C)C)c2)CCOCC1
Yield: 28 %

Procedure:
Using a similar procedure to that described in Example 12, 5-iodo-1,1,3,3-tetramethyl-1,3-dihydrobenzo[c]thiophene-2,2-dioxide was reacted with 4-(3-mercaptophenyl)-4-methoxytetrahydropyran to give 4-methoxy-4-[3-(1,1,3,3-tetramethyl-2,2-dioxo-1,3-dihydrobenzo[c]thien-5-ylthio)phenyl]tetrahydropyran in 28% yield, m.p. 133°-135° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:9]([C:11]2[CH:30]=[CH:29][C:14]3[N:15]([CH3:28])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])=[CH:4][CH:3]=1.[ClH:38].C(O)C.C(=O)([O-])[O-].[NH4+:46].[NH4+]>ClCCl.CO>[ClH:38].[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:9]([C:11]2[CH:30]=[CH:29][C:14]3[N:15]([CH3:28])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:46])[NH2:27])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])=[CH:6][CH:7]=1
Reactant: [NH4+]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C#N)cc1)n2C)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccc(F)cc1
Yield: 90 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-(4-fluorophenyl)-N-(2-ethoxycarbonylethyl)amide and ethanolic hydrochloric acid, ethanol, and ammonium carbonate. Yield: 90% of theory, C28H29FN6O3 (516.6); Rf value: 0.29 (silica gel; dichloromethane/methanol=5:1); EKA mass spectrum: (M+H)+=517; (M+H+Na)++=270.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].[N:16]#[C:17][NH2:18].[N+:19]([O-:22])([OH:21])=[O:20].CCOCC>C(O)C>[N+:19]([O-:22])([O-:21])=[O:20].[C:5]([C:4]1[CH:3]=[C:2]([NH:1][C:17]([NH2:18])=[NH2+:16])[CH:15]=[CH:14][CH:13]=1)(=[O:6])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Nc1cccc(C(=O)c2ccccc2)c1
Reactant: O=[N+]([O-])O
Reactant: N#CN
Solvent: CCO
Solvent: CCOCC
Product: NC(=[NH2+])Nc1cccc(C(=O)c2ccccc2)c1
Product: O=[N+]([O-])[O-]
Temperature: 25 °C
Yield: 41 %

Procedure:
To a room temperature solution of 3-aminobenzophenone (4.0 g, 20.2 mmol) in ethanol (50 mL) was added cyanamide (1.8 mL, 50 wt % in water, 23.3 mmol) followed by the dropwise addition of concentrated nitric acid (1.42 mL). The mixture was heated at reflux for 2 hours and then additional cyanamide (1.8 mL, 50 wt % in water, 23.3 mmol) and nitric acid (1.42 mL) were added. The mixture was heated for an additional 1 hour then allowed to cool to room temperature. Ether was added and the precipitate collected on a filter. This material was recrystallized from ethyl acetate/methanol/ether to yield N-(3-benzoylphenyl)guanidinium nitrate (2.5 g, 41%) as a white crystalline solid. 1H NMR (DMSO-d6): δ 9.75 (s, 1 H), 7.76 (d, 2 H), 7.69 (t, 1 H), 7.61 (d, 2 H), 7.58-7.49 (m, 9 H); 13C NMR (DMSO-d6): δ 195.01, 155.76, 138.31, 136.65, 135.80, 132.99, 130.05, 129.71, 128.67, 128.44, 127.39, 125.34; MS m/z 240 (M+1 of free base).
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:11]2[C:12]([O:15][CH2:16][CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[N:13][O:14][C:10]=2[CH:9]=[CH:8][CH:7]=1)[CH:2]([CH3:4])[CH3:3].O=[CH:24][CH2:25][C:26]1([C:32]([O:34][CH3:35])=[O:33])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.C(C1(C(OC)=O)CCCC1)=O>>[CH2:1]([O:5][C:6]1[C:11]2[C:12]([O:15][CH2:16][CH:17]3[CH2:22][CH2:21][N:20]([CH2:24][CH2:25][C:26]4([C:32]([O:34][CH3:35])=[O:33])[CH2:27][CH2:28][O:29][CH2:30][CH2:31]4)[CH2:19][CH2:18]3)=[N:13][O:14][C:10]=2[CH:9]=[CH:8][CH:7]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: COC(=O)C1(CC=O)CCOCC1
Reactant: CC(C)COc1cccc2onc(OCC3CCNCC3)c12
Agent: COC(=O)C1(C=O)CCCC1
Product: COC(=O)C1(CCN2CCC(COc3noc4cccc(OCC(C)C)c34)CC2)CCOCC1

Procedure:
The title compound was prepared according to the procedure described in Step 3 of EXAMPLE 2 using 4-isobutoxy-3-(piperidin-4-ylmethoxy)-1,2-benzisoxazole (EXAMPLE 10, Step 1) and methyl 4-(2-oxoethyl)tetrahydro-2H-pyran-4-carboxylate (WO 2004/043958) instead of 3-(piperidin-4-ylmethoxy)-4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazole and methyl 1-formylcyclopentanecarboxylate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1.[NH:15]1[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)=[O:21])[CH2:16]1>>[NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][CH2:12][CH:11]([N:15]2[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:32])[F:33])[CH:26]=3)=[O:21])[CH2:16]2)[CH2:10][CH2:9]1
Reactant: Nc1ccncc1C1CCC(=O)CC1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: Nc1ccncc1C1CCC(N2CC(NC(=O)CNC(=O)c3cccc(C(F)(F)F)c3)C2)CC1

Procedure:
The title compounds were prepared as white solids from the reductive amination of 4-(4-amino-pyridin-3-yl)-cyclohexanone (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step F of Example 1.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:35])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[C:13]([OH:34])=[CH:14][C:15]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:17]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)[C:16]=2[CH:33]=1)([CH3:3])[CH3:2].[CH3:36]I>>[CH:1]([O:4][C:5](=[O:35])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[C:13]([O:34][CH3:36])=[CH:14][C:15]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:17]([C:26]3[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=3)[C:16]=2[CH:33]=1)([CH3:3])[CH3:2]
Reactant: Cc1ccc(-n2c(-c3ccccc3)nc3cc(O)c(OCCCCCC(=O)OC(C)C)cc32)cc1
Reactant: CI
Product: COc1cc2nc(-c3ccccc3)n(-c3ccc(C)cc3)c2cc1OCCCCCC(=O)OC(C)C

Procedure:
6-[[5-Hydroxy-1-(4-methylphenyl)-2-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid isopropyl ester was methylated with methyl iodide according to general operating instructions 8.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C([N:25]=[C:26]=[S:27])(=O)C1C=CC=CC=1.CO.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O>[C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:26]([NH2:25])=[S:27])=[CH:13][CH:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1ccc(N)cc1
Reactant: O=C(N=C=S)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1ccc(NC(N)=S)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 3 g (13.5 mmol) (4-Amino-benzyl)-carbamic acid tert-butyl ester and 1.81 ml (13.5 mmol) benzoyl isothiocyanate in 60 ml THF was stirred at room temperature for 1 h and afterwards evaporated under reduced pressure. 80 ml MeOH and 5.6 g (40.5 mmol) potassium carbonate in 80 ml water were added and the mixture was stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure and extracted with ethyl acetate. The organic layers were washed with saturated NaHCO3 solution and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica eluting with a gradient of hexane/ethyl acetate to yield after evaporation of the product fractions 3.67 g (97%) of the title compound as yellow amorphous solid.
Reaction SMILES: CS[C:3](SC)(SC)[CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[CH:32]=[CH:31][C:15]2[NH:16][C:17]([CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)=[N:18][C:14]=2[CH:13]=1)[OH:5].[CH3:37][OH:38].[OH2:39]>>[CH3:37][O:38][C:3](=[O:39])[CH:4]([OH:5])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[CH:32]=[CH:31][C:15]2[NH:16][C:17]([CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)=[N:18][C:14]=2[CH:13]=1
Reactant: CSC(SC)(SC)C(O)c1ccccc1-c1ccc2[nH]c(COc3ccc(C(F)(F)F)cc3)nc2c1
Reactant: O
Reactant: CO
Product: COC(=O)C(O)c1ccccc1-c1ccc2[nH]c(COc3ccc(C(F)(F)F)cc3)nc2c1
Reaction time: 12 h
Yield: 78 %

Procedure:
To a solution of 2,2,2-tris-methylsulfanyl-1-{2-[2-(4-trifluoromethyl-phenoxymethyl)-1H-benzoimidazol-5-yl]-phenyl}-ethanol (0.482 g, 0.875 mmol) in a mixed solvent (16 mL, MeOH: H2O=9:1) at rt was added mercuric chloride (0.855 g, 3.15 mmol) and mercuric oxide (0.303 g, 1.40 mmol). The reaction mixture was stirred for 12 hours. The solid was removed by filtration, and the collected filtrate was concentrated under reduced pressure. The residue was purified by chromatography (silica, hexanes: EtOAc, 1:1) to afford the title compound as a white solid (0.312 g, 78%). 1H NMR (400 MHz, CD3OD) δ (ppm): 7.71 (s, 1H), 7.62 (d, 2H, J=8.4 Hz), 7.50-7.46 (m, 1H), 7.7.41-7.36 (m, 2H), 7.34-7.31 (m, 2H), 7.25 (d, 2H, J=8.8 Hz), 5.49 (s, 2H), 5.27 (s, 1H), 3.62 (s, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C24H20F3N2O4: 457.4 (M+H), Found 457.3.
Reaction SMILES: [OH:1][C:2]1([CH:14]([CH3:27])[CH2:15][C:16]2[CH:21]=[C:20]([S:22]([O-:25])(=[O:24])=[O:23])[CH:19]=[CH:18][C:17]=2[CH3:26])[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:28][N:29]([CH3:31])[CH3:30]>C(O)C>[C:17]1([CH3:26])[CH:18]=[CH:19][C:20]([S:22]([O-:25])(=[O:23])=[O:24])=[CH:21][CH:16]=1.[OH:1][C:2]1([CH:14]([CH3:27])[CH2:15][N+:29]([CH3:31])([CH3:30])[CH3:28])[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1CC(C)C1(O)CCCCC1c1ccccc1
Reactant: CN(C)C
Solvent: CCO
Product: CC(C[N+](C)(C)C)C1(O)CCCCC1c1ccccc1
Product: Cc1ccc(S(=O)(=O)[O-])cc1

Procedure:
2-(1-Hydroxy-2-phenylcyclohexyl)propyl p-toluenesulfonate (Example II, Compound III) (10 g) in 75 ml ethanol is stirred at room temperature for 54 hours with 15 ml trimethylamine. The mixture is then heated at 75° for 7 hours in a pressure bottle, concentrated and 125 ml water added. The solution is seeded and the resultant solid filtered and washed to give 6.5 g product, m. 85°-7°.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C@:10]([CH2:28][O:29][CH2:30][CH3:31])([CH2:11][C:12]3[CH:20]=[N:19][N:18]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[C:13]=3[CH:14]=2)[CH2:9]1)=O)(C)(C)C.[Cl:32][C:33]1[N:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1>>[Cl:32][C:33]1[N:38]=[CH:37][C:36]([S:39]([N:8]2[CH2:17][CH2:16][C:15]3[C@:10]([CH2:28][O:29][CH2:30][CH3:31])([CH2:11][C:12]4[CH:20]=[N:19][N:18]([C:21]5[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=5)[C:13]=4[CH:14]=3)[CH2:9]2)(=[O:41])=[O:40])=[CH:35][CH:34]=1
Reactant: CCOC[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(C(=O)OC(C)(C)C)C2
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Product: CCOC[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(Cl)nc1)C2

Procedure:
The title compound was prepared by the method of Preparation 1c using (R)-4a-ethoxymethyl-1-(4-fluorophenyl)-1,4,4a,5,7,8-hexahydro-1,2,6-triazacyclopenta[b]naphthalene-6-carboxylic acid tert-butyl ester and 6-chloropyridine-3-sulfonyl chloride. LCMS (Method B): 503 (M+H)+, Retention time 4.1 minutes.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=O.[CH2:14]([NH2:16])[CH3:15]>>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH2:4][NH:16][CH2:14][CH3:15]
Reactant: CCN
Reactant: O=Cc1cc(C(F)(F)F)ccc1Br
Product: CCNCc1cc(C(F)(F)F)ccc1Br

Procedure:
Prepared according to the procedure described in Example 11, Step 4, using the following starting materials: 2-bromo-5-(trifluoromethyl)benzaldehyde and ethylamine (2M in THF).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[CH:6]=[C:7]([CH:9]([CH:13]([CH3:15])[CH3:14])[C:10]([OH:12])=[O:11])[S:8][C:4]=2[CH:3]=1.CS(O[CH2:23][C:24]1[NH:25][CH:26]=[CH:27][C:28]=1[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=O)=O>C1COCC1.CN(C=O)C.CCOCC>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[CH:6]=[C:7]([CH:9]([CH:13]([CH3:14])[CH3:15])[C:10]([O:12][CH2:23][C:24]3[NH:25][CH:26]=[CH:27][C:28]=3[CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:11])[S:8][C:4]=2[CH:3]=1
Reactant: CS(=O)(=O)OCc1[nH]ccc1Cc1ccccc1
Reactant: CC(C)C(C(=O)O)c1cc2ccc(Cl)cc2s1
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)C(C(=O)OCc1[nH]ccc1Cc1ccccc1)c1cc2ccc(Cl)cc2s1
Reaction time: 48 h

Procedure:
2-(6-Chloro-2-benzothienyl)-3-methylbutanoic acid (3.40 mmol) is stirred together with 0.34 g (3.40 mmol) KHCO3 in 10 ml THF/DMF (1:1) for 15 minutes. Then 3.40 mmol of 3-benzylpyrrolylmethyl methanesulfonate in 5 ml THF/DMF (1:1) is added and the mixture stirred for approximately 48 hours. The reaction is diluted with ether, washed with water (3×) and sat. NaCl, dried and solvent is removed to yield 3-benzylpyrrolylmethyl 2-(6-chloro-2-benzothienyl)-3-methylbutanoate.