Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:15])=[C:4](S(O)(=O)=O)[CH:5]=[C:6]([Cl:10])[C:7]=1[CH2:8][CH3:9].[N+:16]([O-])([OH:18])=[O:17]>>[Cl:1][C:2]1[C:7]([CH2:8][CH3:9])=[C:6]([Cl:10])[CH:5]=[C:4]([N+:16]([O-:18])=[O:17])[C:3]=1[OH:15]
Reactant: O=[N+]([O-])O
Reactant: CCc1c(Cl)cc(S(=O)(=O)O)c(O)c1Cl
Product: CCc1c(Cl)cc([N+](=O)[O-])c(O)c1Cl
Yield: 83.4 %

Procedure:
In the same manner as in Example 13 except that an aqueous solution of 3,5-dichloro-4-ethyl-2-hydroxybenzenesulfonic acid is added dropwise to a 50% aqueous nitric acid solution which have been preliminarily charged, the aimed product of 2,4-dichloro-3-ethyl-6-nitrophenol is obtained.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([CH:7]=[O:8])[CH:6]=1.[CH:9]#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(N(CC)CC)C>O1CCCC1>[C:9]([C:2]1[S:3][CH:4]=[C:5]([CH:7]=[O:8])[CH:6]=1)#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: O=Cc1csc(Br)c1
Reactant: C#CCCCCCCCCCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCC#Cc1cc(C=O)cs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-bromo-4-thiophenecarboxaldehyde (45.3 g), 1-dodecyne (43.4 g), and triethylamine (99 ml), in dry tetrahydrofuran (250 ml) was chilled to 5° C. and degassed under nitrogen. bis(Triphenylphosphine)palladium(II)chloride (1.66 g) and copper(I)iodide (0.23 g) were added to the reaction mixture. The mixture was degassed and stirred overnight, under nitrogen, as it was allowed to warm to room temperature. The precipitate was filtered off, washed with ethyl acetate, and the filtrate was evaporated. Ethyl acetate was added to the residue. The solution was washed with brine, dried over magnesium sulfate, filtered, and the filtrate was concentrated. The residue was chromatographed through a silica gel pad eluting with heptane/1% ethyl acetate. The appropriate fractions were collected and evaporated. The residue and that from a similar reaction on a 0.05 mole scale were combined and distilled to give 30.7 g (79.5%), bp 181°-185° C. @0.35 mm Hg.
Reaction SMILES: Cl.Cl.[N:3]1([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH2:8][CH2:7][CH:6]([N:9]2[C@H:13]3[CH2:14][CH2:15][CH2:16][CH2:17][C@@H:12]3[NH:11][C:10]2=[O:18])[CH2:5][CH2:4]1.C(N(CC)CC)C.Cl[C:33]([O:35][CH:36]([CH3:38])[CH3:37])=[O:34].[OH-].[Na+]>ClCCl>[O:18]=[C:10]1[N:9]([CH:6]2[CH2:5][CH2:4][N:3]([CH:19]3[CH2:24][CH2:23][N:22]([C:33]([O:35][CH:36]([CH3:38])[CH3:37])=[O:34])[CH2:21][CH2:20]3)[CH2:8][CH2:7]2)[C@H:13]2[CH2:14][CH2:15][CH2:16][CH2:17][C@@H:12]2[NH:11]1
Reactant: CC(C)OC(=O)Cl
Reactant: O=C1N[C@H]2CCCC[C@@H]2N1C1CCN(C2CCNCC2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)N1CCC(N2CCC(N3C(=O)N[C@H]4CCCC[C@@H]43)CC2)CC1
Reaction time: 2 h
Yield: 79.7 %

Procedure:
(3aS,7aS)-1-(1,4′-bipiperidin-4-yl)hexahydro-1H-benzo[d]imidazol-2(3H)-one dihydrochloride (0.68 g, 1.79 mmol) was dissolved in dichloromethane (20 mL) and triethylamine (0.75 mL, 5.38 mmol) was added. Isopropyl chloroformate (1.792 mL, 1.79 mmol) (solution 1M in toluene) was added drop wise at 0° C. The mixture was stirred for 2 hours then diluted in dichloromethane (60 mL) and the mixture made basic with 1N NaOH. The phases were separated and aq. phase was extracted with dichloromethane (2×25 mL). The combined organic phases were washed with brine (5 mL) and concentrated under reduced pressure. The crude was then purified by high pH prep LCMS to provide the title compound as a white solid (560 mg, 80%). 1H NMR (400 MHz, CHLOROFORM-D): δ ppm 1.22 (d, J=6.25 Hz, 6H), 1.26-1.49 (m, 6H), 1.58-1.70 (m, 2H), 1.72-1.84 (m, 7H), 1.94 (d, J=11.33 Hz, 1H), 2.14-2.32 (m, 3H), 2.33-2.47 (m, 1H), 2.69 (t, J=13.09 Hz, 2H), 2.84-2.96 (m, 2H), 2.96-3.06 (m, 1H), 3.65-3.81 (m, 1H), 4.07-4.28 (m, 2H), 4.43 (s, 1H), 4.80-4.94 (m, 1H). MS (M+1): 393.2
Reaction SMILES: C([O:3][C:4](=[O:48])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:28]3[CH:32]=[CH:31][S:30][CH:29]=3)[CH:25]=[C:24]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH:23]=2)[C:10]=1[CH2:41][CH2:42][C:43]([O:45]CC)=[O:44])C.[OH-].[Na+]>>[CH2:34]([O:33][C:24]1[CH:23]=[C:22]([CH:27]=[C:26]([C:28]2[CH:32]=[CH:31][S:30][CH:29]=2)[CH:25]=1)[O:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:11]1[C:10]([CH2:41][CH2:42][C:43]([OH:45])=[O:44])=[C:9]([CH:14]=[CH:13][CH:12]=1)[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:48])=[O:3])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(OCc3ccccc3)cc(-c3ccsc3)c2)c1CCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCCOc1cccc(CCCCCCOc2cc(OCc3ccccc3)cc(-c3ccsc3)c2)c1CCC(=O)O
Yield: 87.1 %

Procedure:
A similar procedure as described in Example 43, step 5 was used, starting from 4-[3-[6-(3-benzyloxy-5-thiophen-3-yl-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (160 mg, 0.24 mmol) and 1.0 N aqueous sodium hydroxide (5 mL) to afford 4-[3-[6-(3-benzyloxy-5-thiophen-3-yl-phenoxy)-hexyl]-2-(2-carboxy-ethyl)-phenoxy]-butyric acid (129 mg, 88%) as a light brown waxy solid: ES(+)-HRMS m/e calcd for C36H40O7S (M+Na)+ 639.2387. found 639.2386.
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[Si](C)(C)N=C=O
Reactant: C/C(=N\O[C@H]1CCNC1)c1cnc2nnn(Cc3cc4cccnc4cc3F)c2n1
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: [C:1]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.CO.[C:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][C@@H:44]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=2[CH3:53])[C@@H:43]([C:54]([OH:56])=[O:55])[CH2:42]1)=[O:40])([CH3:37])([CH3:36])[CH3:35]>C1COCC1>[CH3:1][O:55][C:54]([C@@H:43]1[C@H:44]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=2[CH3:53])[CH2:45][CH2:46][N:41]([C:39]([O:38][C:34]([CH3:37])([CH3:35])[CH3:36])=[O:40])[CH2:42]1)=[O:56]
Reactant: Cc1ccccc1[C@@H]1CCN(C(=O)OC(C)(C)C)C[C@@H]1C(=O)O
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)[C@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1c1ccccc1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of triphenylphosphine (2.66 g) in THF (30 ml) was added diethyl azodicarboxylate (1.58 mL) at 0° C. After 30 minutes, methanol (1.58 mL) and a solution of (3R,4R)-4-o-tolyl-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester in THF (30 mL) were added subsequently at 0-5° C. The reaction mixture was stirred for 3 h at room temperature. The reaction was quenched with a saturated aqueous solution of NH4Cl, tert-butyl methyl ether was added, and the phases were separated. The inorganic one was extracted with tert-butyl methyl ether (3×100 ml). The combined organic layers were dried (Na2SO4), filtered and evaporated. Purification by chromatography (SiO2, CH2Cl2 to CH2Cl2/MeOH 95:5) yielded (3R,4R)-4-o-tolyl-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester as a colorless gum, MS: 334.1 ([M+H])+.
Reaction SMILES: [C:1]([C:6]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=[CH:8][C:7]=1[NH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])([O:3][CH2:4][CH3:5])=[O:2].S(Cl)([Cl:25])(=O)=O.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[C:1]([C:6]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=[C:8]([Cl:25])[C:7]=1[NH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)Nc1ccc(OC)c(OC)c1C(=O)OCC
Reactant: O=S(=O)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)Nc1c(Cl)cc(OC)c(OC)c1C(=O)OCC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The chloroform solution of ethyl 2-carboethoxy-3,4-dimethoxybenzenecarbamate prepared in A above was treated with sulfuryl chloride (30.2 g, 0.22 mole) and optionally with sodium bicarbonate (33.3 g, 0.40 mole) and the mixture was stirred at room temperature for 4 hours. An additional charge of sodium bicarbonate (3.3 g, 0.04 mole) and sulfuryl chloride (3.0 g, 0.02 mole) was added and stirring was continued for 16 hours. Filtration and concentration of the filtrate provided crude product as an oil which was crystallized from aqueous methanol. The resultant solid was dissolved in chloroform and the solution was dried, filtered and concentrated to give an oil which was crystallized from hexanes; 37.3 g (85%), mp 111°-113° C.
Reaction SMILES: Cl[CH2:2][CH2:3][S:4](Cl)(=[O:6])=[O:5].[CH:8]([OH:11])([CH3:10])[CH3:9].N1C=CC=CC=1>ClCCl>[CH:8]([O:11][S:4]([CH:3]=[CH2:2])(=[O:6])=[O:5])([CH3:10])[CH3:9]
Reactant: O=S(=O)(Cl)CCCl
Reactant: CC(C)O
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=CS(=O)(=O)OC(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-Chloroethylsulfonyl chloride (2 g, 12.3 mmol), isopropanol (1 mL), and pyridine (2.7 mL) were dissolved in dichloromethane (20 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was washed successively with 1N hydrochloric acid and water, and the organic layer was dried over anhydrous magnesium sulfate. The drying agent was filtered, and the solvent was evaporated to give the title compound (1.06 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:28][OH:29])[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][CH:17]=2)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[S:30](Cl)([CH3:33])(=[O:32])=[O:31]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH:12]([CH2:28][O:29][S:30]([CH3:33])(=[O:32])=[O:31])[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][CH:17]=2)=[O:14])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1ccc(NC(=O)C(CO)NS(=O)(=O)c2ccc(Cl)cc2)cc1
Reactant: CS(=O)(=O)Cl
Product: CCOC(=O)Cc1ccc(NC(=O)C(COS(C)(=O)=O)NS(=O)(=O)c2ccc(Cl)cc2)cc1

Procedure:
The procedure described in Example 65 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-hydroxypropanamide (1.32 g) was reacted with mesyl chloride to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-methanesulfonyloxypropanamide (1.04 g).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH2:40][CH2:41][CH2:42][CH3:43])[C:35](=[O:39])[CH2:36][CH2:37][CH3:38])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH2:40][CH2:41][CH2:42][CH3:43])[C:35](=[O:39])[CH2:36][CH2:37][CH3:38])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(N(CCCC)C(=O)CCC)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2ccc(N(CCCC)C(=O)CCC)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-(N-(n-butanoyl)-n-butyl-amino)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[C:4]([O:11][CH3:12])[CH:3]=1.Br[CH2:14][CH2:15][CH2:16]Br.[H-].[Na+]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:9]#[N:10])[CH2:16][CH2:15][CH2:14]2)=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: COc1cc(Br)ccc1CC#N
Reactant: BrCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(Br)ccc1C1(C#N)CCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 34.8 %

Procedure:
To a stirring mixture of (4-bromo-2-methoxyphenyl)acetonitrile (904 mg, 4.00 mmol), 1,3-dibromo-propane (880 mg, 4.40 mmol) in dimethylformamide (10 mL) was added sodium hydride (352 mg, 8.80 mmol) at 0° C. After addition, the mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with water and extracted with dichloromethane (50 mL×3). The organic phases were combined, dried over sodium sulfate and concentrated in vacuo to give a brown solid. The solid was purification by combiflash chromatography (Petroleum ether/EtOAc=20:1 to 5:1) to give the title compound (370 mg, 34.8%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.10 (dd, 1H), 7.02 (d, 1H), 7.00 (d, 1H), 3.87 (s, 3H), 2.78 (m, 2H), 2.50 (m, 3H), 1.95 (m, 1H)
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2.Cl[CH2:18][C:19]1[N:20]=[CH:21][S:22][CH:23]=1>>[CH3:1][C:2]1[N:3]([CH2:18][C:19]2[N:20]=[CH:21][S:22][CH:23]=2)[C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:12])([F:14])[F:13])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Reactant: ClCc1cscn1
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1cscn1

Procedure:
Synthesized as described in Example 4 using 2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile and 4-(chloromethyl)-1,3-thiazole: 1H NMR (400 MHz, CDCl3) δ 8.80 (d, J=2.0 Hz, 1H), 7.50 (m, 2H), 6.75 (s, 1H), 6.64 (s, 1H), 5.50 (s, 2H), 2.53 (s, 3H); MS (ES) m/z 322 (M+1).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1Br)=[O:3].[C:12]([OH:15])(=[O:14])[CH3:13].C(N(CC)CC)C>C(#N)C>[Cl:10][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH2:1][O:15][C:12](=[O:14])[CH3:13])=[CH:5][CH:6]=1
Reactant: CC(=O)c1ccc(Cl)cc1Br
Reactant: CC(=O)O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)OCC(=O)c1ccc(Cl)cc1
Temperature: 4 °C
Yield: 90.1 %

Procedure:
To a cooled (4° C.) and stirred solution of 2-bromo-4-chloroacetophenone (5.0 g, 21.41 mmol) and glacial acetic acid (2.8 mL, 49.25 mmol) in acetonitrile was added triethylamine (6.1 mL, 44.97 mmol). The reaction mixture was warmed to room temperature, than refluxed for 3 hours. The reaction mixture was extracted with ether, acetate, washed with 1N hydrochloric acid, brine, dried, and concentrated to yield 4.1 g of acetic acid 2-(4-chlorophenyl)-2-oxo-ethyl ester.
Reaction SMILES: [ClH:1].[CH3:2][CH:3]1[CH2:8][CH:7]([C:9]2[NH:14][C:13]3=[CH:15][CH:16]=[N:17][C:12]3=[CH:11][N:10]=2)[CH2:6][CH:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[NH:4]1.[Br:24]Br>CC(O)=O.O>[ClH:1].[Br:24][C:15]1[CH:16]=[N:17][C:12]2[C:13]=1[NH:14][C:9]([CH:7]1[CH2:6][CH:5]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[NH:4][CH:3]([CH3:2])[CH2:8]1)=[N:10][CH:11]=2
Reactant: CC1CC(c2ncc3nccc-3[nH]2)CC(c2ccccc2)N1
Reactant: BrBr
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: CC1CC(c2ncc3ncc(Br)c-3[nH]2)CC(c2ccccc2)N1
Temperature: 45 °C
Reaction time: 2 h
Yield: 79.4 %

Procedure:
To an oven-dried, 50-mL, round-bottomed flask was added 2-methyl-6-phenyl-4-(piperidinyl)pyrrolo[3,2-d]pyrimidine (Example 35)) (500 mg, 1.71 mmol) which was dissolved in glacial AcOH (15 mL). To this solution was added Br2 (Aldrich Chemical Company) (90.0 mL, 1.8 mmol) dropwise over 2 min. The resulting dark mixture was diluted with H2O (10 mL) and the mixture was warmed to 45° C. and stirred for 2 h. The reaction was allowed to cool to room temperature and the crude material was extracted with EtOAc (50 mL) and washed with saturated NaHCO3 (3×50 mL). The organic layer was washed with brine (50 mL), dried over MgSO4, filtered and evaporated in vacuo to give an oily residue. The residue was purified by silica gel chromatography with 50% EtOAc/hexanes as eluant to give 500 mg (79.4% yield) of a yellow solid. Mp: 239-240 ° C. 1H NMR (DMSO-d6; 400 MHz): d 1.74 (s, 6), 2.63 (s, 3), 3.83 (s, 4), 7.44 (t, 1, J=2.4), 7.5 (t, 2, J=7.0), 7.80 (d, 2, J=7.1). MS m/z: 373.0 (M+1); 369.0, 371.0 (M−1).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]([C:24]([F:27])([F:26])[F:25])([C:5]1[NH:6][C:7]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:9]=1)[NH2:4].ClC1C=CC=C(C(OO)=[O:38])C=1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[F:29][C:2]([F:28])([F:1])[C:3]1([C:24]([F:25])([F:26])[F:27])[C:5](=[CH:9][C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[O:38])[NH:6][C:7]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[N:4]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: NC(c1cc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)[nH]1)(C(F)(F)F)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: O=C(C=C1NC(c2ccc(F)cc2)=NC1(C(F)(F)F)C(F)(F)F)c1ccc(F)cc1
Temperature: 25 °C
Yield: 19.6 %

Procedure:
To a solution of α,α-bis(trifluoromethyl)-4,5-bis(4-fluorophenyl)-1H-pyrrole-2-methanamine (5.0 g, 0.012 mole) in chloroform (100 mL) was added portionwise, m-chloroperbenzoic acid (MCPBA, 4.09 g, 0.024 mole). The reaction mixture was refluxed under nitrogen for one hour. Then additional MCPBA (2.05 g, 0.012 mole) was added and the mixture was refluxed for 1 hour. The solution was cooled to room temperature and poured into saturated sodium bicarbonate (200 ml). The organic layer was washed successively with saturated sodium bicarbonate solution, 10% sodium sulfite solution, water, and saturated sodium chloride solution, dried over magnesium sulfate and evaporated under vacuum. The residue was columned in silica gel eluted with hexane-ethyl acetate 20:1 then 10:1 to give the 2-[4,4-bis(trifluoromethyl)-2-(4-fluorophenyl)-4,5-dihydro-1H-imidazol-5-ylidene]-1-(4-fluorophenyl)-1-ethanone (1.02 g, 20%) as a yellow solid: mp 121°-123°; MS m/e 435 (M+ +H); 1H NMR (CDCl3 /TMS) δ 6.73(s,1H,C=CH), 7.17-7.30(m,4H,Harom), 8.00-8.10(m,4H,Harom), 11.80(s,1H,NH). Another product, N[2-(4-fluorophenyl)-4,5-dihydro-1-methyl-5,5-bis(trifluoromethyl)-1H-imidazol-5-yl]-N-methylacetamide (2.09 g, 56%) was also isolated as a solid: mp 114°-115°; MS m/e 437 (M+ +H); 1H NMR (CDCl3 /TMS) δ 2.57(s,2H,NH2), 3.87(s,1H,NH), 6.77(s,1H,C=CH), 6.90-7.03(m,4H,Harom), 7.23-7.40(m, 2H,Harom), 7.15-7.17(m,2H,Harom).
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][C:6]([N:9]2[C:16](=[O:17])[C:12]3([CH2:15][CH2:14][CH2:13]3)[N:11]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[C:20]([F:27])[CH:19]=3)[C:10]2=[S:28])=[CH:5][C:4]=1[C:29]([F:32])([F:31])[F:30])#[N:2].C[N:34](C=O)C.C(Cl)(=O)C(Cl)=O.N>C(Cl)Cl.CO>[C:1]([C:3]1[N:8]=[CH:7][C:6]([N:9]2[C:16](=[O:17])[C:12]3([CH2:15][CH2:14][CH2:13]3)[N:11]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([NH2:34])=[O:23])=[C:20]([F:27])[CH:19]=3)[C:10]2=[S:28])=[CH:5][C:4]=1[C:29]([F:31])([F:32])[F:30])#[N:2]
Reactant: N#Cc1ncc(N2C(=O)C3(CCC3)N(c3ccc(C(=O)O)c(F)c3)C2=S)cc1C(F)(F)F
Reactant: CN(C)C=O
Agent: N
Agent: O=C(Cl)C(=O)Cl
Solvent: CO
Solvent: ClCCl
Product: N#Cc1ncc(N2C(=O)C3(CCC3)N(c3ccc(C(N)=O)c(F)c3)C2=S)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a suspension of 4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-fluorobenzoic acid (Compound 224, 500 mg, 1.08 mmol) in DCM was added DMF (cat., 0.1 mL), followed by oxalyl chloride (0.14 mL, 1.61 mmol). The mixture was stirred at room temperature for 4 h then concentrated in vacuo to produce a yellow residue that was further dried on a high vacuum pump. Ammonia (0.5M in dioxane, 40 mL, 20 mmol) was directly added to the residue and the mixture was stirred at room temperature overnight. MeOH was added and the mixture was absorbed onto silica gel and purified by flash chromatography (50 to 100% EtOAc/Hexanes) to afford impure desired product that was repurified by reverse phase HPLC (acetonitrile/water:TFA). The fractions containing the desired compound were combined, acetonitrile was removed in vacuo, and the remaining aqueous layer was treated with a saturated solution of sodium bicarbonate. The aqueous layer was extracted with DCM (3×), the organics were combined, dried over sodium sulfate, and evaporated to dryness to afford 100 mg of 4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-fluorobenzamide as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.21 (s, 1H), 8.75 (s, 1H), 7.95 (s, 1H), 7.87 (t, 1H), 7.80 (s, 1H), 7.46 (dd, 1H), 7.37 (dd, 1H), 2.69-2.62 (m, 2H), 2.55-2.47 (m, 2H), 2.00 (m, 1H), 1.58 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[C:27]4[O:26][CH2:25][CH2:24][N:23]([CH2:28][CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])[CH2:22][C:21]=4[CH:20]=[CH:19][CH:18]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+].C(O)(=O)C>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[C:27]4[O:26][CH2:25][CH2:24][N:23]([CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])[CH2:22][C:21]=4[CH:20]=[CH:19][CH:18]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CCOC(=O)CCCN1CCOc2c(cccc2-c2noc(-c3ccc(OC(C)C)c(Cl)c3)n2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3OCCN(CCCC(=O)O)C4)no2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
A solution of ethyl 4-[9-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]butanoate (Preparation 68) (61.7 g, 123 mmol) in ethanol (600 ml) was treated with 2M sodium hydroxide (123 ml, 247 mmol) and the mixture stirred at room temperature overnight. The solvent was evaporated and the residue dissolved in water (1 liter). The aqueous solution was cooled in ice/water and treated slowly with glacial acetic acid (28.3 ml, 494 mmol). The resulting gum was stirred vigorously until a filterable solid was obtained which was then collected by filtration and washed with more water (2×500 ml). After sucking the pad dry the material was dissolved in a 95:5 mixture of dichloromethane/methanol and dried (sodium sulphate). The solvent was removed by evaporation and the resulting solid was triturated under diethyl ether (200 ml), collected by filtration, washed with diethyl ether and dried to give the title compound as a colourless solid (54 g).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-])=O)[CH:24]=3)[CH2:18][CH2:17]2)=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].[H][H]>[Pd].C(OCC)(=O)C>[NH2:29][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][CH:26]=1)[O:22][CH:19]1[CH2:20][CH2:21][N:16]([CH2:15][C:12]2[CH:11]=[CH:10][C:9]([C:3]([OH:8])([C:2]([F:33])([F:1])[F:32])[C:4]([F:5])([F:6])[F:7])=[CH:14][CH:13]=2)[CH2:17][CH2:18]1
Reactant: O=[N+]([O-])c1cccc(OC2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1cccc(OC2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)c1
Yield: 98.7 %

Procedure:
A mixture of 1,1,1,3,3,3-hexafluoro-2-(4-((4-(3-nitrophenoxy)piperidin-1-yl)methyl)-phenyl)propan-2-ol (8.36 mmol, 4 g) and palladium on carbon (10%) (0.251 mmol, 0.267 g) in ethyl acetate was hydrogenated at 3 bar until the desired amount of hydrogen was consumed. The reaction was filtered through celite and concentrated under reduced pressure. Chromatography on silica, eluting with ethyl acetate, gave the title compound (3.7 g). MS (ESI) m/z 449.2 [M+H]+