Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:5]=[C:6]([CH:8]=[C:9]([CH2:17][NH:18][CH3:19])[C:10]=1[O:11][C@@H:12]([CH3:16])[CH2:13][O:14][CH3:15])[NH2:7].C(N(CC)C(C)C)(C)C.[CH2:29]([O:36][C:37]([O:39]N1C(=O)CCC1=O)=O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C=O)C>[NH2:7][C:6]1[CH:5]=[C:4]([F:3])[C:10]([O:11][C@@H:12]([CH3:16])[CH2:13][O:14][CH3:15])=[C:9]([CH:8]=1)[CH2:17][N:18]([CH3:19])[C:37](=[O:39])[O:36][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CNCc1cc(N)cc(F)c1O[C@@H](C)COC
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC[C@H](C)Oc1c(F)cc(N)cc1CN(C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
To a solution of 37A (472 mg, 1.497 mmol) and N,N-diisopropylethylamine (1.043 ml, 5.99 mmol) in DMF (10 ml), was added N-(benzyloxycarbonyloxy) succinimide (411 mg, 1.647 mmol). The mixture was stirred rt for 1 h, then quenched with water, extracted with EtOAc (3×30 ml). The organic layer was washed with brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (0-60% EtOAc in hexanes) to give 37B (520 mg, 1.381 mmol, 92% yield). MS (ESI) m/z: 377.3 (M+H)+.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[Na+].[Br:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1[OH:14]>S(=O)(=O)(O)O.O>[Br:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[C:9]([N+:1]([O-:4])=[O:2])[C:8]=1[OH:14]
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1ccc(O)c(Br)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Cc1cc(Br)c(O)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 29045.2 %

Procedure:
Sodium nitrate (28 g, 0.33 mmol) was dissolved in the solvent mixture of 70 mL of concentrated sulfuric acid and 210 mL of water at −5° C., followed by slowly dropwise addition of 2-bromo-4-methyl-phenol 11a (30.8 g, 0.165 mol). The reaction mixture was reacted for 2 hours upon cooling by an ice-water bath. The mixture was warmed up to room temperature and reacted for another 1 hour. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was extracted with 200 mL of ethyl acetate. The combined organic extracts were washed with water (100 mL×5), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound 2-bromo-4-methyl-6-nitro-phenol 11b (22.24 g, yield 58.1%) as a yellow solid.
Reaction SMILES: C([N:3]([CH2:6][CH3:7])CC)C.[CH3:8][Si:9](Cl)([CH3:11])[CH3:10].[CH2:13]([Cl:15])Cl>>[Cl:15][CH2:13][CH2:7][CH2:6][N:3]([Si:9]([CH3:11])([CH3:10])[CH3:8])[Si:9]([CH3:11])([CH3:10])[CH3:8]
Reactant: CCN(CC)CC
Reactant: ClCCl
Reactant: C[Si](C)(C)Cl
Product: C[Si](C)(C)N(CCCCl)[Si](C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 77.3 %

Procedure:
In a first step a 500 mL flask was charged with 13.002 g (100 mmol) of [ClCH2CH2CH2NH3]Cl that was dissolved in 300 mL of CH2Cl2 and 46.4 mL (300 mmol) of triethylamine. After ca. 10 min, a precipitate began to evolve. The flask was cooled to 0° C. and a solution containing 28.2 mL (222.2 mmol) of TMSCl and 50 mL of CH2Cl2 was added slowly over 2 h. The solution was stirred for an additional 2 h and then allowed to return to ambient temperature where it was stirred for 3 days. The supernatant liquid was decanted and then all volatile components were remove in vacuo to produce both a solid residue and a liquid. The liquid was extracted using ca. 200 mL of hexanes and subsequently the volatile components were removed under reduced pressure to yield 18.3898 g (77.30 mmol, 77.3%) of ClCH2CH2CH2N(SiMe3)2 as a colorless liquid. The product had the following NMR features: 1H NMR (300 MHz, CD3CN) δ=0.11 (s, —Si(CH3)3, 18H), 1.83 (m, CH2N, 2H, JHH=5.29 Hz), 3.52 (t, ClCH2, 2H, JHH=6.3 Hz); 13C{1H} NMR (75 MHz, CD3CN) 2.30, 38.50, 43.74, 43.93.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][C:19](=[O:21])[N:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:17][C:16]1([CH3:29])[CH3:28])=O)(C)(C)C>C(Cl)Cl>[CH3:28][C:16]1([CH3:29])[CH2:17][N:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19](=[O:21])[CH2:20][NH:15]1
Reactant: CC(C)(C)OC(=O)N1CC(=O)N(c2ccccc2)CC1(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)CN(c2ccccc2)C(=O)CN1
Reaction time: 0.5 h
Yield: 85.7 %

Procedure:
1.0 ml of trifluoroacetic acid (13 mmol) was added to a solution of 0.40 g of 2,2-dimethyl-5-oxo-4-phenylpiperazine-1-carboxylic acid t-butyl ester obtained in the above reaction (1.31 mmol) in methylene chloride (2 ml) at room temperature, and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. A saturated sodium bicarbonate aqueous solution was added, followed by extraction with methylene chloride. Then, the organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:methylene chloride/methanol=10/1) to obtain 0.23 g of the title compound (yield: 99%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([O:15][CH3:16])=[CH:7][C:8]2[N:12]=[C:11]([SH:13])[NH:10][C:9]=2[CH:14]=1)=[O:4].[ClH:17].[Cl:18][CH2:19][C:20]1[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=1[NH2:22]>>[ClH:18].[ClH:17].[NH2:22][C:21]1[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=1[CH2:19][S:13][C:11]1[NH:10][C:9]2[CH:14]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[C:6]([O:15][CH3:16])=[CH:7][C:8]=2[N:12]=1
Reactant: Nc1ccccc1CCl
Reactant: COC(=O)c1cc2[nH]c(S)nc2cc1OC
Agent: Cl
Product: COC(=O)c1cc2[nH]c(SCc3ccccc3N)nc2cc1OC

Procedure:
To a mixture of 29.0 g (0.16 mole) of methyl-4-amino-2-methoxybenzoate, 0.5 g of 4-dimethylaminopyridine, and 16.0 gm (0.16 mole) of triethylamine in 500 ml of dichloromethane was added in batches 22 ml (ca. 0.23 mole) of acetic acid. After two hours the reaction mixture was neutralized with sodium bicarbonate (in solution and as a solid). The organic phase was washed successively with aqueous sodium bicarbonate. The organic phase was washed successively with aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. Recrystallization from toluene gave 30 g of methyl-4-acetamido-2-methoxybenzoate. To 100 ml of fuming nitric acid, stirred at −40° C., was slowly added 22.3 g (0.10 mole)of the acetylated intermediate. After about twenty minutes the mixture was warmed to 0° C. and stirred for another twenty minutes. The mixture was poured onto one liter of ice and the resultant precipitate was collected. Recrystallization from toluene/ethanol gave 14.2 g of the nitrated and deacetylated compound, methyl-4-amino-2-methoxy-5-nitrobenzoate. (Under similar conditions in which the acetyl group is not removed, saponification with methanolic sodium hydroxide gives the same product.) Hydrogenation of the nitro intermediate in tetrahydrofuran using Raney nickel as catalyst gave methyl-4,5-diamino-2-methoxybenzoate. A mixture of 4.83 g (24.6 mmole) of the diamine and 7.08 g (49.2 mmole) of potassium ethylxanthate was heated at reflux under argon in 40 ml of water. The resultant product mixture was chromatographed on silica gel to give 1.5 g of methyl-2-mercapto-5-methoxy-1H-benzimidazole-6-carboxylate. (Analysis. Calc'd. for C10H10N2O3S: C, 50.41; H, 4.23; N, 11.76; S, 13.46. Found: C, 50.30; H, 4.19; N, 11.71; S, 13.12.) The title compound was then prepared by the method of Example 1 using 1.19 g (5.0 mmole) of methyl-2-mercapto-5-methoxy-1H-benzimidazole-6-carboxylate instead of 2-mercaptobenzimidazole and 0.97 g (5.5 mmole)of 2-(chloromethyl)aniline hydrochloride instead of 2-(chloromethyl)-N,N-dimethylaniline. Analysis. Calc'd. for C17H17N3O3S*2HCl: C, 49.05; H,4.60; N, 10.09; S, 7.70; C1, 17.03. Found: C, 49.37; H, 4.77; N, 9.72; S, 7.43; C1, 16.77.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:11][NH2:12])=[S:10])=[CH:5][CH:4]=1.[C:13]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:16])[CH:14]=O>CO>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[S:10][CH:14]([C:13]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[NH:12][N:11]=2)=[CH:7][CH:8]=1
Reactant: CSc1ccc(C(=S)NN)cc1
Reactant: CC(C)(C)OC(=O)C=O
Solvent: CO
Product: CSc1ccc(C2=NNC(C(=O)OC(C)(C)C)S2)cc1

Procedure:
The product of step d) (3.0 g) was stirred at room temperature under nitrogen with t-butyl glyoxylate (2.0 g) in methanol (100 ml) for 18 hours. The mixture was evaporated and the residue purified by flash chromatography (ether/petroleum ether 1:3) to afford the sub-title compound (3.9 g) as a pale yellow solid. mp 71°-72°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[Cl:15])[O:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.[CH:16]([CH:18]1[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19]1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>O1CCCC1.C(O)(=O)C>[NH3:9].[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[Cl:15])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:16][CH:18]2[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[CH2:19]2)[CH2:8][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCCC(C=O)C1
Reactant: Clc1ccc(OC2CCNCC2)cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCCC(CN2CCC(Oc3ccc(Cl)c(Cl)c3)CC2)C1
Product: N
Reaction time: 0.17 h

Procedure:
4-(3,4-Dichlorophenoxy)piperidine (1 g) and 1,1-dimethylethyl 3-formyl-1-piperidinecarboxylate (Bioorg. Med. Chem. Lett., 1998, 8, 1595) were combined in tetrahydrofuran (4 ml) at 0° C., acetic acid (0.25 ml) was added and the mixture was stirred for 10 min, then at RT for 5 min. Sodium triacetoxyborohydride (1.25 g) was added in two portions and the resulting mixture was stirred for 16 h. Sodium hydroxide solution (2M) was added to neutralize the acid. The mixture was extracted with diethyl ether, the extracts were dried, filtered and evaporated to give an oil which was chromatographed eluting with dichloromethane:methanol:aqueous ammonia (97:2:1) to give the subtitle compound (1.63 g).
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:10][CH2:11][NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].[Li+].[OH-]>C1COCC1.CO.O>[CH3:18][C:16]([CH3:19])([O:15][C:13]([NH:12][CH2:11][CH2:10][C:5]1([C:3]([OH:4])=[O:2])[CH2:6][CH2:7][CH2:8][CH2:9]1)=[O:14])[CH3:17]
Reactant: COC(=O)C1(CCNC(=O)OC(C)(C)C)CCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NCCC1(C(=O)O)CCCC1
Temperature: 50 °C
Reaction time: 2.5 h

Procedure:
To a solution of the 1-[2-[[(1,1-dimethylethoxy)carbonyl]amino]ethyl]cyclopentane carboxylic acid methyl ester (10.6 g, 39.0 mmol) in THF/MeOH (3:1, 40 mL) was added a solution of LiOH (4.20 g, 98.0 mmol) in water (10 mL). The mixture was stirred for 2.5 h at 50° C. and then cooled to room temperature. The reaction mixture was poured into a round bottom flask and concentrated in vacuo. The mixture was diluted with H2O (60 mL) and acidified with 1M HCl. The aqueous phase was extracted with ethyl acetate (3×200 mL) and the combined organic layer was dried over MgSO4, filtered and concentrated in vacuo. Purification by flash column chromatography, using hexane-ethyl acetate (3:1), afforded 5.80 g (58%) as a white powder. HR MS (C13H23NO4): Calcd mass, 258.1705. Obs mass, 258.1700 [(M+H).
Reaction SMILES: Br[CH2:2][C:3]([OH:5])=[O:4].[H-].[Na+].[C:8]([C:10]1[CH:23]=[CH:22][C:13]([CH2:14][N:15]2[C:19]([CH2:20][OH:21])=[CH:18][N:17]=[CH:16]2)=[CH:12][CH:11]=1)#[N:9].O>C1COCC1.CCOC(C)=O>[C:8]([C:10]1[CH:23]=[CH:22][C:13]([CH2:14][N:15]2[C:19]([CH2:20][O:21][CH2:2][C:3]([OH:5])=[O:4])=[CH:18][N:17]=[CH:16]2)=[CH:12][CH:11]=1)#[N:9]
Reactant: O=C(O)CBr
Reactant: N#Cc1ccc(Cn2cncc2CO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#Cc1ccc(Cn2cncc2COCC(=O)O)cc1

Procedure:
A solution of 2-bromoacetic acid in THF at room temperature is treated with excess sodium hydride for 15 minutes. To this mixture is added 1-(4-cyanobenzyl)-5-(hydroxymethyl)imidazole (Example 1) and the mixture is then heated. Upon cooling, the mixture is poured into H2O and EtOAc, extracted with EtOAc (3×), washed with brine, dried (MgSO4), filtered and evaporated to give the desired compound.
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4]2)[CH2:2]1.[CH3:14][NH:15][CH3:16]>>[CH3:14][N:15]([CH2:2][C:3]1([OH:1])[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4]1)[CH3:16]
Reactant: CNC
Reactant: CCOC(=O)N1CCC2(CC1)CO2
Product: CCOC(=O)N1CCC(O)(CN(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5.2 g (28 mmol) of ethyl 6-aza-1-oxaspiro[2,5]octane-6-carboxylate are added dropwise to 30 ml of dimethylamine solution (40% in water) and the mixture is stirred overnight at room temperature. It is then concentrated and distilled.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:17]=[N:16][CH:15]=[CH:14][C:10]=2[C:11](O)=[O:12])=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:22]>>[I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:17]=[N:16][CH:15]=[CH:14][C:10]=2[C:11]([NH2:22])=[O:12])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Product: NC(=O)c1ccncc1Nc1ccc(I)cc1

Procedure:
3-(4-iodo-phenylamino)-isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.2 mmol of 3-(4-iodophenyl)amino-isonicotinic acid and 0.4 mmol of ammonium acetate. LC/MS [5.03 min; 340 (M+1)]
Reaction SMILES: CC1C=CC=C(C)N=1.[N+](C1C=CC(C=O)=CC=1)([O-])=[O:10].[N+:20]([C:23]1[CH:47]=[CH:46][C:26]([CH:27]=[CH:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]=[CH:36][C:37]3[CH:42]=[CH:41][C:40]([N+:43]([O-:45])=[O:44])=[CH:39][CH:38]=3)[N:30]=2)=[CH:25][CH:24]=1)([O-:22])=[O:21].ClC1C=CC=C(C(OO)=O)C=1>ClCCl>[N+:20]([C:23]1[CH:47]=[CH:46][C:26]([CH:27]=[CH:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]=[CH:36][C:37]3[CH:42]=[CH:41][C:40]([N+:43]([O-:45])=[O:44])=[CH:39][CH:38]=3)[N+:30]=2[O-:10])=[CH:25][CH:24]=1)([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1ccc(C=Cc2cccc(C=Cc3ccc([N+](=O)[O-])cc3)n2)cc1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: O=[N+]([O-])c1ccc(C=Cc2cccc(C=Cc3ccc([N+](=O)[O-])cc3)[n+]2[O-])cc1

Procedure:
More specifically, the synthesizing procedure is as follows. 2,6-dimethylpyridine or a substituted product thereof, is reacted with p-nitrobenzenealdehyde or a substituted product according to a method described, for example, in Journal of Organic Chemistry, vol. 15, P. 1184 (1950) to synthesize 2,6-di(p-nitrostyryl)pyridine (K). 30 g of this nitro compound is reacted wtih 27 g of m-chloroperbenzoic acid in three liter of dichloromethane to obtain 24 g of 2,6-di(p-nitrostyryl)pyridine-N-oxide. 24 g of this pyridine-N-oxide is reacted with 90 g of sodium sulfide in a solution mixed four liter of water with four liter of ethanol to reduce nitro group selectively and form 18 g of 2,6-di(p-aminostyryl)pyridine-N-oxide (M). The N-oxide amino compound is converted into a diazo compound according to a conventional method, and thereby tetrazonium salt is isolated as 15 g of hydroborofluoric salt (N). 5.0 g of the tetrazonium salt (N) and 5.0 g of 2-hydroxy-3-phenylcarbamoylnaphthalene (O) were dissolved in one liter of DMF, to which aqueous sodium acetate solution (7 g/100 ml) was added to perform coupling reaction. After two hours of stirring, the resultant crystals were separated by filtration, and the crystals were rinsed three times respectively with five liter water, three times respectively with five liter THF, then dried, to obtain 4.0 g of the final product, azo compound (P - 1).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])[CH3:3].Br[CH:18]([CH2:24][CH2:25][CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20].[OH-].[K+]>CC(C)=O>[CH3:4][C:2]([C:5]1[CH:10]=[C:9]([S:11][CH:18]([CH2:24][CH2:25][CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:1])[CH3:3]
Reactant: CCCC(Br)C(=O)OCC
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CCCC(Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2,6-bis(1,1-dimethylethyl)-4-mercaptophenol (2.38 g, 0.01 mole) and ethyl 2-bromopentanoate (2.09 g, 0.01 mole) in acetone (100 ml) was added potassium hydroxide flakes (1.68 g, 0.03 mole) The mixture was stirred at room temperature for one hour and then concentrated in vacuo to an oil. The oil was added to water (50 ml) and extracted with diethyl ether, dried over sodium sulfate, filtered, and concentrated in vacuo to an oil. Chromatography on silica gel gave the title compound.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:16]1[C:21](=[O:22])[CH2:20][CH2:19][CH2:18][C:17]=1[NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=1)[C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][C:5]=1[S:12]([CH3:15])(=[O:14])=[O:13].[C:34](N1C=CN=C1)(N1C=CN=C1)=[O:35].C(N(CC)CC)C>C(#N)C>[O:35]=[C:34]1[NH:2][CH:3]([C:4]2[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][C:5]=2[S:12]([CH3:15])(=[O:14])=[O:13])[C:16]2[C:21](=[O:22])[CH2:20][CH2:19][CH2:18][C:17]=2[N:23]1[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:31])[F:32])[CH:25]=1
Reactant: CS(=O)(=O)c1cc(C#N)ccc1C(N)C1=C(Nc2cccc(C(F)(F)F)c2)CCCC1=O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1cc(C#N)ccc1C1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)CCC2
Temperature: 25 °C

Procedure:
To a solution of 4-{amino-[6-oxo-2-(3-trifluoromethyl-phenylamino)-cyclohex-1-enyl]-methyl}-3-methanesulfonyl-benzonitrile hydrochloride (INTERMEDIATE 17, 529 mg, 0.95 mmol) in acetonitrile (5.0 mL) is added 1,1′-carbonyldiimidazole (192 mg, 1.19 mmol) and triethylamine (33 μL, 0.24 mmol). After stirring at room temperature over night, the reaction mixture is concentrated under reduced pressure. The residue is treated with water and the precipitate is filtered off, washed with water and dried. Yield: 468 mg. ESI mass spectrum: [M+H]+=490; Retention time HPLC: 0.57 min (X012_S01).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:8]=1)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[N:6][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:8]=1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)n1cc([N+](=O)[O-])cn1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)n1cc(N)cn1
Yield: 95.7 %

Procedure:
A solution of tert-butyl 4-nitro-1H-pyrazole-1-carboxylate (1.0 g, 4.7 mmol) in MeOH (120 ml) was passed through the H-Cube with full hydrogen mode at 60° C. and 1 bar with a 10% Pd/C cartridge using 1 ml/min flow rate. The solution was then passed through the H-Cube for a second time using identical conditions and the solvent removed in vacuo to afford tert-butyl 4-amino-1H-pyrazole-1-carboxylate (0.82 g, 4.5 mmol, 95%). 1H NMR (DMSO) δ 1.54 (9H, s), 4.42 (2H, s), 7.33 (1H, s), 7.35 (1H, s). LCMS (2) Rt: 1.45 min; m/z (ES+) 206 M+Na+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][CH2:27][C@H:26]([NH:30]C(=O)OC(C)(C)C)[CH2:25]2)=[N:22][CH:23]=1.[Cl:38][C:39]1[CH:44]=[C:43](B2OC(C)(C)C(C)(C)O2)[CH:42]=[C:41]([Cl:54])[C:40]=1[OH:55]>>[NH2:30][C@H:26]1[CH2:27][CH2:28][CH2:29][N:24]([C:21]2[N:22]=[CH:23][C:18]([NH:17][C:5]3[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([C:43]5[CH:44]=[C:39]([Cl:38])[C:40]([OH:55])=[C:41]([Cl:54])[CH:42]=5)[CH:3]=4)[N:8]=[CH:7][C:6]=3[C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])=[CH:19][CH:20]=2)[CH2:25]1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)C1
Product: N[C@H]1CCCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(-c5cc(Cl)c(O)c(Cl)c5)cc34)cn2)C1
Yield: 31.1 %

Procedure:
Following general procedure D, (S)-tert-butyl 1-(5-(6-bromo-3-(cyclopropanecarbonyl)quinolin-4-ylamino)pyridin-2-yl)piperidin-3-ylcarbamate (100 mg, 0.17 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (75 mg, 0.26 mmol) to obtain the protected intermediate which was subjected to general procedure A-2 to afford the desired product (29 mg, 31% over 2 steps) as a light orange solid: 1H NMR (500 MHz, MeOD+TFA-d) δ 9.40 (br s, 1H), 8.25-8.19 (m, 2H), 8.11 (br s, 1H), 8.01 (d, J=8.8 Hz, 1H), 7.65 (dd, J=9.1, 2.8 Hz, 1H), 7.32 (s, 2H), 7.7 (d, J=9.1 Hz, 1H), 4.53 (br s, 1H), 4.00 (dt, J=12.8, 4.0 Hz, 1H), 3.39-3.23 (m, 3H), 2.86 (br s, 1H), 2.22-2.12 (m, 1H), 1.98-1.88 (m, 1H), 1.78-1.64 (m, 2H), 1.26-1.16 (m, 4H). ESI MS m/z 548 [C29H27Cl2N5O2+H]+; HPLC>99.0% (AUC), tR=10.97 min.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH2:21][CH2:20][CH2:19][N:11]3[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:29][O:30][CH2:31]Br>C(Cl)Cl>[CH3:29][O:30][CH2:31][S:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[CH2:21][CH2:20][CH2:19][N:11]3[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: Sc1ccc(-c2nc3n(c2-c2ccncc2)CCC3)cc1
Reactant: COCBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCSc1ccc(-c2nc3n(c2-c2ccncc2)CCC3)cc1
Temperature: 25 °C

Procedure:
To an ice-bath cooled solution containing 1.0 g (3.4 mmole) of 2-(4-mercaptophenyl)-3-(4-pyridyl)-6,7-dihydro-[5H]-pyrrolo[1,2 -a]imidazole prepared as in Example 16 and 0.5 ml (3.6 mmole) of triethylamine in 10 ml of methylene chloride is added 0.27 ml (3.5 mmole) of bromomethyl methyl ether. The reaction is allowed to warm to room temperature and stirred at room temperature for several hours. Workup and chromatography in a manner analogous to that outlined in example 18 affords the desired titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:20]=3)=[C:15]([C:29]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=O)[CH:14]=2)=[CH:11][C:10]([C:37]([F:40])([F:39])[F:38])=[N:9]1.CO>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([S:25]([CH3:28])(=[O:26])=[O:27])[CH:20]=3)=[C:15]([CH2:29][N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[CH:14]=2)=[CH:11][C:10]([C:37]([F:38])([F:39])[F:40])=[N:9]1
Reactant: CS(=O)(=O)c1cccc(-c2ccc(-c3cc(C(F)(F)F)nn3-c3ccccc3Cl)cc2C(=O)N2CCOCC2)c1
Solvent: C1CCOC1
Solvent: CO
Product: CS(=O)(=O)c1cccc(-c2ccc(-c3cc(C(F)(F)F)nn3-c3ccccc3Cl)cc2CN2CCOCC2)c1
Temperature: 20 °C
Reaction time: 8 h
Yield: 44.5 %

Procedure:
To a solution of BH3 (1 M, 4 mL) in THF was added (4-(1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-3′-(methylsulfonyl)biphenyl-2-yl)(morpholino)-methanone (4.60 mg, 0.78 mmol) and the solution was stirred overnight at 20° C. MeOH was added to quench borane and solvent was evaporated to afford a crude, which was purified by column chromatography on silica gel eluting with MeOH-DCM (1:19) to afford 4-((4-(1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-3′-(methylsulfonyl)biphenyl-2-yl)methyl)morpholine (0.2 g). 1H-NMR (CDCl3): δ 8.25 (m, 1H), 7.93 (m, 1H), 7.72 (m, 1H), 7.60 (m, 1H), 7.55 (m, 1H), 7.49-7.39 (m, 3H), 7.33-7.26 (m, 2H), 7.18 (m, 1H), 6.85 (s, 1H), 3.58 (m, 4H), 3.16 (s, 3H), 3.07 (s, 3H), 2.14 (m, 4H). MS(ES): 576 [M+H]+.