Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:5]1[C:14](=[O:15])[C:13]2[C:8](=[N+:9]([O-])[CH:10]=[C:11]([N+:16]([O-:18])=[O:17])[CH:12]=2)[C:6]1=[O:7])([CH3:4])([CH3:3])[CH3:2].P(Cl)(Cl)([Cl:22])=O>>[C:1]([N:5]1[C:14](=[O:15])[C:13]2[C:8](=[N:9][C:10]([Cl:22])=[C:11]([N+:16]([O-:18])=[O:17])[CH:12]=2)[C:6]1=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N1C(=O)c2cc([N+](=O)[O-])c[n+]([O-])c2C1=O
Reactant: O=P(Cl)(Cl)Cl
Product: CC(C)(C)N1C(=O)c2cc([N+](=O)[O-])c(Cl)nc2C1=O

Procedure:
100 ml of phosphoryl chloride were treated with 7.5 g (0.028 mol) of N-tert-butyl-5-nitropyridine-2,3-dicarboximide-1-oxide at 60° C. and in portions in the course of 2 minutes with stirring and the mixture was stirred under reflux for 2 hours. The reaction mixture was concentrated under reduced pressure, the residue was taken up in methylene chloride and the solution was stirred into ice-water. The organic phase was extracted in succession with water, saturated sodium hydrogencarbonate and sodium chloride solution and dried. After filtering off with suction through neutral alumina, it was concentrated and the residue was stirred with ether and ether/pentane, filtered off with suction and dried. 4.49 g (56% of theory) of the title compound of m.p. 100-104° C. were obtained (active compound Example 1.019).
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[N:14][N:13]3[CH:16]=[CH:17][N:18]=[C:12]3[CH:11]=2)=[CH:6][CH:5]=1.C([O-])(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(OCC)(=O)C>[Br:1][C:16]1[N:13]2[N:14]=[CH:15][C:10]([C:7]3[CH:6]=[CH:5][C:4]([F:3])=[CH:9][CH:8]=3)=[CH:11][C:12]2=[N:18][CH:17]=1
Reactant: BrBr
Reactant: Fc1ccc(-c2cnn3ccnc3c2)cc1
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Fc1ccc(-c2cnn3c(Br)cnc3c2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Bromine (0.12 mL, 2.34 mmol) was added dropwise to a stirred mixture of 7-(4-fluorophenyl)imidazo[1,2-b]pyridazine (500 mg, 2.34 mmol) and sodium acetate (289 mg, 3.52 mmol) in Acetic Acid (12 mL) and the mixture was stirred at room temperature for 1 h. The mixture was poured into ethyl acetate and aqueous sodium hydrogen carbonate (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organics were washed with water, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography to afford the title compound as a white solid. 1H NMR (500 MHz, CD3SOCD3) δ 9.10 (d, 1H); 8.49 (d, 1H); 7.98 (dd, 2H); 7.96 (s, 1H); 7.38 (t, 2H). LRMS (APCI) calc'd for (C12H8BrFN3) [M+H]+, 292.0. found 292.0.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][NH2:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:31]([C:33]1[CH:34]=[C:35]([S:39](Cl)(=[O:41])=[O:40])[CH:36]=[CH:37][CH:38]=1)#[N:32]>ClCCl>[C:31]([C:33]1[CH:34]=[C:35]([S:39]([NH:23][CH2:22][C:16]2([C:13]3[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:11][CH:12]=3)[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)(=[O:41])=[O:40])[CH:36]=[CH:37][CH:38]=1)#[N:32]
Reactant: NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1cccc(S(=O)(=O)NCC2(c3ccc(OCCCN4CCCC4)cc3)CCOCC2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of {4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-yl}methylamine (100 mg, 0.314 mmol) and triethylamine (0.1 mL, 0.63 mmol) in anhydrous dichloromethane (3 mL) under nitrogen atmosphere at 0° C. was added 3-cyanobenzenesulfonylchloride (100 mg, 0.47 mmol). The reaction mixture was stirred for 2 h allowing it to warm up to room temperature. It was then diluted with dichloromethane and quenched with water. The organic layer was separated and washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with DCM:MeOH (95:5 to 90:10) to give the title compound. 1H NMR (400 MHz, CDCl3) δ7.97 (s, 1H), 7.93-7.91 (d, 1H), 7.83-7.81 (d, 1H), 7.62-7.58 (m, 1H), 7.11-7.09 (d, 2H), 6.89-6.86 (d, 2H), 4.06-4.03 (m, 3H), 3.77-3.72 (m, 2H), 3.56-3.51 (m, 2H), 3.08 (br s, 2H), 2.70-2.67 (m, 2H), 3.08 (br s, 4H), 2.08-2.01 (m, 4H), 1.85-1.82 (m, 6H).
Reaction SMILES: [F:1][CH:2]([F:32])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH:11]=[C:10]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[C:29]([O:30][CH3:31])[C:5]=2[N:4]=1.C([O-])([O-])=O.[K+].[K+].[CH3:39][S:40](Cl)(=[O:42])=[O:41].O>C(Cl)Cl>[F:32][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:9]=[C:10]([N:20]3[CH2:25][CH2:24][N:23]([S:40]([CH3:39])(=[O:42])=[O:41])[CH2:22][CH2:21]3)[CH:11]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:13]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[C:29]([O:30][CH3:31])[C:5]=2[N:4]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCNCC2)cc(N2CCOCC2)n1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)cc(N2CCN(S(C)(=O)=O)CC2)n1
Temperature: 25 °C
Yield: 67.2 %

Procedure:
A solution of 0.223 g (0.5 mmol) of 2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(1-piperazinyl)-2-pyrimidinyl]-1H-benzimidazole (WO 2008/032064) and 0.345 g (2.5 mmol) of powdered K2CO3 in 20 mL CH2Cl2 was cooled to 0° C., and 0.086 g (0.75 mmol) of methanesulfonyl chloride was added. The reaction mixture was allowed to warm to room temperature, and after stirring overnight water was added. The organic layer was separated, washed successively with aqueous acetic acid and aq. ammonia, and dried. Chromatography on silica, eluting with CH2Cl2/EtOAc (4:1) gave 0.176 g (67% yield) of 2-(difluoromethyl)-4-methoxy-1-[4-[4-(methylsulfonyl)-1-piperazinyl]-6-(4-morpholinyl)-2-pyrimidinyl]-1H-benzimidazole: mp (MeOH) 273-274° C.; 1H NMR (CDCl3) δ7.74 (dd, J=8.4, 0.6 Hz, 1H), 7.38 (t, JHF=53.5 Hz, 1H), 7.33 (t, J=8.2 Hz, 1H), 6.79 (t, J=7.6 Hz, 1H), 5.54 (s, 1H), 4.05 (s, 3H), 3.83-3.79 (m, 8H), 3.64 (m, 4H), 3.35 (m, 4H), 2.82 (s, 3H); Anal. Calcd. for C22H27F2N7O4S: C, 50.5; H, 5.2; N, 18.7. Found: C, 50.7; H, 5.3; N, 18.75%.
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].Br[CH2:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([N:4]([CH:9]=[C:10]1[CH:11]=[CH:12][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:18][CH2:19]1)[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3]
Reactant: CCCNCCC
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCN(C=C1C=CC(C(=O)OC)=CC1)CCC

Procedure:
1.37 cm3 of N,N-di-n-propylamine are added to a suspension of 2.29 g of methyl 4-(bromomethyl)benzoate and 1.52 g of potassium carbonate in 40 cm3 of acetonitrile, at a temperature close to 20° C. The reaction mixture is heated under reflux for about 16 hours, and then after cooling to a temperature close to 20° C., it is filtered on sintered glass. The sintered glass is rinsed with 3 times 30 cm3 of ethyl acetate. The filtrate is concentrated to dryness under reduced pressure at a temperature close to 40° C. After dissolution of the residue in 100 cm3 of ethyl acetate, the organic phase is successively washed with 3 times 100 cm3 of distilled water, 100 cm3 of a saturated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated to dryness under reduced pressure (about 1 kPa) at a temperature close to 40° C. 2.5 g of methyl 4-(N,N-di-n-propylaminomethylene)benzoate are thus obtained in the form of a yellow oil.
Reaction SMILES: [CH3:1][CH:2]([CH3:38])[C@H:3]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]4SC(C5C=CC=CC=5)=CN=4)=[O:25])=[CH:19][CH:18]=3)=[CH:13][CH:14]=2)[C:9]1=[O:37])[C:4]([O:6][CH3:7])=[O:5].NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1.[Cl:64][C:65]1[CH:70]=[CH:69][C:68]([C:71]2[CH:75]=C(C(OCC)=O)[O:73][N:72]=2)=[CH:67][CH:66]=1>>[Cl:64][C:65]1[CH:66]=[CH:67][C:68]([C:71]2[CH:75]=[C:26]([C:24]([NH:23][C:20]3[CH:19]=[CH:18][C:17]([C:12]4[CH:11]=[C:10]5[C:15]([CH2:16][N:8]([C@@H:3]([CH:2]([CH3:1])[CH3:38])[C:4]([O:6][CH3:7])=[O:5])[C:9]5=[O:37])=[CH:14][CH:13]=4)=[CH:22][CH:21]=3)=[O:25])[O:73][N:72]=2)=[CH:69][CH:70]=1
Reactant: CCOC(=O)c1cc(-c2ccc(Cl)cc2)no1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ncc(-c5ccccc5)s4)cc3)cc2C1=O
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4cc(-c5ccc(Cl)cc5)no4)cc3)cc2C1=O
Yield: 48 %

Procedure:
The compound of example 617 was prepared analogous to the compound of example 611 by reaction of compound of example 6 with ethyl 3-(4-chlorophenyl)isoxazole-5-carboxylate.
Reaction SMILES: Cl.[OH:2][CH2:3][C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][N:5]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][CH2:19][O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1>C(#N)C>[O:22]1[CH2:23][CH2:24][CH2:25][CH2:26][CH:21]1[O:20][CH2:19][CH2:18][O:10][C:9]1[C:4]([CH2:3][OH:2])=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: BrCCOC1CCCCO1
Reactant: OCc1ncccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: OCc1ncccc1OCCOC1CCCCO1
Reaction time: 8 h
Yield: 86.2 %

Procedure:
A suspension of 85% pure 2-(hydroxymethyl)pyridin-3-ol hydrochloride (24.9 g, 130 mmol) and potassium carbonate (60 g, 434 mmol) in acetonitrile (200 mL) was heated at reflux for 15 minutes after which 2-(2-bromoethoxy)tetrahydro-2H-pyran (32.9 g, 160 mmol) was added in one portion and the heating was continued overnight. Solids were filtered off and the solvent was removed under reduced pressure and the resulting oil was chromatographed on a column of silica (100 mm, i.d.=60 mm) with CHCl3 as eluent followed by CHCl3/MeOH/NH4OH (95:5:0.2) to give 28.4 g (93%) of the title compound as a light brown oil. HRMS m/z calcd for C13H19NO4 (M)+ 253.1314. found 253.1326.
Reaction SMILES: Cl[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[S:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:10]=[N:9]1>C1(C)C=CC=CC=1>[N:5]([S:2]([O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:11]1[N:10]=[N:9][S:8][CH:12]=1)(=[O:4])=[O:3])=[C:6]=[O:7]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Oc1ccccc1-c1csnn1
Solvent: Cc1ccccc1
Product: O=C=NS(=O)(=O)Oc1ccccc1-c1csnn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.5 %

Procedure:
By the procedure of Example 1, 7.9 g of chlorosulfonyl isocyanate was reacted with 10 g of 2-(1,2,3-thiadiazol-4-yl)phenol [prepared by the procedure of U.S. Pat. No. 3,940,407] in 125 ml of dry toluene. The reaction mixture was stirred at 25° C. for 1 hour, then heated at 100° to 110° C. for 1 hour. The resulting solution was cooled to 25° C., filtered, and the filtrate was concentrated in vacuo to yield 14 g of the title compound as a crude oil. The IR showed an isocyanate absorption at 2220 cm-1.
Reaction SMILES: [O:1]=[C:2]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([C:23]23[CH2:32][CH:27]4[CH2:28][CH:29]([CH2:31][CH:25]([CH2:26]4)[CH2:24]2)[CH2:30]3)[CH:16]=1)[C:3]#[C:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11]C)=[O:10])=[CH:7][CH:6]=1.C1COCC1.[OH-].[Li+].Cl>O>[O:1]=[C:2]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([C:23]23[CH2:24][CH:25]4[CH2:31][CH:29]([CH2:28][CH:27]([CH2:26]4)[CH2:32]2)[CH2:30]3)[CH:16]=1)[C:3]#[C:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]([OH:11])=[O:10])=[CH:13][CH:14]=1
Reactant: COC(=O)c1ccc(C#CC(=O)c2ccc(OC)c(C34CC5CC(CC(C5)C3)C4)c2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)C#Cc2ccc(C(=O)O)cc2)cc1C12CC3CC(CC(C3)C1)C2

Procedure:
962 mg (2.2 mmol) of the above methyl ester (b) and 10 ml of THF were introduced into a round-bottomed flask and 283 mg (6.7 mmol) of lithium hydroxide were added. The reaction medium was heated at reflux for 5 hours and was then poured into water and acidified to pH 1 with concentrated hydrochloric acid. The organic phase was separated out after settling had taken place, dried over magnesium sulfate and evaporated. The solid obtained was triturated from hexane, filtered off and dried. 600 mg (85%) of the expected acid, having a melting point of 232°-4° C., were recovered.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:15]([OH:17])=O)[N:9]2[CH2:14][CH2:13][O:12][CH2:11][C:10]=12)=[O:5])[CH3:2].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[F:40][C:41]1[CH:46]=[CH:45][C:44]([C@H:47]([NH2:49])[CH3:48])=[CH:43][CH:42]=1>CN(C)C=O.O>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:15](=[O:17])[NH:49][C@@H:47]([C:44]2[CH:45]=[CH:46][C:41]([F:40])=[CH:42][CH:43]=2)[CH3:48])[N:9]2[CH2:14][CH2:13][O:12][CH2:11][C:10]=12)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(C(=O)O)n2c1COCC2
Reactant: C[C@@H](N)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(C(=O)N[C@H](C)c2ccc(F)cc2)n2c1COCC2
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 98 %

Procedure:
To a solution of 3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-6,8-dicarboxylic acid 8-ethyl ester (Comp. No. 5a) (6.09 g, 25.5 mmol) in dimethylformamide (60 ml) was added 1-hydroxybenzotriazole (3.785 g, 0.028 mol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (5.37 g, 28 mmol). The mixture was stirred for 90 min at 50° C., then (R)-1-(4-fluoro-phenyl)ethylamine (3.9 g, 28 mmol) was added and the mixture was stirred at 25° C. overnight. An excess of water was added, the solid which precipitated was filtered off, washed with a small amount of water to give 9.0 g (98%) of 6-[(R)-1-(4-fluoro-phenyl)-ethylcarbamoyl]-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid ethyl ester.
Reaction SMILES: [CH3:1][C:2]([O:41][CH2:42][C@@H:43]1[CH2:45][O:44]1)([CH3:40])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=3[F:24])[C:15]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[F:34])([C:25]#[N:26])[CH:14]([CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[NH:13]2)=[O:11])=[N:5]1.O.CC(C)=[O:49].Cl(O)(=O)(=O)=O>C(OCC)(=O)C>[OH:49][C@@H:43]([CH2:45][OH:44])[CH2:42][O:41][C:2]([CH3:40])([CH3:1])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=3[F:24])[C:15]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[F:34])([C:25]#[N:26])[CH:14]([CH2:35][C:36]([CH3:39])([CH3:37])[CH3:38])[NH:13]2)=[O:11])=[N:5]1
Reactant: CC(C)(C)CC1NC(C(=O)Nc2ccn(CC(C)(C)OC[C@@H]3CO3)n2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: CC(C)=O
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)CC1NC(C(=O)Nc2ccn(CC(C)(C)OC[C@@H](O)CO)n2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 42 %

Procedure:
A mixture of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid {1-[2-methyl-2-((S)-1-oxiranylmethoxy)-propyl]-1H-pyrazol-3-yl}-amide (51.2 mg, 0.078 mmol), water (2 mL), and acetone (10 mL) was cooled to 0° C., then a solution of 35% perchloric acid (0.1 mL) was added dropwise. The reaction was stirred an additional 0.5 h. Then an additional 1 mL of the 35% perchloric acid solution was added at 0° C., the reaction was allowed to warm to rt for 12 h. The mixture was then diluted with ethyl acetate and washed with sodium bicarbonate (sat'd). The organic phase was separated, dried over Na2SO4 and filtered. The mixture was then concentrated and purified by reverse phase chromatography (20-95% of ACN/water) to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid {1-[2-((S)-2,3-dihydroxy-propoxy)-2-methyl-propyl]-1H-pyrazol-3-yl}-amide (22.1 mg, 42%) as an white powder. HRMS (ES+) m/z Calcd for C33H39Cl2F2N5O4S+H [(M+H)+]: 678.2420. found: 078.2416; C33H39Cl2F2N5O4+[(Na+H)+]: 700.2239. found: 700.2235.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:20]3[C:21]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:22][CH:23]=[CH:24][C:19]=3[N:18]=[C:17]2[CH3:30])=[CH:11][CH:10]=1)#[N:2].[N-:31]=[N+:32]=[N-:33].[Na+].[Cl-].[NH4+]>CN(C=O)C>[CH3:30][C:17]1[N:16]([CH2:15][C:12]2[CH:11]=[CH:10][C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:1]3[NH:33][N:32]=[N:31][N:2]=3)=[CH:14][CH:13]=2)[C:20]2[C:21]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=1
Reactant: CCOC(=O)c1cccc2nc(C)n(Cc3ccc(-c4ccccc4C#N)cc3)c12
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc2nc(C)n(Cc3ccc(-c4ccccc4-c4nnn[nH]4)cc3)c12
Reaction time: 96 h

Procedure:
A mixture of ethyl 1-[(2'-cyanobiphenyl-4-yl)methyl]-2-methylbenzimidazole-7-carboxylate (2.5 g), sodium azide (3.9 g) and ammonium chloride (3.2 g) in DMF (30 ml) was stirred for 4 days at 110°-120° C. The reaction mixture was worked up according to the procedure described in Working Example 23 to give crystals. Recrystallization from ethanol afforded colorless prisms (1.36 g, 49%), m.p. 205°-206° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.ON1C(=O)N(O)C(=O)N(O)[C:11]1=[O:20].[O:21]=O>C([O-])(=O)C.[Co+2].C([O-])(=O)C.C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:11]([OH:20])=[O:21])=[CH:4][CH:3]=1.[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1
Reactant: O=O
Reactant: O=c1n(O)c(=O)n(O)c(=O)n1O
Agent: [Co+2]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Solvent: Cc1ccc(Cl)cc1
Product: O=C(O)c1ccc(Cl)cc1

Procedure:
A mixture of 0.380 g of 4-chlorotoluene, 0.027 g of hexahydro-1,3,5-trihydroxy-1,3,5-triazine-2,4,6-trione (5% by mole relative to 4-chlorotoluene), 5 g of acetic acid and 0.004 g of cobalt(II) acetate.4H2O was stirred at 100° C. in an atmosphere of oxygene gas (1 atm=0.1 MPa) for 14 hours. The resulting product in the reaction mixture was analyzed by gas chromatography and was found to yield 4-chlorobenzoic acid in 99% yield at 100% conversion of 4-chlorotoluene.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([Cl:15])[C:12]([O:16][CH2:17][CH2:18][CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=2)=[C:11]([Cl:31])[CH:10]=1)C1C=CC=CC=1.[H][H]>[C].[Pd].C(OCC)(=O)C>[Cl:31][C:11]1[CH:10]=[C:9]([OH:8])[CH:14]=[C:13]([Cl:15])[C:12]=1[O:16][CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:23][N:22]=1
Reactant: FC(F)(F)c1ccc(OCCCOc2c(Cl)cc(OCc3ccccc3)cc2Cl)nc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Oc1cc(Cl)c(OCCCOc2ccc(C(F)(F)F)cn2)c(Cl)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 89 %

Procedure:
A reaction vessel was charged with 0.5 g of 1 -benzyloxy-3,5-dichloro-4-(3-(5-trifluoromethylpyridin-2-yloxy)propyloxy)benzene and 50 ml of ethyl acetate, and the air in the vessel was- replaced with nitrogen. Then, 0.3 g of 10% palladium carbon was added, and the nitrogen in the vessel was replaced with hydrogen, followed by stirring at room temperature for 24 hours. The hydrogen in the vessel was replaced with nitrogen, after which the reaction mixture was filtered through Celite, and the filtrate was concentrated, which afforded 0.36 g of 3,5-dichloro-4-(3-(5-trifluoromethylpyridin-2-yloxy)propyloxy)phenol (92% yield).
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].CC(C)([O-])C.[K+].F[C:16]1[CH:17]=[C:18]([O:25][CH3:26])[CH:19]=[CH:20][C:21]=1[N+:22]([O-:24])=[O:23].Cl>C1COCC1.O>[CH2:7]([O:6][C:4](=[O:5])[CH:3]([C:1]#[N:2])[C:16]1[CH:17]=[C:18]([O:25][CH3:26])[CH:19]=[CH:20][C:21]=1[N+:22]([O-:24])=[O:23])[CH3:8]
Reactant: COc1ccc([N+](=O)[O-])c(F)c1
Reactant: CCOC(=O)CC#N
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(C#N)c1cc(OC)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 107.2 %

Procedure:
To an ice-cold solution of ethyl cyanoacetate (10.9 mL, 102.4 mmol) in anhydrous THF (170 mL) under N2 is added of potassium tert-butoxide (12.07 g, 107.5 mmol). The formed white suspension is stirred for 15 min then treated with 3-fluoro-4-nitroanisole [Halfpenny, P. R.; Horwell, D. C.; Hughes, J.; Hunter, J. C.; Rees, D. C. J. Med. Chem. (1990), 33, 286-91] (8.86 g, 51.2 mmol). The suspension is heated at reflux for 1.5 h. The solution is poured into H2O; and the aqueous mixture is acidified to pH 2 with concentrated HCl. The mixture is extracted three times with ether then the combined organic phases are dried (MgSO4) and concentrated to an oil that is pumped at 0.3 mm for 2 days. The oil is dissolved in dichloromethane and purified by flash silica gel chromatography eluting with dichloromethane. The product fractions are combined and concentrated to leave cyano-(5-methoxy-2-nitrophenyl)acetic acid ethyl ester (14.5 g) as a light yellow oil that is about 93-95% pure. 1H NMR (CDCl3): δ8.29 (1H, d, J=9.2 Hz), 7.22 (1H, d, J=2.7 Hz), 7.04 (1H, dd, J=9.2, 2.7 Hz), 5.69 (1H, s), 4.31 (2H, q, J=7.0 Hz), 1.34 (3H, t, J=7.2 Hz).
Reaction SMILES: Cl[C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=2)=[O:7])=[CH:4][N:3]=1.[NH2:20][NH2:21].O>C(O)(C)C>[C:16]([C:13]1[CH:14]=[CH:15][C:10]([CH2:9][NH:8][C:6](=[O:7])[C:5]2[CH:18]=[CH:19][C:2]([NH:20][NH2:21])=[N:3][CH:4]=2)=[CH:11][CH:12]=1)#[N:17]
Reactant: N#Cc1ccc(CNC(=O)c2ccc(Cl)nc2)cc1
Reactant: NN
Solvent: O
Solvent: CC(C)O
Product: N#Cc1ccc(CNC(=O)c2ccc(NN)nc2)cc1
Yield: 20.5 %

Procedure:
Combined 6-chloro-N-(4-cyanobenzyl)nicotinamide (500 mg, 1.840 mmol) and hydrazine (0.578 mL, 18.40 mmol) in isopropanol (5 mL) and heated at 90° C. for 5 h. The supernatant was decanted and concentrated in vacuo to give a white solid which was stirred vigorously with water (ca. 10 mL) for 2 hours, then was filtered and the solid dried to give the title compound (batch 1, 101 mg) as a pink solid. The fine solids from the reaction (after supernatant was removed) was stirred vigorously with water (ca. 10 mL) for 2 hours, then filtered and dried in the lyophilizer to give the title compound (batch 2, 179 mg) as a tan solid. Large solids from the reaction (after supernatant was removed) were crushed and stirred vigorously with water (10 mL) for 1 hour, then filtered and dried in the lyophilizer to give the title (batch 3, 135 mg) as a beige solid. The combined yield was 415 mg (84% yield). MS m/z 268 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[C:9]12(O)[CH2:18][CH:13]3[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]3)[CH2:10]1)[CH2:16]2.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>O>[C:9]12([S:8][C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=3)[CH2:18][CH:13]3[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]3)[CH2:10]1)[CH2:16]2
Reactant: Sc1ccc(Br)cc1
Reactant: OC12CC3CC(CC(C3)C1)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Brc1ccc(SC23CC4CC(CC(C4)C2)C3)cc1
Yield: 91.2 %

Procedure:
3.78 g (20 mmol) of p-bromothiophenol, 3.04 g (20 mmol) of 1-adamantanol and 10 ml of trifluoroacetic acid are stirred at ambient temperature for 8 hours and then poured into water. Sodium bicarbonate is added until the mixture is neutral at which time it is extracted with methylene chloride. The organic phase is dried and evaporated. After recrystallization in isooctane, 5.9 g of the expected product are obtained. Yield - 92%. Melting point: 121°-122° C.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][N:12]([CH3:23])[C:13]1[C:20]([F:21])=[CH:19][C:16]([C:17]#[N:18])=[C:15]([Cl:22])[N:14]=1)(C(C)(C)C)(C)C>C(O)C.Cl.O>[Cl:22][C:15]1[N:14]=[C:13]([N:12]([CH2:11][CH2:10][CH2:9][OH:8])[CH3:23])[C:20]([F:21])=[CH:19][C:16]=1[C:17]#[N:18]
Reactant: CN(CCCO[Si](C)(C)C(C)(C)C)c1nc(Cl)c(C#N)cc1F
Agent: Cl
Solvent: CCO
Solvent: O
Product: CN(CCCO)c1nc(Cl)c(C#N)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.6 %

Procedure:
A mixture of 6-[(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)(methyl)amino]-2-chloro-5-fluoronicotinonitrile (Example 310, 0.73 g, 2.04 mmol) in ethanol/HCl/water (95:1:4) (50 mL) was stirred at rt for 18 h, and then concentrated under reduced pressure. The residue was passed through a plug of silica gel with ethyl acetate as the eluent to give the product (0.5 g, 100%) as a waxy yellow solid. 1H NMR (400 MHz, CD3OD) δ 7.54 (d, 1H), 3.65 (dt, 2H), 3.54 (t, 2H), 3.18 (d, 3H), 1.85-1.77 (m, 2H).