Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:3]=1[CH2:4][NH:5][C:6]1[CH:11]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[N:9]=[CH:8][C:7]=1[CH2:25][C:26]([NH2:28])=[O:27].Br.Br[CH2:36][CH2:37][N:38]([CH2:41][CH3:42])[CH2:39][CH3:40].C(=O)([O-])[O-].[K+].[K+].C(N(CC)C=O)C>>[CH2:37]([N:38]([CH2:41][CH3:42])[CH2:39][CH2:40][N:22]1[CH2:21][CH2:20][N:19]([C:16]2[CH:17]=[CH:18][C:13]([NH:12][C:10]3[N:9]=[CH:8][C:7]([CH2:25][C:26]([NH2:28])=[O:27])=[C:6]([NH:5][CH2:4][C:3]4[CH:29]=[CH:30][CH:31]=[C:32]([F:33])[C:2]=4[F:1])[CH:11]=3)=[CH:14][CH:15]=2)[CH2:24][CH2:23]1)[CH3:36]
Reactant: NC(=O)Cc1cnc(Nc2ccc(N3CCNCC3)cc2)cc1NCc1cccc(F)c1F
Reactant: CCN(CC)CCBr
Agent: Br
Agent: CCN(C=O)CC
Agent: O=C([O-])[O-]
Product: CCN(CC)CCN1CCN(c2ccc(Nc3cc(NCc4cccc(F)c4F)c(CC(N)=O)cn3)cc2)CC1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 50.6 %

Procedure:
120 mg of 4-[(2,3-difluorobenzyl)amino]-6-{[4-(piperazin-1-yl)phenyl]amino}pyridine-3-carboxyamide (the compound of Example 220), 72 mg of 2-bromoethyl-N,N-diethylamine.hydrobromide and 72 mg of potassium carbonate were added to 2 mL of N,N-diethylformamide, and stirred at 70° C. for 1.5 hour. The solvent was evaporated, and the residue was dissolved in chloroform, washed with saturated saline, and dried on anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel thin layer chromatography (chloroform:ammonia methanol=10:1) to obtain 74 mg (60%) of the title compound as a light brown powder.
Reaction SMILES: [OH:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.[CH2:11]([C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:32]=[CH:31][C:25]([CH:26]=[CH:27][C:28](O)=[O:29])=[CH:24][CH:23]=2)=[CH:18][CH:17]=1)[CH2:12][CH2:13][CH2:14][CH3:15].Cl.C(N=C=NCCCN(C)C)C>ClCCl>[CH2:11]([C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:32]=[CH:31][C:25]([CH:26]=[CH:27][C:28]([N:4]3[C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=4[N+:2]([O-:1])=[N:3]3)=[O:29])=[CH:24][CH:23]=2)=[CH:18][CH:17]=1)[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCc1ccc(-c2ccc(C=CC(=O)O)cc2)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CCCCCc1ccc(-c2ccc(C=CC(=O)n3n[n+]([O-])c4ccccc43)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 42.9 %

Procedure:
To a suspension of 1-hydroxybenzotriazole (0.20 g) and 4-(4-pentylphenyl)cinnamic acid (0.40 g) in dichloromethane (12.0 ml) was added 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (0.33 g) (WSCD.HCl), and the mixture was stirred for 12 hours at ambient temperature. The reaction mixture was diluted with dichloromethane, and washed with brine, and dried over magnesium sulfate. After magnesium sulfate was filtered off, evaporation of the filtrate and trituration with acetonitrile gave 1-[4-(4-Pentylphenyl)cinnamoyl]benzotriazole 3-oxide (0.24 g).
Reaction SMILES: [S:1]([C:5]1[S:13][C:8]2=[CH:9][N:10]=[CH:11][CH:12]=[C:7]2[CH:6]=1)(=[O:4])(=[O:3])[NH2:2].CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>C(#N)C.C(Cl)(Cl)Cl>[CH3:16][N:17]([CH3:19])[CH:18]=[N:2][S:1]([C:5]1[S:13][C:8]2=[CH:9][N:10]=[CH:11][CH:12]=[C:7]2[CH:6]=1)(=[O:3])=[O:4]
Reactant: COC(OC)N(C)C
Reactant: NS(=O)(=O)c1cc2ccncc2s1
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: CN(C)C=NS(=O)(=O)c1cc2ccncc2s1
Reaction time: 2 h
Yield: 96.1 %

Procedure:
To a partial suspension of 2-sulfamoylthieno[2,3-c]pyridine (1.81 g, 8.5 mmol) in acetonitrile (20 ml), under a nitrogen atmosphere, was added dropwise dimethylformamide dimethyl acetal (1.3 ml, 9.7 mmol). After 2 hours, the mixture was diluted with chloroform, washed with water, dried over anhydrous sodium sulfate, filtered and evaporated to give 2.2 g of product. This material was recrystallized from ethyl acetate to give 2.05 g (90% yield); m.p. 169°-171° C. Analysis calculated for C10H11N3O2S2 : N, 15.60; C, 44.59, H, 4.12. Found: N, 15.79; C, 44.95; H, 4.08.
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:6][CH:5]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[Cl:21])[C:4]=1[C:22]([O:24][CH3:25])=[O:23].Cl.[NH:27]1[CH2:32][CH2:31][O:30][CH:29]([C:33]([OH:35])=[O:34])[CH2:28]1>>[Cl:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[CH:5]1[N:6]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[NH:8][C:3]([CH2:2][N:27]2[CH2:32][CH2:31][O:30][CH:29]([C:33]([OH:35])=[O:34])[CH2:28]2)=[C:4]1[C:22]([O:24][CH3:25])=[O:23]
Reactant: O=C(O)C1CNCCO1
Reactant: COC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Cl
Agent: Cl
Product: COC(=O)C1=C(CN2CCOC(C(=O)O)C2)NC(c2nccs2)=NC1c1ccc(F)cc1Cl
Yield: 40.4 %

Procedure:
Methyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (1.11 g, 2.5 mmol) was reacted with morpholine-2-carboxylic acid hydrochloride (0.5 g, 3 mmol) according to the procedure as described in Example 3 to give the title compound as a yellow solid (0.5 g, 40%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][C:15]=2[F:21])=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:23]1[C:32]2[C:27](=[CH:28][C:29]([O:35][CH3:36])=[C:30]([O:33][CH3:34])[CH:31]=2)[N:26]=[CH:25][N:24]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([O:20][C:23]3[C:32]4[C:27](=[CH:28][C:29]([O:35][CH3:36])=[C:30]([O:33][CH3:34])[CH:31]=4)[N:26]=[CH:25][N:24]=3)[CH:17]=[CH:16][C:15]=2[F:21])=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cc(O)ccc2F)no1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Oc3ccc(F)c(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OC
Temperature: 35 °C
Reaction time: 15 h
Yield: 7.6 %

Procedure:
To a stirred solution of 1-(5-tert-butylisoxazol-3-yl)-3-(2-fluoro-5-hydroxyphenyl)urea (200 mg, 0.68 mmol) and 4-chloro-6,7-dimethoxyquinazoline (153 mg, 0.68 mmol) in DMF (4 mL) at rt, was added potassium carbonate (188 mg, 1.36 mmol). The reaction mixture was stirred at 35° C. for 15 h. The mixture was poured into water, and the resulting brown solid was filtrated, washed with water, and dried to afford the crude product. Purification via reverse-phase preparative HPLC afforded 1-(5-tert-butylisoxazol-3-yl)-3-(5-(6,7-dimethoxyquinazolin-4-yloxy)-2-fluorophenyl)urea (25 mg, 8%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ 9.86 (brs, 1H), 8.85 (brs, 1H), 8.57 (s, 1H), 8.16 (m, 1H), 7.55 (s, 1H), 7.40-7.44 (m, 2H), 7.16 (m, 1H), 6.50 (s, 1H), 3.99 (s, 3H), 3.97 (s, 3H), 1.30 (s, 9H); LC-MS (ESI) m/z 482 (M+H)+.
Reaction SMILES: [F:1][C:2]1[N:9]=[C:8](F)[C:7]([F:11])=[CH:6][C:3]=1[C:4]#[N:5].C(N(CC)CC)C.[CH:19]([O:22][C:23]1[NH:27][N:26]=[C:25]([NH2:28])[CH:24]=1)([CH3:21])[CH3:20]>C(#N)C.O>[F:1][C:2]1[N:9]=[C:8]([NH:28][C:25]2[CH:24]=[C:23]([O:22][CH:19]([CH3:21])[CH3:20])[NH:27][N:26]=2)[C:7]([F:11])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CC(C)Oc1cc(N)n[nH]1
Reactant: N#Cc1cc(F)c(F)nc1F
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)Oc1cc(Nc2nc(F)c(C#N)cc2F)n[nH]1
Temperature: 0 °C
Reaction time: 1 h
Yield: 9 %

Procedure:
To a solution of 2,5,6-trifluoronicotinonitrile (3.0 g, 19.0 mmol) and triethylamine (2.5 g, 24.7 mmol) in ACN (30 ml) at 0° C. was added 5-isopropoxy-1H-pyrazol-3-amine (2.95 g, 20.9 mmol) in ACN (15 ml). The reaction was stirred at 0° C. for 1 hour, at which point the reaction was diluted with water (50 ml) and extracted with DCM (2×50 ml). The combined organic fractions were dried over Na2SO4, filtered, and then concentrated. The resulting oil was purified by column chromatography (DCM-MeOH=100:1) to give the title compound (0.48 g, 9%). MS: Calcd.: 279. Found: [M+H]+ 280.
Reaction SMILES: [C:1]1([C@@H:7]2[C:11]([CH3:13])([CH3:12])[O:10][C:9](=[O:14])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[C:20](Cl)(=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22].C(OCC)(=O)C>O1CCCC1>[CH3:22][C:21]([CH3:24])([CH3:23])[C:20]([N:8]1[C@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:11]([CH3:12])([CH3:13])[O:10][C:9]1=[O:14])=[O:25]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC1(C)OC(=O)N[C@@H]1c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)N1C(=O)OC(C)(C)[C@H]1c1ccccc1
Reaction time: 3 h
Yield: 57.4 %

Procedure:
Reaction of the auxiliary (15) (0.155 g, 0.81 mmol) in solution in tetrahydrofuran at -78° C. with butyllithium (1.0M, 0.819 ml, 0.821 mmol) and pivaloyl chloride (0.110 ml, 0.89 mmol) for 30 minutes and then at room temperature for 3 hours with work-up and flash column chromatography using 20% ethyl acetate/40-60 petroleum ether as eluant furnished the title compound (22) as an oil (0.128 g, 57%); νmax (CHCl3) 1687 and 1775 cm-3 ; [α]D25 (c 0.4 in CHCl3)=-60.3; (Found: C, 69.94; H, 7.84; N, 4.93. C16H21 NO3 requires C, 69.80; H, 7.69; N, 5.09%); δH (CDCl3 ; 300 MHz) 0.98 (3H, s, C(CH3)2), 1.39 (9H, s, C(CH3)3), 1.60 (3H, s, C(CH3)2), 5.11 (1H, s, CHPh), 7.14-7.37 (5H, m, ArCH; δC (125 MHz; CDCl3) 23.66 (CH3), 26.20 (CH3), 28.68 (CH3), 41.63 (C), 69.03 (CH), 81.80 (C), 126.10 (ArCH), 128.44 (ArCH), 128.85 (ArCH), 136.80 (C), 153.50 (CO), 178.00 (CO); m/z (CI+, NH3) 276 (M+ +1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][OH:17])[CH2:11][CH2:10]2)[CH:3]=1.[NH2:18][C:19]1[S:20][C:21]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][N:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.Cl>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[OH:17][CH2:16][CH2:15][N:12]1[CH2:13][CH2:14][N:9]([C:4]2[N:5]=[C:6]([CH3:8])[N:7]=[C:2]([NH:18][C:19]3[S:20][C:21]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][N:23]=3)[CH:3]=2)[CH2:10][CH2:11]1
Reactant: Cc1nc(Cl)cc(N2CCN(CCO)CC2)n1
Reactant: COC(=O)c1cnc(N)s1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Product: COC(=O)c1cnc(Nc2cc(N3CCN(CCO)CC3)nc(C)n2)s1
Yield: 75.3 %

Procedure:
2-(4-(6-chloro-2-methylpyrimidin-4-yl)piperazin-1-yl)ethanol (Compound 4) (25.7 g, 0.1 mol), methyl 2-aminothiazole-5-formate (Compound 5) (18.9 g, 0.12 mol), cesium carbonate (45.6 g, 0.14 mol), palladium acetate (2.2 g, 0.01 mol) and BINAP (6.2 g, 0.01 mol) were mixed with toluene (1100 mL) in reaction flask, and heated by stirring to reflux for 16 h. The reactant was cooled and 2 mol/L hydrochloric acid was added and stirred for 10 mins. After vacuum filtration the filtrate was phase-separated and the aqueous phase was extracted by toluene (500 mL). The separated aqueous phase was neutralized by NaOH solution (6 mol/L) at 10-15° C., and then grew the grains for 1 h. After vacuum filtration the cake was rinsed by water to give yellow solid target Compound 6 (28.5 g, yield: 75.2%).
Reaction SMILES: [OH-].[Na+].ClCCl.[C:6]([N:10]1[C:15](=[O:16])[C:14]([Br:17])=[C:13](Br)[CH:12]=[N:11]1)([CH3:9])([CH3:8])[CH3:7].[C:19]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27][SH:28])=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20]>O.[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C>[C:6]([N:10]1[C:15](=[O:16])[C:14]([Br:17])=[C:13]([S:28][CH2:27][C:26]2[CH:29]=[CH:30][C:23]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:24][CH:25]=2)[CH:12]=[N:11]1)([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)n1ncc(Br)c(Br)c1=O
Reactant: CC(C)(C)c1ccc(CS)cc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)c1ccc(CSc2cnn(C(C)(C)C)c(=O)c2Br)cc1
Reaction time: 10 h
Yield: 70 %

Procedure:
Sodium hydroxide 0.22 g was dissolved in 5 ml of water, and thereto were added 10 ml of dichloromethane, 1.55 g of 2-tert.-butyl-4,5-dibromo-3(2H)-pyridazinone and 0.05 g of triethylbenzylammonium chloride. The resulting solution was incorporated with 0.83 g of 4-tert.-butyl-benzyl mercaptan at room temperature and then stirred for 10 hours. After completion of the reaction, about 50 ml of CH2Cl2 was added to the solution and the organic layer was separated therefrom, washed with 5% aqueous solution of sodium hydroxide and then with water, and dried over anhydrous sodium sulfate. Solvent was distilled away therefrom under reduced pressure and the resulting solid residue was recrystallized from a benzene/n-hexane mixed solvent to obtain 1.32 g of the intended compound (yield: 65%).
Reaction SMILES: C([O:4][Si:5]([CH2:10][CH3:11])([CH2:8][CH3:9])[CH2:6][CH3:7])(=O)C.S[C:13]1[CH:18]=CN=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>>[CH2:6]([Si:5]([O:4][Si:5]([CH2:6][CH3:7])([CH2:8][CH3:9])[CH2:10][CH3:11])([CH2:18][CH3:13])[CH2:8][CH3:9])[CH3:7]
Reactant: CC[Si](CC)(CC)OC(C)=O
Reactant: Sc1ccncc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC[Si](CC)(CC)O[Si](CC)(CC)CC
Yield: 71 %

Procedure:
This solution of chloride (4) is mixed with 4-mercaptopyridine (2.45 g; 1.3 equivalents) and sodium carbonate (1.8 g; 1 equivalents) and concentrated in vacuum. The residue is dissolved in toluene, filtered to remove solid, and extracted with toluene. This is extracted with 2N-hydrochloric acid, mixed with sodium hydrogen carbonate, reextracted with toluene, and worked up as usual to give 4-pyridylsulfide (7) (7.87 g). Yield: 71%. IR (CHCl3)ν: 3100-2900, 1735, 1707, 1610, 1430 cm-1.
Reaction SMILES: [O-]CC.[Na+].[C:5]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:6][SH:7].[Cl:12][C:13]1[C:18]([C:19](OCC)=[O:20])=[C:17](Cl)[C:16]([CH3:25])=[C:15]([CH3:26])[N:14]=1.Cl>C(O)C>[Cl:12][C:13]1[C:18]2[C:19]([OH:20])=[C:6]([C:5]([O:9][CH2:10][CH3:11])=[O:8])[S:7][C:17]=2[C:16]([CH3:25])=[C:15]([CH3:26])[N:14]=1
Reactant: CCOC(=O)CS
Reactant: CCOC(=O)c1c(Cl)nc(C)c(C)c1Cl
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1sc2c(C)c(C)nc(Cl)c2c1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.5 %

Procedure:
A 20% solution (1.73 g, 5.08 mmol) of sodium ethoxide in ethanol was diluted with ethanol (5 mL), and ethyl thioglycolate (610 mg, 5.08 mmol) was added. Ethyl 2,4-dichloro-5,6-dimethylpyridine-3-carboxylate (630 mg, 2.54 mmol) was added to the mixture, and the mixture was stirred at room temperature for 18 hr. 2N Hydrochloric acid (3 mL) was added to the reaction mixture and the mixture was partitioned between brine and ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated. The obtained solid was washed with diisopropyl ether-hexane, and dried under reduced pressure to give the title compound (374 mg, 52%) as a white powder.
Reaction SMILES: [CH2:1]([N:3]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[N:14]=[N:15][C:16](Cl)=[CH:17][CH:18]=2)[CH:8]=1)[C:4](=[O:6])[CH3:5])[CH3:2].[CH3:20][NH:21][C:22](=S)[NH:23][NH2:24]>C(O)C>[CH2:1]([N:3]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]3[N:15]([C:22]([NH:21][CH3:20])=[N:23][N:24]=3)[N:14]=2)[CH:8]=1)[C:4](=[O:6])[CH3:5])[CH3:2]
Reactant: CNC(=S)NN
Reactant: CCN(C(C)=O)c1cccc(-c2ccc(Cl)nn2)c1
Solvent: CCO
Product: CCN(C(C)=O)c1cccc(-c2ccc3nnc(NC)n3n2)c1
Yield: 26.7 %

Procedure:
A solution of 7.0 g N-ethyl-N-[3-(6-chloro-3-pyridazinyl)phenyl]acetamide and 5.3 g 4-methyl thiosemicarbazide in 200 ml ethanol was refluxed for 18 hours. The mixture was worked up and the product chromatographed as described in Example 70. Recrystalization of the product fractions from dichloromethone-hexane afforded 2.1 g of yellow crystals, mp 193°-195° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:7][C:8]([C:27]([F:30])([F:29])[F:28])=[C:9]([C:25]#[N:26])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]#[N:24])=[CH:13][CH:12]=1)=[O:5])C.N>>[C:25]([C:9]1[C:10]([C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])=[CH:15][CH:16]=2)=[C:6]([C:4]([OH:5])=[O:3])[S:7][C:8]=1[C:27]([F:30])([F:28])[F:29])#[N:26]
Reactant: CCOC(=O)c1sc(C(F)(F)F)c(C#N)c1-c1ccc(-c2ccccc2C#N)cc1
Agent: N
Product: N#Cc1ccccc1-c1ccc(-c2c(C(=O)O)sc(C(F)(F)F)c2C#N)cc1

Procedure:
Using a method substantially in accordance with the method of example A-2, starting with the compound from example 4-cyano-3-(2′-cyano-biphenyl-4-yl)-5-trifluoromethyl-thiophene-2-carboxylic acid ethyl ester: 1H NMR (400 MHz, CDCl3) δ 7.57-7.20 (m, 8H), 19F NMR (CDCl3) δ-57.21 ppm (s), MS found (M−1) 397.0 and (M+1) +NH3 416.
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][C@H:10]([N:13]([CH:21]2[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH2:22]2)[C:14](=[O:20])[C:15]([CH3:19])([CH3:18])[CH:16]=[O:17])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:29][Mg]Br.Cl>C1COCC1>[C:1]([N:8]1[CH2:12][CH2:11][CH:10]([N:13]([CH:21]2[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH2:22]2)[C:14](=[O:20])[C:15]([CH3:19])([CH3:18])[CH:16]([OH:17])[CH3:29])[CH2:9]1)([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: C[Mg]Br
Reactant: CC1(C)CCC(N(C(=O)C(C)(C)C=O)[C@H]2CCN(C(=O)OC(C)(C)C)C2)CC1
Agent: Cl
Solvent: C1CCOC1
Product: CC(O)C(C)(C)C(=O)N(C1CCC(C)(C)CC1)C1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
To a solution of (3S)-1-Boc-3-[(4,4-dimethylcyclohexyl)(2,2-dimethyl-3-oxopropanoyl)amino]pyrrolidine (250 mg, 0.63 mmol) prepared in Step A of Example C3 in THF was slowly added dropwise methylmagnesium bromide (in diethylether, 3.0M, 0.25 ml, 0.76 mmol) at 0° C., and the solution was stirred at rt for 2 h. After the reaction finished, to the solution was added 1N-HCl at 0° C., and extracted with EtOAc. The organic layer was dried over MgSO4, concentrated in vacuo, and purified by column chromatography (eluent: EtOAc/Hex=1/2) to give the title compound (238 mg, 92%).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([N:13]2[CH2:17][CH2:16][CH:15]([S:18][CH2:19][C:20]([OH:22])=[O:21])[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.ClC1C=CC=C(C(OO)=[O:33])C=1>ClCCl>[F:24][C:2]([F:1])([F:23])[C:3]1[CH:4]=[C:5]([N:13]2[CH2:17][CH2:16][CH:15]([S:18]([CH2:19][C:20]([OH:22])=[O:21])=[O:33])[CH2:14]2)[CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:8]=1
Reactant: O=C(O)CSC1CCN(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=C(O)CS(=O)C1CCN(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1
Yield: 90.3 %

Procedure:
A solution of ({1-[3,5-bis(trifluoromethyl)phenyl]pyrrolidin-3-yl}sulfanyl)acetic acid (500 mg) obtained in Example 1 and m-chloroperbenzoic acid (321 mg) in dichloromethane (25 mL) was stirred at room temperature for 2 hr. The solvent was evaporated, and the residue was purified by preparative HPLC (instrument: Gilson Inc., High throughput purification system; column: YMC Combiprep ODS-A, S-5 μm, 50×20 mm; solvent: SOLUTION A; 0.1% trifluoroacetic acid-containing water, SOLUTION B; 0.1% trifluoroacetic acid-containing acetonitrile; gradient cycle: 0.00 min (SOLUTION A/SOLUTION B=90/10), 1.00 min (SOLUTION A/SOLUTION B=90/10), 4.20 min (SOLUTION A/SOLUTION B=10/90), 5.40 min (SOLUTION A/SOLUTION B=10/90), 5.50 min (SOLUTION A/SOLUTION B=90/10), and 5.60 min (SOLUTION A/SOLUTION B=90/10); flow rate: 25 mL/min; detection method: UV 220 nm) to give the title compound (471 mg, yield 90%).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH2:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1[Cl:19].N1C=CC=CC=1>C1COCC1>[Cl:19][C:18]1[CH:17]=[CH:16][N:15]=[CH:14][C:13]=1[NH:12][C:2](=[O:3])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Nc1cnccc1Cl
Reactant: O=C(Cl)OCc1ccccc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(Nc1cnccc1Cl)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 34 %

Procedure:
A solution of benzyl chloroformate (1.1 equiv.) in THF (1.85 M) was slowly added to a solution of 3-amino-4-chloropyridine (1.0 equiv.) and pyridine (1.5 equiv.) in THF (1.0 M) and stirred at rt for 3.5 hours (formation of a precipitate over time). The reaction was quenched with H2O (100 mL), extracted with EtOAc (200 mL), washed with NaCl(sat.) (75 mL), dried over MgSO4, filtered and the volatiles were removed in vacuo. The product precipitated from a mixture of hexane/EtOAc yielding benzyl 4-chloropyridin-3-ylcarbamate (34%). LCMS (m/z): 263.1 (MH+); LC Rt=2.33 min.
Reaction SMILES: [N+:1]([C:4]1[C:9]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:18][C:19]([O:21]CC)=[O:20])([O-:3])=[O:2].[OH-].[K+].O.Cl>CO>[N+:1]([C:4]1[C:9]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:18][C:19]([OH:21])=[O:20])([O-:3])=[O:2]
Reactant: CCOC(=O)Cc1cccc(Oc2ccccc2F)c1[N+](=O)[O-]
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)Cc1cccc(Oc2ccccc2F)c1[N+](=O)[O-]

Procedure:
A solution of ethyl 2-[2-nitro-3-(2-fluorophenoxy)phenyl]acetate in methanol (50 ml) was added to a solution of potassium hydroxide (20 g) in methanol (50 ml) with stirring under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. Water (700 ml) was added to the reaction mixture and the resultant aqueous solution was adjusted to pH 2.0 with conc. hydrochloric acid. The precipitating crystals were collected by filtration, washed with water and recrystallized from a mixture of ethyl acetate and n-hexane (1:1) to give 2-[2-nitro-3-(2-fluorophenoxy)phenyl]acetic acid (31.9 g). mp 144°-146° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([P:19]([CH2:24][CH2:25][CH3:26])([CH2:21][CH2:22][CH3:23])=[O:20])=[CH:15][CH:14]=2)[N:3]=1.[NH2:27][C:28]1[CH:29]=[CH:30][C:31]([C@H:39]2[CH2:44][CH2:43][C@H:42]([OH:45])[CH2:41][CH2:40]2)=[C:32]2[C:36]=1[C:35](=[O:37])[N:34]([CH3:38])[CH2:33]2>>[CH2:21]([P:19]([C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:27][C:28]3[CH:29]=[CH:30][C:31]([C@H:39]4[CH2:44][CH2:43][C@H:42]([OH:45])[CH2:41][CH2:40]4)=[C:32]4[C:36]=3[C:35](=[O:37])[N:34]([CH3:38])[CH2:33]4)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[CH:14][CH:15]=1)([CH2:24][CH2:25][CH3:26])=[O:20])[CH2:22][CH3:23]
Reactant: CCCP(=O)(CCC)c1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1
Reactant: CN1Cc2c(c(N)ccc2[C@H]2CC[C@H](O)CC2)C1=O
Product: CCCP(=O)(CCC)c1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc([C@H]4CC[C@H](O)CC4)c4c3C(=O)N(C)C4)n2)cc1

Procedure:
The title compound was prepared according to the procedure for Example 102 using 4-chloro-N-[4-(dipropylphosphoryl)phenyl]-5-(trifluoromethyl)pyrimidin-2-amine Compound 198A, (75.0 mg, 0.185 mmol) and 7-amino-4-(trans-4-hydroxycyclohexyl)-2-methyl-2,3-dihydro-1H-isoindol-1-one (48.1 mg, 0.185 mmol). The reaction mixture was concentrated in vacuo purified on an ISCO Combiflash unit (0-5% MeOH/DCM) to isolate the desired product as 66 mg of a white solid. 1H NMR (400 MHz, DMSO-d6) d 0.93 (t, J=7.33 Hz, 6H), 1.24-1.40 (m, 4H), 1.42-1.58 (m, 4H), 1.79 (d, J=12.88 Hz, 2H), 1.82-1.89 (m, 2H), 1.89-1.98 (m, 4H), 3.08 (s, 3H), 3.42-3.54 (m, 1H), 4.54 (s, 2H), 4.64 (br. s., 1H), 7.26 (br. s., 1H), 7.63-7.72 (m, 2H), 7.79 (d, J=6.57 Hz, 2H), 8.52 (s, 1H), 8.62 (br. s., 1H), 10.14 (s, 1H), 10.59 (br. s., 1H). MS (ES+): m/z=630.27 [MH+]. HPLC: tR=3.17 min (ZQ3, polar—5 min)
Reaction SMILES: C([O:5][CH2:6][C:7]([N:9]1[CH2:14][CH2:13][C:12]2[N:15]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=3[F:34])[N:16]=[C:17]([C:18]3[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=3)[C:21]#[N:22])[C:11]=2[CH2:10]1)=[O:8])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[F:34][C:28]1[CH:29]=[C:30]([F:33])[CH:31]=[CH:32][C:27]=1[CH2:26][N:15]1[C:12]2[CH2:13][CH2:14][N:9]([C:7](=[O:8])[CH2:6][OH:5])[CH2:10][C:11]=2[C:17]([C:18]2[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=2)[C:21]#[N:22])=[N:16]1
Reactant: CC(C)(C)OCC(=O)N1CCc2c(c(-c3cccc(C#N)c3)nn2Cc2ccc(F)cc2F)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cccc(-c2nn(Cc3ccc(F)cc3F)c3c2CN(C(=O)CO)CC3)c1
Yield: 60.9 %

Procedure:
A solution of 3-[5-(2-tert-Butoxy-acetyl)-1-(2,4-difluoro-benzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile (8d) (90 mg, 0.193 mmol) and trifluoroacetic acid (221 mg, 1.94 mmol) in CH2Cl2 was stirred at 25° C. for 1 day. Solvents were evaporated and the residue purified by reverse phase HPLC (CH3CN/water gradient with 0.1% trifluoroacetic acid) to give 48 mg of 3-[1-(2,4-Difluoro-benzyl)-5-(2-hydroxy-acetyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile (14a).