Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([CH:23]5[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1.FC(F)(F)S(O[CH2:42][C:43]([F:46])([F:45])[F:44])(=O)=O>>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([CH:23]5[CH2:28][CH2:27][N:26]([CH2:42][C:43]([F:46])([F:45])[F:44])[CH2:25][CH2:24]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1C1CCNCC1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1C1CCN(CC(F)(F)F)CC1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]-1,3-thiazolidine-2,4-dione was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-piperidin-4-yl-1,3-thiazolidine-2,4-dione (Example 113) and 2,2,2-trifluoroethyl trifluoromethanesulfonate following General Procedure S.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5][NH2:6].[CH3:11][CH2:12][CH2:13][C:14](=O)[CH2:15][CH2:16][CH3:17].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl.C(O)(=O)C>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5][NH:6][CH:14]([CH2:15][CH2:16][CH3:17])[CH2:13][CH2:12][CH3:11]
Reactant: CCCC(=O)CCC
Reactant: NCCc1ccccc1Br
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCCC(CCC)NCCc1ccccc1Br
Reaction time: 20 h

Procedure:
10 g of 2-bromophenethylamine and 5.71 g of 4-heptanone are dissolved in 250 cm3 of 1,2-dichloroethane at a temperature close to 20° C. 14.84 g of sodium triacetoxyborohydride and 2.9 cm3 of glacial acetic acid are added to the reaction medium. Stirring is continued for 20 h. 300 cm3 of 1M sodium hydroxide are added to the reaction medium. The aqueous phase is extracted with 3 lots of 100 cm3 of ethyl acetate. The organic phases are combined and washed with 4 lots of 100 cm3 of water then 100 cm3 of a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and concentrated using a rotary evaporator under reduced pressure (5 kPa). The yellow liquid obtained is purified by flash chromatography over silica (column: 400 g; particle size: 20-40 μm, spherical; flow rate: 30 cm3/min; eluent: 100% heptane to 70% ethyl acetate/30% heptane gradient). After concentrating the fractions under reduced pressure, 17.33 g of N-[2-(2-bromophenyl)ethyl]heptan-4-amine are obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:55])[CH2:5][N:6]([C:8](=[O:54])[C@@H:9]([NH:25][C:26](=[O:53])[C@@H:27]([NH2:52])[CH2:28][CH2:29][CH2:30][NH:31]/[C:32](/[NH2:51])=[N:33]\[S:34]([C:37]1[C:38]([CH3:50])=[C:39]([CH3:49])[C:40]2[O:44][C:43]([CH3:46])([CH3:45])[CH2:42][C:41]=2[C:47]=1[CH3:48])(=[O:36])=[O:35])[CH2:10][N:11]([CH3:24])[S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22])(=[O:14])=[O:13])[CH3:7])[CH3:2].CCN(C(C)C)C(C)C.[CH3:65][C:66](OC(C)=O)=[O:67]>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:55])[CH2:5][N:6]([C:8](=[O:54])[C@@H:9]([NH:25][C:26](=[O:53])[C@@H:27]([NH:52][C:66](=[O:67])[CH3:65])[CH2:28][CH2:29][CH2:30][NH:31]/[C:32](/[NH2:51])=[N:33]\[S:34]([C:37]1[C:38]([CH3:50])=[C:39]([CH3:49])[C:40]2[O:44][C:43]([CH3:45])([CH3:46])[CH2:42][C:41]=2[C:47]=1[CH3:48])(=[O:35])=[O:36])[CH2:10][N:11]([CH3:24])[S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22])(=[O:14])=[O:13])[CH3:7])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)CN(C)C(=O)[C@H](CN(C)S(=O)(=O)c1ccccc1[N+](=O)[O-])NC(=O)[C@@H](N)CCCN/C(N)=N\S(=O)(=O)c1c(C)c(C)c2c(c1C)CC(C)(C)O2
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CN(C)C(=O)[C@H](CN(C)S(=O)(=O)c1ccccc1[N+](=O)[O-])NC(=O)[C@H](CCCN/C(N)=N\S(=O)(=O)c1c(C)c(C)c2c(c1C)CC(C)(C)O2)NC(C)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.7 %

Procedure:
To a solution of compound F (6.6 g, 7.8 mmol) in CHCl3 (50 mL) at 5° C. was added DIPEA (4.8 mL, 27.4 mmol) followed by Ac2O (0.9 mL, 9.4 mmol). The reaction mixture was stirred at ambient temperature for 30 min. Solvents were removed in vacuo, and then the residue was diluted with water (500 mL) and EtOAc (500 mL). The organic layer was separated and washed with water (300 mL), 2% aqueous H2SO4 (200 mL), water (2×300 mL) and brine (100 mL). The organic layer was separated, dried over Na2SO4 and solvent removed in vacuo to afford compound G (5.5 g, 82%). LC-MS [M+H] 853.4 (C36H52N8O12S2+H, calc: 853.9). Purity >95% (UV/254 nm). Compound G was used without further purification.
Reaction SMILES: [F:1][C:2]([F:57])([C:53]([F:56])([F:55])[F:54])[CH2:3][CH2:4][CH2:5][C:6]([CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]2[C:37]3[C:32](=[CH:33][C:34]([O:38]COC)=[CH:35][CH:36]=3)[O:31][CH2:30][C:29]2([CH3:52])[C:42]2[CH:47]=[CH:46][C:45]([O:48]COC)=[CH:44][CH:43]=2)=[CH:24][CH:23]=1)(C(OCC)=O)[C:7]([O:9]CC)=[O:8].[OH-].[K+].Cl>C(O)C.O>[OH:38][C:34]1[CH:33]=[C:32]2[C:37]([CH:28]([C:25]3[CH:26]=[CH:27][C:22]([O:21][CH2:20][CH2:19][CH2:18][CH2:17][CH:6]([CH2:5][CH2:4][CH2:3][C:2]([F:57])([F:1])[C:53]([F:54])([F:55])[F:56])[C:7]([OH:9])=[O:8])=[CH:23][CH:24]=3)[C:29]([C:42]3[CH:47]=[CH:46][C:45]([OH:48])=[CH:44][CH:43]=3)([CH3:52])[CH2:30][O:31]2)=[CH:36][CH:35]=1
Reactant: CCOC(=O)C(CCCCOc1ccc(C2c3ccc(OCOC)cc3OCC2(C)c2ccc(OCOC)cc2)cc1)(CCCC(F)(F)C(F)(F)F)C(=O)OCC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC1(c2ccc(O)cc2)COc2cc(O)ccc2C1c1ccc(OCCCCC(CCCC(F)(F)C(F)(F)F)C(=O)O)cc1
Yield: 121.2 %

Procedure:
To a solution of diethyl 2-(4,4,5,5,5-pentafluoropentyl)-2-(4-((3RS,4RS)-4-(3-methyl-7-(methyloxymethyloxy)-3-(4-(methyloxymethyloxy)phenyl)chroman-4-yl)phenyloxy)butyl)propane-1,3-dioate (0.552 g, 0.68 mmol) in ethanol (10 ml) was added the solution of potassium hydroxide (1.53 g, 27.23 mmol) in water (5 ml) and the mixture was stirred at refluxed overnight. After the reaction was completed, the reaction mixture was treated with 2N-HCl solution (pH=4) and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (0.513 g, quantitative) as a foamy oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][CH2:12][CH:13]2[O:18][CH2:17][CH2:16][NH:15][CH2:14]2)=[O:10])=[CH:4][CH:3]=1.Cl[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]=[CH2:28])=[CH:23][CH:22]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][CH2:12][CH:13]2[O:18][CH2:17][CH2:16][N:15]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([CH:27]=[CH2:28])=[CH:23][CH:22]=3)[CH2:14]2)=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(NCC1CNCCO1)Nc1ccc(Cl)cc1
Reactant: C=Cc1ccc(CCl)cc1
Product: C=Cc1ccc(CN2CCOC(CNC(=O)Nc3ccc(Cl)cc3)C2)cc1
Yield: 49.6 %

Procedure:
Example 38 was prepared in an analogous manner to Example 19 using a mixture of Intermediate 9 (0.01 g) and 1-(chloromethyl)-4-vinylbenzene (0.0062 g) to give the title compound (0.0071 g). LC-MS (System A): Rt 2.72 mins, Mass Spectrum m/z 386 [MH+].
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:10][N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)=O)(C)(C)C.[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24]>C(Cl)Cl>[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24].[O:14]1[CH2:15][CH2:16][N:11]([CH2:10][C@@H:9]([NH2:8])[CH2:17][CH:18]([CH3:19])[CH3:20])[CH2:12][CH2:13]1
Reactant: CC(C)C[C@@H](CN1CCOCC1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C[C@H](N)CN1CCOCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Crude N-tert-butoxycarbonyl-1-morpholino-2- (S) -amino-4-methylpentane (6.3 mmol) was dissolved in DCM (50 ml) and treated with excess trifluoroacetic acid (0.48 ml) at 0° C. The mixture was allowed to warm up to room temperature and was stirred for 3 h. The mixture was concentrated to dryness to give 1-morpholino-2-(S)-amino-4-methylpentane trifluoroacetate salt which was used immediately.
Reaction SMILES: [NH2:1][CH:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([O:9][CH3:10])[N:3]1[CH:11]([F:13])[F:12].[N+:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([N:26]=[C:27]=[O:28])(=[O:25])=[O:24])([O-:16])=[O:15]>C(Cl)Cl>[Cl:8][C:6]1[N:5]=[C:4]([O:9][CH3:10])[N:3]([CH:11]([F:12])[F:13])[CH:2]([NH:1][C:27]([NH:26][S:23]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N+:14]([O-:16])=[O:15])(=[O:24])=[O:25])=[O:28])[N:7]=1
Reactant: COC1=NC(Cl)=NC(N)N1C(F)F
Reactant: O=C=NS(=O)(=O)c1ccccc1[N+](=O)[O-]
Solvent: ClCCl
Product: COC1=NC(Cl)=NC(NC(=O)NS(=O)(=O)c2ccccc2[N+](=O)[O-])N1C(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 35.2 %

Procedure:
A solution of 4.2 g of 2-amino-4-chlorodifluoromethyl-6-methoxy-1,3,5-triazine (20 mmol) in 20 ml of methylene chloride was treated at 25° C. with a solution of 4.6 g of 2-nitrobenzenesulfonyl isocyanate (20 mmol) in 5 ml of methylene chloride. The mixture was subsequently stirred at 25° C. for 16 h, and the deposited product was filtered off with suction, washed with a little ether and dried at 40° C. in a water-jet vacuum. 3.1 g of the title compound (35% of theory) of m.p. 181° C. were thus obtained.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]2[C:3]=1[CH:4]=[C:5]([CH3:14])[C:6](=[O:13])[NH:7]2.Br[CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19]>>[CH3:19][C:18]([CH3:20])=[CH:17][CH2:16][O:1][C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]2[C:3]=1[CH:4]=[C:5]([CH3:14])[C:6](=[O:13])[NH:7]2
Reactant: CC(C)=CCBr
Reactant: Cc1cc2c(O)ccc(C)c2[nH]c1=O
Product: CC(C)=CCOc1ccc(C)c2[nH]c(=O)c(C)cc12
Yield: 73.9 %

Procedure:
Reaction, post-treatment, and recrystallization (chloroform-n-hexane) were performed in a manner similar to that described in Reference Example 31 using 5-hydroxy-3,8-dimethylcarbostyril (1.4 g, 7.41 mmol) and 4-bromo-2-methyl-2-butene (1.21 g, 8.15 mmol). As a result, 1.41 g of the title compound was obtained as colorless crystals (74.1%).
Reaction SMILES: [Br:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][C:3]=1[F:11].[BH4-].[Na+].O>CO.Cl[Ni]Cl>[Br:1][C:2]1[C:3]([F:11])=[CH:4][CH:5]=[CH:6][C:7]=1[NH2:8]
Reactant: O=[N+]([O-])c1cccc(F)c1Br
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Nc1cccc(F)c1Br
Reaction time: 0.08 h
Yield: 63.2 %

Procedure:
To a solution of 2-bromo-1-fluoro-3-nitrobenzene (1.0 g, 5.0 mmol) in CH3OH (50 mL) was added NiCl2 (2.2 g 10 mmol) and NaBH4 (0.50 g 14 mmol) at 0° C. After the addition, the mixture was stirred for 5 min. Water (20 mL) was added and the mixture was extracted with EtOAc (20 mL×3). The organic layers were dried over anhydrous Na2SO4 and evaporated under vacuum to give 2-bromo-3-fluoroaniline (600 mg, 70%). 1H NMR (400 MHz, CDCl3) δ 7.07-7.02 (m, 1H), 6.55-6.49 (m, 1H), 4.22 (br s, 2H).
Reaction SMILES: ClCCl.C(O[C@@:8]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28])([C@H:15]([S:17](Cl)(=[O:19])=[O:18])[CH3:16])[CH2:9][N:10]1[CH:14]=[N:13][CH:12]=[N:11]1)(=O)C.[NH3:29]>C(OCC)(=O)C>[F:28][C:22]1[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:21]=1[C:8]([CH2:9][N:10]1[CH:14]=[N:13][CH:12]=[N:11]1)=[C:15]([S:17]([NH2:29])(=[O:19])=[O:18])[CH3:16]
Reactant: CC(=O)O[C@@](Cn1cncn1)(c1ccc(F)cc1F)[C@@H](C)S(=O)(=O)Cl
Reactant: N
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(=C(Cn1cncn1)c1ccc(F)cc1F)S(N)(=O)=O

Procedure:
A dichloromethane (30 ml) solution of (2R,3R)-3-chlorosulfonyl-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butyl acetate (2.0 g) was cooled to -30° C., to which was introduced ammonia for 10 minutes. To the mixture was introduced nitrogen to eliminate ammonia. To the reaction mixture was added ethyl acetate (50 ml), then precipitating crystals were collected by filtration, followed by recrystallization from methanol to give 3-(2,4-difluorophenyl)-4-(1H-1,2,4-triazol-1-yl)-2-butene-2-sulfonamide (isomer A, Compound 36, 0.54 g) as colorless crystals.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH:6]([O:9][C:10]([N:12]1[CH2:18][CH2:17][CH2:16][CH:15]([N:19]([C:35](=[O:37])[CH3:36])[CH2:20][C:21]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=2)[C:14]2[CH:38]=[C:39]([NH2:42])[CH:40]=[CH:41][C:13]1=2)=[O:11])([CH3:8])[CH3:7].N1C=CC=CC=1>ClCCl>[C:35]([N:19]([CH2:20][C:21]1[CH:22]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:24]=[C:25]([C:27]([F:30])([F:28])[F:29])[CH:26]=1)[CH:15]1[CH2:16][CH2:17][CH2:18][N:12]([C:10]([O:9][CH:6]([CH3:8])[CH3:7])=[O:11])[C:13]2[CH:41]=[CH:40][C:39]([NH:42][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:38][C:14]1=2)(=[O:37])[CH3:36]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2ccc(N)cc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2ccc(NS(C)(=O)=O)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.6 %

Procedure:
Add methanesulfonyl chloride (8 μl, 0.103 mmol) dropwise to a suspension of isopropyl-5-[acetyl-(3,5-bistrifluoromethylbenzyl)amino]-7-amino-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (0.050 g, 0.094 mmol) and pyridine (8 μl, 0.103 mmol) in dichloromethane (2 mL) at 0° C. under atmosphere of nitrogen. Stir the suspension for 30 min, then remove the cooling bath and warm to room temperature while stirring overnight. Dilute the mixture with dichloromethane (30 mL) and wash with 2 N hydrochloric acid, water, and brine (10 mL each). Dry the organic layer over anhydrous sodium sulfate, filter and remove the solvent under reduced pressure. Chromatograph the residue over silica gel, eluting with ethyl acetate/hexanes (10:1 to 1:2), to provide the title compound as a white solid (0.037 g, 65%): ESI MS 610 (M+H).
Reaction SMILES: [Cl:1][C:2]1[S:17][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:10][CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:4]=2[CH:3]=1.Br[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:21]=1>>[CH3:29][S:26]([C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[CH2:19][N:14]1[CH2:13][CH2:12][CH:11]([NH:10][C:9]2[C:4]3[CH:3]=[C:2]([Cl:1])[S:17][C:5]=3[N:6]=[CH:7][N:8]=2)[CH2:16][CH2:15]1)(=[O:27])=[O:28]
Reactant: CS(=O)(=O)c1cccc(CBr)c1
Reactant: Clc1cc2c(NC3CCNCC3)ncnc2s1
Product: CS(=O)(=O)c1cccc(CN2CCC(Nc3ncnc4sc(Cl)cc34)CC2)c1

Procedure:
The title compound was prepared (70 mg, 43%) from 6-chloro-N-(piperidin-4-yl)thieno[2,3-d]pyrimidin-4-amine (100 mg, 0.37 mmol) and 1-(bromomethyl)-3-(methylsulfonyl)benzene (139 mg, 0.55 mmol) by following the general procedure described for Preparation 12. 1H NMR (400 MHz, CDCl3): δ 8.40 (s, 1H), 7.95 (s, 1H), 7.80 (d, 1H), 7.60 (d, 1H), 7.50 (t, 1H), 7.05 (s, 1H), 5.25 (d, 1H), 4.20 (m, 1H), 3.60 (s, 2H), 3.05 (s, 3H), 2.80 (m, 2H), 2.20 (m, 2H), 2.05 (m, 2H), 1.60 (m, 2H). MS (EST) m/z: Calculated: 436.98; Observed: 437.2 (M++1).
Reaction SMILES: [Cl-].[CH3:2][O:3]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[O:34]=[C:35]1[N:43]([CH2:44][CH2:45][CH3:46])[C:42]2[NH:41][C:40]([C:47]34[CH2:54][CH2:53][C:50]([CH:55]=O)([CH2:51][CH2:52]3)[CH2:49][CH2:48]4)=[N:39][C:38]=2[C:37](=[O:57])[N:36]1[CH2:58][CH2:59][CH3:60]>C1COCC1>[O:34]=[C:35]1[N:43]([CH2:44][CH2:45][CH3:46])[C:42]2[NH:41][C:40]([C:47]34[CH2:54][CH2:53][C:50]([CH2:55][CH:2]=[O:3])([CH2:51][CH2:52]3)[CH2:49][CH2:48]4)=[N:39][C:38]=2[C:37](=[O:57])[N:36]1[CH2:58][CH2:59][CH3:60]
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCn1c(=O)c2nc(C34CCC(C=O)(CC3)CC4)[nH]c2n(CCC)c1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCn1c(=O)c2nc(C34CCC(CC=O)(CC3)CC4)[nH]c2n(CCC)c1=O
Reaction time: 1.5 h
Yield: 75 %

Procedure:
To a stirred suspension of methoxymethyl triphenylphosphonium chloride (1.1 g, 3.2 mmol) in THF (60 ml) at −78° C. was added a solution of KHMDS (0.5 M in toluene, 10 ml, 5 mmol). The resulting yellow mixture was stirred at this temperature for 1.5 h and a solution of 4-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]octane-1-carbaldehyde (372 mg, 1.0 mmol) in THF (12 ml) was added over a period of 20 minutes. The mixture was held at −78° C. for 6 h and allowed to reach ambient temperature overnight (12 h). The reaction mixture was partitioned between saturated aqeuous NH4Cl (100 ml) and EtOAc (100 ml) and the aqueous phase was extracted with EtOAc (50 ml). The combined organic extracts were washed with saturated aqeuous NaCl (100 ml), concentrated in vacuo, redissolved in THF and concentrated to a volume of approx. 20 ml. To the solution was added an equal volume of 1 N HCl and the mixture was stirred overnight. The mixture was diluted with EtOAc (20 ml), the aqueous phase was separated and extracted with EtOAc (10 ml). The combined organic phases were then washed with saturated aqeuous NaCI (2×, 25 ml), dried (MgSO4), filtered and concentrated in vacuo. The resulting orange oil was purified in batches by radial chromatography (2 mm plate) using 3% MeOH and 3% THF in CH2Cl2 as eluent. Product-containing fractions were combined and concentrated to afford 290 mg (75%) of a white solid. MS: 387 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.[B:16]([O:25]C(C)C)([O:21]C(C)C)[O:17]C(C)C.C([Li])CCC>O1CCCC1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([O:17][B:16]([OH:25])[OH:21])=[CH:3][CH:4]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Clc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: OB(O)Oc1ccc(Cl)cc1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
4-Bromochlorobenzene (70.6 g) is added into a four mouth flask connecting with a mechanical stirring apparatus, two constant pressure funnels and a temperature probe. Toluene (588.3 ml) and tetrahydrofuran (THF) (147 ml) are added under stiffing at room temperature under argon, and dissolved to obtain a colorless transparent liquid. Then triisopropyl borate (109.2 ml) and n-butyllithium (176.4 ml, 2.5M in hexane) are respectively added into two constant pressure funnels, and cooled the inner temperature to below −78° C., then n-butyllithium solution is dropped to the flask under controlling a dropping speed to keep the inner temperature below −78° C. After addition, the mixture is kept at the temperature for 1 hour, then triisopropyl borate is dropped into the mixture under the temperature below −78° C., and kept at the temperature for 1 hour after addition, and then the cooling system is removed to naturally warm up to −20° C. HCl solution (360.4 ml, 2.2M) is added to the mixture to warm up to about 10° C., and then placed for layer separation. The aqueous phase is reextracted with toluene (58.8 ml, 2 times). The organic phase is combined together and washed with saturated brine to pH=7 to obtain a colorless transparent liquid, dried with anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to remove most of solvents and the white solid is finally precipitated, filtered to obtain a crystal of 4-chlorophenylboric acid (48 g).
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]2[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=2[Cl:14])=[N:5][N:6]=1.BrC1S[C:19]([N:21](C)[CH:22]2[CH2:27][C:26]([CH3:29])([CH3:28])[NH:25][C:24]([CH3:31])([CH3:30])[CH2:23]2)=NN=1>CN1C(=O)CCC1.C(Cl)Cl>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([C:4]2[S:3][C:2]([N:21]([CH3:19])[CH:22]3[CH2:23][C:24]([CH3:30])([CH3:31])[NH:25][C:26]([CH3:29])([CH3:28])[CH2:27]3)=[N:6][N:5]=2)=[C:8]([Cl:14])[CH:9]=1
Reactant: Clc1cc(Br)ccc1-c1nnc(Br)s1
Reactant: CN(c1nnc(Br)s1)C1CC(C)(C)NC(C)(C)C1
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: CN(c1nnc(-c2ccc(Br)cc2Cl)s1)C1CC(C)(C)NC(C)(C)C1
Temperature: 25 °C

Procedure:
A stirred solution of 2-bromo-5-(4-bromo-2-chlorophenyl)-1,3,4-thiadiazole (700 mg, 1.975 mmol) and 5-bromo-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine (Intermediate 4) (1009 mg, 5.92 mmol) in NMP (4 mL) was heated to 120° C. for 3 hours. The reaction mixture was allowed to cool to room temperature then diluted with DCM (100 mL) and washed with saturated NaHCO3(aq) (100 mL). The organic phase was separated, dried over MgSO4, and filtered. The filtrate was concentrated in vacuo to a brown liquid. The crude material was purified by silica flash chromatography, running a gradient from 0-10% [2M NH3 in MeOH]/DCM over 30 minutes, collecting at 320 nm to afford the title compound as a light brown glass-like solid (750 mg, 86% yield). LC-MS: Rt 1.10 min; MS m/z 445.1 [M+2H]+ [Method A]. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.96 (d, J=8.59 Hz, 1H), 7.93 (d, J=2.02 Hz, 1H), 7.70 (dd, J=8.59, 2.02 Hz, 1H), 4.36 (tt, J=12.38, 3.28 Hz, 1H) 3.01 (s, 3H), 1.62 (dd, J=12.13, 3.03 Hz, 2H), 1.43 (t, J=12.13 Hz, 2H), 1.28 (br. s., 1H), 1.20 (s, 6H), 1.09 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([C:21]2[C:25]([NH2:26])=[CH:24][NH:23][N:22]=2)=[O:20])=[CH:14][CH:13]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CS(C)=O>[F:11][C:12]1[CH:13]=[CH:14][C:15]([NH:18][C:19]([C:21]2[C:25]([NH:26][C:4](=[O:6])[C:3]3[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=3[F:1])=[CH:24][NH:23][N:22]=2)=[O:20])=[CH:16][CH:17]=1
Reactant: Nc1c[nH]nc1C(=O)Nc1ccc(F)cc1
Reactant: O=C(O)c1ccccc1F
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CS(C)=O
Product: O=C(Nc1c[nH]nc1C(=O)Nc1ccc(F)cc1)c1ccccc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 19.1 %

Procedure:
2-Fluorobenzoic acid (36 mg, 0.25 mmol) was added to a solution of 4-amino-1H-pyrazole-3-carboxylic acid (4-fluoro-phenyl)-amide (50 mg, 0.23 mmol), EDC (53 mg, 0.27 mmol) and HOBt (37 mg, 0.27 mmol) in DMSO (1 ml). The reaction mixture was stirred at room temperature for 24 hours and purified by preparative LC/MS. Evaporation of product-containing fractions yielded the product as a white solid (15 mg, 19%). (LC/MS: Rt 3.91, [M+H]+ 342.66).
Reaction SMILES: [CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=2)[C:7]([CH:20]=[CH:21][CH2:22][CH2:23][CH3:24])=[C:6]([CH:25]([CH3:27])[CH3:26])[N:5]=1)([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:36])C=1>C(Cl)Cl>[CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:13]=[CH:14][C:15]([S:18]([CH3:19])=[O:36])=[CH:16][CH:17]=2)[C:7]([CH:20]=[CH:21][CH2:22][CH2:23][CH3:24])=[C:6]([CH:25]([CH3:26])[CH3:27])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CCCC=Cc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(SC)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCCC=Cc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(S(C)=O)cc1
Temperature: 0 °C
Yield: 50 %

Procedure:
2,6Diisopropyl-3-hydroxymethyl-4-[4-(methylthio)phenyl]-5-(pent-1-enyl)pyridine (100 mg, 0.261 mmol) (Example 174) was dissolved in methylene chloride (1.5 mL) and stirred at 0° C. under an argon atmosphere. To this mixture was added a solution containing 3-chloroperoxybenzoic add (“mCPBA”) (85%, 53 mg, 0.261 mmol) in methylene chloride (1 mL). The mixture was stirred for 1.5 h at 0° C. and quenched with the addition of a saturated aqueous solution of NaHSO3 (3 mL). The reaction mixture was further diluted through the addition of water (5 mL) and then extracted with methylene chloride (3×10 mL). The combined organic layer was washed sequentially with a saturated aqueous solution of sodium bicarbonate (10 mL) and brine (10 mL), dried (Na2SO4), and concentrated under reduced pressure. The resultant residue was purified by flash chromatography to yield the title compound (52 mg, 50%) as a white solid, mp 133-135° C. 1H NMR (300 MHz, CDCl3): δ 0.77 and 0.69 (t, J=7.5 Hz, 3 H), 1.08-1.36 (m, 14 H), 1.70-1.92 (m, 3 H), 2.75 and 2.76 (s, 3 H), 3.19-3.51 (m, 2 H), 4.32-4.40 (m, 2 H), 5.20-5.45 (m, 1 H), 5.93-6.00 (m, 1 H), 7.31-7.38 (m, 2 H), 7.59-7.70 (m, 2 H). Anal. calc. for C24H33NO2S: C, 71.86; H, 8.29; N, 3.39; S, 7.73. Found: C, 72.14; H, 8.32; N, 3.51; S, 8.02.