Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:8][NH:7][CH2:6]1)=[O:4].Br[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=1[C:21]([F:24])([F:23])[F:22].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:22][C:21]([F:23])([F:24])[C:12]1[CH:13]=[C:14]([C:17]([F:20])([F:18])[F:19])[CH:15]=[CH:16][C:11]=1[CH2:10][N:7]1[CH2:8][CH:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:6]1
Reactant: FC(F)(F)c1ccc(CBr)c(C(F)(F)F)c1
Reactant: COC(=O)C1CNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C1CN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.9 %

Procedure:
To a solution of methylazetidine-3-carboxylate (5 g) and 1-(bromomethyl)-2,4-bis(trifluoromethyl)benzene (13.3 g) in DMF (100 mL) was added potassium carbonate (7.20 g) at room temperature. The reaction mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (5.45 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)=O.Cl.[NH2:20][OH:21].N1C=CC=CC=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)=[N:20][OH:21]
Reactant: COc1ccc(C(=O)c2ccc(F)cc2F)cc1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(C(=NO)c2ccc(F)cc2F)cc1
Temperature: 100 °C
Yield: 99 %

Procedure:
Mix (2,4-difluoro-phenyl)-(4-methoxy-phenyl)-methanone (257 g, 1.04 mol), hydroxylamine hydrochloride (143.9 g, 2.07 mol) and pyridine (1.29 L, 15.89 mol), under a nitrogen atmosphere and heat (100° C.). Cool reaction mixture to room temperature and concentrate to an oily residue. Partition residue between ethyl acetate (2700 mL) and water (1600 mL). Wash organic layer with 1 N HCl solution (2×800 mL), water (2×1 L), saturated sodium chloride (1 L), dry (MgSO4) and concentrate to give the title compound as an oil. (270.84 g, 99% Yield): 1H NMR (CDCl3, 200 MHz) δ 3.8-3.82 (2 s, 3H), 6.8-7.0 (m, 3H), 7.2 (m, 1H), 7.4 (d, 2H), 7.5 (d, 1H), 8.4-8.6 (br s, 1H). Purity by LC/MS (APCl)=100% area, [M+H]+=264 m/e.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.Cl.[F:48][C:49]1[CH:54]=[CH:53][C:52]([C:55]2([OH:60])[CH2:59][CH2:58][NH:57][CH2:56]2)=[CH:51][CH:50]=1>CN(C=O)C>[F:48][C:49]1[CH:50]=[CH:51][C:52]([C:55]2([OH:60])[CH2:59][CH2:58][N:57]([C:13]([C:9]3[CH:10]=[N:11][O:12][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=3)=[O:15])[CH2:56]2)=[CH:53][CH:54]=1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Reactant: OC1(c2ccc(F)cc2)CCNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2oncc2C(=O)N2CCC(O)(c3ccc(F)cc3)C2)cc1
Reaction time: 2 h
Yield: 81.9 %

Procedure:
A solution of 5-(4-methylphenyl)isoxazole-4-carboxylic acid (20 mg, 0.1 mmol), TBTU (39 mg, 0.12 mmol, 1,2 equ.) and N-ethyl-N-isopropylpropan-2-amine (35 μL, 0.2 mmol, 2 equ) in DMF (1 mL) was added to 3-(4-fluorophenyl)pyrrolidin-3-ol hydrochloride (22 mg, 0.1 mmol) and the reaction mixture was left at rt for 2 h. The solvent was evaporated and the crude product was purified by RP-HPLC. After evaporation of the solvents the product was dried in vacuum to yield the title compound (30 mg). MS (ESI, pos. ion) m/z calcd for C21H19FN2O3: 366.1380, found 366.1380.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[F:19][C:20]([F:37])([F:36])[O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[O:32][CH:31]=[N:30][C:29]=2[C:33](O)=[O:34])=[CH:24][CH:23]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:33]([C:29]3[N:30]=[CH:31][O:32][C:28]=3[C:25]3[CH:24]=[CH:23][C:22]([O:21][C:20]([F:36])([F:19])[F:37])=[CH:27][CH:26]=3)=[O:34])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)c1ncoc1-c1ccc(OC(F)(F)F)cc1
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)c3ncoc3-c3ccc(OC(F)(F)F)cc3)cn2)o1

Procedure:
Following general procedure B followed by T, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 5-(4-trifluoromethoxy-phenyl)-oxazole-4-carboxylic acid. LC-MS-conditions 01b: tR=1.01 min; [M+H]+=461.11.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.CC1C=CC(S(O[C@@H:22]([CH2:33][O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:23][CH:24]([C:31]#[N:32])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:25]1([C@@:24]2([C:31]#[N:32])[CH2:23][C@H:22]2[CH2:33][O:34][CH2:35][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: Cc1ccc(S(=O)(=O)O[C@@H](COCc2ccccc2)CC(C#N)c2ccccc2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: Cc1ccccc1
Product: N#C[C@]1(c2ccccc2)C[C@H]1COCc1ccccc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To 765 mL toluene cooled to 0° C. was added 1.0 M LHMDS in hexanes (148.1 mL, 148.1 mmol, 1 eq). To this solution was added (1R)-3-cyano-3-phenyl-1-{[(phenylmethyl)oxy]methyl}propyl 4-methylbenzenesulfonate (43.0 g, 98.73 mmol, 1 eq), accessed via the method of Preparation 2, in 236 mL toluene. The reaction mixture was stirred at 0° C. for 16 h, then washed successively with water and brine, dried over MgSO4, filtered and concentrated to give a yellow oil that was shown to be an 8:2 diastereomeric mixture of the title compound to the product of Preparation 3A. The desired diastereomer (16.0 g, 62%) was separated by silica gel flash chromatography using 9:1→8:2 hexanes in ethyl acetate. 1H NMR (300 MHz, CDCl3) δ 7.44-7.15 (m, 10H), 4.28-4.19 (m, 2H), 3.31-3.27 (m, 1H), 2.94-2.84 (m, 1H), 2.22-2.15 (m,1H), 1.76-1.72 (m, 1H), 1.47-1.44 (m, 1H). ES-LCMS m/z 264.1 (M+H).
Reaction SMILES: O.[F:2][CH:3]1[CH:8]([OH:9])[NH:7][C:6](=[O:10])[NH:5][C:4]1=O.Cl[Si:13]([CH2:18][CH3:19])([CH2:16][CH3:17])[CH2:14][CH3:15]>>[CH2:14]([Si:13]([C:4]1[NH:5][C:6](=[O:10])[N:7]([Si:13]([CH2:18][CH3:19])([CH2:16][CH3:17])[CH2:14][CH3:15])[C:8](=[O:9])[C:3]=1[F:2])([CH2:18][CH3:19])[CH2:16][CH3:17])[CH3:15]
Reactant: CC[Si](Cl)(CC)CC
Reactant: O=C1NC(=O)C(F)C(O)N1
Solvent: O
Product: CC[Si](CC)(CC)c1[nH]c(=O)n([Si](CC)(CC)CC)c(=O)c1F

Procedure:
5-fluoro-6-hydroxy-5,6-dihydrouracil monohydrate, 4.15 g, was boiled under reflux with chlorotriethylsilane, 50 ml. Distillation of the resulting product gave a quantitative recovery of bis-triethylsilyl-5-fluorouracil.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([OH:19])([C:15]([F:18])([F:17])[F:16])[C:11]([F:14])([F:13])[F:12])=[CH:6][CH:5]=1)[CH3:2].[N+:20]([C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1)([O-:22])=[O:21].CN(C1C=CC=CN=1)C>N1C=CC=CC=1>[CH2:1]([N:3]([C:4]1[CH:5]=[CH:6][C:7]([C:10]([OH:19])([C:11]([F:13])([F:14])[F:12])[C:15]([F:16])([F:18])[F:17])=[CH:8][CH:9]=1)[S:29]([C:26]1[CH:25]=[CH:24][C:23]([N+:20]([O-:22])=[O:21])=[CH:28][CH:27]=1)(=[O:30])=[O:31])[CH3:2]
Reactant: CCNc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Product: CCN(c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 16 h
Yield: 75.4 %

Procedure:
To a solution of 104 mg 2-(4-Ethylamino-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol in 3 ml of pyridine was added 104 mg 4-Nitro-benzenesulfonyl chloride and 10 mg of dimethylaminopyridine. The mixture was stirred for 16 hrs and then concentrated in vacuo. After chromatography (1:3 Ethyl Acetate:Hexane), 129 mg of the named product was obtained. 1H NMR was consistent with the structure.
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:14]2[C:9](=[C:10]([CH2:17][CH:18]3[S:22][C:21](=[O:23])[NH:20][C:19]3=[O:24])[CH:11]=[CH:12][C:13]=2[O:15][CH3:16])[CH2:8][CH2:7][C:6]1=[O:25])(O)=[O:2].[F:26][C:27]([F:36])([F:35])[C:28]1[CH:29]=[C:30]([CH:32]=[CH:33][CH:34]=1)[NH2:31].ON1C2C=CC=CC=2N=N1.O>CN(C=O)C>[F:26][C:27]([F:35])([F:36])[C:28]1[CH:29]=[C:30]([NH:31][C:1]([CH2:4][N:5]2[C:14]3[C:9](=[C:10]([CH2:17][CH:18]4[S:22][C:21](=[O:23])[NH:20][C:19]4=[O:24])[CH:11]=[CH:12][C:13]=3[O:15][CH3:16])[CH2:8][CH2:7][C:6]2=[O:25])=[O:2])[CH:32]=[CH:33][CH:34]=1
Reactant: COc1ccc(CC2SC(=O)NC2=O)c2c1N(CC(=O)O)C(=O)CC2
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CC2SC(=O)NC2=O)c2c1N(CC(=O)Nc1cccc(C(F)(F)F)c1)C(=O)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
500 mg of 5-(1-carboxymethyl-8-methoxy-2-oxo-1,2,3,4-tetrahydroquinolin-5-ylmethyl)thiazolidine-2,4-dione was dissolved in 5 ml of DMF. 0.35 ml of 3-trifluoromethyl aniline, 0.32 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(WSC), and 0.25 g of 1-hydroxybenzotriazole (HOBT) were added to the solution, followed by stirring at room temperature overnight. Water was added to the reaction liquid, and the solid thus obtained was separated by filtration. The solid was dissolved in methylene chloride, washed with sodium chloride solution, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride:methanol=50:1), giving 412 mg of 5-{1-[N-(3-trifluoromethylphenyl)amino]carbonylmethyl-8-methoxy-2-oxo-1,2,3,4-tetrahydroquinolin-5-ylmethyl}thiazolidine-2,4-dione.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:10](Cl)(=[O:12])=[O:11])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[F:14][C:15]([F:32])([F:31])[C:16]1[N:21]=[CH:20][C:19]([C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[NH:27][CH2:26][CH2:25]3)=[CH:18][CH:17]=1.N1C=CC=CC=1>ClCCl.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([S:10]([N:27]2[C:28]3[C:24](=[CH:23][C:22]([C:19]4[CH:20]=[N:21][C:16]([C:15]([F:31])([F:14])[F:32])=[CH:17][CH:18]=4)=[CH:30][CH:29]=3)[CH2:25][CH2:26]2)(=[O:12])=[O:11])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: FC(F)(F)c1ccc(-c2ccc3c(c2)CCN3)cn1
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: N#Cc1ccc(S(=O)(=O)N2CCc3cc(-c4ccc(C(F)(F)F)nc4)ccc32)cc1Cl
Temperature: 80 °C

Procedure:
1.18 g of commercially available 3-Chloro-4-cyano-benzenesulfonyl chloride were dissolved in 30 ml dichloromethane. Then 880 mg 5-(6-Trifluoromethyl-pyridin-3-yl)-2,3-dihydro-1H-indole were added followed by 15 ml pyridine and 407 mg 4-dimethylaminopyridine. The mixture was stirred at 80° C. for thirty minutes. The mixture was diluted with 100 ml of dichloromethane and washed with 100 ml water and 100 ml saturated NaHCO3 solution. The organic layer was then separated and dried over MgSO4. The solvent was removed in vacuo to obtain 1.49 g 2-Chloro-4-[5-(6-trifluoromethyl-pyridin-3-yl)-2,3-dihydro-indole-1-sulfonyl]-benzonitrile.
Reaction SMILES: Br[CH:2]([CH2:18]Br)[C:3]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:4]#[N:5].C(O[K])(C)(C)C.CCOCC.[NH4+].[Cl-]>C1COCC1>[C:12]1([C:3]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)([C:2]#[CH:18])[C:4]#[N:5])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: N#CC(c1ccccc1)(c1ccccc1)C(Br)CBr
Agent: CC(C)(C)O[K]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C#CC(C#N)(c1ccccc1)c1ccccc1

Procedure:
A solution of 3,4-dibromo-2,2-diphenylbutanenitrile 45 (7.5 g, 19.8 mmol) in THF (50 ml) was added dropwise to a suspension of tert-BuOK (11.1 g, 99 mmol) in THF (250 ml) at −78° C. After 1 h30, the brown mixture was poured into a mixture of ether and a saturated aqueous NH4Cl solution. After separation, the organic phase was washed twice with water and finally with brine. Drying over MgSO4 and evaporation gave an brown-orange oil which was chromatographied over silica gel (CH2Cl2/Hexane 25/75). The alkyne 46 was obtained as a slightly yellow oil (4 g, 93%).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]([CH3:27])[C:20](=[O:26])[O:21][CH2:22][C:23]([CH3:25])=[CH2:24])=[CH:15][CH:14]=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([N:19]([CH3:27])[C:20](=[O:26])[O:21][CH2:22][C:23]2([CH3:25])[CH2:24][O:9]2)=[CH:17][CH:18]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C(C)COC(=O)N(C)c1ccc(Cl)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CN(C(=O)OCC1(C)CO1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 99.2 %

Procedure:
m-Chloroperbenzoic acid (2.5 g, 10.1 mmol) was added to a solution of 2-methyl-2-propenyl N-(4-chlorophenyl)-N-methylcarbamate (1.78 g, 6.7 mmol) in methylene chloride (20 ml) while cooling in an ice-bath, and the mixture was stirred at room temperature for 6.5 hours. To which sodium thiosulfate aqueous solution was added and the mixture was filtered, and sodium hydrogencarbonate aqueous solution was added to the filtrate. The organic layer was separated, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol=20/1) to afford (2-methyl-2-oxiranylmethyl) N-(4-chlorophenyl)-N-methylcarbamate (1.7 g, quantitative) as a pale yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].I[CH:11]([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+].O>C(O)(C)C>[CH:11]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])([CH3:13])[CH3:12]
Reactant: O=Cc1cccc(O)c1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Product: CC(C)Oc1cccc(C=O)c1
Yield: 66.7 %

Procedure:
EX-645A) 3-Hydroxybenzaldehyde (5.60 g, 45.9 mmol) and 2-iodopropane (7.86 g, 46.2 mmol) were dissolved in 50 mL of isopropanol. Potassium carbonate (20 g, 145 mmol) was added, and the mixture was heated to reflux for 8 h, at which time TLC analysis indicated that the reaction had gone to completion. Water was added to dissolve all solids, and the mixture was extracted with ether (3×). The combined ether layer was washed with water, 2 M NaOH, again with water until clear (4×), and finally with brine. The solution was dried over MgSO4, filtered, and evaporated to give 5.03 g (67%) of the desired 3-isopropoxybenzaldehyde product as a pale oil. 1H NMR (C6D6) δ 9.62 (s, 1H), 7.29 (s, 1H), 7.03 (m, 1H), 6.91 (t, 1H), 6.84 (m, 1H), 4.03 (septet, 1H), 0.96 (d, 6H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:25])[CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[F:26][C:27]([F:39])([F:38])[C:28]1[CH:29]=[C:30]([S:34](Cl)(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1>>[F:39][C:27]([F:26])([F:38])[C:28]1[CH:29]=[C:30]([S:34]([NH:1][CH2:2][CH2:3][C:4]2[CH:5]=[CH:6][C:7]([C:10]3[CH:15]=[CH:14][C:13]([CH:16]([CH3:25])[CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:12][CH:11]=3)=[CH:8][CH:9]=2)(=[O:35])=[O:36])[CH:31]=[CH:32][CH:33]=1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2ccc(CCN)cc2)cc1
Product: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2ccc(CCNS(=O)(=O)c3cccc(C(F)(F)F)c3)cc2)cc1

Procedure:
The title compound was prepared following the method of Example 147 and using 1 mL of a stock solution of 0.5 g (1.4 mmol) of material from Example 50 and 19 mg (0.11 mmol) 3-trifluoromethyl-benzenesulfonyl chloride. NMR was consistent with the proposed compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[H-].[Na+].[CH3:13][CH:14]([Si:16](Cl)([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])[CH3:15]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([Si:16]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:15])[CH3:13])[CH:9]=[CH:10][C:3]=12
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: Clc1ccnc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(Cl)ccnc21
Temperature: 0 °C
Reaction time: 8 h
Yield: 91.3 %

Procedure:
A flask was charged with 4-chloro-1H-pyrrolo[2,3-b]pyridine (6.0 g, 39 mmol, Arkpharm) and THF (100 mL). The mixture was cooled to about 0° C. and 60 wt % NaH (1.89 g, 47.2 mmol) was added portion-wise. The mixture was warmed to rt and after about 45 min. TIPSCl (12.5 mL, 59.0 mmol) was added drop-wise and mixture was allowed to stir overnight at rt. The mixture was quenched with water (100 mL) and extracted with EtOAc (200 mL). The organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography with a gradient of 0 to 10% EtOAc/heptane to give 4-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (11.0 g, 91%): 1H NMR (d-DMSO) δ 8.20 (d, J=5.17 Hz, 1H), 7.59 (d, J=3.55 Hz, 1H), 7.23 (d, J=5.16 Hz, 1H), 6.68 (d, J=3.50 Hz, 1H), 1.83 (m, 3H), 1.06 (m, 18H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].[CH:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[SH:18])([CH3:11])[CH3:10].C([O-])([O-])=O.[K+].[K+].C(O)CO>[Cu]I.CC(O)C>[CH:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18][C:2]1[C:3]([CH3:8])=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH3:11])[CH3:10]
Reactant: Cc1ccccc1I
Reactant: CC(C)c1ccccc1S
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: OCCO
Product: Cc1ccccc1Sc1ccccc1C(C)C
Yield: 87.9 %

Procedure:
The general procedure in example 39 was followed. 2-Iodotoluene (218 mg, 1.0 mmol), 2-Isopropylbenzenethiol (90% purity, 168 μL, 1.0 mmol), CuI (10 mg, 0.05 mmol), K2CO3 (276 mg, 2.0 mmol), ethylene glycol (111 μL, 2.0 mmol) and 2-propanol (1.0 mL) were used to obtain the 2-tolyl 2-Isopropylphenyl sulfide (213 mg, 88% yield) as colorless liquid. Column chromatographic solvent (hexane). Rf=0.4 (hexane). 1H NMR (CDCl3, 300 MHz) δ 7.32 (d, 1 H, J=7.5 Hz), 7.18-7.26 (m, 2 H), 7.13 (dd, 1 H, J=1.5 Hz, 7.2 Hz), 7.09-7.11 (m, 1 H), 7.01-7.08 (m, 2 H), 7.00 (dd, 1 H, J=1.5 Hz, 7.2 Hz), 3.49 (hept, 1 H, J=6.6 Hz), 2.37 (s, 3 H), 1.25 (s, 3 H), 1.22 (s, 3 H). 13C NMR (CDCl3, 75 MHz) δ 149.6, 138.6, 135.5, 133.1, 132.2, 131.1, 130.6, 127.9, 127.0, 126.8, 126.7, 126.1, 30.9, 23.9, 20.9. IR (neat, cm−1) 3060, 3012, 2962, 2867. MS (EI) m/z (relative intensity) 242 (100), 225 (80). Anal. Cald. for C16H18S, Cald. C, 79.29; H, 7.49. Found C, 79.33; H, 7.62.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:14]([CH3:16])[CH3:15]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH:14]([CH3:16])[CH3:15])[CH:6]=1
Reactant: Brc1cn[nH]c1
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)n1cc(Br)cn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 76.9 %

Procedure:
To a solution of 4-bromo-1H-pyrazole (5 g, 34.24 mmol, 1.0 eq) in DMF were added K2CO3 (11.83 g, 85.60 mmol, 2.5 eq.) and 2-bromopropane (6.31 g, 51.36 mmol, 1.5 eq.) The mixture was stirred at RT for 12 h. The mixture was quenched and extracted as in Intermediate Example 5(a). The solvent was distilled off to afford the product in 76.9% yield (5.0 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH3:25][C:26]1([O:29][CH2:28]1)[CH3:27].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[N:15]([CH2:25][C:26]([OH:29])([CH3:28])[CH3:27])[N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1
Reactant: CC1(C)CO1
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(O)Cn1nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn2c1=O
Temperature: 85 °C
Reaction time: 8 h
Yield: 76.5 %

Procedure:
To a solution of 7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (20 mg, 0.056 mmol), prepared as described in Example 1, in 0.6 mL of DMF was added isobutylene oxide (4.0 mg, 0.056 mmol), followed by K2CO3 (15.5 mg, 0.112 mmol). The mixture was heated to 85° C. After stirring overnight, the reaction was allowed to cool to RT The reaction mixture was filtered (to remove excess of K2CO3). The collected solution was concentrated under reduced pressure. The crude product was purified by reverse phase HPLC to give the title compound, 7,8-bis(4-chlorophenyl)-2-(2-hydroxy-2-methylpropyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (18.4 mg, 77% yield) as a yellow oil. MS [M+H]+: found 429; 1H NMR (CDCl3, 400 MHz) δ 8.28 (s, 1H), 7.39-7.27 (m, 6H), 7.16-7.12 (m, 2H), 4.16 (s, 2H), 4.00 (s, 1H), 1.34 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1.[CH:16]1([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([C:26]3[O:30][N:29]=[C:28]([CH:31]([CH3:33])[CH3:32])[N:27]=3)[CH2:22][CH2:21]2)[CH2:18][CH2:17]1.C(N(C(C)C)C(C)C)C>ClCCl>[CH:16]1([N:19]([CH:20]2[CH2:25][CH2:24][N:23]([C:26]3[O:30][N:29]=[C:28]([CH:31]([CH3:33])[CH3:32])[N:27]=3)[CH2:22][CH2:21]2)[C:11](=[O:12])[C:10]2[CH:14]=[CH:15][C:7]([C:6]3[O:5][CH:4]=[N:3][C:2]=3[CH3:1])=[CH:8][CH:9]=2)[CH2:17][CH2:18]1
Reactant: Cc1ncoc1-c1ccc(C(=O)Cl)cc1
Reactant: CC(C)c1noc(N2CCC(NC3CC3)CC2)n1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ncoc1-c1ccc(C(=O)N(C2CC2)C2CCN(c3nc(C(C)C)no3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-(4-Methyl-oxazol-5-yl)-benzoyl chloride (89 mg) is added portionwise to a mixture of cyclopropyl-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-amine (100 mg) and ethyldiisopropylamine (100 μL) in dichloromethane (5 mL). The mixture is stirred for 1 h at room temperature, washed with water and 1 M HCl, dried over Na2SO4 and concentrated in vacuo. The residue is triturated with diethyl ether to give the title compound. LC (method 6): tR=1.83 min; Mass spectrum (ESI+): m/z=436 [M+H]+.
Reaction SMILES: [NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:2]([C:6]([OH:8])=O)[CH:3]([CH3:5])[CH3:4].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:27]([O:34][C:35](=[O:41])[C@H:36]([CH:38]([CH3:40])[CH3:39])[NH2:37])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([O:34][C:35](=[O:41])[C@H:36]([CH:38]([CH3:39])[CH3:40])[NH:37][C:6](=[O:8])[C@H:2]([CH:3]([CH3:4])[CH3:5])[NH:1][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)[C@H](N)C(=O)OCc1ccccc1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)OCc1ccccc1)C(C)C

Procedure:
Boc-Val-OH (2.86 g, 13.2 mmol) was coupled to valine benzyl ester p-toluenesulfonate (5.0 g, 13.2 mmol) using the procedure of Example 55 to give 5.41g, (100%) of the desired product (RF 0.15; 20% ethyl acetate in hexane) as a colorless gum. Mass spectrum M+H)+ =407.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:12])=[C:4]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[CH:5]=O.Cl[CH2:14][C:15]([N:17]([CH3:19])[CH3:18])=[O:16].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[C:3]2[O:12][C:14]([C:15]([N:17]([CH3:19])[CH3:18])=[O:16])=[CH:5][C:4]=2[CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1
Reactant: CN(C)C(=O)CCl
Reactant: COc1cc(Br)c(O)c(C=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(Br)c2oc(C(=O)N(C)C)cc2c1

Procedure:
3-Bromo-2-hydroxy-5-methoxybenzaldehyde (1.5 g, 6.49 mmol), 2-chloro-N,N-dimethylacetamide (0.73 mL, 7.14 mmol) and potassium carbonate (1.8 g, 13.0 mmol) were heated to reflux in dimethylformamide (15 mL) for 2 h. The solvent was removed in vacuo and the residue was taken up in ethyl acetate and washed with water and brine. The organic phase was dried over MgSO4, filtered and then concentrated by rotary evaporation. The crude product was purified by flash chromatography (SiO2; heptane/EtOAc, gradient 0-100%).