Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].Cl.[NH2:3][CH2:4][CH2:5][C:6]1[CH:38]=[CH:37][C:9]([O:10][C:11]2[CH:12]=[CH:13][C:14]3[N:18]=[C:17]([CH2:19][O:20][C:21]4[CH:34]=[CH:33][C:24]([CH2:25][CH:26]5[S:30][C:29](=[O:31])[NH:28][C:27]5=[O:32])=[CH:23][CH:22]=4)[N:16]([CH3:35])[C:15]=3[CH:36]=2)=[CH:8][CH:7]=1.C(N(CC)CC)C.Cl.[C:47](N)(=[O:54])[C:48]1[CH:53]=[CH:52][CH:51]=[N:50][CH:49]=1>CN(C)C=O>[ClH:1].[ClH:1].[O:31]=[C:29]1[NH:28][C:27](=[O:32])[CH:26]([CH2:25][C:24]2[CH:33]=[CH:34][C:21]([O:20][CH2:19][C:17]3[N:16]([CH3:35])[C:15]4[CH:36]=[C:11]([O:10][C:9]5[CH:8]=[CH:7][C:6]([CH2:5][CH2:4][NH:3][C:47](=[O:54])[C:48]6[CH:53]=[CH:52][CH:51]=[N:50][CH:49]=6)=[CH:38][CH:37]=5)[CH:12]=[CH:13][C:14]=4[N:18]=3)=[CH:22][CH:23]=2)[S:30]1
Reactant: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(CCN)cc3)cc21
Reactant: NC(=O)c1cccnc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(CCNC(=O)c4cccnc4)cc3)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.6 %

Procedure:
A mixture of 5-[4-[6-[4-(2-aminoethyl)phenoxy]-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione dihydrochloride (0.3 g), triethylamine (0.17 g) and anhydrous N,N-dimethylformamide (15 ml) was stirred at room temperature for 30 minutes. To the mixture was added nicotinamide hydrochloride (0.1 g) and this mixture was irradiated with ultrasound for 30 minutes, stirred at room temperature for 6 hours and then allowed to stand overnight. The reaction mixture was concentrated and partitioned between a mixture of ethyl acetate:tetrahydrofuran (1:1) and water. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by liquid chromatography (LiChroprepDIOL (MERCK)) using ethyl acetate:tetrahydrofuran=3:1 as the eluant. To a solution of the glassy product in tetrahydrofuran (5 ml) was added 4N hydrogen chloride in 1,4-dioxane (5 ml) and the mixture was irradiated with ultrasound for 30 minutes. The precipitate was isolated by filtration to afford the title compound (0.15 g, pale yellow powder, mp 176-180° C. (dec)).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]#[N:12])[CH:10]=1)[NH:7][N:6]=[C:5]2[CH:13]1[CH2:18][CH2:17][N:16]([S:19]([CH2:22][CH3:23])(=[O:21])=[O:20])[CH2:15][CH2:14]1.[F:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:22]([S:19]([N:16]1[CH2:17][CH2:18][CH:13]([C:5]2[C:4]3[C:8](=[C:9]([C:11]#[N:12])[CH:10]=[C:2]([C:28]4[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=4)[CH:3]=3)[NH:7][N:6]=2)[CH2:14][CH2:15]1)(=[O:21])=[O:20])[CH3:23]
Reactant: CCS(=O)(=O)N1CCC(c2n[nH]c3c(C#N)cc(Br)cc23)CC1
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCS(=O)(=O)N1CCC(c2n[nH]c3c(C#N)cc(-c4ccc(F)cc4)cc23)CC1

Procedure:
Following the general procedure of Example 65, a mixture of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indazole-7-carbonitrile (Intermediate 10) (50 mg, 0.102 mmols), 4-fluorophenyl boronic acid (42 mg, 0.306 mmols), potassium carbonate (84 mg, 0.612 mmol), and Pd(PPh3)4 (10 mg) in dioxane/water (6/1, 3.5 mL) were reacted to give the crude title compound.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=O.[S:12]1[CH2:18][C:16](=[O:17])[NH:15][C:13]1=[S:14].C(O)(=O)C>C1(C)C=CC=CC=1.C([O-])(=O)C.[NH4+]>[F:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[C:18]1[S:12][C:13](=[S:14])[NH:15][C:16]1=[O:17]
Reactant: COc1ccc(F)c(C=O)c1
Reactant: O=C1CSC(=S)N1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COc1ccc(F)c(C=C2SC(=S)NC2=O)c1
Temperature: 120 °C
Reaction time: 12 h
Yield: 91.5 %

Procedure:
To a suspension of 2-fluoro-5-methoxybenzaldehyde (5.00 g, 32.46 mmol) and rhodanine (4.31 g, 32.46 mmol) in dry toluene (1000 mL) was added ammonium acetate (50 mg) and acetic acid (2 mL). The resulting suspension was allowed to stir at 120° C. for 12 h under Dean-Stark apparatus before being allowed to cool and filtered. Resultant solid was washed with hexane and allowed to dry in vacuo to give an orange crystalline solid (8.00 g, 91%); δH (300 MHz, CDCl3) 7.50 (1H, s, CH═C); 7.31 (1H, t, Ar), 7.20–7.11 (1H, m, Ar), 6.95–6.89 (1H, m, Ar), 3.80 (3H, s, OCH3).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9]([NH:10][C@@H:11]3[CH2:22][C@@H:14]4[CH2:15][N:16]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:17][C@@H:13]4[C@H:12]3[CH3:23])=[C:8]([C:24]([NH2:26])=[O:25])[CH:7]=[N:6][N:5]2[CH:27]=1.[Cu][C:29]#[N:30]>CN1CCCC1=O.C(OCC)(=O)C>[C:29]([C:2]1[CH:3]=[C:4]2[C:9]([NH:10][C@@H:11]3[CH2:22][C@@H:14]4[CH2:15][N:16]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:17][C@@H:13]4[C@H:12]3[CH3:23])=[C:8]([C:24]([NH2:26])=[O:25])[CH:7]=[N:6][N:5]2[CH:27]=1)#[N:30]
Reactant: C[C@@H]1[C@H]2CN(S(C)(=O)=O)C[C@H]2C[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Reactant: N#C[Cu]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: C[C@@H]1[C@H]2CN(S(C)(=O)=O)C[C@H]2C[C@H]1Nc1c(C(N)=O)cnn2cc(C#N)cc12
Temperature: 220 °C
Yield: 56.8 %

Procedure:
A mixture of 6-bromo-4-(((3aS,4R,5R,6aS)-4-methyl-2-(methylsulfonyl)octahydrocyclopenta[c]pyrrol-5-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide from Step 3 of Example 59 (70 mg, 0.153 mmol) and copper(I) cyanide (27.5 mg, 0.307 mmol) in 1-methyl-2-pyrrolidinone (1 mL) was heated to 220° C. under microwave for 2 h. The resulting mixture was diluted with ethyl acetate (80 mL), washed with saturated NH4Cl, water, brine, dried (MgSO4) and concentrated. The residue was purified by silica gel chromatography, eluting with 60-100% ethyl acetate in hexanes, to give 6-cyano-4-(((3aS,4R,5R,6aS)-4-methyl-2-(methylsulfonyl)octahydrocyclopenta[c]pyrrol-5-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide (35 mg, 56% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.43 (d, J=1.8 Hz, 1H), 8.37 (s, 1H), 7.61 (d, J=1.5 Hz, 1H), 4.24-4.01 (m, 1H), 3.26-3.11 (m, 2H), 3.05 (m, 1H), 2.93 (s, 3H), 2.93-2.83 (m, 1H), 2.61-2.54 (m, 1H), 2.36-2.17 (m, 1H), 1.93-1.82 (m, 1H), 1.70-1.55 (m, 1H), 1.36-1.25 (m, 1H), 1.10-1.02 (m, 3H).
Reaction SMILES: BrC1C=C[C:5](NCC(OC)=O)=[N:6]C=1.[F:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:23]=1[N:22]([CH3:24])[CH:21]=[C:20]2[CH:25]=O.CN1C2C(=CC=CC=2)C(C)=C1C=O>>[F:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:23]=1[N:22]([CH3:24])[CH:21]=[C:20]2[CH2:25][NH:6][CH3:5]
Reactant: COC(=O)CNc1ccc(Br)cn1
Reactant: Cn1cc(C=O)c2cccc(F)c21
Agent: Cc1c(C=O)n(C)c2ccccc12
Product: CNCc1cn(C)c2c(F)cccc12
Yield: 72 %

Procedure:
According to the procedure of Preparation 11 (c), except substituting 7-fluoro-1-methyl-1H-indole-3-carboxaldehyde (0.23, 1.3 mmole) for the 1,3-dimethyl-1H-indole-2-carboxaldehyde, the title compound (0.18 g, 72%) was prepared as a viscous oil: MS (ES) m/e 193 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.[Cl:11][C:12]1[N:17]=[C:16](Cl)[CH:15]=[C:14]([Cl:19])[N:13]=1.C([O-])(=O)C.[Na+]>O.C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:16]2[CH:15]=[C:14]([Cl:19])[N:13]=[C:12]([Cl:11])[N:17]=2)[NH2:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(NN)cc1
Reactant: Clc1cc(Cl)nc(Cl)n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(N(N)c2cc(Cl)nc(Cl)n2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of p-methoxyphenylhydrazine (59 g.), 2,4,6-trichloropyrimidine (78.5 g.), and a solution of anhydrous sodium acetate (63 g.) in a mixture of water (260 ml.) and ethanol (1200 ml.) was shaken at room temperature for 2 hours. The crystalline precipitate which had formed was collected by filtration, washed with ethanol (50 ml.) and recrystallised from a mixture of chloroform (200 ml.) and ethanol (800 ml.) to give N-(p-methoxyphenyl)-N-(2,6-dichloropyrimidin-4-yl)hydrazine as a pale yellow solid, m.p. 156°-158° C. From the crystallisation mother liquors there was obtained, after chromatography on silica gel (300 g.) using a mixture containing equal parts by volume of ether and petroleum ether (b.p. 40° C.), N-(p-methoxyphenyl)-N-(4,6-dichloropyrimidin-2-ylhydrazine as a pale yellow solid, m.p. 113°-115° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:24]([O:31][C:32](=[O:43])[CH:33]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:34](O)=[O:35])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(CC)CC>CN(C=O)C>[CH2:24]([O:31][C:32](=[O:43])[CH:33]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:34]([N:11]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:16][CH:15]=1)=[O:35])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C(O)C(C(=O)OCc1ccccc1)c1ccccc1
Reactant: COc1ccc(NCCc2ccc(C(F)(F)F)cc2)cc1OC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(N(CCc2ccc(C(F)(F)F)cc2)C(=O)C(C(=O)OCc2ccccc2)c2ccccc2)cc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 28.9 %

Procedure:
A mixture of 0.7 g (2.1 mmol) (3,4-Dimethoxy-phenyl)-[2-(4-trifluoromethyl-phenyl)-ethyl]-amine, 0.58 g (2.1 mmol) 2-phenyl-malonic acid monobenzylester (commercially available), 0.83 g (2.5 mmol) TBTU and 0.43 g (4.3 mmol) NEt3 in 15 mL DMF was stirred at room temperature for 16 h. After evaporation to dryness the residue was treated with HCl aq. and DCM. The combined organic phases were washed with HCl aq., dried with MgSO4 and evaporated to dryness. The residue was purified by flash column chromatography on silica eluting with a gradient formed from ethyl acetate and heptane. The product containing fractions were combined and evaporated to dryness to yield 0.35 g (29%) of the title compound. MS(m/e): 578.3 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)O.[CH2:18](O)[CH3:19]>>[CH2:18]([O:11][C:10](=[O:12])[CH2:9][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=1)[CH3:19]
Reactant: CCO
Reactant: O=C(O)CCc1cccc(O)c1
Agent: O=S(=O)(O)O
Product: CCOC(=O)CCc1cccc(O)c1

Procedure:
To a solution of commercially available 3-(3-hydroxy-phenyl)-propionic acid (25 g, 150.4 mmol) in ethanol (250 mL) was added concentrated sulfuric acid (3.0 mL). The solution was heated to reflux overnight. The solvent was removed in vacuo, and the resulting oil was diluted ethyl acetate and placed in a separatory funnel. The organic portion was extracted 2× with 5% NaHCO3 and once with brine. The solution was dried (MgSO4), filtered and concentrated to a dark tan oil (30 g). This material was carried on to the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1.Br[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=1>>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][N:15]([CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=4)[C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1
Reactant: Fc1cccc(CBr)c1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Product: Cc1noc(C)c1Cn1cc(N2C(=O)CN(Cc3cccc(F)c3)C2=O)cn1
Yield: 27 %

Procedure:
Prepared as in example 10-5 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 10-1) and 1-(bromomethyl)-3-fluorobenzene. Yield 27%. MS M+H calculated 384.1. Found 384.1. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.06 uM.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:9]=[CH:8][S:7][CH:6]=1)=[O:4].O[CH2:11][NH:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15]>S(=O)(=O)(O)O.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>[CH3:1][NH:2][C:3]([C:5]1[CH:9]=[C:8]([CH2:11][NH:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[S:7][CH:6]=1)=[O:4]
Reactant: CNC(=O)c1ccsc1
Reactant: O=C(NCO)C(F)(F)F
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CNC(=O)c1csc(CNC(=O)C(F)(F)F)c1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
To suspension of N-methyl-3-thiophenecarboxamide (1.12 g) (prepared according to J. Org. Chem. (1976), 41(23), 3668-74) in concentrated aqueous sulphuric acid (25 ml) at 0-5° C. was added N-(hydroxymethyl)trifluoroacetamide (1.134 g). The suspension was allowed to warm to 20° C. and stirred for 2 h. The mixture was poured onto ice (150 g) and diluted with ethyl acetate (200 ml). The biphase mixture was diluted with saturated sodium hydrogen carbonate (200 ml) and treated with sodium hydrogen carbonate (21 g). The phases were separated and the organic phase washed with saturated sodium hydrogen carbonate (150 ml×2). The combined aqueous phases were extracted with ethyl acetate (100 ml). The combined organic extracts were concentrated in vacuo. The residue was pre-absorbed onto silica and purified by biotage (90 g) eluting with 1:1 to 0:1 cyclohexane:ethyl acetate to give the title compound as a white solid (0.7129).
Reaction SMILES: N([CH2:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[C:12]1[N:16]([C:17]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:15]=[N:14][N:13]=1)=[N+]=[N-].C1C(=O)N([Br:43])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)Cl>[Br:43][CH2:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[C:12]1[N:16]([C:17]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:15]=[N:14][N:13]=1
Reactant: [N-]=[N+]=NCc1cc(Cl)ccc1-c1nnnn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: Clc1ccc(-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c(CBr)c1
Temperature: 25 °C
Yield: 74.1 %

Procedure:
5-(2-Azidomethyl-4-chloro-phenyl)-1-trityl-1H-tetrazole: To 114A (4 g, 9.15 mmol) in chloroform (20 mL) was added NBS (1.711 g, 9.61 mmol) and benzoyl peroxide (30 mg, 0.124 mmol) and the reaction was heated at reflux overnight. Additional NBS and peroxide were added and the reaction was heated an addition 2 h. The reaction was cooled to rt, filtered, and purified by flash chromatography to give 5-(2-bromomethyl-4-chloro-phenyl)-1-trityl-1H-tetrazole (3.5 g, 74.1%). 1HNMR (400 MHz, CDCl3) δ: 4.78 (s, 2H), 7.04-7.14 (m, 5H), 7.24-7.35 (m, 11H), 7.40 (d, J=2.02 Hz, 1H), 8.06 (d, J=8.34 Hz, 1H). This intermediate (1.57 g, 3.04 mmol) and sodium azide (0.198 g, 3.04 mmol) in DMF (8 mL) were stirred for two days. The reaction was partitioned with EtOAc/water/brine and extracted with EtOAc. The combined organic layers were washed with water and brine, dried (MgSO4), and purified by flash chromatography to give 114B. LCMS m/z 195.2 (M+H—N3)+; 152.1 (M+H—N6).
Reaction SMILES: [CH3:1][C:2]1[S:12][C:5]2[N:6]=[C:7]([CH3:11])[CH:8]=[C:9]([NH2:10])[C:4]=2[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:31]1([S:37](Cl)(=[O:39])=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1COCC1.O>[CH3:1][C:2]1[S:12][C:5]2=[N:6][C:7]([CH3:11])=[CH:8][C:9]([NH:10][S:37]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)(=[O:39])=[O:38])=[C:4]2[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COc1cccc(-c2c(C)sc3nc(C)cc(N)c23)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(-c2c(C)sc3nc(C)cc(NS(=O)(=O)c4ccccc4)c23)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 58.9 %

Procedure:
To a stirred solution of 2,6-dimethyl-3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridin-4-amine (100 mg, 0.352 mmol) (Description 4) in THF (2 mL), cooled in an ice bath, was added LiHMDS (1M solution in THF) (0.774 mL, 0.774 mmol). The reaction mixture was stirred at RT for 45 min before the addition of benzenesulfonyl chloride (0.155 g, 0.879 mmol). The reaction mixture was then stirred at RT for a further 12 h. The reaction mixture was then diluted with water (15 mL) and the aqueous layer extracted with DCM (3×30 mL) and the combined organic extracts dried over a phase separating column and concentrated. MeOH (ca. 0.5 mL) was added to the residue which resulted in the precipitation of a solid. The solid was filtered, washed with MeOH (2 mL) and dried, to afford the title compound (88 mg). LCMS (A) m/z: 425 [M+1]+, Rt 1.40 min (basic).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:15]2[C:19](OCC)=[C:18]([C:23](=[O:27])[N:24]([CH3:26])[CH3:25])[S:17](=[O:29])(=[O:28])[N:16]=2)=[CH:7][CH:6]=1)[CH3:3].C(#[N:32])C>>[CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:15]2[C:19]([NH2:32])=[C:18]([C:23](=[O:27])[N:24]([CH3:26])[CH3:25])[S:17](=[O:29])(=[O:28])[N:16]=2)=[CH:7][CH:6]=1)[CH3:3]
Reactant: CCOC1=C(C(=O)N(C)C)S(=O)(=O)N=C1NCCSCc1ccc(CN(C)C)o1
Reactant: CC#N
Product: CN(C)Cc1ccc(CSCCNC2=NS(=O)(=O)C(C(=O)N(C)C)=C2N)o1

Procedure:
Into a solution of 3-[2-[(5-dimethylaminomethyl-2-furanyl)methylthio]ethyl]amino-4-ethoxy-5-dimethylcarbamylisothiazole-1,1-dioxide (1.4 g, 3.2 mmol) in acetonitrile (12 ml) warmed at 65° C., ammonia gas was slowly bubbled over a 1-2 hour period. Solvent was evaporated, residue chromatographed on silica gel eluting with 3-5% methanol/chloroform to give 0.96 g of title compound which could be crystallized from nitromethane/ether, mp 101°-104°.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][NH:14][C:15]2[C:16](=[O:32])[N:17]([C:28]([CH3:31])([CH3:30])[CH3:29])[S:18](=[O:27])(=[O:26])[C:19]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=O)=O)=CC=1.[SH:33][CH:34]1[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35]1.C(=O)([O-])[O-].[K+].[K+]>CC#N>[C:28]([N:17]1[C:16](=[O:32])[C:15]([NH:14][CH2:13][CH2:12][S:33][CH:34]2[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35]2)=[C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[S:18]1(=[O:26])=[O:27])([CH3:31])([CH3:30])[CH3:29]
Reactant: Cc1ccc(S(=O)(=O)OCCNC2=C(c3ccccc3)S(=O)(=O)N(C(C)(C)C)C2=O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(S)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(SCCNC2=C(c3ccccc3)S(=O)(=O)N(C(C)(C)C)C2=O)C1
Temperature: 120 °C
Yield: 84 %

Procedure:
2-[(2-tert-Butyl-1,1-dioxido-3-oxo-5-phenyl-2,3-dihydroisothiazol-4-yl)amino]ethyl 4-methylbenzenesulfonate (150 mg, 0.313 mmol) was dissolved in dry MeCN (3 mL) under nitrogen atmosphere. tert-Butyl 3-mercaptopyrrolidine-1-carboxylate (70 mg, 0.345 mmol) was added followed by potassium carbonate (217 mg, 1.567 mmol). The reaction mixture was heated in a microwave reactor at 120° C. for 15 mins. Potassium carbonate was filtered off and the reaction mixture was evaporated to dryness in a vacuum centrifuge. The crude product was purified by preparative HPLC affording the title compound (134 mg, 83.4%). The product is a mixture of cis and trans isomers. 1H NMR (CDCl3, 500 MHz): δ 1.47 (s, 9H), 1.73 (s, 10H), 2.05 (s, 1H), 2.46-2.51 (m, 2H), 2.88 (bs, 1H), 3.01-3.13 (m, 3H), 3.29 (s, 1H), 3.41-3.57 (m, 2H), 5.65 (bs, 1H), 7.43-7.46 (m, 3H), 7.49-7.53 (m, 2H); 13C NMR (CDCl3, 125 MHz): δ 27.83, 28.73, 31.29, 32.33, 32.86, 41.74, 42.41, 43.23, 44.86, 45.09, 52.27, 52.53, 61.86, 79.79, 108.04, 125.15, 129.04, 130.04, 131.65, 134.81, 154.41, 159.66; Mass Spectrum: M+H+ 509.9.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[CH:7]=[CH:6][C:5]=1[O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[O:3].[CH:22](=O)[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1>>[F:21][C:18]([F:19])([F:20])[CH2:17][O:16][C:5]1[CH:6]=[CH:7][C:8]([O:10][CH2:11][C:12]([F:13])([F:14])[F:15])=[CH:9][C:4]=1[C:2](=[O:3])[CH:1]=[CH:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1
Reactant: COc1ccc(C=O)cc1
Reactant: CC(=O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Product: COc1ccc(C=CC(=O)c2cc(OCC(F)(F)F)ccc2OCC(F)(F)F)cc1

Procedure:
The title compound was prepared by heating a mixture of 2,5-bis(2,2,2-trifluoroethoxy)acetophenone (200 mg, 0.633 mmol) and p-anisaldehyde (77 ul, 0.633 mmol) similar to Example 1 and isolated as a yellow solid (75 mg, 27.3%). 1H NMR (CDCl3): 7.66 (d, J=15.9 Hz, 1H), 7.56 (d, J=9.0 Hz, 2H), 7.32 (d, J=15.6 Hz, 1H), 7.28 (d, J=3.3 Hz, 2H), 7.11 (dd, J=3.3, 9.0 Hz, 1H), 6.94 (t, J=8.7 Hz, 2H), 4.44-4.33 (m, 4H), 3.86 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[N:22]1[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].[N:28]1[CH:33]=[CH:32][CH:31]=[C:30](B(O)O)[CH:29]=1>>[OH:27][C@@H:24]1[CH2:25][CH2:26][N:22]([C:21]2[CH:20]=[CH:19][C:4]([C:5]([NH:7][C:8]3[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=3)=[O:6])=[CH:3][C:2]=2[C:30]2[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=2)[CH2:23]1
Reactant: OB(O)c1cccnc1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(N2CC[C@@H](O)C2)c(Br)c1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(N2CC[C@@H](O)C2)c(-c2cccnc2)c1

Procedure:
The title compound was prepared in analogous fashion to that described in Example 1 using (R)-3-bromo-4-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)benzamide (Stage 2.1) and pyridin-3-ylboronic acid to afford a white solid. UPLC-MS (condition 1) tR=1.94 min, m/z=444.1 [M+H]+, m/z=442.1 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.68-1.79 (m, 1H) 1.85 (dt, J=8.62, 4.37 Hz, 1H) 2.66 (d, J=9.78 Hz, 1H) 2.98-3.07 (m, 2H) 3.16-3.25 (m, 1H) 4.18 (br. s, 1H) 4.84 (br. s, 1H) 6.95 (d, J=8.80 Hz, 1H) 7.33 (d, J=8.56 Hz, 2H) 7.50 (dd, J=7.82, 4.89 Hz, 1H) 7.80 (d, J=2.20 Hz, 1H) 7.81-7.89 (m, 3H) 7.92 (dd, J=8.68, 2.32 Hz, 1H) 8.56 (d, J=3.91 Hz, 1H) 8.65 (br. s, 1H) 10.10 (s, 1H).
Reaction SMILES: CS([C:5]1(C)[C:8](=[C:9]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=2)[S:10]([CH3:13])(=[O:12])=[O:11])[CH2:7][N:6]1[C@H:22]([C:30]1[CH:35]=[CH:34][C:33]([CH2:36]Cl)=[CH:32][CH:31]=1)[C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)(=O)=O.[NH:39]1[CH2:44][CH2:43][S:42][CH2:41][CH2:40]1>ClCCl>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([C@@H:22]([C:30]2[CH:35]=[CH:34][C:33]([CH2:36][N:39]3[CH2:44][CH2:43][S:42][CH2:41][CH2:40]3)=[CH:32][CH:31]=2)[N:6]2[CH2:7][C:8](=[C:9]([C:14]3[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=3)[S:10]([CH3:13])(=[O:12])=[O:11])[CH2:5]2)=[CH:24][CH:25]=1
Reactant: CC1(S(C)(=O)=O)C(=C(c2cc(F)cc(F)c2)S(C)(=O)=O)CN1[C@@H](c1ccc(Cl)cc1)c1ccc(CCl)cc1
Reactant: C1CSCCN1
Solvent: ClCCl
Product: CS(=O)(=O)C(=C1CN([C@@H](c2ccc(Cl)cc2)c2ccc(CN3CCSCC3)cc2)C1)c1cc(F)cc(F)c1
Yield: 79.4 %

Procedure:
The operation is carried out as described in Example 87, starting with 0.05 g of methylsulfonyl methyl 1-{(R*)-[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine, form A isomer, 1.0 cm3 of dichloromethane and 0.025 g of thiomorpholine. The crude product is chromatographed on a silica gel column (particle size 0.06-0.200 mm, diameter 8 mm, height 8 cm), eluting with 80 cm3 of dichloromethane and then with a dichloromethane and methanol mixture (95/5 by volume), collecting 2.5 cm3 fractions immediately after using this eluent mixture. Fractions 3 to 8 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 0.038 g of 1-{(R*)-(4-chlorophenyl)[4-(thiomorpholin-4-ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine, form A isomer, is obtained in the form of a white foam [1H NMR spectrum (300 MHz, CDCl3, δ in ppm): from 2.60 to 2.75 (mt, 8H) 2.80 (s, 3H), 3.44 (s, 2H), 3.84 (mt, 2H), 4.33 (mt, 2H), 4.50 (s, 1H), 6.83 (tt, J=8.5 and 2.5 Hz, 1H), 6.97 (mt, 2H), from 7.20 to 7.40 (mt, 8H)].