Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[C:8]([S:10][CH3:11])[N:7]=[C:6]([C:12]2[S:16][C:15]([C:17](=[O:19])[CH3:18])=[CH:14][CH:13]=2)[CH:5]=1)[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:30][C:31]([F:38])([F:37])[C:32](OCC)=[O:33].Cl>C1COCC1.O>[CH2:1]([O:3][C:4]1[N:9]=[C:8]([S:10][CH3:11])[N:7]=[C:6]([C:12]2[S:16][C:15]([C:17](=[O:19])[CH2:18][C:32](=[O:33])[C:31]([F:38])([F:37])[F:30])=[CH:14][CH:13]=2)[CH:5]=1)[CH3:2]
Reactant: CCOC(=O)C(F)(F)F
Reactant: CCOc1cc(-c2ccc(C(C)=O)s2)nc(SC)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCOc1cc(-c2ccc(C(=O)CC(=O)C(F)(F)F)s2)nc(SC)n1
Temperature: -78 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
1-[5-(6-Ethoxy-2-methylsulfanyl-pyrimidin-4-yl)-thiophen-2-yl]-ethanone (210 mg, 0.71 mmol) was dissolved in anhydrous THF (7 mL) and cooled to −78° C. under nitrogen atmosphere. A solution of lithium bis(trimethylsilyl)amide (0.71 mL, 1.0 M) in THF was added. The reaction mixture was stirred at −20° C. under nitrogen atmosphere for 1 h. The reaction mixture was then cooled to −78° C. To this reaction mixture was added ethyl trifluoroacetate (170 μL, 1.43 mmol). The vigorously stirred solution was allowed to warm to ambient temperature overnight. The reaction mixture was poured into 20 mL of ice and water and was brought to pH=3˜4 by adding 10% HCl aqueous solution. The mixture was then extracted with diethyl ether (20 mL×3) three times. The ether layer was separated and dried with anhydrous MgSO4 and concentrated in vacuo to give crude product 1-[5-(6-ethoxy-2-methylsulfanyl-pyrimidin-4-yl)-thiophen-2-yl]-4,4,4-trifluoro-butane-1,3-dione (272 mg, 98% yield). 1H-NMR (CDCl3): δ 7.81 (m, 1H), 7.68 (m, 1H), 6.70 (s, 1H), 6.47 (s, 1H), 4.47 (q, J=7.1 Hz, 2H), 2.61 (s, 3H), 1.41 (t, J=7.1 Hz, 3H).
Reaction SMILES: [NH2:1][CH:2]([C:4]([OH:6])=[O:5])[CH3:3].[CH3:7][CH:8](O)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[NH2:1][CH:2]([CH3:3])[C:4]([O:6][CH:18]([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH3:7])[CH3:19])=[O:5]
Reactant: CCCCCCCCCCCC(C)O
Reactant: CC(N)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCC(C)OC(=O)C(C)N
Yield: 87.4 %

Procedure:
To a stirred solution of DL-alanine 1 (15 g, 168.5 mmol) in toluene (300 mL) was added 2-tridecanol 68 (30.3 g, 151.68 mmol) in one lot, followed by pTSA (35.26 g, 185.38 mmol). After the addition, the temperature of the reaction mixture was slowly raised to reflux temperature, the water was separated azeotropically and the reaction mixture was monitored by TLC. The reaction mixture was concentrated under vacuum, the obtained residue was taken in ethyl acetate (200 mL) and washed with aqueous 5% Na2CO3 (3×50 mL) followed by brine solution. The organic layer was dried over Na2SO4 and concentrated under vacuum to afford 69 (36 g, yield: 78.9%) as a liquid.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[S:4][C:3]=1/[CH:8]=[CH:9]/[C:10](N(C)C)=O.[CH3:15][N:16]([CH3:27])[C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH2:26])=[NH:25])=[CH:19][CH:18]=1.[OH-].[Na+]>O(CCO)C>[CH3:15][N:16]([CH3:27])[C:17]1[CH:18]=[CH:19][C:20]([NH:23][C:24]2[N:26]=[C:8]([C:3]3[S:4][C:5]([CH3:7])=[N:6][C:2]=3[CH3:1])[CH:9]=[CH:10][N:25]=2)=[CH:21][CH:22]=1
Reactant: CN(C)c1ccc(NC(=N)N)cc1
Reactant: Cc1nc(C)c(/C=C/C(=O)N(C)C)s1
Agent: [Na+]
Agent: [OH-]
Solvent: COCCO
Product: Cc1nc(C)c(-c2ccnc(Nc3ccc(N(C)C)cc3)n2)s1
Temperature: 120 °C

Procedure:
A mixture of 3-dimethylamino-1-(2,4-dimethyl-thiazol-5-yl)-propenone (0.95 mmol, 0.19 g) and N-(4-dimethylamino-phenyl)-guanidine (2 mmol) in 2-methoxylethanol (5 mL) was added NaOH (40 mg). The reaction mixture was heated at 120° C. for 18 h. The solvent was evaporated and the residue was purified by chromatography, using EtOAc/PE to afford N,N-dimethyl-N′-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-benzene-1,4-diamine {119} (74 mg) as a reddish-brown solid. 1H-NMR (300 MHz, d6-DMSO) δ 2.62 (s, 3H, CH3), 2.65 (s, 3H, CH3), 2.86 (s, 6H, CH3), 6.73 (m, 2H, Ph-H), 6.97 (d, 1H, J=5.1 Hz, pyrimidinyl-H), 7.56 (m, 2H, Ph-I), 8.44 (d, 1H, J=5.0 Hz, pyrimidinyl-H), 9.33 (s, 1H, NH). DE MALDI-TOF MS: {M+H}+=329.51 (C17H19N5S requires 325.43).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH:5]([NH2:8])[C:6]#[N:7])[CH3:2].CN(C1C=CC=CN=1)C.C1(N=C=NC2CCCCC2)CCCCC1.[CH3:34][O:35][CH2:36][CH2:37][C:38](O)=[O:39]>C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:9])[CH:5]([C:6]#[N:7])[NH:8][C:38](=[O:39])[CH2:37][CH2:36][O:35][CH3:34])[CH3:2]
Reactant: CCOC(=O)C(N)C#N
Reactant: COCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C#N)NC(=O)CCOC
Temperature: 0 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
A solution of aminocyanacetic acid ethyl ester (1.00 g, 7.80 mmol) in ethyl acetate (16.00 ml) was cooled to 0° C. and treated with dimethylaminopyridine (0.09 g, 0.78 mmol) and dicyclohexylcarbodiimide (1.93 g, 9.36 mmol). 3-Methoxy-propionic acid (0.81 g, 7.80 mmol) was added portionwise. After completed addition, the mixture was stirred at 0° C. for 1 h) then at room temperature for 3 h. The precipitated dicyclohexylurea was filtered off and the mother liquors washed with water, dried over sodium sulphate and evaporated. The residue was purified by trituration in diisopropylether to yield cyano-(3-methoxy-propionylamino)-acetic acid ethyl ester (1.27 g, 76%), MS (ISP): m/e=215.3 (M+H+).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([OH:16])=[O:15])[CH2:6][CH2:5]2.[C:19]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:19][O:15][C:14]([C:7]1([CH3:17])[CH2:6][CH2:5][C:4]2[C:9](=[C:10]([CH3:13])[C:11]([CH3:12])=[C:2]([OH:1])[C:3]=2[CH3:18])[O:8]1)=[O:16]
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)O)O2
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC(=O)C1(C)CCc2c(C)c(O)c(C)c(C)c2O1

Procedure:
A mixture of 6-hydroxy-2,5,7,8-tetramethychroman-2-carboxylic acid (5.0 g), methanol (100 ml) and p-toluenesulfonic acid (5 mg) is heated at reflux for 18 hr. The mixture is allowed to cool to 20°-25° and the solid collected and washed with ether and dried to give methyl-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylate. Methyl-6-hydroxy-2,5,7,8-tetramethychroman-2-carboxylate in THF (50 ml), is added to a suspension of lithium aluminum hydride (1.58 g) in THF (50 ml) at 0° dropwise over 15-20 min. The mixture is stirred at 0° for 30 min then at 20°-25° for 18 hr. The mixture is cooled to 0° and quenched by dropwise addition of ethyl acetate (10 ml), water (1.6 ml), aqueous sodium hydroxide (15%, 1.6 ml) and then water (4.8 ml). The mixture is stirred at 0° for 30 min then filtered. The solids are washed with THF (25 ml, 2×). The combined washes and filtrate are concentrated at reduced pressure and the residue is dissolved in ethyl acetate (150 ml), washed with water (100 ml), dried over sodium sulfate and the solvent removed at reduced pressure to a solid. A mixture of the solid (3.0 g), pyridine (3 ml) and chloroform (15 ml) is cooled to 0°. To this mixture is added p-toluenesulfonyl chloride (3.6 g ) in several small portions. The mixture is allowed to stand at 15° for 3 days then chloroform (50 ml) is added. The mixture is washed with water (100 ml), aqueous hydrochloric acid (5%, 100 ml), dried over sodium sulfate and the solvent removed at reduced pressure to give a crude tosylate (5.0 g). The crude tosylate is heated at 120° with piperazine (21.5 g) for 5 hr. The mixture was allowed to cool and distributed between dichloromethane (150 ml) and water (100 ml). The phases are separated and the organic phase is washed with water (100 ml), dried over sodium sulfate and the solvent removed at reduced pressure to leave an oil. This material is flash chromatographed on silica gel (200 g) eluting with ammonia, methanol, ethyl acetate (0.5/4.5/95). The appropriate fractions are pooled and concentrated to give a residue. A mixture of the residue (0.3 g), chlorodipyridinylpyrimidine (J.A.C.S., 32, 1591 (1967), 0.27 g), potassium carbonate (0.14 g) and acetonitrile (15 ml) is heated at reflux for 2 days. The solvent is removed at reduced pressure, the residue was distributed between methylene chloride (30 ml) and water (30 ml). The phases are separated and the organic phase is dried over sodium sulfate and the solvent removed at reduced pressure to leave a solid. This material was flash chromatographed on silica gel (30 g) eluting with ammonia, methanol, ethyl acetate (1/9/90) to give a solid which upon crystallization from ethyl acetate give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19]([O:21]C)=[O:20])[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([OH:23])[CH:3]=1.[OH-].[Na+].Cl>CO.C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19]([OH:21])=[O:20])[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([OH:23])[CH:3]=1
Reactant: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3O)c2c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3O)c12

Procedure:
Intermediate III (333 mg), sodium hydroxide solution 1M (5 ml) in 10 ml methanol and 10 ml THF were stirred at rt overnight. Then the mixture was acidified with hydrochloric acid and filtrated.
Reaction SMILES: OC(C(F)(F)F)=O.[NH2:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[OH:14].[C:15]1([C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=N)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)Cl>[C:15]1([C:21](=[N:8][C@@H:9]2[CH2:13][CH2:12][CH2:11][C@H:10]2[OH:14])[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: N[C@@H]1CCC[C@H]1O
Reactant: N=C(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O[C@@H]1CCC[C@H]1N=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.6 %

Procedure:
To a solution of (1R,2R)-2-aminocyclopentanol TFA salt (630 mg, 2.93 mmol) was added diphenylmethanimine (490 uL, 2.93 mmol) and TEA (0.5 mL, 3.58 mmol) in CH2Cl2 (3 mL). The reaction mixture was stirred at rt for 2 h and concentrated under reduced pressure and purified by ISCO flash chromatography using EtOAc and hexane as eluting solvent to yield (1R,2R)-2-(diphenylmethyleneamino)cyclopentanol (697 mg, 90% yield) as a colorless gum. HPLC: RT=1.96 min [M+H] 266.13 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm); 1H NMR (400 MHz, CDCl3) δ ppm 1.49-1.64 (m, 2H), 1.66-1.91 (m, 3H), 2.08-2.24 (m, 1H), 3.55-3.71 (m, 1H), 4.31-4.47 (m, 1H), 7.15-7.25 (m, 2H), 7.29-7.53 (m, 6H), 7.61-7.67 (m, 2H).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:14]=[C:15]([C:19]4[C:20]5[C:25]([C:26](Br)=[C:27]6[C:32]=4[CH:31]=[CH:30][CH:29]=[CH:28]6)=[CH:24][CH:23]=[CH:22][CH:21]=5)[CH:16]=[CH:17][CH:18]=3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:34]1([C:40]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)=[CH:41][C:42]2[CH:47]=[CH:46][C:45](OB(O)O)=[CH:44][CH:43]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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>[C:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:14]=[C:15]([C:19]4[C:20]5[C:25]([C:26]([C:45]6[CH:46]=[CH:47][C:42]([CH:41]=[C:40]([C:52]7[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=7)[C:34]7[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=7)=[CH:43][CH:44]=6)=[C:27]6[C:32]=4[CH:31]=[CH:30][CH:29]=[CH:28]6)=[CH:24][CH:23]=[CH:22][CH:21]=5)[CH:16]=[CH:17][CH:18]=3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)Oc1ccc(C=C(c2ccccc2)c2ccccc2)cc1
Reactant: Brc1c2ccccc2c(-c2cccc(-c3ccc(-c4ccccc4)cc3)c2)c2ccccc12
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: [Na+]
Solvent: Cc1ccccc1
Product: C(=C(c1ccccc1)c1ccccc1)c1ccc(-c2c3ccccc3c(-c3cccc(-c4ccc(-c5ccccc5)cc4)c3)c3ccccc23)cc1
Yield: 73 %

Procedure:
Under an atmosphere of argon, 9-(3-(4-phenylphenyl)phenyl)-10-bromoanthracene (3.0 g, 6.2 mmole), 4-(2,2-diphenylvinyl)phenylboric acid (2.0 g, 6.7 mmole, 1.1 eq) and tetrakis(triphenylphosphine)palladium(0) (0.14 g, 0.12 mmole, 2% Pd) were suspended in toluene (20 ml). To the obtained suspension, a 2M aqueous solution of sodium carbonate (2.1 g, 20 mmole, 3 eq/10 ml) was added, and the resultant mixture was refluxed for 10 hours. The reaction mixture was filtered and washed with water and methanol, and a light yellow solid substance was obtained. The obtained solid substance was suspended in boiling toluene (30 ml). After the suspension was cooled while being left standing, the suspension was filtered, and a light yellow solid substance (3.0 g, the yield: 73%) was obtained. The result of examination of the obtained product in accordance with 1H-NMR was as follows:
Reaction SMILES: C[O:2][C:3](=[O:18])[CH2:4][C:5]1[C:6]2[CH:13]=[C:12]([S:14](Cl)(=[O:16])=[O:15])[CH:11]=[CH:10][C:7]=2[S:8][CH:9]=1.[CH3:19][C@H:20]1[NH:25][C@@H:24]([CH3:26])[CH2:23][N:22]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=2)[CH2:21]1>>[CH3:26][C@H:24]1[CH2:23][N:22]([CH2:27][C:28]2[CH:29]=[CH:30][C:31]([O:34][C:35]([F:38])([F:36])[F:37])=[CH:32][CH:33]=2)[CH2:21][C@@H:20]([CH3:19])[N:25]1[S:14]([C:12]1[CH:11]=[CH:10][C:7]2[S:8][CH:9]=[C:5]([CH2:4][C:3]([OH:2])=[O:18])[C:6]=2[CH:13]=1)(=[O:16])=[O:15]
Reactant: COC(=O)Cc1csc2ccc(S(=O)(=O)Cl)cc12
Reactant: C[C@@H]1CN(Cc2ccc(OC(F)(F)F)cc2)C[C@H](C)N1
Product: C[C@@H]1CN(Cc2ccc(OC(F)(F)F)cc2)C[C@H](C)N1S(=O)(=O)c1ccc2scc(CC(=O)O)c2c1

Procedure:
The compound {5-[cis-2,6-dimethyl-4-(4-trifluoromethoxy-benzyl)-piperazine-1-sulfonyl]-benzo[b]thiophen-3-yl}-acetic acid was synthesized according to the procedure in Example 37 using (5-chlorosulfonyl-benzo[b]thiophen-3-yl)-acetic acid methyl ester and cis-3,5-dimethyl-1-(4-trifluoromethoxy-benzyl)-piperazine from Example 95, Step 1. 1H NMR (400 MHz, CD3OD) δ 8.48 (s, 1H), 7.96 (d, 1H), 7.88-7.80 (m, 2H), 7.57 (d, 2H), 7.28 (d, 2H), 4.60-4.50 (m, 2H), 4.36 (s, 2H), 3.97 (s, 2H), 3.38-3.28 (m, 2H), 2.74-2.64 (m, 2H), 1.55 (d, 6H); LCMS 542.9 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:29][C:30]2[C:35]([C:36]3[CH:41]=[CH:40][N:39]=[N:38][CH:37]=3)=[CH:34][C:33]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[F:48])=[C:32]([Cl:49])[CH:31]=2)=[CH:4][C:5]([F:28])=[C:6]([S:8]([N:11](CC2C=CC(OC)=CC=2OC)[C:12]2[S:13][CH:14]=[N:15][N:16]=2)(=[O:10])=[O:9])[CH:7]=1>Cl.O1CCOCC1>[Cl:1][C:2]1[C:3]([O:29][C:30]2[C:35]([C:36]3[CH:41]=[CH:40][N:39]=[N:38][CH:37]=3)=[CH:34][C:33]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[F:48])=[C:32]([Cl:49])[CH:31]=2)=[CH:4][C:5]([F:28])=[C:6]([S:8]([NH:11][C:12]2[S:13][CH:14]=[N:15][N:16]=2)(=[O:10])=[O:9])[CH:7]=1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(Oc3cc(Cl)c(-c4ccccc4F)cc3-c3ccnnc3)cc2F)c(OC)c1
Agent: Cl
Solvent: C1COCCO1
Product: O=S(=O)(Nc1nncs1)c1cc(Cl)c(Oc2cc(Cl)c(-c3ccccc3F)cc2-c2ccnnc2)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 4.8 %

Procedure:
The crude 5-chloro-4-(2-chloro-2′-fluoro-5-(pyridazin-4-yl)biphenyl-4-yloxy)-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide (220 mg) was dissolved in a 4M solution of HCl in 1,4-dioxane (10 mL) and stirred at room temperature for 3 hours. The resulting precipitate was collected and purified by reverse phase chromatography using acetonitrile:water:0.05% formic acid followed by chromatography on silica gel eluting with dichloromethane/methanol 9:1 to give the title compound (8.5 mg, 3.5%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:15][CH:14]3[NH:16][CH:10]([CH2:11][C:12](=[O:17])[CH2:13]3)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[F:18][C:19]([F:31])([F:30])[C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>N1C=CC=CC=1.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:15][CH:14]3[N:16]([S:26]([C:23]4[CH:22]=[CH:21][C:20]([C:19]([F:18])([F:30])[F:31])=[CH:25][CH:24]=4)(=[O:28])=[O:27])[CH:10]([CH2:11][C:12](=[O:17])[CH2:13]3)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CC2CC(c3cccc(Br)c3)CC(C1)N2
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C1CC2CC(c3cccc(Br)c3)CC(C1)N2S(=O)(=O)c1ccc(C(F)(F)F)cc1
Yield: 19 %

Procedure:
7-(3-Bromophenyl)-9-azabicyclo[3.3.1]nonan-3-one (90) and 4-(trifluoromethyl)benzene-1-sulfonyl chloride (12.25 g, 50.1 mmol) in pyridine (100 ml) and CH2Cl2 (100 ml) was stirred for 24 h. The solution was concentrated and flash chromatographed with CH2Cl2 as the eluant to yield 2.29 g (19% yield over 4 steps) of compound 91 as a pink solid.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[N:10]=[CH:9][C:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:14][C:13]([C:22]([N:24]3[CH2:30][CH2:29][C:28](=[O:31])[NH:27][CH2:26][CH2:25]3)=[O:23])=[N:12]2)=[CH:7][CH:6]=1.[CH3:32]I>CN(C)C=O>[CH3:3][O:4][C:5]1[N:10]=[CH:9][C:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:14][C:13]([C:22]([N:24]3[CH2:30][CH2:29][C:28](=[O:31])[N:27]([CH3:32])[CH2:26][CH2:25]3)=[O:23])=[N:12]2)=[CH:7][CH:6]=1
Reactant: COc1ccc(-n2nc(C(=O)N3CCNC(=O)CC3)cc2-c2ccccn2)cn1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(-n2nc(C(=O)N3CCC(=O)N(C)CC3)cc2-c2ccccn2)cn1
Reaction time: 0.25 h

Procedure:
At 0° C., the sodium hydride (washed with pentan and dried, 20.4 mg) was added to a solution of 1-[1-(6-methoxy-3-pyridyl)-5-(2-pyridyl)pyrazole-3-carbonyl]-5-oxo-1,4-diazepane (0.253 g) obtained in Example 108 in N,N-dimethylformamide (5.0 mL), and the mixture was stirred for 15 minutes. To the reaction mixture, methyl iodide (0.0602 mL) was added, and the mixture was stirred at room temperature for 14 hours. The resultant mixture was partitioned between water and chloroform-methanol (5%). The aqueous layer was further extracted with chloroform-methanol (5%), and the organic layers were combined, followed by washing with saturated brine and drying over sodium sulfate anhydrate. After filtration, the solvent was removed under reduced pressure, and the residue was purified through silica gel column chromatography (chloroform-methanol), to thereby give the title compound as an amorphous product (0.231 g, 88%).
Reaction SMILES: CCN(C(C)C)C(C)C.FC(F)(F)S([O:15][Si:16]([CH2:21][CH3:22])([CH2:19][CH3:20])[CH2:17][CH3:18])(=O)=O.[Br:25][C:26]1[N:30]2[CH:31]=[CH:32][C:33]([C:36](O)([CH3:38])[CH3:37])=[C:34]([F:35])[C:29]2=[N:28][CH:27]=1>C(Cl)Cl>[Br:25][C:26]1[N:30]2[CH:31]=[CH:32][C:33]([C:36]([O:15][Si:16]([CH2:17][CH3:18])([CH2:19][CH3:20])[CH2:21][CH3:22])([CH3:38])[CH3:37])=[C:34]([F:35])[C:29]2=[N:28][CH:27]=1
Reactant: CC[Si](CC)(CC)OS(=O)(=O)C(F)(F)F
Reactant: CC(C)(O)c1ccn2c(Br)cnc2c1F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(Br)cnc2c1F
Temperature: 25 °C
Yield: 101.7 %

Procedure:
Hünig's base (0.44 ml, 3.8 mmol) and triethylsilyl trifluoromethane-sulfonate (0.57 ml, 2.6 mmol) were added sequentially to a cold (−78° C.), stirred solution of 2-(3-bromo-8-fluoroimidazo[1,2-α]pyridin-7-yl)propan-2-ol (637 mg, 2.3 mmol) in CH2Cl2 (13 ml) and the solution warmed to ambient temperature. The mixture was partitioned between CH2Cl2 (50 ml) and water (50 ml) and the organic phase dried over anhydrous MgSO4, filtered through a short plug of silica (eluent CH2Cl2) and concentrated to afford 3-bromo-8-fluoro-7-[2-(triethylsilyloxy)prop-2-yl]imidazo[1,2-α]pyridine (906 mg, quant.): δH (360 MHz, CDCl3) 0.70 (6H, q, J 7.8), 0.99 (9H, t, J 7.8), 1.71 (6H, s), 7.32 (1H, t, J 6.9), 7.59 (1H, s), 7.88 (1H, d, J 7.3).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CS(O[CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]2[O:25][N:24]=[C:23]([CH:26]([CH3:28])[CH3:27])[N:22]=2)[CH2:17][CH2:16]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:14][CH:15]2[CH2:20][CH2:19][N:18]([C:21]3[O:25][N:24]=[C:23]([CH:26]([CH3:28])[CH3:27])[N:22]=3)[CH2:17][CH2:16]2)=[CH:6][N:7]=1
Reactant: Oc1ccc(Br)nc1
Reactant: CC(C)c1noc(N2CCC(COS(C)(=O)=O)CC2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1noc(N2CCC(COc3ccc(Br)nc3)CC2)n1
Temperature: 80 °C
Reaction time: 8 h
Yield: 80.3 %

Procedure:
A mixture of 6-bromo-3-pyridinol (1 g, 5.75 mmol), {1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methyl methanesulfonate (prepared as in Example 100, Steps 1-4, 1.74 g, 5.75 mmol), potassium carbonate (1.59 g, 11.49 mmol), and DMF (15 mL) stirred at 80° C. overnight. The mixture was cooled to room temperature, charged with water (100 mL), and was extracted with EtOAc. The organics were dried over MgSO4, filtered, and concentrated. The crude product was purified by chromatography on a silica gel column using 0 to 50% EtOAc/hexane to give 1.76 g (80%) of 2-bromo-5-[({1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methyl)oxy]pyridine as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 8.03 (d, 1H, J=3.1 Hz), 7.36 (d, 1H, J=8.7 Hz), 7.07 (dd, 1H, Ja=8.7 Hz, Jb=3.1 Hz), 4.21 (dd, 2H, Ja=11.0 Hz, Jb=2.1 Hz), 3.84 (d, 2H, J=6.3 Hz), 3.09 (m, 2H), 2.94-2.83 (m, 1H), 2.12-1.98 (m, 1H), 1.92 (d, 2H, J=12.2 Hz), 1.36-1.53 (m, 2H), 1.28 (d, 6H, J=7.0 Hz); LRMS (ESI), m/z 381/383 (M+H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[CH2:6][CH2:7][OH:8].[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.C(N(CC)CC)C>CCOCC>[S:20]([C:17]1[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=1)([O:8][CH2:7][CH2:6][C:5]1[CH:9]=[CH:10][CH:11]=[C:3]([C:2]([F:12])([F:13])[F:1])[CH:4]=1)(=[O:22])=[O:21]
Reactant: OCCc1cccc(C(F)(F)F)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)OCCc2cccc(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.7 %

Procedure:
A solution of 10.0 g (52.6 mmol) of 3-(trifluoromethyl)phenethyl alcohol in 75 mL of ether under nitrogen was treated with 10.53 g (55.2 mmol, 1.05 eq) p-toluenesulfonyl chloride. The solution was cooled to 0° and treated with 7.67 mL (5.57 g, 55.0 mmol, 1.05 eq) of triethylamine. The mixture was stirred at 0° for 30 minutes then warmed to room temperature and stirred for 16 hours. The precipitate was removed by filtration and washed with ether. The combined filtrate and ether was were evaporated under vacuum. The residue was redissolved in ethyl acetate and washed with 0.5N HCl and brine; the organic layer was removed, dried over sodium sulfate, filtered and concentrated under vacuum. Purification by flash chromatography on silica, eluting with 30% ethyl acetate/hexane, afforded 15.14 g (44.0 mmol, 84%) of the product. 1H NMR (200MHz, CDCl3): 2.44 (s,3H), 3.03 (t,7Hz,2H), 4.26 (t,7Hz,2H), 7.2-7.5 (m,6H), 7.66 (d,8Hz,2H). FAB-MS: calculated for C16H15F3SO3 344; found 345 (M+H,8%).
Reaction SMILES: [CH2:1]([C:3]1([CH2:8][C:9](OC)=[O:10])[O:7][CH2:6][CH2:5][O:4]1)[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].C(OCC)(=O)C>C1COCC1>[CH2:1]([C:3]1([CH2:8][CH2:9][OH:10])[O:7][CH2:6][CH2:5][O:4]1)[CH3:2]
Reactant: CCC1(CC(=O)OC)OCCO1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC1(CCO)OCCO1
Temperature: 90 °C
Reaction time: 8 h
Yield: 27.7 %

Procedure:
To a solution of methyl 2-(2-ethyl-1,3-dioxolan-2-yl)acetate (1 g, 5.75 mmol) in anhydrous THF (40 mL) was added LAH (900 mg, 23.7 mmol) at 0° C. under nitrogen atmosphere, the resulting mixture was stirred at 90° C. overnight. The mixture was cooled to room temperature, and ethyl acetate was added to the mixture. The resulting slurry was filtered and the filtrate was concentrated to dryness. The crude product was purified by silica gel chromatography eluting with DCM/methanol (100:1 to 20:1) to give 2-(2-ethyl-1,3-dioxolan-2-yl)ethanol (233 mg, 27.4%) as yellow oil that was used without purification.