Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.[NH2:11][C:12]1[CH:13]=[CH:14][C:15](Br)=[C:16]([CH:21]=1)[C:17]([O:19][CH3:20])=[O:18].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1.C(O)C>C(OCC)C.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>[NH2:11][C:12]1[CH:21]=[C:16]([C:17]([O:19][CH3:20])=[O:18])[C:15]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Br:1])=[CH:14][CH:13]=1
Reactant: OB(O)c1ccccc1Br
Reactant: COC(=O)c1cc(N)ccc1Br
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: CCOCC
Solvent: Cc1ccccc1
Solvent: CCO
Product: COC(=O)c1cc(N)ccc1-c1ccccc1Br
Temperature: 90 °C

Procedure:
A mixture of 2-bromophenyl boronic acid (600 mg, 3.0 mmol), methyl 5-amino-2-bromobenzoate (1.5 g, 6.5 mmol), potassium carbonate (2.07 g, 15 mmol) and tetrakis(triphenylphosphine)palladium (0) (345 mg, 5 mol %) in 1:1 toluene/ethanol (20 ml) was stirred and heated at 90° C. under nitrogen for 12 hours. After cooling the mixture was diluted with diethyl ether and water and the organic phase dried (MgSO4) and evaporated to dryness. The residue was chromatographed with dichloromethane/iso-hexane (1:2->1:1) to yield the title compound as a pale yellow gum. (682 mg, 74%).
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:16]([OH:18])=O)[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH2:19]([O:21][C:22](=[O:32])[CH2:23][NH:24][C:25]1[C:30]([CH3:31])=[CH:29][CH:28]=[CH:27][N:26]=1)[CH3:20].C(OCC)(=O)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:19]([O:21][C:22](=[O:32])[CH2:23][N:24]([C:16](=[O:18])[C@H:12]([CH:13]([CH3:14])[CH3:15])[NH:11][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])[C:25]1[C:30]([CH3:31])=[CH:29][CH:28]=[CH:27][N:26]=1)[CH3:20]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CCOC(=O)CNc1ncccc1C
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)CN(C(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)c1ncccc1C
Temperature: 25 °C

Procedure:
CBZ-L-Valine (15.4 g, 0.0612 mol) was dissolved in CH2Cl2 (300 mL) and the following reagents were added in equal molar amounts in the stated order; 4-dimethylaminopyridine (DMAP), ethyl-N-(3-methylpyridinyl)glycinate and WSCDI. The reaction mixture was allowed to stir at room temperature over night. Evaporation of the solvent yielded a viscous semisolid which was treated with ethyl acetate and then with water and separated. The organic extract was washed with water followed by 5% aqueous Na2CO3 and saturated aqueous NaCl-solution. After drying over MgSO4, filtration and evaporation under reduced pressure yielded an oil (11.1 g) which was purified over silica gel using CH2Cl2 : CH3OH 97.3 as eluent. Isolated 9.2 g of an amber oil.
Reaction SMILES: [CH3:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[CH2:15]([C:18]1[C:26]2[O:25][N:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[C:22]=2[CH:21]=[CH:20][C:19]=1[O:31][CH2:32][CH2:33][CH2:34]Br)[CH2:16][CH3:17]>>[CH3:1][C:2]1([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:6][C:5](=[O:7])[N:4]([CH2:34][CH2:33][CH2:32][O:31][C:19]2[CH:20]=[CH:21][C:22]3[C:23]([C:27]([F:29])([F:30])[F:28])=[N:24][O:25][C:26]=3[C:18]=2[CH2:15][CH2:16][CH3:17])[C:3]1=[O:8]
Reactant: CCCc1c(OCCCBr)ccc2c(C(F)(F)F)noc12
Reactant: CC1(c2ccccc2)NC(=O)NC1=O
Product: CCCc1c(OCCCN2C(=O)NC(C)(c3ccccc3)C2=O)ccc2c(C(F)(F)F)noc12

Procedure:
rac-5-Methyl-5-phenyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione was prepared as for Example 10 from 5-methyl-5-phenylimidazolidine-2,4-dione and the bromide from Example 7. After aqueous work-up and silica gel chromatography, the title compound was obtained.
Reaction SMILES: [C:1]([C:3]1([OH:13])[CH2:12][CH2:11][C:6]2([O:10][CH2:9][CH2:8][O:7]2)[CH2:5][CH2:4]1)#[CH:2].C([Li])CCC.[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1.[Cl-].[NH4+]>O1CCCC1>[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]([OH:25])[C:2]#[C:1][C:3]2([OH:13])[CH2:12][CH2:11][C:6]3([O:7][CH2:8][CH2:9][O:10]3)[CH2:5][CH2:4]2)=[CH:22][CH:21]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: C#CC1(O)CCC2(CC1)OCCO2
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC(C#CC1(O)CCC2(CC1)OCCO2)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.3 %

Procedure:
To a solution of 8-ethynyl-1,4-dioxaspiro[4.5]decan-8-ol (Reference Example 1) (5.03 g, 27.6 mmol) in tetrahydrofuran (100 mL), 2.63 M n-butyllithium (solution in n-hexane, 22.1 mL, 57.9 mmol) was added dropwise at −72° C. for 15 minutes, and the obtained solution was stirred at the same temperature for 60 minutes. Thereafter, 4-chlorobenzaldehyde (4.06 g, 28.9 mmol) was added dropwise at −72° C. for 10 minutes, and the obtained solution was stirred at the same temperature for 60 minutes. The reaction solution was allowed to warm to room temperature and poured into saturated aqueous ammonium chloride solution. The reaction solution was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, n-hexane/ethyl acetate) to obtain the captioned compound (8.13 g, 25.2 mmol, 91%) as an amorphous product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]([C:17]#[N:18])[C:6]1[CH:11]=[CH:10][C:9]([C:12]#[N:13])=[CH:8][C:7]=1[N+:14]([O-])=O)[CH3:2]>C(O)(=O)C.[Zn]>[CH2:1]([O:3][C:4]([C:5]1[C:6]2[C:7](=[CH:8][C:9]([C:12]#[N:13])=[CH:10][CH:11]=2)[NH:14][C:17]=1[NH2:18])=[O:19])[CH3:2]
Reactant: CCOC(=O)C(C#N)c1ccc(C#N)cc1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Product: CCOC(=O)c1c(N)[nH]c2cc(C#N)ccc12
Temperature: 95 °C
Yield: 69.4 %

Procedure:
Zinc powder (2.40 g) was added portionwise to a solution of Cyano-(4-cyano-2-nitro-phenyl)-acetic acid ethyl ester (1.15 g, 4.4 mmol) in 10 mL acetic acid at 80° C. The mixture was then heated at 95° C. for 30 minutes. The reaction was then cooled to room temperature, filtered and the catalyst rinsed with acetic acid. The filtrate was concentrated to near dryness then neutralised with saturated sodium bicarbonate solution. The product was then isolated by filtration and washing with ethyl acetate to give the title compound as a tan solid (700 mg, 69%). 1H NMR (DMSO) δ 11.07 (1H, s), 7.62 (1H, d, J=8.1), 7.49 (1H, d, J=1.1), 7.33 (1H, dd, J=8.1, 1.5), 7.10 (2H, br, s), 4.24 (2H, q, J=7.3), 1.32 (3H, t, J=7.1); LC-MS (1) Rt 1.84 min; m/z 228 (ES−).
Reaction SMILES: [OH:1][C@H:2]([CH3:38])[C@H:3]([NH:7][C:8]([C:10]1[C:18]2[C:13](=[N:14][CH:15]=[C:16]([C:19]3[C:27]4[C:22](=[CH:23][C:24]([F:28])=[CH:25][CH:26]=4)[N:21]([CH3:29])[N:20]=3)[N:17]=2)[N:12](COCC[Si](C)(C)C)[CH:11]=1)=[O:9])[CH2:4][O:5][CH3:6].C(O)(C(F)(F)F)=O.C(N)CN>ClCCl>[OH:1][C@H:2]([CH3:38])[C@H:3]([NH:7][C:8]([C:10]1[C:18]2[C:13](=[N:14][CH:15]=[C:16]([C:19]3[C:27]4[C:22](=[CH:23][C:24]([F:28])=[CH:25][CH:26]=4)[N:21]([CH3:29])[N:20]=3)[N:17]=2)[NH:12][CH:11]=1)=[O:9])[CH2:4][O:5][CH3:6]
Reactant: COC[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)[C@@H](C)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: NCCN
Product: COC[C@@H](NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)[C@@H](C)O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 48.5 %

Procedure:
In a 10 mL round-bottom flask, 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((1R,2R)-2-hydroxy-1-methoxymethyl-propyl)-amide (30 mg, 0.055 mmol) and TFA (0.3 ml, 3.9 mmol) were combined with dichloromethane (1 ml) to give an orange solution. The reaction mixture was stirred at room temperature for 2.5 h then concentrated under reduced pressure. The resultant crude solid was dissolved in dichloromethane (1 mL) and ethylenediamine (0.26 ml, 3.9 mmol) was added. The reaction mixture was stirred at room temperature for 18 h then concentrated and the residue was precipitated with water. The suspension was stirred for 1 h and the crude solid collected by filtration. The crude solid was purified by trituration (hot dichloromethane/heptane) to afford 11 mg (47%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((1R,2R)-2-hydroxy-1-methoxymethyl-propyl)-amide as a light yellow solid. 1H NMR (300 MHz, DMSO-d6) δ: 12.85 (br. s., 1H), 9.16 (s, 1H), 8.78 (dd, J=8.9, 5.5 Hz, 1H), 8.43 (s, 1H), 8.15 (d, J=9.4 Hz, 1H), 7.65 (dd, J=9.6, 2.1 Hz, 1H), 7.15 (td, J=9.2, 2.5 Hz, 1H), 5.17 (d, J=4.2 Hz, 1H), 4.20-4.33 (m, 1H), 4.15 (s, 3H), 3.98-4.09 (m, 1H), 3.59 (dd, J=9.8, 6.8 Hz, 1H), 3.50 (dd, J=9.4, 6.4 Hz, 1H), 3.27 (s, 3H), 1.13 (d, J=6.4 Hz, 3H).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[S:8][C:9]=1[CH2:10][OH:11])[CH2:2][CH2:3][CH3:4].[H-].[Na+].Br[CH2:25][C:26]1[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[C:28]([F:34])[CH:27]=1.O>CN(C)C=O>[CH2:1]([C:5]1[N:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:21])[F:19])=[CH:14][CH:13]=2)[S:8][C:9]=1[CH2:10][O:11][CH2:25][C:26]1[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[C:28]([F:34])[CH:27]=1)[CH2:2][CH2:3][CH3:4]
Reactant: N#Cc1ccc(CBr)cc1F
Reactant: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1CO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1COCc1ccc(C#N)c(F)c1
Reaction time: 0.25 h
Yield: 18.7 %

Procedure:
To a solution of 2.255 g of [4-butyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-yl]-methanol in 25 ml of dimethylformamide was added 0.286 g of a 60% dispersion of sodium hydride in mineral oil. After stirring for 15 minutes, 3 g of 4-bromomethyl-2-fluoro-benzonitrile was added. The resulting mixture was stirred at room temperature overnight, then poured into water, extracted with diisopropyl ether. The combined organic extracts were washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (heptane 95/ethyl acetate 5) to give 0.6 g of 4-[4-butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxymethyl]-2-fluoro-benzonitrile, which was transformed into 3-{4-[4-butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxymethyl]-2-fluoro-phenyl}-4H-[1,2,4]oxadiazol-5-one according to the method described in example 1.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][C:4](O)=[O:5].C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[C@H:39]1([NH:48][C:49]2[CH:58]=[CH:57][C:56]3[C:55]([NH2:59])=[CH:54][CH:53]=[CH:52][C:51]=3[N:50]=2)[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH2:41][CH2:40]1.C([O-])(O)=O.[Na+]>ClCCl.CN(C=O)C>[CH3:1][N:2]([CH3:7])[CH2:3][C:4]([NH:59][C:55]1[CH:54]=[CH:53][CH:52]=[C:51]2[C:56]=1[CH:57]=[CH:58][C:49]([NH:48][C@H:39]1[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[CH2:41][CH2:40]1)=[N:50]2)=[O:5]
Reactant: Nc1cccc2nc(N[C@@H]3CCc4ccccc43)ccc12
Reactant: CN(C)CC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(C)CC(=O)Nc1cccc2nc(N[C@@H]3CCc4ccccc43)ccc12
Reaction time: 17 h
Yield: 58.3 %

Procedure:
To a stirred solution of N,N-dimethylglycine (124 mg, 1.2 mmol) in dichloromethane (20 ml) and DMF (10 ml) were added at room temperature N-ethyldiisopropylamine (452 mg, 3.5 mmol) and TBTU (514 mg, 1.6 mmol) and the mixture was allowed to stir for 90 min. (R)—N2-indan-1-yl-quinoline-2,5-diamine (example 16) (275 mg, 1.0 mmol) was added and the reaction mixture was allowed to stir for 17 h, poured into sat. NaHCO3 solution (30 ml) and extracted with dichloromethane (2×30 ml). The combined organic layers were washed with water (30 ml), dried (MgSO4) and evaporated. The crude product was further purified by flash chromatography on silica gel (heptane/ethyl acetate) and crystallization (ethyl acetate/heptane) to yield the title compound as white solid (210 mg, 58%). M.p. 153° C.; MS: m/e=361.2 (M+H+).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][OH:17])=[CH:11][C:10]=1[F:18])C1C=CC=CC=1.[CH3:19][C:20]([Si:23](Cl)([CH3:25])[CH3:24])([CH3:22])[CH3:21].CCN(CC)CC>C(Cl)Cl>[C:20]([Si:23]([CH3:25])([CH3:24])[O:17][CH2:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([F:18])[CH:11]=1)([CH3:22])([CH3:21])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCc1ccc(OCc2ccccc2)c(F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCc1ccc(O)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
To a solution of 2-(4-benzyloxy-3-fluoro-phenyl)-ethanol (9.2 g, 37.4 mmol) in CH2Cl2 (150 mL) and TBDMS-Cl (5.6 g, 37.4 mmol), was added Et3N (5.2 mmol, 37.4 mmol) portionwise at 0° C. The reaction mixture was warmed to room temperature and stirred for 2 hours at the same temperature. The reaction was washed with H2O (150 mL). The CH2Cl2 was dried over MgSO4 and concentrated under vacuum. To a solution of the residue in MeOH (100 mL), was Pd/C (150 mg) added. The reaction was stirred under H2 (1 atm) for 5 hours. The solid material was filtrated off and the filtrate was concentrated under vacuum to afford the desired compound (8.9 g, 88.3%) as a grayish solid. The crude compound was used for the next step without further purification. 1H NMR (400 Mz, DMSO-d6) δ 9.53 (s, 1H), 6.99˜6.96 (m, 1H), 6.83˜6.81 (m, 2H), 3.70 (t, 2H), 2.63 (t, 2H), 0.83 (s, 9H), 0.01 (s, 6H).
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1O)=[CH:13][C:12]([CH:17]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:11][CH:10]=2)([O:3][CH2:4][CH3:5])=[O:2].O.P(Cl)(Cl)([Cl:27])=O>>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[Cl:27])=[CH:13][C:12]([CH:17]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:11][CH:10]=2)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)c1cnc2ccc(C3CCCCCC3)cc2c1O
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Product: CCOC(=O)c1cnc2ccc(C3CCCCCC3)cc2c1Cl

Procedure:
A solution of 100 g of 3-carboethoxy-4-hydroxy-6-cycloheptyl-quinoline in 670 ml of phosphorus oxychloride is boiled for 21/2 hours under reflux, with exclusion of water. It is then evaporated to dryness in vacuo, the residue is partitioned between 3 times 500 ml of methylene chloride and 3 times 500 ml of 2 N sodium hydroxide solution and the organic solution is washed until neutral, dried over sodium sulphate and evaporated to dryness in vacuo. The evaporation residue is treated with active charcoal and then recrystallised twice from petroleum ether. 3-Carboethoxy-4-chloro-6-cycloheptyl-quinoline of melting point 61°-62°C is thus obtained.
Reaction SMILES: N[C:2]1[C:7]([Br:8])=[CH:6][N:5]=[C:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:3]=1.Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18]>C(Cl)Cl.N1C=CC=CC=1>[Br:8][C:7]1[C:2]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:3][C:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[N:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)c1cc(N)c(Br)cn1
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1cc(C(=O)OC(C)(C)C)ncc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.3 %

Procedure:
To a solution of tert-butyl 4-amino-5-bromopicolinate (546 mg, 2 mmol) in CH2Cl2 (5 mL) and pyridine (1 mL) at 0° C., was added ethyl chloroformate (271 mg, 2.5 mmol). The mixture was stirred at rt for 2 h, diluted with dichloromethane, washed with 5% citric acid, and sat. K2HPO4 aq. solution. The organic layer was dried over MgSO4 and the product was purified by flash column chromatography (SiO2, eluting with 20% EtOAc/CH2Cl2) to give a white solid (570 mg, 83%). LC-MS: m/z 345 (M+).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH:6]=O.[CH3:17][O:18][CH2:19][CH2:20][NH2:21].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH2:6][NH:21][CH2:20][CH2:19][O:18][CH3:17]
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COCCNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 90.5 %

Procedure:
In 43 ml of dichloromethane were dissolved 2.45 g of 3,5-bistrifluoromethylbenzaldehyde, 835 mg of 2-methoxyethylamine and 687 μl of acetic acid, added thereto was 3.12 g of sodium triacetoxy borohydride, and the mixture was stirred at room temperature for an hour under nitrogen atmosphere. The reaction mixture was washed with a 0.5M aqueous sodium hydroxide solution, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=19:1→9:1), to give 2.76 g of 3,5-bistrifluoromethylbenzyl-2-methoxyethylamine.
Reaction SMILES: C([O:3][C:4](=[O:35])/[C:5](/[CH3:34])=[CH:6]/[C:7]1[C:12]([F:13])=[CH:11][C:10]([C:14](=[O:32])[NH:15][C:16]2[S:17][C:18]3[CH2:28][O:27][C:26]4[C:25]([CH:29]([CH3:31])[CH3:30])=[CH:24][CH:23]=[CH:22][C:21]=4[C:19]=3[N:20]=2)=[CH:9][C:8]=1[F:33])C.CO.[OH-].[Na+].Cl>C1COCC1>[F:33][C:8]1[CH:9]=[C:10]([C:14](=[O:32])[NH:15][C:16]2[S:17][C:18]3[CH2:28][O:27][C:26]4[C:25]([CH:29]([CH3:31])[CH3:30])=[CH:24][CH:23]=[CH:22][C:21]=4[C:19]=3[N:20]=2)[CH:11]=[C:12]([F:13])[C:7]=1/[CH:6]=[C:5](\[CH3:34])/[C:4]([OH:35])=[O:3]
Reactant: CCOC(=O)/C(C)=C/c1c(F)cc(C(=O)Nc2nc3c(s2)COc2c-3cccc2C(C)C)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C/C(=C\c1c(F)cc(C(=O)Nc2nc3c(s2)COc2c-3cccc2C(C)C)cc1F)C(=O)O

Procedure:
(E)-3-[2,6-difluoro-4-(6-isopropyl-4H-chromeno[4,3-d]thiazol-2-ylcarbamoyl)phenyl]-2-methylacrylic acid ethyl ester (620 mg) was dissolved in THF (2 mL), methanol (2 ml), and 2N sodium hydroxide aqueous solution (2 mL), and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was acidified with hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, and brine, dried over magnesium sulfate, and evaporated. The residue was recrystallized from ethyl acetate to obtain the compound (A1309) 460 mg.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[CH2:17][CH:16]2[N:18](C(OCC)=O)[CH:13]([CH2:14][CH2:15]2)[CH:12]=1.O.NN.[OH-].[K+].O>C(O)CO>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[CH2:12][CH:13]2[NH:18][CH:16]([CH2:15][CH2:14]2)[CH:17]=1
Reactant: CCOC(=O)N1C2C=C(c3ccc4ccccc4c3)CC1CC2
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: C1=C(c2ccc3ccccc3c2)CC2CCC1N2
Temperature: 25 °C

Procedure:
A mixture of 5.0 gm (16.3 mMol) 3-(naphth-2-yl)-8-ethoxycarbonyl-8-azabicyclo[3.2.1]oct-2-ene, 4.07 gm (81.3 mMol) hydrazine hydrate, and 5.49 gm (97.8 mMol) potassium hydroxide in 120 mL ethylene glycol was heated at reflux for 2 hours. The reaction mixture was allowed to cool gradually to room temperature. After 16 hours the reaction mixture was poured into water and extracted well with diethyl ether. The organic phase was dried over sodium sulfate and concentrated under reduced pressure. The residue was dissolved in 1N hydrochloric acid and the solution washed with diethyl ether. The aqueous phase was basified and the mixture extracted well with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated under reduced pressure to provide the title compound as a yellow oil.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][SH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[C:1]1([CH2:7][CH2:8][S:9][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: SCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(SCCc2ccccc2)cc1
Yield: 66.8 %

Procedure:
A mixture of 2-phenylethylmercaptan (72.3 mmol, 10.0 g), 4-bromobenzaldehyde (79.6 mmol, 14.7 g) and potassium carbonate (116 mmol, 16 g) were stirred in dimethylformamide (100 ml) at 110° C. for 48 hours. The solution was cooled and diluted with water (200 ml). The aqueous was extracted with ether (3×200 ml) and the combined ether layers were dried (Na2SO4) and concentrated in vacuo. The residue was purified on silica gel using hexane:ethyl acetate (9:1) as eluant to afford 11.7 g (67%) of present title product as a yellow oil. 1H-NMR(CDCl3)delta(ppm): 3.1 (d of t), 7.2 (s), 7.3 (d), 7.7 (d), 9.9 (s). MS (m30 ) 242.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[C:9]([C:10]3[CH:11]=[C:12]([C:34]4[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][CH:35]=4)[CH:13]=[CH:14][C:15]=3[O:16][C:17]3[C:22]([Cl:23])=[CH:21][C:20]([S:24]([NH:27][C:28]4[S:29][CH:30]=[N:31][N:32]=4)(=[O:26])=[O:25])=[C:19]([F:33])[CH:18]=3)=[CH:8][CH:7]=[N:6]2)[CH2:2]1.C=O.[C:46](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.ClCCl.C(O)(=O)C>[Cl:23][C:22]1[C:17]([O:16][C:15]2[CH:14]=[CH:13][C:12]([C:34]3[CH:35]=[CH:36][C:37]([C:40]([F:42])([F:43])[F:41])=[CH:38][CH:39]=3)=[CH:11][C:10]=2[C:9]2[N:5]([CH:3]3[CH2:2][N:1]([CH3:46])[CH2:4]3)[N:6]=[CH:7][CH:8]=2)=[CH:18][C:19]([F:33])=[C:20]([S:24]([NH:27][C:28]2[S:29][CH:30]=[N:31][N:32]=2)(=[O:26])=[O:25])[CH:21]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=S(=O)(Nc1nncs1)c1cc(Cl)c(Oc2ccc(-c3ccc(C(F)(F)F)cc3)cc2-c2ccnn2C2CNC2)cc1F
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: ClCCl
Product: CN1CC(n2nccc2-c2cc(-c3ccc(C(F)(F)F)cc3)ccc2Oc2cc(F)c(S(=O)(=O)Nc3nncs3)cc2Cl)C1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 122.7 %

Procedure:
To a suspension of 4-{[3-(1-azetidin-3-yl-1H-pyrazol-5-yl)-4′-(trifluoromethyl)biphenyl-4-yl]oxy}-5-chloro-2-fluoro-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide (Preparation 41, 46.3 mg, 0.0711 mmol) in methanol (0.11 mL), dichloromethane (1.86 mL) and acetic acid (0.11 mL) was added formaldehyde (37% w/w, 19.6 μL, 0.263 mmol). The reaction was then stirred under nitrogen at room temperature for 45 minutes. Sodium triacetoxyborohydride (45.9 mg, 0.217 mmol) was added to the reaction which was stirred for 18 hours at room temperature. The reaction was diluted with dichloromethane (20 mL) and washed with water (3×2 mL). The combined aqueous phases were extracted with dichloromethane (3×5 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford a clear gum (58.0 mg). The clear gum was purified by B-HPLC to afford the title compound.
Reaction SMILES: C(OC(=O)[CH:5]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:22][C:21]=2[CH2:33][CH:34]=[CH2:35])=[CH:11][CH:10]=1)[CH2:6][O:7][CH3:8])C.[C:37]([O:40]CC)(=[O:39])C>>[CH3:8][O:7][C@@H:6]([CH2:5][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:22][C:21]=2[CH2:33][CH2:34][CH3:35])=[CH:13][CH:14]=1)[C:37]([OH:40])=[O:39]
Reactant: C=CCc1cc(Oc2ccccc2)ccc1OCCCOc1ccc(C(COC)C(=O)OCC)cc1
Reactant: CCOC(C)=O
Product: CCCc1cc(Oc2ccccc2)ccc1OCCCOc1ccc(C[C@H](OC)C(=O)O)cc1

Procedure:
The title compound was prepared from 2-{4-[3-(2-Allyl-4-phenoxy-phenoxy)-propoxy]-phenyl}-3-methoxy-propionic acid ethyl ester from Example 160, Step B which was treated in ethyl acetate with Pd(C) and H2 in balloon presure to give after filtration the corresponding reduced product which was hydrolyzed under Standard Procedure C to give the title compound.