Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.ClC1C=CC(CN[C:9](=[O:29])[C:10]([F:28])([F:27])[C:11]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])([OH:18])[CH2:12][N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)=CC=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-:40].[Na+].[Na+]>O>[F:26][C:20]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=1[C:11]([OH:18])([CH2:12][N:13]1[CH:17]=[N:16][CH:15]=[N:14]1)[C:10]([F:27])([F:28])[C:9]([OH:29])=[O:40]
Reactant: O=C(NCc1ccc(Cl)cc1)C(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: O=C([O-])[O-]
Agent: Br
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(O)C(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
To 4 ml of 47% hydrobromic acid was added 500 mg of N-(4-chlorobenzyl)-3-(2,4-difluorophenyl)-2,2-difluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butanamide. The resulting mixture was refluxed for 6 hours. Thereto were added 20 ml of toluene and 20 ml of water. The resulting solution was adjusted to pH 8.5 with sodium carbonate. The aqueous layer was separated and 20 ml of ethyl acetate was added thereto. The resulting mixture was adjusted to pH 1.0 with 6N hydrochloric acid. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. Thereafter, the solvent was removed by distillation under reduced pressure to obtain 230 mg of 3-(2,4-difluorophenyl)-2,2-difluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butyric acid.
Reaction SMILES: C([Li])(CC)C.[N:6]1([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7]1.Br[C:19]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:20]=1[CH2:21][C:22](=[O:28])[NH:23]2.F[B-](F)(F)F.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>CC(OC)(C)C.[Cl-].[Zn+2].[Cl-].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCOC(C)=O>[O:28]=[C:22]1[CH2:21][C:20]2[C:24](=[CH:25][CH:26]=[CH:27][C:19]=2[C@H:7]2[CH2:8][CH2:9][CH2:10][N:6]2[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[NH:23]1
Reactant: CC(C)(C)OC(=O)N1CCCC1
Reactant: O=C1Cc2c(Br)cccc2N1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: COC(C)(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1c1cccc2c1CC(=O)N2
Temperature: -78 °C
Reaction time: 1 h
Yield: 26.6 %

Procedure:
sec-Butyl lithium (25.3 mL, 35.4 mmol) was added into a solution of tert-butyl 1-pyrrolidinecarboxylate (6.2 mL, 35.4 mmol) and (−)-spartiene (8.29 g, 35.4 mmol) in MTBE (100 mL) at −78° C. The mixture was stirred for 1 hour at −78° C. Zinc chloride solution (35.4 mL, 35.4 mmol) was added, and the reaction was stirred for 15 minutes at −78° C. The reaction was allowed to warm up to room temperature. 4-Bromoindolin-2-one (5.00 g, 23.6 mmol), palladium (II) acetate (0.53 g, 2.4 mmol) and tri-tert-butylphosphine tetrafluoroborate (0.68 g, 2.4 mmol) was added into the reaction mixture. The reaction was stirred for 12 hours at room temperature. The reaction mixture was poured into EtOAc (200 mL), and the suspension was filtered with a pad of celite. The filtrate was concentrated, and the residue was purified by flash chromatography (silica gel eluted with 4:1 hexanes:ethyl acetate) to give (R)-tert-butyl 2-(2-oxoindolin-4-yl)pyrrolidine-1-carboxylate (1.9 g, 27%) as a solid. 1H NMR (CDCl3, 400 MHz) δ 7.80 (s, 1H), 7.10-7.20 (m, 1H), 6.75-6.82 (m, 1H), 6.62-6.78 (m, 1H), 4.65-4.93 (m, 1H), 3.34-3.73 (m, 4H), 2.20-2.40 (m, 1H), 1.84-2.00 (m, 2H), 1.68-1.83 (m, 1H), 1.45 (2, 4H), 1.14 (s, 5H). MS (APCI+) [M+H]+ 303.
Reaction SMILES: Br[CH:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[N:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:3]1=[O:21].[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O>[CH3:10][N:7]1[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[N:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:3](=[O:21])[CH:2]([NH:29][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:8]1=[O:9]
Reactant: NCc1ccccc1
Reactant: CN1C(=O)C(Br)C(=O)N(c2ccccc2)c2ccccc21
Solvent: O
Product: CN1C(=O)C(NCc2ccccc2)C(=O)N(c2ccccc2)c2ccccc21
Temperature: 100 °C

Procedure:
A mixture of 50 mg of the product of Step B and 2 ml of benzylamine was heated at 100° C. for 3 hours and the reaction medium was poured into water. The product obtained was separated, washed, and dried in the presence of phosphoric anhydride to obtain 50 mg of the sought product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:10][C@@H:11]([CH2:25][OH:26])[N:12]([S:15]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH2:13][CH:14]=2)=[CH:5][CH:4]=1.B.[O:28]1CCCC1>O1CCCC1>[OH:26][CH2:25][C@H:11]1[N:12]([S:15]([C:18]2[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH2:13][C@H:14]([OH:28])[C@@H:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH2:10]1
Reactant: COc1ccc(C2=CCN(S(=O)(=O)c3ccc(C)cc3)[C@H](CO)C2)cc1
Reactant: C1CCOC1
Agent: B
Product: COc1ccc([C@H]2C[C@@H](CO)N(S(=O)(=O)c3ccc(C)cc3)C[C@@H]2O)cc1
Temperature: 40 °C

Procedure:
To a stirred solution of 108.1 g of [(S)-4-(4-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1,2,3,6-tetrahydro-pyridin-2-yl]-methanol in 1000 ml of tetrahydrofuran are added 504 ml of a solution of borane-tetrahydrofuran (1M) at room temperature. The reaction mixture is heated to 40° C. for 2-6 hours, cooled to room temperature, and quenched by the addition of 150 ml of 2N sodium hydroxide solution and 150 ml of 30% hydrogen peroxide solution. The organic phase is separated, dried over sodium sulfate and concentrated under reduced pressure. The residue is purified by flash chromatography (SiO2 60 F) to afford the title compound as a white solid. Rf=0.19 (EtOAc-heptane 1:1); Rt=3.67.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[S:8]C#N.O.O.O.O.O.O.O.O.O.[S-2].[Na+].[Na+].C(O)(=O)C>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[SH:8]
Reactant: N#CSc1ccc(O)cc1Br
Agent: [Na+]
Agent: [S-2]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: Oc1ccc(S)c(Br)c1
Temperature: 85 °C
Reaction time: 0.33 h
Yield: 92.2 %

Procedure:
To a hot (85° C.) solution of 3-bromo-4-thiocyanato-phenol (315 mg, 1.37 mmol) in absolute ethanol (10 mL) under nitrogen, sodium sulfide nonahydrate (403 mg, 2.05 mmol) was added. The resulting mixture was stirred at 85° C. for 20 min. More sodium sulfide nonahydrate (230 mg) was added and heating was continued for 15 min. The mixture was cooled down, made acidic with 5N acetic acid (10 mL) and extracted with methylene chloride (×1). The organic layer was washed once with water, dried and concentrated in vacuo to give the title compound as a yellow solid (259 mg, 92%) which was quickly submitted to the next reaction without further treatment. EIMS M−1: 203.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][O:4][N:3]=1.Cl[C:8]([O:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)=[O:9]>C1COCC1>[O:4]1[CH:5]=[CH:6][C:2]([NH:1][C:8](=[O:9])[O:10][C:11]2[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=2)=[N:3]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccon1
Solvent: C1CCOC1
Product: O=C(Nc1ccon1)Oc1ccc([N+](=O)[O-])cc1

Procedure:
A solution of 3-amino isoxazole (220 uL, 2.973 mmol) and p-nitrophenyl chloroformate (659 mg, 3.271 mmol) in THF (8 mL) was stirred for 15 min at RT before the solution was concentrated in vacuo. The title compound was used immediately in the following reaction without further purification. MS (ESI, pos. ion) m/z: 250 (M+1). Mass calc'd for C10H7N3O5: 249.18.
Reaction SMILES: S(=O)(=O)(O)O.O1CCCCC1[O:12][C:13]1[CH:14]=[C:15]([CH:26]=[CH:27][C:28]2[CH:29]=[C:30]([CH:34]=[CH:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40]([CH3:43])([OH:42])[CH3:41])[CH:31]=[CH:32][CH:33]=2)[CH:16]=[C:17]([O:19]C2CCCCO2)[CH:18]=1>C1COCC1.O>[OH:42][C:40]([CH3:43])([CH3:41])[CH2:39][CH2:38][CH2:37][CH2:36][CH:35]=[CH:34][C:30]1[CH:29]=[C:28]([CH:27]=[CH:26][C:15]2[CH:14]=[C:13]([OH:12])[CH:18]=[C:17]([OH:19])[CH:16]=2)[CH:33]=[CH:32][CH:31]=1
Reactant: CC(C)(O)CCCCC=Cc1cccc(C=Cc2cc(OC3CCCCO3)cc(OC3CCCCO3)c2)c1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(O)CCCCC=Cc1cccc(C=Cc2cc(O)cc(O)c2)c1

Procedure:
In a manner similar to Example 25(d), by reacting 0.037 ml of concentrated sulphuric acid with 374 mg (0.72 mmol) of 8-(3-{2-[3,5-bis(tetrahydropyran-2-yloxy)phenyl]vinyl}phenyl)-2-methyloct-7-en-2-ol in 4 ml of THF and 2 ml of water, after purification on a silica column (ethyl acetate 40-heptane 60), a beige powder (m=40 mg; Y=16%) is obtained. m.p.=152-4° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[O:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[O:13][CH:12]=[C:11]([C:23](O)=[O:24])[C:10]2=[O:26])=[O:5])[CH3:2].S(Cl)([Cl:29])=O>C1C=CC=CC=1>[CH2:1]([O:3][C:4]([O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[O:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[O:13][CH:12]=[C:11]([C:23]([Cl:29])=[O:24])[C:10]2=[O:26])=[O:5])[CH3:2]
Reactant: CCOC(=O)Oc1cc2occ(C(=O)O)c(=O)c2cc1OC(=O)OCC
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CCOC(=O)Oc1cc2occ(C(=O)Cl)c(=O)c2cc1OC(=O)OCC

Procedure:
6,7-Bis(ethoxycarbonyloxy)chromone-3-carboxylic acid (1.1 g) was dissolved in benzene (20 ml) and thionyl chloride (2 ml) was added dropwise at room temperature with stirring. Then, the mixture was relfuxed with stirring. The reaction mixture was concentrated, and n-hexane was added to the concentrate to crystallize it. The resulting crystals were collected by filtration, washed with n-hexane and dired to afford the desired product (980 mg).
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]2[CH:33]=[CH:32][CH:31]=[CH:30][C:6]=2[C:7]=1[C:8]([C:10]1[CH:11]=[C:12]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:13]([O:22]C)=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:15]=1)=[O:9])[CH3:2].B(Br)(Br)Br.C(Cl)Cl.C(=O)=O.CC(C)=O>C(Cl)Cl>[CH2:1]([C:3]1[O:4][C:5]2[CH:33]=[CH:32][CH:31]=[CH:30][C:6]=2[C:7]=1[C:8]([C:10]1[CH:15]=[C:14]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:13]([OH:22])=[C:12]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:11]=1)=[O:9])[CH3:2]
Reactant: CCc1oc2ccccc2c1C(=O)c1cc(-c2ccccc2)c(OC)c(-c2ccccc2)c1
Agent: BrB(Br)Br
Agent: O=C=O
Solvent: ClCCl
Solvent: CC(C)=O
Product: CCc1oc2ccccc2c1C(=O)c1cc(-c2ccccc2)c(O)c(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 83 %

Procedure:
At -78° C., to a stirred solution of (2-ethyl-benzofuran-3-yl)-(2'-methoxy-[1,1';3',1"]terphenyl-5'-yl)-methanone (1.07 g, 2.47 mmol) in CH2Cl2 (10.1 mL) was added dropwise 1M boron tribromide/CH2Cl2 (5.2 mL). After the addition was complete, the dry ice/acetone bath was replaced with an ice water bath and the reaction was stirred for 72 h, eventually warming to ambient temperature. The reaction was carefully quenched with crushed ice, diluted with H2O (16 mL) and extracted with ether. The ethereal extracts were dried (MgSO4) and concentrated. Purification on Biotage KP-Sil eluting with 15% acetone/hexane gave 0.86 g, (83%) of the title compound as a white solid, mp 142-143° C. 1H NMR (DMSO-d6) δ 1.24 (t, 3 H), 2.90 (quartet, 2 H), 7.28-7.66 (m, 16 H), 9.37 (s, 1 H). IR (KBr) 3200, 2950, 1625, 1560 and 1175 cm-1. mass spectrum (EI), m/z 418 (M+). Anal. Calcd. for C29H22O3.0.35H2O: C, 82.00; H, 5.39; N, 0.00. Found: C, 82.06; H, 5.40; N, 0.07.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:13](O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.ClC(OCC)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:1]([O:8][C:9](=[O:10])[NH:11][C@H:12]([CH2:13][OH:14])[CH2:16][CH2:17][NH:18][C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CCOC(=O)Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)NCC[C@@H](CO)NC(=O)OCc1ccccc1

Procedure:
Preparation takes place in analogy to Example 83A from 300 mg (0.85 mmol) of (2S)-2-{[(benzyloxy)carbonyl]amino}-4-[(tert-butoxycarbonyl)amino]butanoic acid in 10 ml of tetrahydrofuran with 86 mg (0.85 mmol) of 4-methylmorpholine, 92 mg (0.85 mmol) of ethyl chloroformate and 1.7 ml (1.70 mmol) of a 1M solution of lithium aluminum hydride in tetrahydrofuran. The product is reacted without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]2([CH2:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][CH:17]=[C:18](Br)[CH:19]=3)[O:14]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:25]([O:29][CH3:30])(=[O:28])[CH:26]=[CH2:27]>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:30][O:29][C:25](=[O:28])/[CH:26]=[CH:27]/[C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[O:14][C:10]1([CH2:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]1)[CH2:22][C:21]2=[O:23]
Reactant: CC(C)(C)OC(=O)N1CCCC2(CC(=O)c3cc(Br)ccc3O2)C1
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCCN(C(=O)OC(C)(C)C)C1)O2
Temperature: 100 °C
Yield: 98.4 %

Procedure:
A mixture of (±)-6-bromo-4-oxo-spiro(chromane-2,3′-piperidine)-1′-carboxylic acid tert-butyl ester (6.0 g, 15.19 mmol), Pd(OAc)2 (68.1 mg, 0.304 mmol), P(o-tol)3 (184.7 mg, 0.608 mmol), TEA (6.33 ml, 45.6 mmol), methyl acrylate (4.10 ml, 45.57 mmol) in dry DMF (15 ml) was heated under N2 atmosphere to 100° C. for 3 h. After cooling down to RT, the solution was filtered on a celite pad and washed 3 times with EtOAc (100 ml). The filtrate was washed with water and brine. The organic phase was dried over Na2SO4 and evaporated under vacuum. The crude residue was purified by column chromatography (eluent: petroleum ether/EtOAc 8:2 to 7:3) to give (±)-(E)-3-[1′-tert-butoxycarbonyl-4-oxo-spiro(chromane-2,3′-piperidine)-6-yl]-acrylic acid methyl ester (6.0 g) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[O:10][CH3:11].[Cl:12]CCOCCCl>C(O)(=O)C.O>[CH3:11][O:10][C:3]1[C:4]([O:8][CH3:9])=[CH:5][CH:6]=[C:7]([Cl:12])[C:2]=1[CH3:1]
Reactant: ClCCOCCCl
Reactant: COc1cccc(C)c1OC
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(Cl)c(C)c1OC
Yield: 67980.1 %

Procedure:
To a mixture of 25 g (0.16 mmol) of 1-methyl-2,3-dimethoxybenzene in 25 mL of acetic acid, was slowly added 26.4 g (0.33 mmol) of 1-chloromethylmethylether. The resultant reaction mixture was reacted overnight at 30° C. and then diluted with cold water, resulting in the formation of a precipitate. This precipitate was purified by recrystallization from hot hexanes and then reduced to dryness under reduced pressure to provide 20.3 g of a white solid (m.p. 69°-70° C.).
Reaction SMILES: COC1C=C(C[CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=2[OH:21])C=C(OC)C=1.[CH3:22][O:23][C:24]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[C:28]([O:34][CH3:35])[C:25]=1[CH:26]=O>>[CH3:22][O:23][C:24]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[C:28]([O:34][CH3:35])[C:25]=1[CH2:26][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=1[OH:21]
Reactant: COc1cc(OC)c(C=O)c(OC)c1
Reactant: COc1cc(CCCc2ccc(O)cc2O)cc(OC)c1
Product: COc1cc(OC)c(CCCc2ccc(O)cc2O)c(OC)c1

Procedure:
Compound 31 was synthesized following a similar procedure as described for compound 28 above using as starting materials 2,4-dibenzyloxyacetophenone and 2,4,6-trimethoxybenzaldehyde. 1H-NMR (MeOD, 500 MHz): δ 6.822 (d, 1H, J=8.0 Hz), 6.250 (d, 1H, J=2.5 Hz), 6.197 (dd, 1H, J=2.5 & 8.0 Hz), 6.165 (s, 2H), 3.768 (s, 3H), 3.764 (s, 6H), 2.562 (t, 2H, J=7.5 Hz), 2.461 (t, 2H, J=7.5 Hz), 1.617-1.653 (m, 2H). 13C-NMR (MeOD, 125 MHz): δ 159.273 (C), 158.729 (2C), 155.556 (C), 155.449 (C), 129.655 (2CH), 120.426 (C), 111.382 (C), 105.789 (CH), 101.968 (CH), 90.285 (CH), 54.655 (2CH3), 54.274 (CH3), 29.716 (CH2), 29.064 (CH2), 22.142 (CH2).
Reaction SMILES: CS([C:5]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[S:7][N:6]=1)(=O)=O.[CH2:17]([OH:21])[C:18]#[C:19][CH3:20].[H-].[Na+].[Cl-].[Na+]>CN(C)C=O>[Cl:16][C:12]1[CH:11]=[C:10]([C:8]2[S:7][N:6]=[C:5]([O:21][CH2:17][C:18]#[C:19][CH3:20])[N:9]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: CS(=O)(=O)c1nsc(-c2cccc(Cl)c2)n1
Reactant: CC#CCO
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC#CCOc1nsc(-c2cccc(Cl)c2)n1
Reaction time: 0.5 h
Yield: 86 %

Procedure:
In 2.5 ml of N,N-dimethylformamide, 350 mg of 3-methylsulfonyl-5-(3-chlorophenyl)-1,2,4-thiadiazole and 98 mg of 2-butyne-1-ol were dissolved, to the resulting solution was added 56 mg of sodium hydride (60% oily) with ice-cooling, and the mixture was stirred for 30 minutes, and further stirred at room temperature for 1 hour. Then, the reaction mixture was poured into an aqueous saturated sodium chloride solution, and the mixture was extracted with t-butyl methyl ether. The residue obtained by concentration of the organic layer was subjected to silica gel column chromatography to obtain 290 mg of 5-(3-chlorophenyl)-3-(2-butynyloxy)-1,2,4-thiadiazole (the compound (9) of the present invention).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[CH3:11][NH:12][CH3:13]>O>[CH3:11][N:12]([CH3:13])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1
Reactant: CNC
Reactant: O=C(O)c1ccc(Cl)nc1
Solvent: O
Product: CN(C)c1ccc(C(=O)O)cn1

Procedure:
6-Chloronicotinic acid (0.5 g, 3.17 mmol) and dimethyl amine 10 ml, 40% in water) were heated in a sealed pressure vessel at 130° C. for 6 h. The solvent was then removed and the residue was taken up in water and the pH was adjusted to 4-5. Extraction with dichloromethane yielded the pure intermediate depicted above (0.1 g, 20%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C@@:7]1([CH2:17][CH2:18][NH2:19])[CH2:16][C:11]2([CH2:15][CH2:14][CH2:13][CH2:12]2)[O:10][CH2:9][CH2:8]1.C(NCC[C@]1(C2C=CC(F)=CC=2)CC2(CCCC2)OCC1)C1C=CC=CC=1.Br[CH2:48][C:49]1[S:50][CH:51]=[CH:52][C:53]=1[CH2:54]Br.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[S:50]1[C:49]2[CH2:48][N:19]([CH2:18][CH2:17][C@:7]3([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[CH2:16][C:11]4([CH2:15][CH2:14][CH2:13][CH2:12]4)[O:10][CH2:9][CH2:8]3)[CH2:54][C:53]=2[CH:52]=[CH:51]1
Reactant: NCC[C@@]1(c2ccccn2)CCOC2(CCCC2)C1
Reactant: BrCc1ccsc1CBr
Agent: Fc1ccc([C@]2(CCNCc3ccccc3)CCOC3(CCCC3)C2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: c1ccc([C@]2(CCN3Cc4ccsc4C3)CCOC3(CCCC3)C2)nc1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethan-1-amine (0.030 g, 0.115 mmol; prepared by following a sequence described for Compound 81 in dried ACN (5.8 mL) was added 2,3-bis(bromomethyl)thiophene (31.1 mg, 0.115 mmol) followed by addition of K2CO3 (79.62 mg, 0.576 mmol). After 30 min, LCMS showed that the reaction was done and the major peak had the corresponding mass to the desired product. It was then subjected to HPLC purification. HPLC purification method: Luna acid medium column, 10-50% acetonitrile in H2O over 15 min, followed by flashing with 100% acetonitrile, 0.1% TFA modifier was employed. The fractions containing the desired product were pooled, basified with 2N NaOH and extracted with DCM (3×20 mL). The combined organics were concentrated and purified with flash chromatography (10 g silica gel column, eluted by 0-10% MeOH in DCM, based upon TLC measurement: DCM/MeOH (10/1) Rf=0.60) to afford 5 mg of 2-[(9R)-9-(2-{4H,5H,6H-thieno[2,3-c]pyrrol-5-yl}ethyl)-6-oxaspiro[4.5]decan-9-yl]pyridine as a colorless oil in 12% yield.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][CH:3]=1.Br[CH2:14][C:15]([CH3:17])=[CH2:16].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH3:16][C:15](=[CH2:14])[CH2:17][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:11][CH:12]=1
Reactant: C=C(C)CBr
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C=C(C)COc1ccc(C(=O)O)cc1

Procedure:
The reaction of Ethyl 4-hydroxyl-benzoate and 3-Bromo-2-methyl-propene in 2-butanone in the presence of potassium carbonate was performed as described in Example 2 to give 4-(2-Methyl-allyloxy)-benzoic acid as white powder. 1H-NMR (400 MHz, d6-DMSO):12.59 (s, —CO2H); 7.86 (d-like, J=8.0, 2 arom. H); 7.02 (d-like, J=8.0, 2 arom. H); 5.04, 4.96 (2 s, —C(CH3)═CH2); 4.53 (s, CH2—C(CH3)═CH2); 1.72 (s, C(CH3)═CH2). 13C-NMR (100 MHz, d6-DMSO): 166.93 (—C═O); 161.87; 140.39; 131.27 (2 arom. C); 123.05; 114.42 (2 arom. C); 112.52; 70.97; 19.12.
Reaction SMILES: [F:1][C:2]([F:25])([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=1)[C:3]1[N:12]=[C:11](SC)[C:10]2[C:5](=[CH:6][C:7]([C:15]([NH2:17])=[O:16])=[CH:8][CH:9]=2)[N:4]=1.ClC1C=CC=C(C(OO)=O)C=1.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-].[Na+].[CH3:49][C:50]1[NH:54][N:53]=[C:52]([NH2:55])[CH:51]=1>C(Cl)Cl.C1COCC1>[F:1][C:2]([F:25])([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=1)[C:3]1[N:12]=[C:11]([NH:55][C:52]2[CH:51]=[C:50]([CH3:49])[NH:54][N:53]=2)[C:10]2[C:5](=[CH:6][C:7]([C:15]([NH2:17])=[O:16])=[CH:8][CH:9]=2)[N:4]=1
Reactant: CSc1nc(C(F)(F)c2ccc(F)cn2)nc2cc(C(N)=O)ccc12
Reactant: Cc1cc(N)n[nH]1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1cc(Nc2nc(C(F)(F)c3ccc(F)cn3)nc3cc(C(N)=O)ccc23)n[nH]1
Reaction time: 1.5 h
Yield: 9.2 %

Procedure:
To 2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-(methylthio)quinazoline-7-carboxamide (203 mg, 0.55 mmol) in DCM (5 mL) at 0° C. was added 3-chloroperbenzoic acid (70%, 205 mg, 0.84 mmol) and the mixture was stirred for 90 min. An additional amount of 3-chloroperbenzoic acid (70%, 68 mg, 0.28 mmol) was then added and the mixture was stirred for 15 min. The mixture was diluted with DCM and then aq sodium thiosulfate was added, followed by saturated aq sodium bicarbonate. The organic layer was separated, dried over sodium sulfate, and concentrated under reduced pressure. To the residue were added THF (5 mL) and 5-methyl-1H-pyrazol-3-amine (160 mg, 1.65 mmol) and the mixture was stirred at rt for 20 min and then concentrated under reduced pressure. The residue was purified by preparative HPLC (Varian diphenyl reverse phase column, eluted with gradient of solvent B=0.05% AcOH/ACN and solvent A=5% ACN/0.05% AcOH/H2O) to afford 2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazoline-7-carboxamide (21 mg, 10%). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.19 (s, 3H) 6.04 (s, 1H) 7.69 (s, 1H) 7.97-8.10 (m, 3H) 8.26-8.42 (m, 2H) 8.67 (s, 1H) 8.76 (d, J=8.67 Hz, 1H) 10.85 (br s, 1H) 12.20 (br s, 1H); LC-MS (ESI) m/z 414 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:4]=1[O:5][C:6]1[CH:7]=[C:8]([C:12]([CH3:17])([CH3:16])[C:13]([OH:15])=[O:14])[CH:9]=[CH:10][CH:11]=1)=[O:2].[BH4-].[Na+]>CO>[OH:2][CH2:1][C:3]1[CH:21]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:19]=[CH:18][C:4]=1[O:5][C:6]1[CH:7]=[C:8]([C:12]([CH3:17])([CH3:16])[C:13]([OH:15])=[O:14])[CH:9]=[CH:10][CH:11]=1
Reactant: CC(C)(C(=O)O)c1cccc(Oc2ccc(C(F)(F)F)cc2C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C(=O)O)c1cccc(Oc2ccc(C(F)(F)F)cc2CO)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To 2-[3-(2-formyl-4-trifluoromethyl-phenoxy)-phenyl]-2-methyl-propionic acid (0.15 g, 0.43 mmol) in MeOH (5 mL) was added sodium borohydride (0.019 g, 0.51 mmol), and the mixture was stirred at room temperature for 15 minutes. The solution was concentrated, and the residue was partitioned between H2O and EtOAc. The aqueous layer was acidified and extracted with EtOAc, and the combined organic layers were dried over MgSO4, filtered, and concentrated to give the desired product.