Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][C:5]2[C:6]([O:9][CH2:10][O:11][CH3:12])=[N:7][O:8][C:4]=2[CH:3]=1.[Br:15]N1C(=O)CCC1=O.C(OCC)(=O)C.O>C1C=CC=CC=1.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:15][CH2:1][C:2]1[CH:14]=[CH:13][C:5]2[C:6]([O:9][CH2:10][O:11][CH3:12])=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COCOc1noc2cc(C)ccc12
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: COCOc1noc2cc(CBr)ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101.2 %

Procedure:
20.0 g of methoxymethyl 6-methyl-1,2-benzisoxazol-3-yl ether was dissolved in 200 mL of benzene, to which 20.3 g of N-bromosuccinimide and 1.7 g of 2,2′-azobisisobutyronitrile were successively added at room temperature, and this mixture was stirred for 30 minutes while heating it under reflux. The reaction mixture was cooled to room temperature, and added to a mixture of ethyl acetate and water, and then the organic phase was separated therefrom. After the resultant organic phase was washed with a saturated aqueous solution of sodium hydrogen carbonate and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure to yield 28.5 g of 6-(bromomethyl)-3-(methoxymethoxy)-1,2-benzisoxazole as light brown oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[CH:7](O)[CH:6]([CH2:13][CH:14]([CH2:20][OH:21])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:5]2.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.FC1C=C2C(=CC=1F)C1OCC(CCCCC)CC1C2>ClCCl.N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[C@@H:7]1[O:21][CH2:20][C@H:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:13][C@H:6]1[CH2:5]2
Reactant: CCCCCC(CO)CC1Cc2cc(F)c(F)cc2C1O
Agent: CCCCCC1COC2c3cc(F)c(F)cc3CC2C1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCC[C@H]1CO[C@H]2c3cc(F)c(F)cc3C[C@@H]2C1
Reaction time: 8 h

Procedure:
6.0 g (21.4 mmol) of 5,6-difluoro-2-(2-hydroxymethylheptyl)indan-1-ol are dissolved in 70 ml of dichloromethane and 10 ml of pyridine, and 9.5 g (50 mmol) of p-toluenesulfonyl chloride are added with ice-cooling. The cooling is removed, and the batch is left to stir at room temp. overnight. After addition of 100 ml of dichloromethane, the solution is washed three times with 2 N hydrochloric acid and once each with water and copper sulfate solution and dried over sodium sulfate. The solvent is removed in vacuo, giving an isomer mixture of 7,8-difluoro-3-pentyl-2,3,4,4a,5,9b-hexahydroindeno[1,2-b]pyran, which is separated by chromatography on silica gel (eluent heptane/toluene 5:1), giving the racemate of (3R*,4aS*,9bR*)-7,8-difluoro-2,3,4,4a,5,9b-hexahydro-3-pentylindeno[1,2-b]pyran and the enantiomer thereof as a colourless solid; Δ∈=13.4; Δn=0.1021.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH2:12][CH:13]([CH3:17])[C:14](=O)[CH3:15])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Br:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:19][C:20]1[CH:26]=[CH:25][C:23]([N:24]2[C:11]([C:8]3[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=3)=[CH:12][C:13]([CH3:17])=[C:14]2[CH3:15])=[CH:22][CH:21]=1
Reactant: CC(=O)C(C)CC(=O)c1ccc(S(C)(=O)=O)cc1
Reactant: Nc1ccc(Br)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1cc(-c2ccc(S(C)(=O)=O)cc2)n(-c2ccc(Br)cc2)c1C
Yield: 66.4 %

Procedure:
A mixture of 1-[4-(methylsulfonyl)phenyl]-3-methylpentane-1,4-dione (110 mg, 0.41 mmol), 4-bromoaniline (71 mg, 0.41 mmol), and p-toluenesulfonic acid (10 mg) in toluene (3 mL) was heated at reflux temperature using Dean-Stark apparatus. After cooling down, volatiles were removed by evaporation. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate/hexane (1/3) to give the subtitle compound (110 mg, 67% yield).
Reaction SMILES: C1([O:7]C)C=CC=CC=1.Cl.[OH-:10].[Na+].[C:12]([O:15]CC)(=[O:14])[CH3:13]>>[OH2:7].[C:12]([OH:15])(=[O:14])[C:13]([OH:7])=[O:10].[C:12]([OH:15])(=[O:14])[C:13]([OH:7])=[O:10]
Reactant: COc1ccccc1
Reactant: CCOC(C)=O
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: O
Product: O=C(O)C(=O)O
Reaction time: 2 h

Procedure:
Under an inert atmosphere, 1.9 g of the previous compound are dissolved in 20 ml of anhydrous ethyl acetate and 5 ml of anisole and 20 ml of a 5N solution of HCl in ethyl acetate are added slowly at 5° C. The mixture is allowed to attain room temperature and after being stirred for 2 hours is cooled to about 5° C. before a 5N aqueous solution of NaOH is added to give a basic pH. The organic phase is then separated, dried and concentrated at about 70° C. under reduced pressure. The residual oil is dissolved in 60 ml of isopropanol and decolorized by means of 50 mg of active charcoal and 50 ml of a 0.5M solution of oxalic acid dihydrate in isopropanol are added; the precipitated salt is isolated by filtration. 1.5 g of oxalate hemihydrate are thus obtained (containing two molecules of oxalic acid), M.p.=130° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=[N:6][NH:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)Cl.[CH2:16]([O:23][C:24](=[O:30])[CH:25]=[CH:26][CH:27]([CH3:29])[CH3:28])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCOCC1>[CH3:1][O:2][C:3]([C:4]1[CH:26]([CH:27]([CH3:29])[CH3:28])[CH:25]([C:24]([O:23][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:30])[N:7]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[N:6]=1)=[O:15]
Reactant: COC(=O)C(Cl)=NNc1ccc(F)cc1
Reactant: CC(C)C=CC(=O)OCc1ccccc1
Solvent: C1COCCO1
Product: COC(=O)C1=NN(c2ccc(F)cc2)C(C(=O)OCc2ccccc2)C1C(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of [(4-fluoro-phenyl)-hydrazono]-chloroacetic acid methyl ester (20.93 g, 90.8 mmol) and 4-methyl-pent-2-enoic acid benzyl ester (18.54 g, 90.8 mmol) in dioxane (400 mL) at 25° C. was added Ag2CO3 (63.0 g, 227 mmol; commercially available from Sigma Aldrich). The reaction was protected from light and stirred at 25° C. for 48 hr. Subsequently, the reaction mixture was filtered through a pad of celite and the filtrate was concentrated. The crude product mixture was subjected to silica gel chromatography (5-20% EtOAc/Hex) to afford 1-(4-fluoro-phenyl)-4-isopropyl-4,5-dihydro-1H-pyrazole-3,5-dicarboxylic acid 5-benzyl ester 3-methyl ester in approximately 90% purity (29.3 g, 73%):: H-NMR (CDCI3) δ 7.30-7.24 (m, 3 H), 7.15-7.12 (m, 2 H), 7.01-6.96 (m, 2 H), 6.93-6.88 (m, 2 H), 5.14 (d, 1 H), 4.58 (d, 1 H), 3.83 (s, 3 H), 3.51-3.49 (m, 1 H), 2.40-2.36 (m, 1 H), 1.00 (d, 3 H), 0.69 (d, 3 H).
Reaction SMILES: C([O:8][CH2:9][CH:10]([CH2:30][O:31]CC1C=CC=CC=1)[O:11][C:12]1[CH:17]=[CH:16][C:15]([C@@H:18]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:19]([OH:21])=[O:20])=[CH:14][CH:13]=1)C1C=CC=CC=1>CO>[C:26]([O:25][C:23]([NH:22][C@H:18]([C:15]1[CH:16]=[CH:17][C:12]([O:11][CH:10]([CH2:9][OH:8])[CH2:30][OH:31])=[CH:13][CH:14]=1)[C:19]([OH:21])=[O:20])=[O:24])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccc(OC(COCc2ccccc2)COCc2ccccc2)cc1
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccc(OC(CO)CO)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A hydrogenation vessel containing a solution of (R)-[4-(2-benzyloxy-1-benzyloxymethyl-ethoxy)-phenyl]-tert-butoxycarbonylamino-acetic acid (1.86 g, 3.57 mmol) in methanol (50 mL) was purged with nitrogen and 10% palladium on carbon (100 mg) added. The atmosphere above the methanol solution was exchanged for hydrogen and the reaction mixture stirred vigorously for 30 minutes at ambient temperature. The reaction mixture was filtered through a pad of Celite and concentrated in vacuo to give (R)-tert-butoxycarbonylamino-[4-(2-hydroxy-1-hydroxymethyl-ethoxy)-phenyl]-acetic acid which was of sufficient purity for subsequent use without additional purification (0.88 g, 73%).
Reaction SMILES: [OH:1][CH:2]1[CH:19]([CH2:20][CH2:21][CH:22]([O:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][O:30]2)[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:5]2[CH2:6][C:7]3[C:12]([CH2:13][CH:4]2[CH2:3]1)=[C:11]([O:14][CH2:15][C:16]([OH:18])=[O:17])[CH:10]=[CH:9][CH:8]=3.[CH2:35](O)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(N(CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>ClCCl.COC(C)(C)C>[CH2:35]([O:17][C:16](=[O:18])[CH2:15][O:14][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[CH2:13][CH:4]1[CH2:3][CH:2]([OH:1])[CH:19]([CH2:20][CH2:21][CH:22]([O:28][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][O:30]3)[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:5]1[CH2:6]2)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: OCc1ccccc1
Reactant: CCCCCC(CCC1C(O)CC2Cc3c(cccc3OCC(=O)O)CC21)OC1CCCCO1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: COC(C)(C)C
Solvent: ClCCl
Product: CCCCCC(CCC1C(O)CC2Cc3c(cccc3OCC(=O)OCc3ccccc3)CC21)OC1CCCCO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of {2-hydroxy-1-[3-(tetrahydropyran-2-yloxy)octyl]-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy}acetic acid (Compound B) (2 g, 4.21 mmol), benzyl alcohol (2.47 g, 22.9 mmol) and triethylamine (7.2 g, 71.3 mmol) in dichloromethane (DCM) (20 mL) was treated with bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP—Cl) (7.8 g, 30.7 mmol) at 0° C. and stirred at room temperature (RT) for 2 hr. The reaction mixture was diluted with methyl-tert-butyl ether (MTBE) and washed with water and then brine, dried over sodium sulfate and concentrated under vacuum. The residue was purified by silica gel chromatography to provide Compound C. MS: m/z 587 [M+Na]+
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][N:14]=[C:13]3[C:8]=2[C:9]2[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=2[C:11](=[O:17])[NH:12]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[N:22]([C:25]1[CH:30]=[CH:29][C:28]([CH:31]([CH3:33])[CH3:32])=[CH:27][CH:26]=1)=[C:23]=[O:24].CCN(C(C)C)C(C)C>O1CCOCC1>[CH:31]([C:28]1[CH:29]=[CH:30][C:25]([NH:22][C:23]([N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:16]=[CH:15][N:14]=[C:13]4[C:8]=3[C:9]3[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=3[C:11](=[O:17])[NH:12]4)[CH2:6][CH2:5]2)=[O:24])=[CH:26][CH:27]=1)([CH3:33])[CH3:32]
Reactant: CC(C)c1ccc(N=C=O)cc1
Reactant: O=c1[nH]c2nccc(N3CCNCC3)c2c2ccccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)c1ccc(NC(=O)N2CCN(c3ccnc4[nH]c(=O)c5ccccc5c34)CC2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 64.7 %

Procedure:
Compound 179 (50 mg, 0.14 mmol), 1-isocyanato-4-isopropyl-benzene (34 mg, 0.21 mmol), and DIEA (0.07 mL, 0.42 mmol) were suspended in dioxane (2 mL), and stirred overnight at 80° C. The reaction mixture was quenched with 1M HCl, and diluted with EtOAc. The mixture was filtered through an Extrelut column. The column was washed with EtOAc, and the filtrate was concentrated. The crude product was purified via Biotage eluting with a gradient of 75 to 100 EtOAc in hexane to provide 197 (40 mg, 64% yield) as a yellow solid. LC-MS (M+H=442, obsd.=442).
Reaction SMILES: [Cl:1][C:2]([Cl:11])([Cl:10])[C:3]([C:5]1[NH:6][CH:7]=[CH:8][CH:9]=1)=[O:4].[Br:12]Br>C(Cl)(Cl)Cl.O>[Br:12][C:8]1[CH:9]=[C:5]([C:3](=[O:4])[C:2]([Cl:1])([Cl:10])[Cl:11])[NH:6][CH:7]=1
Reactant: O=C(c1ccc[nH]1)C(Cl)(Cl)Cl
Reactant: BrBr
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(c1cc(Br)c[nH]1)C(Cl)(Cl)Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 55 %

Procedure:
A solution of 2-trichloracetyl pyrrole (10.6 g, 50 mmoL) in CHCl3 (10 mL) was cooled to 0° C. and to this solution bromine (8.53 g, 53.5 mmoL) was added in a dropwise fashion. The reaction mixture was stirred for 10 minutes at 0° C. then 30 minutes at room temperature. The solution was diluted with H2O and extracted with CHCl3, washed with saturated NaHCO3 solution, dried over anhydrous Na2SO4 then concentrated in vacuo. The crude product was recrystallized from hexane and the product was obtained as white crystalline solid (8.0 g). HPLC Rt 5.66 min and MS 287.9 as M−1 peak.
Reaction SMILES: [CH:1]([N:4]([CH3:12])[C:5]([N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1)=[O:6])([CH3:3])[CH3:2].[C:13](#N)C.[I:16]C>>[I-:16].[CH:1]([N:4]([CH3:12])[C:5]([N:7]1[CH:11]=[CH:10][N+:9]([CH3:13])=[CH:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)N(C)C(=O)n1ccnc1
Reactant: CC#N
Reactant: CI
Product: CC(C)N(C)C(=O)n1cc[n+](C)c1
Product: [I-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 50 mL round-bottomed flask was added N-isopropyl-N-methyl-1H-imidazole-1-carboxamide (0.550 g, 3.29 mmol), acetonitrile (29 mL, 3.29 mmol), iodomethane (0.817 mL, 13.16 mmol). The resulting solution was stirred at room temperature overnight. The solvent was removed under vacuum to afford 1-(isopropyl(methyl)carbamoyl)3-methyl-1H-imidazol-3-ium iodide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1.Cl.[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24]([CH3:29])=[C:23]2[CH2:30][CH2:31][NH2:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24]([CH3:29])=[C:23]2[CH2:30][CH2:31][NH:32][C:10](=[O:12])[C:9]1[CH:8]=[CH:7][C:6]([CH2:5][C:4]2[CH:15]=[CH:16][CH:17]=[C:2]([F:1])[CH:3]=2)=[CH:14][CH:13]=1
Reactant: O=C(O)c1ccc(Cc2cccc(F)c2)cc1
Reactant: Cc1[nH]c2ccc(Cl)cc2c1CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1[nH]c2ccc(Cl)cc2c1CCNC(=O)c1ccc(Cc2cccc(F)c2)cc1
Yield: 33.5 %

Procedure:
N-(2-(5-Chloro-2-methyl-1H-indol-3-yl)ethyl)-4-(3-fluorobenzyl)benzamide was prepared according to method A with 4-(3-fluorobenzyl)benzoic acid (0.080 g, 0.347 mmol), 2-(5-chloro-2-methyl-1H-indol-3-yl)ethanamine hydrochloride (0.094 g; 0.382 mmol), HATU (0.132 g; 0.347 mmol) and N,N-diisopropylethylamine (0.150 mL; 0.869 mmol) in DMF (5 mL). Flash chromatography on silica gel (eluent 20 to 100% ethyl acetate in heptane) furnished 0.049 g (34%) of the title compound as a pale yellow solid.
Reaction SMILES: N.[C:2]([NH:6][C:7]([C@@H:9]1[CH2:18][C@H:17]2[C@H:12]([CH2:13][CH2:14][CH2:15][CH2:16]2)[CH2:11][N:10]1[CH2:19][C@@H:20]([OH:44])[C@@H:21]([NH:30][C:31](=[O:43])[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([O:38]C(=O)C)[C:33]=1[CH3:42])[CH2:22][S:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:8])([CH3:5])([CH3:4])[CH3:3]>CO>[C:2]([NH:6][C:7]([C@@H:9]1[CH2:18][C@H:17]2[C@H:12]([CH2:13][CH2:14][CH2:15][CH2:16]2)[CH2:11][N:10]1[CH2:19][C@@H:20]([OH:44])[C@@H:21]([NH:30][C:31](=[O:43])[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([OH:38])[C:33]=1[CH3:42])[CH2:22][S:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:8])([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(=O)Oc1cccc(C(=O)N[C@@H](CSc2ccccc2)[C@H](O)CN2C[C@H]3CCCC[C@H]3C[C@H]2C(=O)NC(C)(C)C)c1C
Agent: N
Solvent: CO
Product: Cc1c(O)cccc1C(=O)N[C@@H](CSc1ccccc1)[C@H](O)CN1C[C@H]2CCCC[C@H]2C[C@H]1C(=O)NC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 54 %

Procedure:
Aqueous ammonia (28%, 24 ml) was added to a solution of (3S, 4aS, 8aS)-2-[(2R, 3R)-3-(3-acetoxy-2-methyl-benzoylamino)-2-hydroxy-4-phenylthiobutyl]-decahydroisoquinoline-3-carboxylic acid t-butylamide (12.7 g) in methanol (96 ml). The resulting mixture was stirred for 1.5 hours at room temperature. The resulting precipitate was collected by filtration and washed with a mixed solution of methanol (75 ml)/water (25 ml). The residue was dried at 50° C. under vacuum to give (3S, 4aS, 8aS)-2-[(2R, 3R)-2-hydroxy-3-(3-hydroxy-2-methylbenzoylamino)-4-phenylthiobutyl]decahydroisoquinoline-3-carboxylic acid t-butylamide 17, 8.00 g, as colorless crystals (54% yield from (2R, 3R-benzyloxycarbonylamino-4-phenylthio-2-methanesulfonyloxy-1-(4-nitrobenzoyloxy) butane). 1H NMR (CD3OD, 300 MHz) δ 7.49 (m, 2H), 7.27 (m, 2H), 7.17 (m, 1H), 7.01 (m, 1H), 6.90 (m, 1H), 6.79 (m, 1H), 4.43 (M, 1H), 4.06 (m, 1H), 3.54 (dd, J=10.1, 3.5 Hz, 1H), 3.37 (m, 1H), 3.04 (dd, J=8.7, 1.7 Hz, 1H), 2.60 (m, 2H), 2.24 (s, 3H), 2.17 (m, 2H), 2.01 (M, 1H), 1.9–1.1 (m, 11H), 1.17 (s, 9H).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][N:6]2[C:8]([C:11]3[CH:16]=[N:15][CH:14]=[CH:13][N:12]=3)=[N:9][N:10]=[C:5]2[CH2:4][N:3]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C(#N)C.O.I([O-])(=O)(=O)=[O:29].[Na+]>C(Cl)(Cl)Cl.O.[Ru](=O)=O>[CH3:1][C@H:2]1[CH2:7][N:6]2[C:8]([C:11]3[CH:16]=[N:15][CH:14]=[CH:13][N:12]=3)=[N:9][N:10]=[C:5]2[C:4](=[O:29])[N:3]1[C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C[C@H]1Cn2c(nnc2-c2cnccn2)CN1C(=O)OC(C)(C)C
Agent: O=[Ru]=O
Agent: [Na+]
Solvent: CC#N
Solvent: ClC(Cl)Cl
Solvent: O
Product: C[C@H]1Cn2c(nnc2-c2cnccn2)C(=O)N1C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 47.3 %

Procedure:
To a solution of (S)-tert-butyl 6-methyl-3-(pyrazin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxylate (1.0 g, 3.2 mmol) in chloroform (12 mL) was added acetonitrile (12 mL), water (30 mL), sodium metaperiodate (3.2 g, 14.9 mmol) and ruthenium (IV) oxide hydrate (62 mg, 0.4 mmol) and the reaction mixture was vigorously stirred for 30 minutes. The reaction mixture was filtered through celite, extracted with DCM, the organic layers were washed with brine, dried with Na2SO4, filtered, concentrated and purified by flash column chromatography (0-100% EtOAc in hexanes) to provide the desired compound (0.50 g, 48%). 1H NMR (400 MHz, DMSO) δ 9.47 (s, 1H), 8.83 (s, 2H), 5.01-4.92 (m, 1H), 4.89-4.79 (m, 1H), 4.73-4.66 (m, 1H), 1.52 (s, 9H), 1.21 (d, J=6.8 Hz, 3H).
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][O:3][CH2:4][CH2:5][OH:6].[Br:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O.[OH2:17]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:7][CH2:1][CH2:2][O:3][CH2:4][CH2:5][O:6][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][Br:8])=[O:17]
Reactant: O=C(O)CCCCCBr
Reactant: OCCOCCO
Reactant: O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=C(CCCCCBr)OCCOCCOC(=O)CCCCCBr
Temperature: 25 °C

Procedure:
Into a 3-liter 4-neck round bottom flask equipped with a mechanical stirrer was added a solution of diethylene glycol (100 g), 6-Bromo hexanoic acid (386 g) and para-toluene sulphonic acid (5 g) in toluene (1000 ml). The solution was refluxed for 3 hours in a Dean-Stark apparatus with azeotropic removal of water. The solution was cooled to room temperature and the toluene layer was washed with water (600 ml), 5% sodium bicarbonate solution (1500 ml) and water (600 ml). The toluene layer was dried over anhydrous sodium sulphate, filtered and distilled to obtain 6-bromohexanoic acid 2-[2-(6-bromohexanoyloxy)-ethoxy]-ethyl ester (400 g) as light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:15][CH2:16][C:17]([C:19]2[S:20][C:21]([CH3:30])=[C:22]3[CH2:27][C:26]([CH3:29])([CH3:28])[CH2:25][CH2:24][C:23]=23)=[O:18])[CH:5]=[C:6]([O:13][CH3:14])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][OH:12].CCN(C(C)C)C(C)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:15][CH2:16][C:17](=[O:18])[C:19]2[S:20][C:21]([CH3:30])=[C:22]3[CH2:27][C:26]([CH3:28])([CH3:29])[CH2:25][CH2:24][C:23]=23)[CH:5]=[C:6]([O:13][CH3:14])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][O:12][S:41]([CH3:40])(=[O:43])=[O:42]
Reactant: COc1cc(CCC(=O)c2sc(C)c3c2CCC(C)(C)C3)cc(Cl)c1OCCCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(CCC(=O)c2sc(C)c3c2CCC(C)(C)C3)cc(Cl)c1OCCCOS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97.5 %

Procedure:
To a solution of 3-[3-chloro-4-(3-hydroxy-propoxy)-5-methoxy-phenyl]-1-(3,5,5-trimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-propan-1-one (170 mg, 0.38 mmol) in DCM (10 mL) and DIPEA (0.10 mL, 0.60 mmol) is added methane sulfonylchloride (0.04 mL, 0.45 mmol) at 0° C. The reaction mixture is stirred at 0° C. for 30 min. Another portion of methane sulfonylchloride (0.04 mL, 0.45 mmol) is added and stirring is continued for 20 min. The reaction mixture is diluted with DCM, washed with 0.1 N aq. NaOH followed by 10% aq. citric acid solution, dried over MgSO4 and evaporated to give methanesulfonic acid 3-{2-chloro-6-methoxy-4-[3-oxo-3-(3,5,5-trimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-propyl]-phenoxy}-propyl ester (196 mg) as a yellow oil; LC-MS: tR=1.17 min, [M+1]+=529.17.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:7][CH3:8])=[N:5][N:6]=1.[Br:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]#[N:24])=[CH:13][CH:12]=1>C(#N)C>[BrH:9].[CH2:7]([C:4]1[S:3][C:2](=[NH:1])[N:6]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])=[CH:15][CH:16]=2)[N:5]=1)[CH3:8]
Reactant: CCc1nnc(N)s1
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Solvent: CC#N
Product: Br
Product: CCc1nn(Cc2ccc(-c3ccccc3C#N)cc2)c(=N)s1
Yield: 145 %

Procedure:
To 10 ml of acetonitrile, 2.7 g of 2-amino-5-ethyl-1,3,4-thiadiazole and 1.3 g of 4'-bromomethyl-2-cyanobiphenyl were added, followed by heating under reflux for 3 hours. After the reaction mixture was cooled, the crystals so precipitated were collected by filtration, washed successively with acetonitrile and diethyl ether and then dried, whereby 2.78 g of the title compound was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][CH2:13][CH2:14]Cl)[CH:11]=1)[O:8][CH2:7][CH2:6][CH2:5]2.Br[CH2:17][CH2:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21][CH:20]=1.C([N:30](CC)CC)C.O>CS(C)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][CH2:13][CH2:14][NH:30][CH2:17][CH2:18][C:19]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[NH:21][CH:20]=3)[CH:11]=1)[O:8][CH2:7][CH2:6][CH2:5]2
Reactant: BrCCc1c[nH]c2ccccc12
Reactant: Fc1cc2c(c(OCCCl)c1)OCCC2
Reactant: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O
Product: Fc1cc2c(c(OCCNCCc3c[nH]c4ccccc34)c1)OCCC2
Temperature: 90 °C
Reaction time: 12 h
Yield: 38.5 %

Procedure:
A solution of 2-(6-fluorochroman-8-yloxy)ethylchloride (0.41 g, 2.2 mmol), 3-(2-bromoethyl)indole (0.25 g, 1.1 mmol) and triethylamine (0.23 g, 2.2 mmol) in anhydrous dimethylsulfoxide (20 ml) was allowed to stir for 12 hours at 90° C. The mixture was poured into water (100 ml) and extracted with methylene chloride (3×100 ml). The organic layer was washed with water (3×150 ml), dried over anhydrous sodium sulfate, filtered and the solvent was removed under vacuum. Chromatography (10% methanol-methylene chloride plus ammonium hydroxide) afforded 0.15 g (34%) of product as a yellow oil.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:18])[CH:8]=2)[N:3]=1.[CH2:19]([NH2:25])[C:20]1[O:24][CH:23]=[CH:22][CH:21]=1>O>[Cl:18][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:25][CH2:19][C:20]1[O:24][CH:23]=[CH:22][CH:21]=1)[N:11]=[C:10]2[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCc1ccco1
Reactant: Clc1ccc2nc(Cl)nc(-c3ccccc3)c2c1
Solvent: O
Product: Clc1ccc2nc(NCc3ccco3)nc(-c3ccccc3)c2c1
Yield: 83.4 %

Procedure:
A mixture of 275 mg of 2,6-dichloro-4-phenylquinazoline (compound No. Ia1-3) and 486 mg of furfurylamine was stirred at 85° C. for 40 minutes and then poured into 50 ml of water. The mixture was extracted with ethyl acetate and the resultant extract was washed with water and then concentrated. The resulting residue was recrystallized from ethanol to obtain 280 mg of the titled compound. Mp.142.0° C. 1H NMR (CDCl3): 4.77 (2H, d, J=5.6 Hz), 5.70 (1H, br. t, J=5.6 Hz), 6.29-6.32 (2H, m), 7.36 (1H, dd, J=1.8, 0.9 Hz), 7.53-7.70 (7H, m), 7.78 (1H, d, J=2.2 Hz).
Reaction SMILES: [CH2:1]([CH:5]1[CH2:11][C:10](=[O:12])[O:9][C:7](=[O:8])[CH2:6]1)[CH:2]([CH3:4])C.[CH2:13]([NH:15][CH2:16][CH3:17])[CH3:14].Cl[CH2:19]Cl>>[CH2:13]([N:15]([CH2:16][CH3:17])[C:10](=[O:12])[CH2:11][CH:5]([CH2:1][CH2:2][CH3:4])[CH:6]([CH3:19])[C:7]([OH:9])=[O:8])[CH3:14]
Reactant: ClCCl
Reactant: CC(C)CC1CC(=O)OC(=O)C1
Reactant: CCNCC
Product: CCCC(CC(=O)N(CC)CC)C(C)C(=O)O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 3-isobutyl glutaric anhydride (5 grams) in dichloromethane (10 ml), added diethyl amine (4.3 grams) and stirred the reaction mixture for 12 hrs at 25° C. The reaction mixture was quenched with water (10 ml) and the pH of the reaction mixture adjusted to 1.0 using hydrochloric acid. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The organic layers were combined and the solvent distilled off to provide the title compound as a residue.