Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH:7]([NH2:10])[CH2:8][OH:9])=[CH:3][CH:2]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[F:28][C:29]([F:34])([F:33])[C:30](=O)[CH3:31]>C1(C)C=CC=CC=1>[CH3:31][C@@:30]1([C:29]([F:34])([F:33])[F:28])[NH:10][CH:7]([C:4]2[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=2)[CH2:8][O:9]1
Reactant: CC(=O)C(F)(F)F
Reactant: NC(CO)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Product: C[C@@]1(C(F)(F)F)NC(c2ccccc2)CO1
Temperature: 110 °C
Yield: 84.3 %

Procedure:
25 g (180 mmol) of (R)-phenylglycinol and then 4 g (16 mmol) of pyridinium para-toluenesulfonate are added to a solution of 25.8 g (230 mmol) of trifluoroacetone in 200 mL of toluene in a three-necked flask on which is mounted Dean-Stark apparatus. The mixture obtained is then heated at 110° C. for 5 hours. After cooling, the reaction mixture is concentrated under reduced pressure. The residue obtained is purified by filtration on silica (eluent: dichloromethane) to give 35.10 g of (R)-2-methyl-4-phenyl-2-trifluoromethyloxazolidine in the form of a colorless liquid, the characteristics of which are as follows:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:4]=[C:3]1[CH:13]=[O:14].C(O)C.[BH4-].[Na+].O>O1CCCC1>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:4]=[C:3]1[CH2:13][OH:14]
Reactant: Cn1cc(-c2ccccc2)nc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc(-c2ccccc2)nc1CO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
To a solution of 1-methyl-4-phenyl-1H-imidazole-2-carbaldehyde (7.24 g) in tetrahydrofuran (50 mL)-ethanol (10 mL) was gradually added sodium borohydride (1.47 g) at room temperature and the mixture was stirred at room temperature for 30 min. Water was added to the reaction mixture and the precipitated crystals were collected by filtration to give (1-methyl-4-phenyl-1H-imidazol-2-yl)methanol as colorless crystals (5.71 g, yield 78%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 191-192° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:14][CH2:15][CH3:16])=[C:8]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:9]=1)(=[O:3])[CH3:2].[CH3:17][O:18][C:19]1[CH:24]=[C:23]([O:25][CH3:26])[N:22]=[C:21]([NH:27][C:28](=O)[O:29]C2C=CC=CC=2)[N:20]=1.C1CCN2C(=NCCC2)CC1.Cl>C(#N)C.O>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:14][CH2:15][CH3:16])=[C:8]([S:10]([NH:13][C:28]([NH:27][C:21]2[N:20]=[C:19]([O:18][CH3:17])[CH:24]=[C:23]([O:25][CH3:26])[N:22]=2)=[O:29])(=[O:11])=[O:12])[CH:9]=1)(=[O:3])[CH3:2]
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Reactant: CCOc1ccc(C(C)=O)cc1S(N)(=O)=O
Agent: Cl
Solvent: CC#N
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: CCOc1ccc(C(C)=O)cc1S(=O)(=O)NC(=O)Nc1nc(OC)cc(OC)n1
Reaction time: 1 h
Yield: 77.4 %

Procedure:
To a stirred suspension of 0.2 g of the compound from Example 8, 0.23 g of 4,6-dimethoxy-2-pyrimidinylcarbamic acid, phenyl ester in 10 ml of dry acetonitrile was added 127 μl of DBU. After being stirred for 1 hr, the mixture was treated with 40 ml of water and 1N HCl in a dropwise manner until the pH was 3. The precipitate was filtered off and washed with water and ether/hexane (1/1), to give 0.27 g of a solid, m.p. 192°-193° C.
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]3)[CH:9]=2)[C:4](=[O:27])[O:3]1.[ClH:28]>O1CCOCC1>[ClH:28].[CH3:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:12][CH2:13][N:14]3[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]3)[CH:9]=2)[C:4](=[O:27])[O:3]1
Reactant: CC1Cc2cc(CCN3CCN(C(=O)OC(C)(C)C)CC3)ccc2C(=O)O1
Agent: Cl
Solvent: C1COCCO1
Product: CC1Cc2cc(CCN3CCNCC3)ccc2C(=O)O1

Procedure:
A solution of tert-butyl 4-[2-(3-methyl-1-oxo-3,4-dihydro-1H-isochromen-6-yl)ethyl]piperazine-1-carboxylate (850 mg, 2.3 mmol) was stirred in 4N HCl in Dioxane for 4 hours. The excess solvent was then removed to give the free amine as the HCl salt. LC-MS (IE, m/z): 275 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11]#[C:12][CH2:13][NH2:14].Cl[CH2:23][C:24](Cl)=[O:25].[NH:27]1[CH2:31][CH2:30][CH2:29][C:28]1=O>C(Cl)Cl>[F:1][C:2]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11]#[C:12][CH2:13][NH:14][C:24](=[O:25])[CH2:23][N:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: O=C(Cl)CCl
Reactant: NCC#Cc1cnccc1Oc1ccc([N+](=O)[O-])cc1F
Reactant: O=C1CCCN1
Solvent: ClCCl
Product: O=C(CN1CCCC1)NCC#Cc1cnccc1Oc1ccc([N+](=O)[O-])cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.6 %

Procedure:
A solution of 3-(4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)prop-2-yn-1-amine (80 mg, 0.26 mmol) in anhydrous CH2Cl2 (2.5 mL) was cooled to 0° C. and treated with chloroacetyl chloride (40 mg, 0.37 mmol) the mixture was stirred at rt for 1 h. The mixture was concentrated under vacuum to removed the solvent and excess reagent and the residue redissolved in CH3CN (1.5 mL), treated with pyrrolidone (55 mg, 0.78 mmol) and stirred at rt for 4 h. The mixture was partitioned between EtOAc and saturated aq. NaHCO3 solution and the organic phase separated, washed with brine, dried (MgSO4) and concentrated to give crude product. The residue was purified by flash chromatography on silica gel eluting with 0-10% MeOH/CH2Cl2 to afford the title compound (40 mg, 39%) as a brown oil. 1H NMR (DMSO-d6) δ 8.66 (s, 1H), 8.50 (d, 1H, J=6.1 Hz), 8.41 (dd, 1H, J=2.8, 10.4 Hz), 8.18-8.15 (m, 2H), 7.51 (dd, 1H, J=8.3, 8.8 Hz), 7.06 (d, 1H, J=5.5 Hz) 4.10 (d, 2H, J=5.5 Hz), 3.01 (s, 2H), 2.47-2.43 (m, 4H), 1.67-1.63 (m, 4H); MS(ESI+): m/z 399.27 (M+H)+.
Reaction SMILES: Cl.[NH2:2][N:3]1[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([CH3:15])[CH:9]=2)[N:5]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:4]1=[O:26].CCN(C(C)C)C(C)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>ClCCl>[CH3:36][S:37]([NH:2][N:3]1[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([CH3:15])[CH:9]=2)[N:5]([CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=2)[C:4]1=[O:26])(=[O:39])=[O:38]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(CCN2C(=O)N(N)CC2c2ccc(C)c(C)c2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CCN2C(=O)N(NS(C)(=O)=O)CC2c2ccc(C)c(C)c2)cc1
Reaction time: 0.75 h
Yield: 48.2 %

Procedure:
A solution of 1-amino-3-[2-(4-methoxyphenyl)-ethyl]-4-(3,4-dimethylphenyl)-2-imidazolidinone hydrochloride (300 mg, 0.80 mmol) in dichloromethane (3.0 mL) and Hunig's base (0.31 mL, 1.8 mmol) is cooled in an ice bath and methanesulfonyl chloride (0.068 mL, 0.88 mmol) is added dropwise. The reaction is stirred cold for 45 minutes and washed with 0.1 N HCl (2×) and H2O. The organic phase is dried (Na2SO4), and concentrated to a white foam. The crude material is purified over silica (1.5% MeOH/dichloromethane) to afford 161 mg (48% yield) of the desired compound. 1H NMR (CDCl3) δ 7.17 (d, J=8.1 Hz, 1H), 7.07 (m, 2H), 7.00 (m, 2H), 6.85 (m, 3H), 4.45 (t, J=8.1 Hz, 1H), 3.96 (t, J=8.1 Hz, 1H), 3.81 (s, 3H), 3.74 (m, 1H), 3.33 (t, J=8.4 Hz, 1H), 3.06 (s, 3H), 2.97 (m, 1H), 2.76 (m, 1H), 2.67 (m, 1H), 2.30 (s, 6H).). MS 418 (MH+). Anal. Calcd. for C21H27N3O4S¼H2O: C, 59.77, H, 6.57; N, 9.96. Found: C, 59.82, H, 6.06; N, 9.85. FAB-HRMS: anal. calcd for C21H27N3O4S: 418.18005. Found: 418.17960.
Reaction SMILES: [F:1][C:2]1[CH2:7][CH2:6][CH:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([CH:14]=[O:15])[CH2:10][CH2:9]2)[CH2:4][CH:3]=1.[CH2:16]([CH:19]([CH2:22]O)[CH2:20][OH:21])[CH2:17][CH3:18].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH2:7][CH2:6][CH:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([C@H:14]3[O:21][CH2:20][C@H:19]([CH2:16][CH2:17][CH3:18])[CH2:22][O:15]3)[CH2:10][CH2:9]2)[CH2:4][CH:3]=1
Reactant: O=C[C@H]1CC[C@H](C2CC=C(F)CC2)CC1
Reactant: CCCC(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCC[C@H]1CO[C@H]([C@H]2CC[C@H](C3CC=C(F)CC3)CC2)OC1

Procedure:
500 mg of trans-4-(4-fluoro-cyclohex-3-enyl)cyclohexanecarbaldehyde, 310 mg of 2-propyl-propane-l,3-diol and 50 mg of p-toluenesulphonic acid in 8 ml of toluene were boiled at reflux for 1 hour in an apparatus which was gassed with nitrogen and which was fitted with a water separator. After cooling the reaction solution was partitioned in water/ether. The organic phase was washed twice with water. The aqueous phases were extracted twice with ether. The organic phases were combined, dried over magnesium sulphate, filtered and the filtrate was evaporated. The crude product was recrystallized several times from ethanol/1% ethyl acetate and gave 350 mg of trans-2-[trans-4-(4-fluoro-cyclohex-3-enyl)cyclohexyl]-5-propyl-[1,3]-dioxane, m.p. (C-N)<room temperature; S-N 104° C., c1.p. (N-I) 118.3° C.;
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[CH:19][N:20]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[CH:19][N:20]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:28][CH:29]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCc1ncn(Cc2ccc(F)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCc1ncn(Cc2ccc(F)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 62.2 %

Procedure:
A mixture of hydroxylammonium chloride (1.25 g), sodium hydrogen carbonate (2.02 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-{[4-butyl-1-(4-fluorobenzyl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.54 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was dissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.23 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.2 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.38 g, 62%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[CH2:11]([O:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH:27]([NH2:29])=[O:28]>CO>[CH2:11]([O:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]([S:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[NH:29][CH:27]=[O:28])=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Reactant: NC=O
Reactant: Cc1ccc(S(=O)O)cc1
Solvent: CO
Product: Cc1ccc(S(=O)(=O)C(NC=O)c2ccc(OCc3ccccc3)cc2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
A mixture of 4-methylbenzenesulfinic acid (3.1 g, 19.9 mmol), 4-(benzyloxy)benzaldehyde (4.2 g, 19.9 mmol), and formamide (4.5 mL ) was heated at 60° C. for 20 h. The mixture was diluted with methanol and stirring was continued for 1 h at rt. The resultant solid was filtered and dried to give 3.81 g (49%) of a white solid. The product was used in the next step without future purification.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12]([CH:14]=O)[CH:11]=[C:10]([OH:16])[C:5]=1[C:6]([O:8]C)=[O:7])[CH3:2].[C:17]1([C:23](=O)[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[NH2:32][C:33]([NH2:35])=[O:34].Cl>CCO>[CH2:1]([O:3][C:4]1[CH:13]=[C:12]([CH:14]2[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[C:23]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[NH:35][C:33](=[O:34])[NH:32]2)[CH:11]=[C:10]([OH:16])[C:5]=1[C:6]([OH:8])=[O:7])[CH3:2]
Reactant: NC(N)=O
Reactant: CCOc1cc(C=O)cc(O)c1C(=O)OC
Reactant: O=C(Cc1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCO
Product: CCOc1cc(C2NC(=O)NC(c3ccccc3)=C2c2ccccc2)cc(O)c1C(=O)O
Temperature: 40 °C
Reaction time: 5 h
Yield: 13.2 %

Procedure:
A mixture of methyl 2-ethoxy-4-formyl-6-hydroxybenzoate (Intermediate 85) (150 mg, 0.67 mmol), 1,2-diphenylethanone (137 mg, 0.70 mmol), urea (120 mg, 2.0 mmol) and conc. HCl (0.5 mL) in EtOH (5 mL) was refluxed under N2 overnight. The mixture was concentrated under reduced pressure. The residue was taken up in MeOH (10 mL) and aq. NaOH (2 M, 10 mL) and was stirred at 40° C. under N2 for 5 hours. The resulting mixture was cooled to room temperature, and then acidified with aqueous HCl (2 M, 12 mL), followed by a standard aqueous/EtOAc workup and purification by prep-HPLC (0.1% TFA as additive) to give Compound 161 (38 mg, 2-step yield 13%). 1H NMR (CD3OD 400 MHz): δ 7.25-7.20 (m, 5H), 7.08-7.00 (m, 3H), 6.89-6.84 (m, 2H), 6.62 (d, J=1.6 Hz, 1H), 6.47 (d, J=1.6 Hz, 1H), 5.24 (s, 1H), 4.17-4.04 (m, 2H), 1.37 (t, J=7.2 Hz, 3H). MS (ESI): m/z 431.5 [M+1]+.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[N:8]=[CH:9][C:10]3[C:11](=[O:21])[NH:12][C:13]4[N:14]([N:16]=[C:17]([S:19][CH3:20])[N:18]=4)[C:15]=3[C:6]=2[CH:5]=[N:4]1)[CH3:2].I([O-])(=O)(=O)=[O:23].[Na+]>>[CH2:1]([N:3]1[C:7]2[N:8]=[CH:9][C:10]3[C:11](=[O:21])[NH:12][C:13]4[N:14]([N:16]=[C:17]([S:19]([CH3:20])=[O:23])[N:18]=4)[C:15]=3[C:6]=2[CH:5]=[N:4]1)[CH3:2]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CCn1ncc2c1ncc1c(=O)[nH]c3nc(SC)nn3c12
Agent: [Na+]
Product: CCn1ncc2c1ncc1c(=O)[nH]c3nc(S(C)=O)nn3c12

Procedure:
3.01 g. of 8-ethyl-2-methylthio-4H-pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidin-5(8H)-one obtained in Example 10a are oxidized with 2.2 g. of sodium metaperiodate in aqueous alcohol for 7 days at room temperature. The precipitate of 8-ethyl-2-methylsulfinyl-4H-pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidin-5(8H)-one is filtered off, washed with water and recrystallized from dimethylformamide, yield 2.8 g. (88%); m.p. >300°.
Reaction SMILES: C([O-])(=O)C.[Na+].[O:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=O)[CH2:8][CH2:7]1.Cl.[NH2:18][OH:19]>O.C(O)C>[O:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[N:18][OH:19])[CH2:8][CH2:7]1
Reactant: NO
Reactant: O=C1CCOc2ccccc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: ON=C1CCOc2ccccc21
Yield: 101.2 %

Procedure:
A mixture of sodium acetate (41.53 g, 0.506 mol) in water at 60° C. was combined with a stirred mixture of chroman-4-one (25 g, 0.169 mol) and hydroxylamine hydrochloride (20.0 g, 0.287 mol) in ethanol at 60° C. The resulting mixture was heated at reflux for 90 minutes, cooled and filtered. The crude solid was washed with water to give chroman-4-one oxime (27.9 g, yield 96%), mp. 114-117° C., purity 95%.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1.[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[S:20](Cl)(=[O:22])=[O:21].C(N(C(C)C)CC)(C)C.C(=O)([O-])O.[Na+]>C(Cl)Cl>[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[S:20]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1)(=[O:22])=[O:21]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Reactant: O=Cc1c[nH]c2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=Cc1cn(S(=O)(=O)c2ccc(Cl)cc2Cl)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.5 %

Procedure:
A solution of 1H-indole-3-carboxaldehyde (0.290 g, 2.00 mmol) in methylene chloride (4 mL) was added with 2,4-dichlorophenylsulfonyl chloride (0.589 g, 2.40 mmol) and diisopropylethylamine (0.310 g, 2.40 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate to terminate the reaction, and then extracted three times with methylene chloride. The organic layer was dried over anhydrous magnesium sulfate, then the solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain 1-(2,4-dichlorophenylsulfonyl)-1H-indole-3-carboxaldehyde (0.620 g, 87%).
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][NH:7][C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:9]=2[N+:15]([O-])=O)=[CH:4][CH:3]=1.O.O.Cl[Sn]Cl>C(O)C>[NH2:15][C:9]1[CH:10]=[C:11]([OH:14])[CH:12]=[CH:13][C:8]=1[NH:7][CH2:6][C:5]1[CH:18]=[CH:19][C:2]([Br:1])=[CH:3][CH:4]=1
Reactant: O=[N+]([O-])c1cc(O)ccc1NCc1ccc(Br)cc1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Nc1cc(O)ccc1NCc1ccc(Br)cc1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
To a solution of 4-((4-bromobenzyl)amino)-3-nitrophenol (20 g, 63 mmol) in ethanol (200 mL) was added SnCl2.2H2O (71 g, 314 mmol) and the resulting mixture stirred at 90° C. for 1 h. The mixture was cooled to RT and concentrated to dryness. The aqueous residue was then treated with sat. aq. NaHCO3 to ˜pH 7 and extracted with DCM (5×1 L). The organics were combined, dried (Na2SO4), filtered and concentrated to dryness. The residue was purified by FCC to afford the title compound. 1H NMR (300 MHz, DMSO-d6) 8.17 (s, 1H), 7.48 (d, J=8.4, 2H), 7.30 (d, J=8.3, 2H), 6.11 (dd, J=17.2, 5.5, 2H), 5.90-5.74 (m, 1H), 4.54 (s, 2H), 4.48 (t, J=5.7, 1H), 4.13 (d, J=5.5, 2H).
Reaction SMILES: N1C=CN=C1.[C:6]([Si:10]([CH3:13])([CH3:12])Cl)([CH3:9])([CH3:8])[CH3:7].[C:14]([C:16]1[CH:17]=[CH:18][C:19]([OH:44])=[C:20]([CH:43]=1)[CH2:21][N:22]1[CH2:26][CH2:25][CH:24]([NH:27][S:28]([C:31]2[S:32][C:33]([C:36]3[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=3)=[CH:34][CH:35]=2)(=[O:30])=[O:29])[C:23]1=[O:42])#[N:15]>CN(C=O)C.CCOC(C)=O>[C:6]([Si:10]([CH3:13])([CH3:12])[O:44][C:19]1[CH:18]=[CH:17][C:16]([C:14]#[N:15])=[CH:43][C:20]=1[CH2:21][N:22]1[CH2:26][CH2:25][C@H:24]([NH:27][S:28]([C:31]2[S:32][C:33]([C:36]3[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=3)=[CH:34][CH:35]=2)(=[O:30])=[O:29])[C:23]1=[O:42])([CH3:9])([CH3:8])[CH3:7]
Reactant: N#Cc1ccc(O)c(CN2CCC(NS(=O)(=O)c3ccc(-c4cccnc4)s3)C2=O)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(C#N)cc1CN1CC[C@H](NS(=O)(=O)c2ccc(-c3cccnc3)s2)C1=O
Reaction time: 8 h
Yield: 74.5 %

Procedure:
Imidazole (0.094 g, 1.37 mol) and t-butyldimethylchlorosilane (0.099 g, 0.66 mmol) are added to a solution of 5-pyridin-3-yl-thiophene-2-sulfonic acid {1-[5-cyano-2-hydroxy-benzyl]-2-oxo-pyrrolidin-3-yl}-amide (0.25 g, 0.55 mmol) in 10 mL of DMF. The resulting mixture is stirred overnight, and then diluted with EtOAc and washed with saturated NaHCO3 (aq) and brine. The organic layer is dried over MgSO4, filtered and concentrated. The product is purified by column chromatography eluting with 3% MeOH/CH2Cl2 to give a brown oil (0.236 g, 0.41 mmol).
Reaction SMILES: [C:1]([C:8]1([C:15]([O:17]C(C)(C)C)=[O:16])[NH:12]C(=O)N[C:9]1=O)(OC(C)(C)C)=O.[OH-].[Na+].O1[CH2:29][CH2:28][O:27][CH2:26]C1.[C:30](Cl)([O:32][CH2:33][CH:34]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:40]2[C:35]1=[CH:36][CH:37]=[CH:38][CH:39]=2)=[O:31]>COCCOC>[C:30]([CH:9]1[CH2:41][CH:46]([C:34]2[CH:35]=[CH:36][CH:29]=[C:28]([O:27][CH3:26])[CH:33]=2)[CH2:45][CH2:1][C:8]1([NH2:12])[C:15]([OH:17])=[O:16])([O:32][CH2:33][CH:34]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:40]2[C:35]1=[CH:36][CH:37]=[CH:38][CH:39]=2)=[O:31]
Reactant: C1COCCO1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: CC(C)(C)OC(=O)C1(C(=O)OC(C)(C)C)NC(=O)NC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Product: COc1cccc(C2CCC(N)(C(=O)O)C(C(=O)OCC3c4ccccc4-c4ccccc43)C2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
The bis-Boc hydantoin (2.30 g, 4.84 mmol) was dissolved in DME (80 mL) to give a clear solution. To this solution was added 1N NaOH (44 mL, 44 mmol) and the reaction was stirred overnight at room temperature, giving a slightly cloudy mixture. HPLC showed completion of the reaction. The reaction mixture was concentrated under reduced pressure to remove DME and extracted with Et2O. Without purification, the resulting aqueous layer containing 1-amino-4-(3-methoxyphenyl)cyclohexane carboxylic acid (3-MeOAPC) was treated with 6N HCl to adjust the pH to 11-12. To this solution (˜40 mL) were added dioxane (80 mL) and Fmoc-Cl (1.73 g, 6.76 mmol, 1.4 equiv) and the reaction was stirred overnight at room temperature. The reaction mixture was then concentrated under reduced pressure to remove DME, neutralized with 3N HCl and extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4 and concentrated. The crude product was purified by flash chromatography on silica gel (CH2Cl2/MeOH, 98/2→90/10) to give the pure product as a white solid (1.98 g, 87% yield from bis-Boc hydantoin). 1H NMR (DMSO-d6), 7.88 (d, 2H), 7.75 (d, 2H), 7.40 (td, 2H), 7.30 (td, 2H), 7.21 (m, 1H), 6.71-6.80 (m, 3H), 3.72 (s, 3H); MS (electrospray) m/e 494 (M+Na), Calcd for C29H29NO5, 471.
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9]Br)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH3:18][N:19]([CH3:31])[C:20]1([C:26]2[S:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.CO.C(Cl)(Cl)Cl>C1COCC1>[CH3:18][N:19]([CH3:31])[C:20]1([C:26]2[S:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24][N:23]([CH2:9][CH2:8][NH:7][C:6](=[O:11])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:22][CH2:21]1
Reactant: CN(C)C1(c2cccs2)CCNCC1
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)C1(c2cccs2)CCN(CCNC(=O)OC(C)(C)C)CC1
Temperature: 70 °C
Yield: 76.5 %

Procedure:
11.1 g (1.5 eq) tert-butyl-2-bromoethylcarbamate dissolved in 65 ml THF and 9.19 g (2 eq) potassium carbonate were added to a solution of 7 g (1 eq) N,N-dimethyl-4-(thiophen-2-yl)piperidin-4-amine in 40 ml THF. The reaction mixture was heated for 6 h at 70° C. The reaction course was monitored by thin-layer chromatography (20% MeOH/CHCl3). Once the conversion was complete, the solvent was distilled off completely, the residue mixed with 200 ml water and the aqueous phase extracted with 20% IPA/CHCl3. The combined organic phases were dried over Na2SO4. Following removal of the solvent under reduced pressure, the residue was purified by column chromatography (silica gel; 10% MeOH/CHCl3). 9 g (76%) of product were obtained in the form of an oil.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:13])[CH2:9][CH2:10][CH2:11][CH3:12].[OH:15][C:16]12[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21](=[O:28])[C:20]1([NH:29][C:30](=[O:32])[CH3:31])[C:19]1[CH:33]=[CH:34][C:35]([CH:37]([CH3:39])[CH3:38])=[CH:36][C:18]=1[O:17]2>C1COCC1>[C:8]([O:17][C:18]1[CH:36]=[C:35]([CH:37]([CH3:38])[CH3:39])[CH:34]=[CH:33][C:19]=1[C:20]1([NH:29][C:30](=[O:32])[CH3:31])[C:21](=[O:28])[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]1=[O:15])(=[O:13])[CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CC(=O)NC12C(=O)c3ccccc3C1(O)Oc1cc(C(C)C)ccc12
Reactant: CCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCC(=O)Oc1cc(C(C)C)ccc1C1(NC(C)=O)C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 32.1 %

Procedure:
Triethylamine (0.24 ml, 1.77 mmol) and Valeroyl chloride (0.18 ml, 1.48 mmol) were added to N-(4b-hydroxy-7-isopropyl-10-oxo-9b,10-dihydro-4bH-benzo[d]indeno[1,2-b]furan-9b-yl)acetamide (0.50 g, 1.48 mmol) in THF (10 ml). The reaction mixture was stirred at room temperature for 12 hrs, concentrated in a vacuum to remove solvent. The reaction mixture was extracted with water and methylene chloride, and purified through silica gel column chromatography (ethylacetate:hexane=1:2) to afford the title compound (0.20 g, 32%).