Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2C1CCN(C)CC=1)([O-:3])=[O:2].[H][H]>C(O)C.Cl.[Pd]>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2]
Reactant: [H][H]
Reactant: CN1CC=C(c2c[nH]c3ccc([N+](=O)[O-])cc23)CC1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: O=[N+]([O-])c1ccc2[nH]ccc2c1
Yield: 208 %

Procedure:
To a solution of 38.2 gm (145 mMol) 5-nitro-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole in 1.9 L ethanol and 30 mL 5N HCl were added 10.0 gm 5% palladium on carbon. The reaction mixture was hydrogenated at ambient for 18 hours with an initial hydrogen pressure of 60 p.s.i. The reaction mixture was filtered and then concentrated under reduced pressure. The residue was dissolved in methanol and the solution filtered. This filtrate was concentrated under reduced pressure and the residue redissolved in ethanol. The solution was concentrated to about 500 mL and product allowed to crystallize. The crystals were filtered to give 48.9 gm (95%) of the title compound as its dihydrochloride salt, ethanol solvate.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[F:17][C:18]1[CH:19]=[C:20]([N:24]=[C:25]=[O:26])[CH:21]=[CH:22][CH:23]=1>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:25]([NH:24][C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([F:17])[CH:19]=2)=[O:26])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: COc1ccc(N)cc1-c1c(Br)cnn1C
Reactant: O=C=Nc1cccc(F)c1
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2cccc(F)c2)cc1-c1c(Br)cnn1C
Yield: 75 %

Procedure:
3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.033 g, 0.12 mmol) was treated with 3-fluorophenyl isocyanate (0.017 g, 14.3 μL, 0.12 mmol, 1.05 equiv.) in CH2Cl2 (1 mL), in a similar manner as described in Example 1.2 to afford Compound 18 (0.040 g, 0.09 mmol, 82%) as a white solid. LCMS m/z (%)=419 (M+H79Br, 100), 421 (M+H81Br, 91). 1H NMR (400 MHz, acetone-d6) δ: 8.31 (s, 1H), 8.17 (s, 1H), 7.69 (dd, J=2.7, 9.0 Hz, 1H), 7.59 (dt, J=2.2, 12.0 Hz, 1H), 7.50 (s, 1H), 7.43 (d, J=2.6 Hz, 1H), 7.27 (dd, J=8.1, 15.0 Hz, 1H), 7.11-7.19 (m, 2H), 6.73 (ddd, J=2.4, 8.4 Hz, 1H), 3.82 (s, 1H), 3.69 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[S:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1)#[N:2].[Li].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH:49]1[CH2:53][CH2:52][CH2:51][C@H:50]1[CH2:54][N:55]1[CH2:59][CH2:58][CH2:57][CH2:56]1>CN(C=O)C.ClCCl>[N:55]1([CH2:54][C@@H:50]2[CH2:51][CH2:52][CH2:53][N:49]2[C:12]([C:11]2[CH:10]=[CH:9][C:8]([C:7]3[CH:6]=[CH:5][S:4][C:3]=3[C:1]#[N:2])=[CH:16][CH:15]=2)=[O:14])[CH2:59][CH2:58][CH2:57][CH2:56]1
Reactant: C1CN[C@H](CN2CCCC2)C1
Reactant: N#Cc1sccc1-c1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#Cc1sccc1-c1ccc(C(=O)N2CCC[C@H]2CN2CCCC2)cc1
Yield: 66 %

Procedure:
The title compound is prepared in a manner substantially analogous to General Procedure D in 5 mL 20% DMF/dichloromethane using 4-(2-cyano-thiophen-3-yl)-benzoic acid, lithium salt (141 mg, 0.60 mmol), EDC-HCl (143 mg, 0.75 mmol), HOBt (101 mg, 0.75 mmol), DIEA (0.24 mL, 1.4 mmol) and (S)(+)-1-(2-pyrrolidinylmethyl)pyrrolidine (77 mg, 0.50 mmol) to give the title compound (120 mg, 66% yield). MS (ES+) 366.3 (M+H)+
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:7][C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:5][CH:4]=1.N1C(C)=CC=CC=1C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[CH3:21][S:22]([O:1][CH2:2][C:3]1[O:7][C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:5][CH:4]=1)(=[O:24])=[O:23]
Reactant: CCOC(=O)c1ccc(CO)o1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CCOC(=O)c1ccc(COS(C)(=O)=O)o1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 93.1 %

Procedure:
To a 0° C. solution of 5-hydroxymethyl-2-carboethoxyfuran (2.94 g, 17.3 mmol), prepared as in step 1, in CH2Cl2 (50 mL) was added 2,6-lutidine (2.50 mL, 21.5 mmol) and methanesulfonyl chloride (1.50 mL, 19.0 mmol). The reaction mixture was stirred for 40 min at 0° C., then the cold bath was removed and stirring was continued for 2 hours. The reaction mixture was extracted with 1N aqueous HCl and saturated aqueous NaHCO3, and the organic phase was dried over MgSO4, filtered, and concentrated in vacuo to give 5-methanesulfonyloxymethyl-2-carboethoxyfuran (4.0 g) as a yellow oil which was used without further purification.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([C:13]2[N:22]([CH2:23][CH2:24][CH2:25]Br)[C:21](=[O:27])[C:20]3[C:15](=[CH:16][C:17]([O:30][CH3:31])=[CH:18][C:19]=3[O:28][CH3:29])[N:14]=2)=[CH:8][C:7]=1[CH3:32].[NH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1.O>CN(C=O)C>[CH3:32][C:7]1[CH:8]=[C:9]([C:13]2[N:22]([CH2:23][CH2:24][CH2:25][N:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)[C:21](=[O:27])[C:20]3[C:15](=[CH:16][C:17]([O:30][CH3:31])=[CH:18][C:19]=3[O:28][CH3:29])[N:14]=2)[CH:10]=[C:11]([CH3:12])[C:6]=1[O:5][CH2:4][CH2:3][CH2:2][N:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: COc1cc(OC)c2c(=O)n(CCCBr)c(-c3cc(C)c(OCCCBr)c(C)c3)nc2c1
Reactant: C1CCNC1
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(OC)c2c(=O)n(CCCN3CCCC3)c(-c3cc(C)c(OCCCN4CCCC4)c(C)c3)nc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-[4-(3-bromo-propoxy)-3,5-dimethyl-phenyl]-3-(3-bromo-propyl)-5,7-dimethoxy-3H-quinazolin-4-one (0.76 g, 1.35 mmol) in DMF (10 mL) were added pyrrolidine (0.77 g, 10.77 mmol). The reaction mixture was stirred at room temperature for 16 hours. Then, water was added and product was extracted with ethyl acetate (2×200 mL). The combined organic layer was washed with water, then brine, and dried over Na2SO4. Solvent was evaporated to give the title compound as a white solid. Yield: 0.12 g (16%). MP 109-111° C. 1H NMR (400 MHz, CDCl3): δ 8.16 (s, 2H), 6.93 (d, J=2.4 Hz, 1H), 6.44 (d, J=2.4 Hz, 1H), 4.71 (t, J=6.4 Hz, 2H), 3.94 (s, 3H), 3.93 (s, 3H), 3.87 (t, J=6.0 Hz, 2H), 2.75 (m, 4H), 2.60 (m, 8H), 2.37 (s, 6H), 2.16 (m, 2H), 2.05 (m, 2H), 1.82 (m, 8H). MS (ES) m/z: 549.75 (M+1). Analysis calculated for C32H44N4O4.0.5H2O (FW 557.73), %: C, 68.91; H, 8.13; N, 10.05. Found, %: C, 68.71; H, 8.56; N, 9.74.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH2:13][C:14]([CH3:16])=[CH2:15])[C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Br:1][C:2]1[C:11]2[O:12][C:14]([CH3:16])([CH3:15])[CH2:13][C:10]=2[CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:3]=1
Reactant: C=C(C)Cc1cc(C(=O)OC)cc(Br)c1O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Br)c2c(c1)CC(C)(C)O2
Yield: 74.3 %

Procedure:
A solution of methyl 3-bromo-4-hydroxy-5-(2-methylprop-2-en-1-yl)benzoate (4.1 g, 14.4 mmol) and boron trifluoride diethyl ether complex (2.0 mL, 15.8 mmol) in toluene (30 mL) was stirred at 100° C. for 90 min. After cooling, the reaction solution was diluted with ethyl acetate, washed successively with water, aqueous sodium hydrogencarbonate solution and aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate:hexane=3:97-15:85) to give the title compound (3.05 g, yield 74%) as colorless prism crystals.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:23])[CH2:21]Cl)=[CH:15][CH:14]=1>C(#N)C.C(Cl)Cl>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([NH:19][C:20](=[O:23])[CH2:21][N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)=[CH:17][CH:18]=1
Reactant: C1CCNC1
Reactant: O=C(CCl)Nc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: O=C(CN1CCCC1)Nc1ccc(Br)cc1
Temperature: 80 °C
Yield: 99.5 %

Procedure:
Add potassium carbonate (2.1 g, 15.5 mmol) and pyrrolidine (9.65 mL, 116 mmol) to a solution of N-(4-bromophenyl)-2-chloroacetamide (2.0 g, 7.7 mmol) in acetonitrile (78 mL) at RT. Heat the mixture at 80° C. for 4 h. Cool the mixture to RT, dilute with CH2Cl2, and wash with brine and water. Dry the organic layer over Na2SO4, filter, and concentrate to give 2.17 g (99%) of the title compound. LC-ES/MS m/z (79Br) 283.0 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Br[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].C([O-])([O-])=O.[K+].[K+]>CC#N>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: Oc1ccccc1Br
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)COc1ccccc1Br
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a solution of 2-bromophenol (2 g, 0.0116 mol) in MeCN (10 mL) was added ethyl bromoacetate (2.12 g, 0.0128 mol) and K2CO3 (4.81 g, 0.035 mol). The mixture was stirred at 80° C. for 4 h, filtered and concentrated. The crude product was used in the next step without further purification.
Reaction SMILES: [N:1]1([CH:6]2[CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:17]>O1CCOCC1>[ClH:17].[ClH:17].[NH:8]1[CH2:9][CH:6]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CC(N2CCCC2)C1
Agent: Cl
Solvent: C1COCCO1
Product: C1CCN(C2CNC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.00 g (4.42 mmol) of tert-butyl 3-(pyrrolidin-1-yl)azetidin-1-carboxylate was initially charged in 5.3 ml of 1,4-dioxane, 5.3 ml of 4 N hydrochloric acid in 1,4-dioxane were added and the mixture was stirred at RT overnight. The reaction mixture was then concentrated, foamed with dichloromethane and dried under high vacuum. This gave 950 mg (99% of theory; purity 92%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])=[CH:12][C:11]=2[Cl:25])=[O:9])[CH:7]=1.[N:27]([C:30]1[CH:39]=[CH:38][CH:37]=[CH:36][C:31]=1[C:32]([O:34][CH3:35])=[O:33])=[C:28]=[O:29]>O1CCOCC1>[CH3:35][O:34][C:32](=[O:33])[C:31]1[CH:36]=[CH:37][CH:38]=[CH:39][C:30]=1[NH:27][C:28]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([C:8](=[O:9])[C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])=[CH:12][C:11]=2[Cl:25])[CH:7]=1)=[O:29]
Reactant: COC(=O)c1ccccc1N=C=O
Reactant: Cc1ccc(N)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Solvent: C1COCCO1
Product: COC(=O)c1ccccc1NC(=O)Nc1ccc(C)c(C(=O)c2ccc(Nc3ccc(F)cc3F)cc2Cl)c1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
Compound 494 (0.03 g, 0.08 mmol) was dissolved in 1,4-dioxan (0.5 mL) and methyl 2-isocyanatobenzoate (0.021 mL, 0.12 mmol) was added. The solution was stirred at 50° C. for 24 h. Methyl 2-isocyanatobenzoate (0.01 mL, 0.06 mmol) was added. The solution was stirred at 50° C. for 24 h. Work up as described in the preparation of compound 259. The crude product was purified by flash chromatography using a gradient of EtOAc/petroleum ether (40-60) 10:90→40:60 as the eluent. This afforded the title compound as yellow oil. 13C NMR (CDCl3) δ 195.8, 169.0, 159.0 (dd), 155.4 (dd), 152.4, 147.6, 142.5, 139.5, 135.6, 135.1, 134.6, 133.6, 133.4, 132.1, 130.8, 129.4, 124.5 (dd), 124.1 (dd), 123.3, 121.7, 121.3, 119.8, 116.3, 114.3, 112.8, 111.5 (dd), 104.9 (dd), 52.2, 19.8
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[C:22]3[C:17](=[CH:18][C:19]([O:25][CH2:26][CH3:27])=[C:20]([O:23][CH3:24])[CH:21]=3)[CH:16]3[CH:11]([CH2:12][CH2:13][CH:14]([O:28]C(=O)C)[CH2:15]3)[N:10]=2)=[CH:7][CH:6]=[C:5]([O:32][CH3:33])[N:4]=1.CO.C(=O)([O-])[O-].[Cs+].[Cs+]>ClCCl>[CH3:1][O:2][C:3]1[C:8]([C:9]2[C:22]3[C:17](=[CH:18][C:19]([O:25][CH2:26][CH3:27])=[C:20]([O:23][CH3:24])[CH:21]=3)[CH:16]3[CH:11]([CH2:12][CH2:13][CH:14]([OH:28])[CH2:15]3)[N:10]=2)=[CH:7][CH:6]=[C:5]([O:32][CH3:33])[N:4]=1
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(OC)nc1OC)=NC1CCC(OC(C)=O)CC21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: ClCCl
Product: CCOc1cc2c(cc1OC)C(c1ccc(OC)nc1OC)=NC1CCC(O)CC21
Reaction time: 19 h
Yield: 59.7 %

Procedure:
423 mg of acetic acid (2RS,4aRS,10bRS)-6-(2,6-dimethoxy-pyridin-3-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-yl ester (Example 18) dissolved in 1 ml of dichloromethane and 9 ml of methanol are added to 152 mg of cesium carbonate and the solution stirred for 19 h. The reaction mixture is adsorbed to silica gel and purified by flash chromatography to give 229 mg of the title compound as a colourless foam.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].[N:12]([O-])=O.[Na+].Cl[Sn]Cl.C([O-])(O)=O.[Na+]>Cl.O>[Br:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH:4][NH2:12]
Reactant: O=N[O-]
Reactant: Nc1cc([N+](=O)[O-])ccc1Br
Agent: Cl
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Solvent: O
Product: NNc1cc([N+](=O)[O-])ccc1Br
Temperature: 0 °C
Reaction time: 3 h
Yield: 52.5 %

Procedure:
To a suspension of 2-bromo-5-nitroaniline (1 g, 4.6 mmol) in conc. HCl (10 mL) at 0° C. was slowly added a solution of NaNO2 (382 mg, 5.5 mmol) in water (1.5 mL). Then, the mixture was stirred at 0° C. for 3 hr until TLC and LCMS analysis showed that most of 2-bromo-5-nitroaniline was consumed. SnCl2 (1.90 g, 10 mmol) in conc. HCl (3 mL) was slowly added. The mixture was then stirred at RT for 2 hr before re-cooled to 0° C. Then, the PH was adjusted with sat. aq. NaHCO3 to 7-8. The mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to get crude product which was further chromatographed on 10 g of silica gel using PE/EA (20/1 to 4/1) as eluant to afford 560 mg (51%) of (2-bromo-5-nitrophenyl)hydrazine as a orange solid. 1H NMR (400 MHz, DMSO-d6) δ 7.89 (d, J=2.8 Hz, 1H), 7.60 (d, J=8.6 Hz, 1H), 7.29 (dd, J=2.8, 8.6 Hz, 1H), 7.04 (s, 1H), 4.38 (s, 2H). MS (ESI) m/e [M+1]+ 232, 234.
Reaction SMILES: [ClH:1].[N:2]1([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27]([CH3:32])=[CH:26]2>>[ClH:1].[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[N:28]([C:16](=[O:18])[C:15]1[CH:14]=[CH:13][C:12]([O:11][CH2:10][CH2:9][CH2:8][N:2]3[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]3)=[CH:20][CH:19]=1)[C:27]([CH3:32])=[CH:26]2
Reactant: O=C(O)c1ccc(OCCCN2CCCCC2)cc1
Reactant: COc1ccc2[nH]c(C)cc2c1
Agent: Cl
Product: COc1ccc2c(c1)cc(C)n2C(=O)c1ccc(OCCCN2CCCCC2)cc1

Procedure:
The title compound (E7) was prepared from 4-(3-piperidin-1-ylpropoxy)benzoic acid hydrochloride (D2) and 5-methoxy-2-methyl-indole using the method described in Example 5 (E5).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:13]([CH3:15])[CH3:14])[C:11]=1[OH:12])[CH:7]=O)([CH3:3])[CH3:2].[C:16]1([CH2:22][CH2:23][CH2:24][NH:25][C:26](=[S:30])[CH2:27][C:28]#[N:29])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.NCCC(O)=O>C(O)C>[CH:1]([C:4]1[CH:5]=[C:6](/[CH:7]=[C:27](/[C:26]([NH:25][CH2:24][CH2:23][CH2:22][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[S:30])\[C:28]#[N:29])[CH:9]=[C:10]([CH:13]([CH3:15])[CH3:14])[C:11]=1[OH:12])([CH3:3])[CH3:2]
Reactant: N#CCC(=S)NCCCc1ccccc1
Reactant: CC(C)c1cc(C=O)cc(C(C)C)c1O
Agent: NCCC(=O)O
Solvent: CCO
Product: CC(C)c1cc(/C=C(\C#N)C(=S)NCCCc2ccccc2)cc(C(C)C)c1O

Procedure:
0.6 g of 3,5-diisopropyl-4-hydroxybenzaldehyde, and 0.6 g of N-3-phenyl-n-propylcyanothioacetamide and 40 mg β-alanine in 40 ml ethanol were refluxed 4 hours. Evaporation and chromatography gave 0.6 g of M24 as an orange viscous oil that did not crystalyze. NMR CDCl3 δ 8.76(1H, S, vinyl), 7.78(2H, S, H2.6), 7.25(5H, m), 5.60(1H, S, OH), 3.90(2H, q, J=7.0 Hz), 3.17(2H, Septet, J=7.0 Hz), 2.76(2H, t, J=7.0 Hz), 2.11(2H, quintet, J=7.0 Hz), 1.29(12H, d, J=7.0 Hz). MS—407(M+1,55), 406(M+, 70), 373(M-CH3-H2O, 100), 363(M-isopropyl, 72), 272(M-NH(CH2)3 Ph. 20), 259 (58), 230 (28), 91 (28), m/e.
Reaction SMILES: Br[C:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10]([NH2:11])[C:5]=2[S:4][CH:3]=1.N#N.[CH2:14]([Sn](CCCC)(CCCC)C=C)[CH2:15]CC.[F-].[K+]>O1CCOCC1.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>[CH:14]([C:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10]([NH2:11])[C:5]=2[S:4][CH:3]=1)=[CH2:15]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Nc1ncnc2c(Br)csc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: [F-]
Solvent: C1COCCO1
Product: C=Cc1csc2c(N)ncnc12
Temperature: 120 °C
Reaction time: 7 h

Procedure:
7-Bromothieno[3,2-d]pyrimidine-4-amine (2.4 g, 10.43 mmol) was dissolved in dioxane (30 mL) and then treated with N2 gas for 20 minutes. Pd(PPh3)4 (723 mg, 0.63 mmol) and tributyl(vinyl)tin (3.35 mL, 11.5 mmol) were added thereto and stirred at 120° C. for 7 hours. The reaction mixture was cooled to room temperature, an aqueous KF solution (10%, 30 mL) was added thereto and stirred for 2 hours. The reaction mixture was filtered with Celite and washed with ethyl acetate. The aqueous layer was separated from the organic layer and extracted with ethyl acetate. The combined organic layer was dried with MgSO4 and concentrated. The resulting mixture was purified by silica gel chromatography (DCM/MeOH=95/5) to obtain the title compound having a yellow color.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:19]2[NH:23][C:22]([C:24]3[CH:29]=[C:28]([CH2:30][OH:31])[CH:27]=[CH:26][N:25]=3)=[CH:21][CH:20]=2)[CH2:12][CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(#N)C.C(OCC)(=O)C>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:19]2[NH:23][C:22]([C:24]3[CH:29]=[C:28]([CH:30]=[O:31])[CH:27]=[CH:26][N:25]=3)=[CH:21][CH:20]=2)[CH2:12][CH:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCOCC2)c2ccc(-c3cc(CO)ccn3)[nH]2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(C(CC2CCOCC2)c2ccc(-c3cc(C=O)ccn3)[nH]2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.5 %

Procedure:
To a solution of [2-(5-{1-[4-(methylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridin-4-yl]methanol (457 mg) in acetonitrile (10 mL) was added Dess-Martin reagent (530 mg), and the mixture was stirred at room temperature for 4 hr. The reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (380 mg, yield 83%) was obtained as a yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[C:6](B(O)O)[CH:7]=1.[Cl:17][C:18]1[CH:23]=[C:22](Cl)[N:21]=[C:20]([NH2:25])[N:19]=1.CC(O)C(O)C.C(=O)([O-])[O-].[Na+].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:17][C:18]1[CH:23]=[C:22]([C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:11][CH2:12][C:13]([F:16])([F:15])[F:14])[N:21]=[C:20]([NH2:25])[N:19]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: OB(O)c1cc(Cl)ccc1OCC(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(O)C(C)O
Solvent: O
Product: Nc1nc(Cl)cc(-c2cc(Cl)ccc2OCC(F)(F)F)n1
Reaction time: 12 h

Procedure:
To a mixture of 5-chloro-2-(2,2,2-trifluoro-ethoxy)-phenylboronic acid (1.6 g, 6.3 mmol), 4,6-dichloro-pyrimidin-2-ylamine (1.2 g, 7.6 mmol), palladium acetate (211 mg, 0.95 mmol), and dimethyl ethylene glycol (100 ml), degassed with argon, was added a solution of sodium carbonate (4.0 g, 37.8 mmol) in water (15 ml) followed by triphenylphosphine (495 mg, 1.9 mmol). After stirring for 12 hours, the mixture was filtered through a pad of celite under suction. The organic layer was separated from the filtrate and dried over magnesium sulfate. The mixture was purified by flash chromatography on silica gel eluting with ethyl acetate-hexane (1:5 followed by 1:4) to give 4-chloro-6-[5-chloro-2-(2,2,2-trifluoro-ethoxy)-phenyl]-pyrimidin-2-ylamine, which was dissolved in ethyl acetate (10 ml) and treated with a solution of hydrogen chloride in dioxane (4 M, 2.5 ml). The solid was filtered to provide the hydrochloride salt of 4-chloro-6-[5-chloro-2-(2,2,2-trifluoro-ethoxy)-phenyl]-pyrimidin-2-ylamine (500 mg, 20% yield). 1H NMR (CD3OD) δ 4.78 (q, 2H, J=8.5 Hz, CH2), 7.31-7.33 (m, 2H, Ar), 7.65 (dd, 1H, J=8.9 Hz, J=2.8 Hz, Ar), 7.82 (d, 1H, J=2.6 Hz, Ar).
Reaction SMILES: [H-].[Na+].[CH:3]1[C:15]2[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH2:16](Br)[CH:17]=[CH2:18]>C1COCC1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:18]([N:14]1[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:7]2[C:15]1=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:17]=[CH2:16]
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: C=CCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [H-]
Solvent: C1CCOC1
Product: C=CCn1c2ccccc2c2ccccc21
Temperature: 65 °C
Reaction time: 0.25 h
Yield: 82 %

Procedure:
Into a 500 mL round bottom flask fitted with a mechanical stirrer, addition funnel, reflux condenser and nitrogen inlet were placed 12 g of sodium hydride (60% dispersion in mineral oil) and 30 mL of THF. Carbazole (33.4 g, 0.2 mole) was dissolved in 200 mL THF and the pale yellow solution was added dropwise to the reaction mixture while stirring and maintaining the temperature at 35˜40° C. Thereafter, 36.2 g (0.3 mole) of allyl bromide was added drop wise to the reaction mixture and stirring continued for an additional 15 minutes. Tetra-n-butyl ammonium bromide (1.3 g) was added followed by stirring for 20 minutes, and then the temperature was raised to 65° C. and kept at that temperature overnight. The reaction mixture was cooled to room temperature and after filtration, the solvent was removed using a rotary evaporator. The resulting yellow solid was twice recrystallized from methanol to give 34 g (81% yield) of colorless crystalline 9-allyl carbazole m.p. 53-54° C.
Reaction SMILES: S(=O)(=O)(O)O.[SH:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].[CH3:16]O>>[SH:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([O:11][CH3:16])=[O:10]
Reactant: CO
Reactant: O=C(O)c1ccccc1S
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccccc1S
Reaction time: 18 h
Yield: 90 %

Procedure:
To a cooled solution of concentrated sulfuric acid (72 g) in methanol (1.5 L) at 0° C., was added 2-sulfanylbenzoic acid (300 g, 1.95 mol) in portions under argon atmosphere. After being refluxed with stirring for 18 hours, the reaction mixture was concentrated in vacuo. The residue was diluted with water (800 mL), basified with a saturated aqueous solution of sodium bicarbonate to about pH 7, and extracted with dichloromethane (600 mL×3). The combined organic layers were washed with brine (800 mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford 300 g of methyl 2-sulfanylbenzoate (yield was 90%) as a light yellow oil, which was used for the next step without further purification.