Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4](O)=[O:5].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.Cl.[CH3:44][O:45][NH:46][CH3:47]>CN(C=O)C>[NH2:1][C:2]1[N:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([N:46]([O:45][CH3:44])[CH3:47])=[O:5]
Reactant: CNOC
Reactant: Nc1ncc(Br)cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1cc(Br)cnc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-Amino-5-bromonicotinic acid (1 g, 4.6 mmol) in DMF (15 ml) is added EDC hydrochloride (1.06 g, 5.53 mmol), HOBt (0.747 g, 5.53 mmol), diisopropylethylamine (2 ml, 11.5 mmol) and N-methoxy-N-methylamine hydrochloride (0.54 g, 5.53 mmol), and the resulting solution is stirred at room temperature overnight. The reaction is concentrated in vacuo, and the residue is dissolved in EtOAc, washed with sat. aq. NaHCO3, dried (MgSO4) and concentrated in vacuo. Purification by flash chromatography (SiO2, 0-10% ethanol in DCM) yields 2-Amino-5-bromo-N-methoxy-N-methyl-nicotinamide.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH:12]([CH3:16])[C:13](O)=[O:14].B.C1COCC1>C1COCC1>[OH:14][CH2:13][CH:12]([C:3]1[CH:4]=[CH:5][C:6]2[C:7](=[O:11])[O:8][CH2:9][C:10]=2[C:2]=1[CH3:1])[CH3:16]
Reactant: Cc1c(C(C)C(=O)O)ccc2c1COC2=O
Agent: B
Solvent: C1CCOC1
Product: Cc1c(C(C)CO)ccc2c1COC2=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)propanoic acid (300 mg, 1.4 mmol) in 18 mL of anhydrous THF was added BH3.THF (2 mL, 2 mmol) dropwise at 0° C. Then the mixture was warmed to room temperature slowly and then stirred for 3 hours. Then the mixture was quenched with MeOH and the solvent was removed under vacuum. The residue was the purified via prep-TLC to give 5-(2-hydroxy-1-methylethyl)-4-methyl-2-benzofuran-1(3H)-one.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].O1CCCC1.[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1.[CH2:21]([Sn:25](Cl)([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH3:24]>CCCCCC>[F:14][C:15]1[C:20]([Sn:25]([CH2:26][CH2:27][CH2:28][CH3:29])([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:21][CH2:22][CH2:23][CH3:24])=[CH:19][CH:18]=[CH:17][N:16]=1
Reactant: Fc1ccccn1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCC[Sn](CCCC)(CCCC)c1cccnc1F
Temperature: -70 °C
Reaction time: 1.5 h

Procedure:
To a mixture of lithium diisopropylamide (1.5M in cyclohexane, 43 mL) and tetrahydrofuran (60 mL) cooled to -70° C. was added 2-fluoropyridine (6.0 mL) at such a rate that the temperature remained below -70° C. After 1.5 hours, tributyltin chloride (15 mL) was added, and the mixture was allowed to warm to room temperature. The mixture was diluted with hexane, washed with water, dried, filtered, and evaporated. Chromatography of the residue over silica gel (cyclohexane/ethyl acetate 98/2) gave 2-fluoro-3-tributylstannylpyridine (17 g).
Reaction SMILES: [O:1]1CCO[CH:2]1[CH2:6][N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[N:15]=2)[CH:10]=[CH:9][C:8]1=[O:19].FC(F)(F)C(O)=O>O>[CH3:18][O:17][C:14]1[N:15]=[C:16]2[C:11]([CH:10]=[CH:9][C:8](=[O:19])[N:7]2[CH2:6][CH:2]=[O:1])=[CH:12][CH:13]=1
Reactant: COc1ccc2ccc(=O)n(CC3OCCO3)c2n1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2ccc(=O)n(CC=O)c2n1
Temperature: 66 °C
Reaction time: 0.33 h
Yield: 77.3 %

Procedure:
To 2.8 g of 1-(1,3-dioxolan-2-ylmethyl)-7-methoxy-1,8-naphthyridin-2(1H)-one, 20 mL of an 80% aqueous trifluoroacetic acid solution was added, and the mixture was stirred at 60 to 72° C. for 3 hours 20 minutes, and at 80 to 85° C. for 2 hours 20 minutes, 4 mL of water was then added thereto and the mixture was further stirred for 4 hours. The reaction mixture was cooled to room temperature and then left overnight, and the solvent was distilled off under reduced pressure. To the resultant residue, a saturated aqueous sodium hydrogen carbonate solution and chloroform were added, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 1.8 g of (7-methoxy-2-oxo-1,8-naphthyridin-1(2H)-yl)acetaldehyde as a yellow solid.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.Br[CH2:16][CH2:17][OH:18].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:9]1([CH2:8][N:5]2[CH2:6][CH2:7][CH:2]([NH:1][CH2:16][CH2:17][OH:18])[CH2:3][CH2:4]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: OCCBr
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: OCCNC1CCN(Cc2ccccc2)CC1
Yield: 93.1 %

Procedure:
To a mixture of 4-amino-1-benzylpiperidine (2.13 g, 11.2 mmol) and 2-bromoethanol (0.15 g, 4.08 mmol) in anhydrous CH2Cl2 (20 ml) was added Hunig's base (2.6 ml, 5.7 mmol). The solution was refluxed for 24 hours. After evaporating off CH2Cl2, the crude material was purified by silica flash chromatography to afford 2-[[1-(phenylmethyl)-4-piperidinyl]amino]ethanol (0.88 g, 3.8 mmol) with 92% yield. FAB Mass [M+1]+35Cl 235.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[C@H:22](/[CH:23]=[CH:24]/[C@@H:25]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C@H:12]2[CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[C:18]([OH:21])[C:19]=3[CH2:20][C@H:11]2[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:39](OC(=O)C)(=[O:41])[CH3:40]>C1(C)C=CC=CC=1.CN(C1C=CN=CC=1)C.C(=O)(O)[O-].[Na+]>[C:39]([O:21][C:18]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:19]=1[CH2:20][C@H:11]1[CH2:10][C@@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[C@H:22](/[CH:23]=[CH:24]/[C@@H:25]([O:31][Si:32]([C:35]([CH3:37])([CH3:36])[CH3:38])([CH3:34])[CH3:33])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C@H:12]1[CH2:13]2)(=[O:41])[CH3:40]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCC[C@@H](/C=C/[C@@H]1[C@H]2Cc3cccc(O)c3C[C@H]2C[C@H]1O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCCC[C@@H](/C=C/[C@@H]1[C@H]2Cc3cccc(OC(C)=O)c3C[C@H]2C[C@H]1O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Yield: 84.1 %

Procedure:
(1R,2R,3aS,9aS)-2,3,3a,4,9,9a-hexahydro-2-(tert-butyldimethylsilyoxy)-1-((S,E)-3-(tert-butyldimethylsilyoxy)oct-1-enyl)-1H-cyclopenta[b]naphthalen-5-ol (0.5 g, 0.89 mmol) in toluene (5 ml) was treated with acetic anhydride (0.1 ml, 1.07 mmol) and DMAP (1.1 mg, 0.09 mmol) at room temperature for 30 minutes. The reaction was diluted with saturated sodium bicarbonate aqueous (10 ml) and extracted with ethyl acetate (10 ml). The reaction mixture was phase separated and the aqueous layer was extracted with ethyl acetate. The organic layers were combined and dried over anhydrous magnesium sulfate. The solid was filtered off. The solvent was evaporated off under vacuum. The crude product was purified by chromatography on silica gel using a mixture of hexane and ethyl acetate as a gradient eluent. 0.45 g (1R,2R,3aS,9aS)-2,3,3a,4,9,9a-hexahydro-2-(tert-butyldimethylsilyoxy)-1-((S,E)-3-(tert-butyldimethylsilyoxy)oct-1-enyl)-1H-cyclopenta[b]naphthalen-5-yl acetate was obtained. The product was then dissolved in tetrahydrofuran (0.9 ml), and treated with acetic acid (2.7 ml) and distilled water (0.9 ml) overnight at room temperature. The reaction was then diluted with saturated sodium bicarbonate aqueous (12 ml) and extracted with ethyl acetate (15 ml). The reaction mixture was phase separated and the aqueous layer was extracted with ethyl acetate. The organic layers were combined and dried over anhydrous magnesium sulfate. The solid was filtered off. The solvent was evaporated off under vacuum. The crude product was purified by chromatography on silica gel using a mixture of hexane and ethyl acetate as a gradient eluent. The titled compound was obtained in a crystalline form. Melting range was 54˜65° C. Yield: 65%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:8][C:7]=1[CH3:25])=[O:5])[CH3:2].[Br:26]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[N:8][C:7]=1[CH2:25][Br:26])=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1sc(N(C(=O)OC(C)(C)C)c2ccccc2)nc1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1sc(N(C(=O)OC(C)(C)C)c2ccccc2)nc1CBr
Temperature: 25 °C
Yield: 82 %

Procedure:
A mixture of 2-(tert-butoxycarbonyl-phenyl-amino)-4-methyl-thiazole-5-carboxylic acid ethyl ester (1.61 g, 4.45 mmol), N-bromosuccinimide (833 mg, 4.68 mol) and benzoyl peroxide (54 mg, 0.22 mmol) in carbon tetrachloride (30 mL) was refluxed for 16 h before it was cooled to room temperature and partitioned between dichloromethane and water. The organic layer was washed with saturated aqueous sodium bicarbonate solution, brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and hexanes to give the title compound as a yellow oil (1.61 g); MS: (+) m/z 341.0, 343.0 (M+1-Boc, 79Br/81Br).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:26](=[O:29])[NH:27][CH3:28])[CH2:15][C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[CH2:10][CH:9]1[CH2:30][CH2:31][OH:32])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:33](OC(=O)C)(=[O:35])[CH3:34].N1C=CC=CC=1>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:26](=[O:29])[NH:27][CH3:28])[CH2:15][C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[CH2:10][CH:9]1[CH2:30][CH2:31][O:32][C:33](=[O:35])[CH3:34])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CNC(=O)C(Cc1ccc2ccccc2c1)N1CCN(C(=O)OC(C)(C)C)C(CCO)C1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CNC(=O)C(Cc1ccc2ccccc2c1)N1CCN(C(=O)OC(C)(C)C)C(CCOC(C)=O)C1

Procedure:
A solution of 2-(2-hydroxyethyl)-4-(1-methylcarbamoyl-2-naphthalen-2-ylethyl)piperazine-1-carboxylic acid tert-butyl ester, 60, (4.4 g, 10 mmol), acetic anhydride (13 mL), pyridine (1 mL) and N,N-dimethylaminopyridine (0.25 g) in dichloromethane (50 mL) is stirred for 1.5 hours. The solution is then extracted with water and 1N HCl. The organic phase is dried, concentrated in vacuo, and the resulting crude product purified over silica gel (EtOAc/hexane 1:3 then 1:1) to afford the desired product.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:12][C:13]2[CH:18]=[C:17]([OH:19])[CH:16]=[CH:15][C:14]=2[CH3:20])[N:8]=1)=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:33][CH2:34][CH2:35][O:36][CH3:37]>CS(C)=O>[F:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:12][C:13]2[CH:18]=[C:17]([O:19][CH2:33][CH2:34][CH2:35][O:36][CH3:37])[CH:16]=[CH:15][C:14]=2[CH3:20])[N:8]=1)=[O:5]
Reactant: Cc1ccc(O)cc1Cn1ccc(NC(=O)c2c(F)cccc2F)n1
Reactant: COCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: COCCCOc1ccc(C)c(Cn2ccc(NC(=O)c3c(F)cccc3F)n2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2,6-difluoro-N-{1-[(5-hydroxy-2-methylphenyl)methyl]-1H-pyrazol-3-yl}benzamide (for a preparation see Intermediate 49)(82 mg, 0.239 mmol) in DMSO (1 ml) was added cesium carbonate (155 mg, 0.476 mmol) and then a solution of 1-bromo-3-(methyloxy)propane (45 mg, 0.294 mmol, Matrix Scientific) in DMSO (0.1 ml). The resulting red solution was stirred at ambient temperature under nitrogen overnight. The solution was filtered using a hydrophobic frit and diluted with methanol (0.9 ml). The mixture was purified by MDAP on a Sunfire C18 column (Method B) using Acetonitrile-Water with a Formic acid modifier. The solvent was evaporated in vacuo to give the title compound as a luminous yellow gum (19.4 mg); LCMS (System 4) MH+=416, tRET=2.79 min.
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C:8]1[CH:25]=[CH:24][C:11]([C:12]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([CH3:23])=[C:20]([F:22])[F:21])=[O:13])=[CH:10][N:9]=1.[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>Cl>[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32]([NH:7][C:8]2[CH:25]=[CH:24][C:11]([C:12]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([CH3:23])=[C:20]([F:22])[F:21])=[O:13])=[CH:10][N:9]=2)(=[O:34])=[O:33])=[CH:28][CH:27]=1
Reactant: CC(CCCCOC(=O)c1ccc(N)nc1)=C(F)F
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(CCCCOC(=O)c1ccc(NS(=O)(=O)c2ccc(C)cc2)nc1)=C(F)F
Reaction time: 0.17 h
Yield: 90.1 %

Procedure:
To 5 ml of pyridine was dissolved 0.62 g (2.3 mmol) of 6,6-difluoro-5-methyl-5-hexenyl 6-aminonicotinate, followed by the addition of 0.48 g (2.5 mmol) of toluene-4-sulfonylchloride under ice-cooling, stirring for 10 minutes and then stirring at room temperature for 15 hours. The reaction liquid was then poured in 5% hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentration under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate:hexane=1:2) to obtain 0.88 g (yield: 90%) of 6,6-difluoro-5-methyl-5-hexenyl 6-(toluene-4-sulfonylamino)nicotinate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH:13]=[O:14])=[N:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:15][CH2:16][Mg+].[Br-]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]([CH:13]([OH:14])[CH2:15][CH3:16])=[N:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=Cc1ncc(-c2ccc(F)cc2)s1
Reactant: CC[Mg+]
Agent: [Br-]
Product: CCC(O)c1ncc(-c2ccc(F)cc2)s1
Yield: 72.7 %

Procedure:
Using 5-(4-fluorophenyl)thiazole-2-carbaldehyde (0.12 g, 0.58 mmol) and EtMgBr (0.577 mL, 1.73 mmol) and following the procedure described for example 7 and step 2, the crude compound was obtained and further purified by column chromatography (using 100-200μ silica gel and 38% ethyl acetate and hexane) to give 1-(5-(4-fluorophenyl)thiazol-2-yl)propan-1-ol as pale yellow liquid (0.1 g, 73% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.01 (s, 1H), 7.68-7.65 (m, 2H), 7.25 (t, 2H), 6.11 (d, 1H), 4.72-4.67 (m, 1H), 1.84 (m, 1H), 1.88-1.67 (m, 1H), 0.91 (t, 3H); LC-MS m/z calculated for [M+H]+ 238.06. found 238.5.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][C:7]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:8]=2[C:9]2[C:10]([CH2:22][O:23][CH3:24])=[C:11]([CH2:20][OH:21])[N:12]=[CH:13][C:14]=2[NH:15]3)=[CH:4][CH:3]=1>ClCCl.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:8]=2[C:9]2[C:10]([CH2:22][O:23][CH3:24])=[C:11]([CH:20]=[O:21])[N:12]=[CH:13][C:14]=2[NH:15]3)=[CH:25][CH:26]=1
Reactant: COCc1c(CO)ncc2[nH]c3cccc(Cc4ccc(Cl)cc4)c3c12
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COCc1c(C=O)ncc2[nH]c3cccc(Cc4ccc(Cl)cc4)c3c12
Yield: 74.3 %

Procedure:
1.3 g (0.00354 mol) of 5-(4-chlorobenzyl)-4-methoxymethyl-β-carboline-3-methanol is stirred for 192 hours under argon at room temperature with 1.74 g (0.02 mol) of manganese dioxide in 200 ml of dichloromethane. The manganese dioxide is suctioned off, the filtrate concentrated by evaporation and the residue recrystallized from ethanol. Thus 0.96 g (74% of theory) of 5-(4-chlorobenzyl)-4-methoxymethyl-β-carboline-3-carbaldehyde is obtained, melting point 248°-250° C.
Reaction SMILES: [CH2:1]1[O:10][C:4]2([CH2:9][CH2:8][NH:7][CH2:6][CH2:5]2)[O:3][CH2:2]1.C(N(CC)CC)C.[N+:18]([C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)([O-:20])=[O:19]>C(OCC)(=O)C>[CH2:1]1[O:10][C:4]2([CH2:9][CH2:8][N:7]([S:27]([C:24]3[CH:23]=[CH:22][C:21]([N+:18]([O-:20])=[O:19])=[CH:26][CH:25]=3)(=[O:28])=[O:29])[CH2:6][CH2:5]2)[O:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: C1CC2(CCN1)OCCO2
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(S(=O)(=O)N2CCC3(CC2)OCCO3)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.3 %

Procedure:
A solution of 4-piperidone ethylene ketal (1.28 ml, 10 mmol) and triethylamine (1.4 ml, 10 mmol) in ethyl acetate (20 ml) was treated with a dropwise addition of 4-nitro-phenylsulphonyl chloride (1.4 ml, 10 mmol) in ethyl acetate (20 ml) and stirred at room temperature for 2 h. The mixture was washed with water, dilute HCl, saturated sodium bicarbonate solution and brine, dried over sodium sulphate and evaporated to leave the title compound as a solid (2.8 g), MS (+EI) 328 (M+), 1H NMR (CDCl3) 8.38 (2H, d, J 8.8 Hz), 7.96 (2H, d, J 8.8 Hz), 3.90 (4H, s), 3.22 (4H, t, J 5.7 Hz), 1.80 (4H, t, J 5.7 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([C:12](=O)[NH2:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]>CN(C=O)C>[Br:1][C:2]1[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(C(N)=O)cc1Br
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C#N)cc1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.6 %

Procedure:
To a solution of methyl 2-bromo-4-carbamoylbenzoate (1.3 g, 5.06 mmol) in dry DMF (20 mL) was added (CNCl)3 (1.85 g, 10.12 mmol) at rt and then stirred at rt for 3 h. The reaction mixture was quenched with water and extracted with EA (100 mL×2). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give crude methyl 2-bromo-4-cyanobenzoate as a white solid (1.1 g). It was used without further purification. 1H NMR (400 MHz, CDCl3): δ 8.36 (s, 1H), 8.01 (d, J=8.0 Hz, 1H), 7.91 (d, J=8.0 Hz, 1H), 3.90 (s, 3H) ppm.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[S:25][C:24]([CH:26]=O)=[CH:23][C:9]=3[N:10]=[C:11]([C:13]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:14]=3[CH:15]=[CH:16][CH:17]=[N:18]4)[N:12]=2)[CH2:3][CH2:2]1.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:26][C:24]2[S:25][C:8]3[C:7]([N:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)=[N:12][C:11]([C:13]4[CH:22]=[CH:21][CH:20]=[C:19]5[C:14]=4[CH:15]=[CH:16][CH:17]=[N:18]5)=[N:10][C:9]=3[CH:23]=2)[CH2:31][CH2:30]1
Reactant: O=Cc1cc2nc(-c3cccc4ncccc34)nc(N3CCOCC3)c2s1
Reactant: CN1CCNCC1
Product: CN1CCN(Cc2cc3nc(-c4cccc5ncccc45)nc(N4CCOCC4)c3s2)CC1

Procedure:
Following General Procedure L for reductive amination, 4-morpholino-2-(quinolin-5-yl)thieno[3,2-d]pyrimidine-6-carbaldehyde and 1-methylpiperazine were reacted to give 120. LCMS m/z: 461.6 (MH+)
Reaction SMILES: [CH3:1][C:2]1([C:9]([OH:11])=O)[CH2:5][C:4]2([CH2:8][CH2:7][CH2:6]2)[CH2:3]1.[CH3:12][Li]>CCOCC>[CH3:1][C:2]1([C:9](=[O:11])[CH3:12])[CH2:3][C:4]2([CH2:6][CH2:7][CH2:8]2)[CH2:5]1
Reactant: CC1(C(=O)O)CC2(CCC2)C1
Reactant: [Li]C
Solvent: CCOCC
Product: CC(=O)C1(C)CC2(CCC2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 5.0 g (33.0 mmol) 2-methylspiro[3.3]heptane-2-carboxylic acid in 33.0 ml of dry ether was stirred under argon at 0° C and 47.6 ml (74.3 mmol) of 1.56 M methyl lithium in ether added dropwise. The reaction mixture was allowed to warm to 25° C and was stirred for 3.0 hr. The reaction mixture was cooled to -20° C and quenched by addition of 10% aqueous HCl. The layers were separated and the aqueous layer extracted with ether. The combined organic layers were washed with saturated aqueous sodium bicarbonate and brine, then dried (MgSO4), filtered, and evaporated in vacuo to afford 2-methyl-2-acetylspiro[3.3]heptane as a light yellow oil (4.91 g 98%).
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16]([C:18]2[C:27]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=3[CH:21]=[CH:20][CH:19]=2)=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[C:18]1([C:16]([NH:15][C:6]2([C:4]([OH:5])=[O:3])[CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7]2)=[O:17])[C:27]2[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=2[CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)C1(NC(=O)c2cccc3c2CCCC3)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(NC1(C(=O)O)Cc2ccccc2C1)c1cccc2c1CCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.3 %

Procedure:
The mixture of 2-[(5,6,7,8-Tetrahydro-naphthalene-1-carbonyl)-amino]-indan-2-carboxylic acid ethyl ester (37) (400 mg, 1.1 mmol) and KOH (1 g, 17.8 mmol) is dissolved in EtOH (10 mL) and water (2 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 8 h. After concentration in vacuo, the residue is dissolved in water (30 mL) and acidified with conc. HCl until no more white precipitate came out of the water. The precipitate is filtered to give a pure product (38) as white solid (300 mg, 82%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][O:12][CH3:13])[C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:7]2.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[S:27](Cl)(=[O:29])=[O:28]>N1C=CC=CC=1>[CH3:13][O:12][CH2:11][N:9]1[C:10]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[NH:1][S:27]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[O:20][CH3:19])(=[O:29])=[O:28])[CH:7]=[C:8]1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)c1cc2cccc(N)c2n1COC
Reactant: COc1ccccc1S(=O)(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1cc2cccc(NS(=O)(=O)c3ccccc3OC)c2n1COC
Temperature: 25 °C
Yield: 82 %

Procedure:
To a mixture of ethyl 7-amino-1-(methoxymethyl)-1H-indole-2-carboxylate (12.0 g) and pyridine (100 mL) was added 2-methoxybenzenesulfonyl chloride (10.0 g) under ice-cooling, and the mixture was stirred from under ice-cooling to room temperature for 20 hr. The reaction mixture was concentrated, and the residue was diluted with ethyl acetate. The solution was washed with aqueous citric acid solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crystals were washed with ethyl acetate-hexane to give the title compound (16.58 g, yield 89%) as pale-gray crystals. melting point: 106-107° C.
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[O:4][CH2:5][CH:6]1[CH:10]=[CH:9][CH2:8][N:7]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].C([SnH](CCCC)CCCC)CCC.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[CH2:9]1[CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]2[CH2:5][O:4][C:3]3[CH:18]=[CH:19][CH:20]=[CH:21][C:2]=3[CH:10]12
Reactant: CC(C)(C)OC(=O)N1CC=CC1COc1ccccc1Br
Agent: CCCC[SnH](CCCC)CCCC
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC2c3ccccc3OCC21
Temperature: 50 °C
Reaction time: 16 h

Procedure:
Tert-butyl 2-[(2-bromo-phenoxy)methyl]-2,5-dihydro-1H-pyrrole-1-carboxylate (14.2 g, 0.38 mol) was dissolved in toluene (707 mL) and heated at 50° C. for 20 min. To this solution was added AlBN (688 mg, 0.049 mol) and tributyltin hydride (16 mL, 0.61 mol) at room temperature. The reaction mixture was stirred at 80° C. for 16 h and then DBU (9.5 mL, 0.62 mol) was added. The resulting suspension was filtered through a pad of silica gel (100 g) and the solids washed with methyl tert-butylether. The filtrate was evaporated. The crude product was purified using an ISCO instrument (330 g RediSep® column), eluting with a gradient of ethyl acetate in heptane (from 10% ethyl acetate in 10 minutes, then 20% ethyl acetate for 15 min) to provide the title product. MS m/z 299 [M+Na]+