Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:22][C:3]=1[C:4]([NH:6][C:7]1[S:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:11]=1)=[O:5].N1C=CC=CC=1.[CH3:38][N:39]([CH2:51][CH2:52][N:53]1[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1)[C:40]([C:42]1[CH:43]=[C:44]([CH:48]=[CH:49][CH:50]=1)[C:45](Cl)=[O:46])=[O:41]>ClCCl.C(OCC)(=O)C>[CH3:38][N:39]([CH2:51][CH2:52][N:53]1[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1)[C:40](=[O:41])[C:42]1[CH:50]=[CH:49][CH:48]=[C:44]([C:45]([NH:1][C:2]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:22][C:3]=2[C:4](=[O:5])[NH:6][C:7]2[S:8][CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:21])[F:19])[CH:13]=3)[N:11]=2)=[O:46])[CH:43]=1
Reactant: Nc1ccc(N2CCCCC2)cc1C(=O)Nc1nc(-c2cccc(C(F)(F)F)c2)cs1
Reactant: CN(CCN1CCOCC1)C(=O)c1cccc(C(=O)Cl)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(CCN1CCOCC1)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2C(=O)Nc2nc(-c3cccc(C(F)(F)F)c3)cs2)c1

Procedure:
Into a 50-mL round bottom flask, was placed a solution of 2-amino-5-(piperidin-1-yl)-N-(4-(3-(trifluoromethyl)phenyl)thiazol-2-yl)benzamide (287 mg, 0.64 mmol, 1.00 equiv) in dichloromethane (3 mL), and pyridine (406 mg, 5.13 mmol, 8.00 equiv). This was followed by dropwise addition of a solution of 3-(methyl(2-morpholinoethyl)carbamoyl)benzoyl chloride (300 mg, 0.97 mmol, 1.50 equiv) in dichloromethane (2 mL) with stirring. The resulting solution was stirred for 1 h at room temperature, then diluted with 50 mL of ethyl acetate. The resulting mixture was washed with 1×20 mL of hydrogen chloride (1 N) and 2×20 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product (300 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 120 mg (20%) of as a yellow solid. 1H-NMR (300 MHz, DMSO, ppm): δ 12.89(s, 1H), 10.93(s, 1H), 9.79(s, 1H), 8.26 (m, 2H), 8.00(m, 4H), 7.69(m, 4H), 7.53(s, 1H), 7.27(d, J=8.7 Hz, 1H), 4.01(s, 2H), 3.85(s, 2H), 3.63(s, 4H), 3.44(s, 2H), 3.17(m, 6H), 2.99(s, 3H), 1.70(m, 6H). MS (ES, m/z): 721 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][C:13]([N+:19]([O-])=O)=[C:12]2[NH:22][CH2:23][C:24]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:26])[CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>[Pt].C(#N)C>[NH2:19][C:13]1[CH:14]=[N:15][C:16]2[C:11]([C:12]=1[NH:22][CH2:23][C:24]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:31])([CH3:32])[CH3:33])([CH3:25])[CH3:26])=[CH:10][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[CH:18][CH:17]=2
Reactant: [H][H]
Reactant: CC(C)(CNc1c([N+](=O)[O-])cnc2ccc(OCc3ccccc3)cc12)NC(=O)OC(C)(C)C
Agent: [Pt]
Solvent: CC#N
Product: CC(C)(CNc1c(N)cnc2ccc(OCc3ccccc3)cc12)NC(=O)OC(C)(C)C
Yield: 103.7 %

Procedure:
tert-Butyl [2-(6-benzyloxy-3-nitroquinolin-4-ylamino)-1,1-dimethylethyl]carbamate (13.75 g), 5% platinum on carbon (1.03 g), and acetonitrile (250 mL) were combined. The mixture was shaken overnight under 50 psi (3.4×105 Pa) of hydrogen. The reaction was filtered through CELITE filter agent, and the filter pad was rinsed with acetonitrile. The filtrate was concentrated under reduced pressure. Residual water was removed by an azeotrope with toluene. Removal of all volatiles under reduced pressure provided 13.34 g of crude tert-butyl [2-(3-amino-6-benzyloxyquinolin-4-ylamino)-1,1-dimethylethyl]carbamate as a brown foam.
Reaction SMILES: [C:1]([C:4]1([CH3:17])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)(=[O:3])[NH2:2].Br[C:19]1[CH:39]=[CH:38][C:22]([CH2:23][N:24]2[CH2:33][CH2:32][C:31]3[C:26](=[CH:27][CH:28]=[C:29]([C:34]([O:36][CH3:37])=[O:35])[CH:30]=3)[CH2:25]2)=[CH:21][CH:20]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:13]([O:12][C:10]([N:7]1[CH2:8][CH2:9][C:4]([C:1]([NH:2][C:19]2[CH:39]=[CH:38][C:22]([CH2:23][N:24]3[CH2:33][CH2:32][C:31]4[C:26](=[CH:27][CH:28]=[C:29]([C:34]([O:36][CH3:37])=[O:35])[CH:30]=4)[CH2:25]3)=[CH:21][CH:20]=2)=[O:3])([CH3:17])[CH2:5][CH2:6]1)=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: COC(=O)c1ccc2c(c1)CCN(Cc1ccc(Br)cc1)C2
Reactant: CC(C)(C)OC(=O)N1CCC(C)(C(N)=O)CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COC(=O)c1ccc2c(c1)CCN(Cc1ccc(NC(=O)C3(C)CCN(C(=O)OC(C)(C)C)CC3)cc1)C2
Temperature: 100 °C
Yield: 45.8 %

Procedure:
A mixture of tert-butyl 4-carbamoyl-4-methylpiperidine-1-carboxylate (178 mg, 0.733 mmol), methyl 2-(4-bromobenzyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylate (240 mg, 0.670 mmol), Pd2(dba)3 (61 mg, 0.066 mmol), Xantphos (116 mg, 0.200 mmol), and Cs2CO3 (434 mg, 1.33 mmol) in dioxane (10.6 mL) was degassed thoroughly and the reaction vessel was sealed. The mixture was heated at 100° C. overnight and then filtered. The filtrate was concentrated. The resulting residue was purified by column chromatography (SiO2, 0-90% EtOAc in hexane) to give methyl 2-[4-({[1-(tert-butoxycarbonyl)-4-methylpiperidin-4-yl]carbonyl}amino)benzyl]-1,2,3,4-tetrahydroisoquinoline-6-carboxylate (160 mg, 46%). LC-MS: (FA) ES+ 522; 1H NMR (400 MHz, CDCl3) δ 7.78 (s, 1H), 7.75 (dd, J=8.0, 1.6 Hz, 1H), 7.48 (d, J=8.5 Hz, 2H), 7.33 (dd, J=9.3, 7.0 Hz, 3H), 7.01 (t, J=7.3 Hz, 1H), 3.91-3.83 (m, 3H), 3.67 (dd, J=19.7, 4.9 Hz, 5H), 3.40-3.27 (m, 2H), 3.00-2.85 (m, 2H), 2.73 (t, J=5.9 Hz, 2H), 2.13-1.96 (m, 3H), 1.55 (t, J=21.0 Hz, 2H), 1.46 (d, J=5.0 Hz, 9H), 1.31 (d, J=9.9 Hz, 3H).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C:11]([C:14]1[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=1[OH:22])([CH3:13])[CH3:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].[Br:25][CH2:26][CH2:27][CH2:28][C:29](Cl)=[O:30].[Cl-].[Na+]>O1CCCC1.O.CCOCC>[C:4]([Si:1]([CH3:2])([CH3:3])[O:8][CH2:9][CH2:10][C:11]([C:14]1[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=1[OH:22])([CH3:12])[CH3:13])([CH3:7])([CH3:6])[CH3:5].[Br:25][CH2:26][CH2:27][CH2:28][C:29]([O-:30])=[O:8]
Reactant: O=C(Cl)CCCBr
Agent: Cc1cc(C)c(C(C)(C)CCO[Si](C)(C)C(C)(C)C)c(O)c1
Agent: [Cl-]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C([O-])CCCBr
Reaction time: 0.67 h

Procedure:
To 3.22 g of 2-{3-(tert-butyldimethylsilyloxy)-1,1-dimethylpropyl}-3,5-dimethyl-phenol in solution in 60 cm3 of tetrahydrofuran, there are added, at 20° C. under an argon atmosphere and in small portions, 0.32 g of sodium hydride (at 75% in mineral oil), and then 15 minutes later 1.16 cm3 of 4-bromobutyryl chloride. After stirring for 40 minutes, 100 cm3 of ether, 10 cm3 of distilled water and 10 cm3 of a saturated aqueous sodium chloride solution are added. After stirring, the organic phase is decanted off, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is filtered on 75 g of silica (particle size 0.063-0.2 mm), eluting successively with cyclohexane and then with a cyclohexane/ethyl acetate mixture (90/10 by volume). 2 g of 2-{3-(tert-butyldimethyl-silyloxy)-1,1-dimethylpropyl}-3,5-dimethylphenol 4-bromobutyrate are thus obtained in the form of a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[C:16]([O:21][CH3:22])[C:17]=1[CH:18]([CH3:20])[CH3:19])[CH2:6]P(=O)(OCC)OCC.[S:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[CH:28]=O>>[CH3:22][O:21][C:16]1[CH:15]=[C:5]([CH:6]=[CH:28][C:24]2[S:23][CH:27]=[CH:26][CH:25]=2)[CH:4]=[C:3]([O:2][CH3:1])[C:17]=1[CH:18]([CH3:19])[CH3:20]
Reactant: CCOP(=O)(Cc1cc(OC)c(C(C)C)c(OC)c1)OCC
Reactant: O=Cc1cccs1
Product: COc1cc(C=Cc2cccs2)cc(OC)c1C(C)C
Yield: 78 %

Procedure:
This material was prepared from diethyl (3,5-dimethoxy-4-i-propylbenzyl)phosphonate obtained in example 15(a) and thiophene carboxaldehyde in 78% yield as the same way as described in the example 15(b), 1HNMR (CDCl3, ppm): δ 1.32 (d, J=7.1 Hz, 6H), 3.70 (qint., J=7.1 Hz, 1H), 3.89 (s, 6H), 6.69 (s, 2H), 6.90 (d, J=16 Hz, 1H), 7.0-7.3 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:9][CH:8]=2)[N:6]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24].N1C=CC=CC=1>ClCCl.CN(C)C1C=CN=CC=1>[C:23]([NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[CH:11][CH:12]=2)[N:6]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)NCCc1ccc(-c2csc(N)n2)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1nc(-c2ccc(CCNC(=O)OC(C)(C)C)cc2)cs1
Reaction time: 8 h
Yield: 85.3 %

Procedure:
tert-Butyl {2-[4-(2-amino-1,3-thiazol-4-yl)phenyl]ethyl}carbamate (290 mg) was dissolved in dichloromethane (5 mL), then acetic anhydride (0.103 mL), 4-dimethylaminopyridine (10 mg) and pyridine (0.147 mL) were added. The mixture was stirred overnight. The mixture was extracted with chloroform, washed with water and saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The solid was washed with ethyl ether, and dried in vacuo to give tert-butyl (2-{4-[2-(acetylamino)-1,3-thiazol-4-yl]phenyl}ethyl)carbamate as a white solid (280 mg, 85.3%).
Reaction SMILES: [CH2:1]1[CH:8]2[N:4]([C:5](=[O:9])[CH2:6][CH2:7]2)[C:3](=[O:10])[CH2:2]1.Cl.[CH2:12]([OH:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([O:19][C:5](=[O:9])[CH2:6][CH2:7][CH:8]1[CH2:1][CH2:2][C:3](=[O:10])[NH:4]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1CCC2CCC(=O)N12
Reactant: OCc1ccccc1
Agent: Cl
Product: O=C1CCC(CCC(=O)OCc2ccccc2)N1
Temperature: 98 °C

Procedure:
Twenty-eight grams of dihydro-1H-pyrrolizine-3,5(2H,6H)-dione (III) are dissolved in 76 g of benzyl alcohol and 0.2 ml of concentrated hydrochloric acid is added. The solution is heated at 98° C. for 104 hours. The mixture is cooled and excess benzyl alcohol is distilled at 0.1 mm pressure to a maximum bath temperature of 100° C. The residual oil is dissolved in 1 l of anhydrous diethylether, 1 g of activated charcoal is added and the resulting suspension is filtered through filter aid. The filtrate is concentrated at reduced pressure and the resulting crystals are isolated by filtration. Recrystallization from cyclohexane containing 12% methylene chloride yields 5-oxo-2-pyrrolidinepropanoic acid benzyl ester with a melting point of 79°-80° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:5]([CH2:16][C:17]1[CH:22]=[C:21]([CH2:23][OH:24])[CH:20]=[CH:19][N:18]=1)[CH2:6]/[CH:7]=[CH:8]/[C:9]#[C:10][C:11]([O:14][CH3:15])([CH3:13])[CH3:12])[CH3:4].Br[CH2:26]/[CH:27]=[CH:28]/[C:29]1[CH:33]=[CH:32][S:31][CH:30]=1.C(OCC)C>O1CCCC1>[CH2:3]([N:5]([CH2:16][C:17]1[CH:22]=[C:21]([CH2:23][O:24][CH2:26]/[CH:27]=[CH:28]/[C:29]2[CH:33]=[CH:32][S:31][CH:30]=2)[CH:20]=[CH:19][N:18]=1)[CH2:6]/[CH:7]=[CH:8]/[C:9]#[C:10][C:11]([O:14][CH3:15])([CH3:13])[CH3:12])[CH3:4]
Reactant: CCN(C/C=C/C#CC(C)(C)OC)Cc1cc(CO)ccn1
Reactant: BrC/C=C/c1ccsc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCN(C/C=C/C#CC(C)(C)OC)Cc1cc(COC/C=C/c2ccsc2)ccn1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 53.6 %

Procedure:
11.6 mg of 60% oily sodium hydride was suspended in 0.5 ml of tetrahydrofuran at 0 ° C., under a nitrogen atmosphere, and a tetrahydrofuran solution( 2 ml) of 87.5 mg of (E)-N-ethyl-N-(6-methoxy-6-methyl-2-hepten-4-ynyl)-4-hydroxymethyl-2-pyridylmethylamine was added dropwise. The mixture was stirred for 20 minutes, and a tetrahydrofuran solution (1 ml) of 50 mg of (E)-3-bromo-1-(3-thienyl)-1-propene was added dropwise. The mixture was stirred overnight at room temperature, and then ice water and ethyl ether were added. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The desiccant was separated by filtration, and the solvent was evaporated under reduced pressure. The residue was purified by medium-pressure liquid chromatography [silica gel column, chloroform→chloroform/methanol=20/1] to give 56 mg (yield 46%) of the captioned compound as a pale yellow oil.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][C:6](=[O:8])[CH2:5][C@H:4]([CH3:9])[NH:3]1.C(N(CC)CC)C.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>C(Cl)Cl>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([N:3]2[C@@H:4]([CH3:9])[CH2:5][C:6](=[O:8])[CH2:7][C@@H:2]2[CH3:1])(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: C[C@H]1CC(=O)C[C@H](C)N1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H]1CC(=O)C[C@H](C)N1S(=O)(=O)c1ccc(Cl)cc1

Procedure:
trans-2,6-Dimethylpiperidin-4-one (93; 5.2 g, 39 mmol) was dissolved in CH2Cl2 (100 mL) and triethylamine (22 mL, 155 mmol) was added. The solution was stirred and treated with 4-chlorobenzenesulfonyl chloride (9.2 g, 43 mmol). The mixture was stirred for 24 hr and then partitioned between water (300 mL) and CH2Cl2 (300 mL). The organic layer was washed with 0.2 N citric acid, water, brine, dried over Na2SO4, filtered and the solvent evaporated. The residue (6.7 g) was purified by flash chromatography, eluting with EtOAc-hexane (1:3) mixture to yield 3.6 g (35%, 2 steps) of product 94.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[OH:22][CH2:23][CH2:24][NH:25][S:26]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]Cl)(=[O:28])=[O:27]>C(N(C(C)C)C(C)C)C>[OH:22][CH2:23][CH2:24][NH:25][S:26]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][N:12]1[CH2:11][CH2:10][N:9]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:14][CH2:13]1)(=[O:28])=[O:27]
Reactant: O=S(=O)(CCCCCCl)NCCO
Reactant: Clc1ccc(C(c2ccc(Cl)cc2)N2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(CCCCCN1CCN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)CC1)NCCO
Yield: 97.5 %

Procedure:
1-[Bis(4-chlorophenyl)methyl]piperazine (642.5 mg, 2.00 mmol) and N-(2-hydroxyethyl)-5-chloropentanesulfonamide (459.5 mg, 2.00 mmol) were refluxed in N-ethyldiisopropylamine (2 ml) for 6 hours. The reaction mixture was concentrated in vacuo, and water was added thereto. The mixture was extracted with chloroform. The chloroform layer was washed with water, and dried over anhydrous magnesium sulfate. Subsequently, the solvent was removed by evaporation in vacuo. The resulting crude product was purified by column chromatography on silica gel with chloroform-methanol (20:1), to give N-(2-hydroxyethyl)-5-[4-[bis(4-chlorophenyl)methyl]-1-piperazinyl]pentanesulfonamide (1003.0 mg) as a pale brown oil (97.5%).
Reaction SMILES: O.Br[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[CH:5][C:4]=1[F:12].C(=O)([O-])[O-].[Na+].[Na+].[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[F:12][C:4]1[CH:5]=[C:6]([CH2:9][C:10]#[N:11])[CH:7]=[CH:8][C:3]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OB(O)c1ccccc1
Reactant: N#CCc1ccc(Br)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: N#CCc1ccc(-c2ccccc2)c(F)c1

Procedure:
A biphasic mixture of water (3 mL) and toluene (10 mL) containing (4-bromo-3-fluoro-phenyl)-acetonitrile (457 mg, 2.14 mmol), sodium carbonate (1.00 g, 9.45 mmol), phenyl boronic acid (781 mg, 6.41 mmol) was sparged with nitrogen for 10 min, tetrakis(triphenylphosphine)palladium (250 mg) was added and the mixture heated to reflux for 48 hrs. After cooling, the solution was diluted with EtOAc, washed with water, the organic phase dried (MgSO4), filtered and evaporated to dryness. The residue was purified by column chromatography (0 to 10% EtOAc in hexanes) to afford (2-fluoro-biphenyl-4-yl)-acetonitrile as a colorless solid. 1H NMR (500 MHz, CDCl3) δ 7.54 (2H, m), 7.46 (3H, m), 7.40 (1H, m), 7.17 (2H, m), 3.79 (3H, s).
Reaction SMILES: CO[C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][N:17]([S:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[Cl:29])(=[O:22])=[O:21])[CH2:16][CH2:15]3)[C:11]2=[O:30])=[CH:6][CH:5]=1.[CH:32]([NH2:35])([CH3:34])[CH3:33].[Cl-].C[Al+]C.O>C1(C)C=CC=CC=1.CCCCCC>[Cl:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[S:20]([N:17]1[CH2:18][CH2:19][C:12]2([C:11](=[O:30])[N:10]([C:7]3[CH:6]=[CH:5][C:4]([C:3]([NH:35][CH:32]([CH3:34])[CH3:33])=[O:31])=[CH:9][CH:8]=3)[CH2:14][CH2:13]2)[CH2:15][CH2:16]1)(=[O:22])=[O:21]
Reactant: COC(=O)c1ccc(N2CCC3(CCN(S(=O)(=O)c4ccccc4Cl)CC3)C2=O)cc1
Reactant: CC(C)N
Agent: C[Al+]C
Agent: [Cl-]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)NC(=O)c1ccc(N2CCC3(CCN(S(=O)(=O)c4ccccc4Cl)CC3)C2=O)cc1
Temperature: 95 °C
Reaction time: 8 h
Yield: 30.4 %

Procedure:
4-[8-(2-Chloro-benzenesulfonyl)-1-oxo-2,8-diaza-spiro[4.5]dec-2-yl]-benzoic acid methyl ester (0.149 g), compound of example 150), was suspended in toluene under an argon atmosphere at RT, isopropylamine (0.057 g) and dimethylaluminium chloride in hexane (1 molar, 1.61 ml) were added and the mixture stirred 10 minutes at 130° than overnight at 95° C. The reaction mixture was cooled to RT, water (0.05 ml) was added, and the mixture was stirred for 10 minutes. Then the solvent was carefully evaporated off in vacuo, the residue was adsorbed on silica gel and chromatographed over silica gel (eluents: AcOEt/heptane, gradient from 0 to 50%) to give the desired compound (0.048 g) as white solid. MS (ESI): 490.15 MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12](Cl)=[O:13])[CH:6]=[CH:5]2.[S:15]1[C:19]2=[CH:20][CH:21]=[CH:22][C:23]([NH2:24])=[C:18]2[N:17]=[C:16]1[NH2:25]>>[NH2:25][C:16]1[S:15][C:19]2[CH:20]=[CH:21][CH:22]=[C:23]([NH:24][C:12]([C:7]3[CH:6]=[CH:5][C:4]4[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=4)[CH:8]=3)=[O:13])[C:18]=2[N:17]=1
Reactant: Nc1nc2c(N)cccc2s1
Reactant: O=C(Cl)c1ccc2cc(Br)ccc2c1
Product: Nc1nc2c(NC(=O)c3ccc4cc(Br)ccc4c3)cccc2s1

Procedure:
This material was prepared analogous to the procedure described for Example 1(b). 6-Bromo-naphthalene-2-carbonyl chloride, Example 1(a), (127 mg, 0.47 mmol) reacted with benzothiazole-2,4-diamine (77 mg, 0.47 mmol, prepared according to the procedure described in WO03099284) to give the title compound as an amorphous solid. MS (ESI, pos. ion.) m/z: 400 (M+1).
Reaction SMILES: Br[CH:2]1[CH2:11][CH2:10][C:9]2[CH:8]=[C:7]([C:12]#[N:13])[CH:6]=[CH:5][C:4]=2[C:3]1=[O:14].[N-:15]=[N+:16]=[N-:17].[Na+]>CN(C=O)C.C(O)(=O)C.O>[N:15]([CH:2]1[CH2:11][CH2:10][C:9]2[CH:8]=[C:7]([C:12]#[N:13])[CH:6]=[CH:5][C:4]=2[C:3]1=[O:14])=[N+:16]=[N-:17]
Reactant: N#Cc1ccc2c(c1)CCC(Br)C2=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(=O)O
Product: N#Cc1ccc2c(c1)CCC(N=[N+]=[N-])C2=O
Reaction time: 1 h
Yield: 40 %

Procedure:
To a solution of racemic 6-bromo-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (100 mg, 0.4 mmol) in DMF (2611 mL) and acetic acid (65.3 mL) was added a solution of sodium azide (52.0 mg, 0.8 mmol) in water (522 mL) dropwise at 0° C. After 1 hour, the reaction was complete. The mixture was directly loaded to a 24 g ISCO column and purified by ISCO Combiflash Companion (0% ethyl acetate-hexane for 3 min then ramped to 20% ethyl acetate-hexane over 7 min then 20% ethyl acetate-hexane for 5 more minutes. The product came out 8-10 min) to afford racemic 6-azido-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (35 mg, 0.16 mmol, 41.2%) as a white solid: LCMS=213.22 [M+H]+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][CH2:13][CH2:14][OH:15].Br[CH2:17][C:18]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:19]=1[O:20][CH2:21][C:22]#[N:23]>>[CH3:17][C:18]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][O:15][CH2:14][CH2:13][O:12][CH2:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)[C:19]=1[O:20][CH2:21][C:22]#[N:23]
Reactant: Cc1cccc(CBr)c1OCC#N
Reactant: OCCOCc1ccc2ccccc2n1
Product: Cc1cccc(COCCOCc2ccc3ccccc3n2)c1OCC#N

Procedure:
MS (ESI) 363 (M+H)+. Prepared from 2-(quinolin-2-ylmethoxy)-ethanol (EXAMPLE 34d) and (2-bromomethyl-6-methyl-phenoxy)-acetonitrile.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([NH:10][C:11](=[O:21])[C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[O:19][CH3:20])=[N:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].I[CH2:29][CH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>CN(C)C=O.O1CCCC1>[C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11](=[O:21])[C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[O:19][CH3:20])/[N:7]([CH2:29][CH:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: ICC1CCOCC1
Reactant: COc1ccc(Cl)cc1C(=O)Nc1ncc(C(C)(C)C)s1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc(Cl)cc1C(=O)/N=c1\sc(C(C)(C)C)cn1CC1CCOCC1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a solution of Example 244A (10 g, 3.1 mmol) in 4:1 N,N-dimethylformamide/tetrahydrofuran (20 mL) were added potassium tert-butoxide (Aldrich, 0.42 g, 3.7 mmol) and 4-(iodomethyl)tetrahydro-2H-pyran (Maybridge, 0.97 g, 4.3 mmol). The reaction mixture was stirred at 80° C. for 16 hours, cooled to room temperature, quenched with saturated aqueous NaHCO3 (20 mL) and extracted with ethyl acetate (3×20 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-100% ethyl acetate in hexanes) to afford the title compound. 1H NMR (300 MHz, dimethylsulfoxide-d6) δ ppm 1.21-1.51 (m, 4H), 1.32 (s, 9H), 2.06-2.35 (m, 1H), 3.20-3.30 (m, 2H), 3.79 (s, 3H), 3.80-3.91 (m, J=9.3, 2.2, 2.0 Hz, 2H), 4.06 (d, J=7.1 Hz, 2H), 7.11 (d, J=8.8 Hz, 1H), 7.30 (s, 1H), 7.45 (dd, J=8.8, 3.1 Hz, 1H), 7.64 (d, J=2.7 Hz, 1H); MS (ESI+) m/z 423 (M+H)+; Anal. Calculated for C21H27ClN2O3S: C, 59.63; H, 6.43; N, 6.62 Found: C, 59.66; H, 6.36; N, 6.56.
Reaction SMILES: [CH3:1][O:2][CH2:3]Cl.C(=O)([O-])[O-].[K+].[K+].[Br:11][C:12]1[C:21]([CH3:22])=[CH:20][C:19]([OH:23])=[C:18]2[C:13]=1[CH:14]=[CH:15][C:16](=[O:24])[NH:17]2>CN(C)C=O>[Br:11][C:12]1[C:21]([CH3:22])=[CH:20][C:19]([O:23][CH2:1][O:2][CH3:3])=[C:18]2[C:13]=1[CH:14]=[CH:15][C:16](=[O:24])[NH:17]2
Reactant: Cc1cc(O)c2[nH]c(=O)ccc2c1Br
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCOc1cc(C)c(Br)c2ccc(=O)[nH]c12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methoxymethyl chloride (410 μL) was added to a suspension of potassium carbonate (1.24 g) in a solution of 5-bromo-8-hydroxy-6-methyl-1H-quinolin-2-one (480 mg) in dimethylformamide (9 mL) at 0° C. The reaction mixture is stirred for 18 hours at room temperature, filtered, the solvent removed in vacuo, and the product purified by flash column chromatography on silica gel, eluting with 2% methanol in dichloromethane.
Reaction SMILES: C[N:2]([CH3:19])[CH:3]=[CH:4][C:5](=O)[C:6]([CH3:17])([C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)[CH3:7].Cl.C(N)=[NH:22].CC[O-].[Na+]>O.CCOC(C)=O>[CH3:17][C:6]([C:5]1[CH:4]=[CH:3][N:2]=[CH:19][N:22]=1)([C:8]1[CH:9]=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=1)[CH3:7]
Reactant: N=CN
Reactant: CN(C)C=CC(=O)C(C)(C)c1ccc([N+](=O)[O-])cc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(c1ccc([N+](=O)[O-])cc1)c1ccncn1
Temperature: 150 °C

Procedure:
A mixture of 1-dimethylamino-4-methyl-4-(4-nitro-phenyl)-pent-1-en-3-one (0.5 g, 1.9 mmol), formamidine hydrochloride (0.305 g, 3.8 mmol), and NaOEt (1.29 g, 4.0 mmol) was heated in Smith synthesizer under microwave for 10 min at 150° C. The resultant was diluted with H2O and EtOAc. The organic layer was dried, and the residue was used without further purification. MS: (ES+) 244 (M+H). Calc'd for C13H14N3O2—244.10.