Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3](O[C:6](=[O:8])[CH:7]=1)=[O:4].C([O-])(=O)C.[Na+].O.[NH2:15][NH2:16].O>C(O)(=O)C.O>[Br:1][C:2]1[C:3](=[O:4])[NH:15][NH:16][C:6](=[O:8])[CH:7]=1
Reactant: NN
Reactant: O=C1C=C(Br)C(=O)O1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=c1cc(Br)c(=O)[nH][nH]1
Temperature: 100 °C
Yield: 37 %

Procedure:
A mixture of bromomaleic anhydride (50 g, 283 mmol) and sodium acetate (76.5 g, 562 mmol) in 40% acetic acid/water (750 ml) was treated with hydrazine monohydrate (16.5 ml, 339 mmol) at room temperature under nitrogen. The brown solution was stirred and heated at 100° C. for 18 hours. Upon cooling the mixture was poured into water (1 l) and extracted with ethyl acetate (6×500 ml). The combined extracts were dried (MgSO4), filtered and evaporated to afford the title compound (20 g, 37%) as an orange solid. 1H NMR (250 MHz, d6-DMSO) δ 7.68 (1H, br s). MS (ES+) m/e 193 [MH]+, 191 [MH]+. This material was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1[F:18].[C:19]([Si:23](Cl)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH3:22])([CH3:21])[CH3:20].N1C=CN=C1.O>CN(C=O)C>[Si:23]([O:9][CH2:8][C:6]1[N:7]=[C:2]([Cl:1])[C:3]([C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=2[F:18])=[CH:4][CH:5]=1)([C:19]([CH3:22])([CH3:21])[CH3:20])([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(F)c(-c2ccc(CO)nc2Cl)c1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(F)c(-c2ccc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)nc2Cl)c1
Reaction time: 14 h
Yield: 252 %

Procedure:
To a solution of (6-chloro-5-(2-fluoro-5-methoxyphenyl)pyridin-2-yl)methanol (3.00 g) and tert-butylchlorodiphenylsilane (1.53 g) in DMF (7.0 mL) was added imidazole (1.53 g) at room temperature, and the mixture was stirred for 14 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (7.10 g) as a pale-yellow crude oil. This compound was used for the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[OH:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21][S:22]([N:25]1[CH2:30][CH2:29][CH2:28][CH:27](O)[CH2:26]1)(=[O:24])=[O:23]>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH:27]2[CH2:28][CH2:29][CH2:30][N:25]([S:22]([CH3:21])(=[O:24])=[O:23])[CH2:26]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2O)CC1
Reactant: CS(=O)(=O)N1CCCC(O)C1
Product: CC(C)(C)OC(=O)N1CCN(c2ccccc2OC2CCCN(S(C)(=O)=O)C2)CC1

Procedure:
The title compound was prepared by using Mitsunobu condition from 4-(2-Hydroxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester and 1-methanesulfonyl-piperidin-3-ol.
Reaction SMILES: [CH3:1][C:2]([CH2:9][CH2:10][CH:11]=[C:12]([CH3:18])[CH2:13][O:14][CH2:15][O:16][CH3:17])=[CH:3][CH2:4][CH2:5][C:6](=[O:8])[CH3:7].[Cl-].[NH4+].O1CC[CH2:23][CH2:22]1>>[CH3:7][C:6]([OH:8])([CH2:5][CH2:4][CH:3]=[C:2]([CH3:1])[CH2:9][CH2:10][CH:11]=[C:12]([CH3:18])[CH2:13][O:14][CH2:15][O:16][CH3:17])[C:22]#[CH:23]
Reactant: C1CCOC1
Reactant: COCOCC(C)=CCCC(C)=CCCC(C)=O
Agent: [Cl-]
Agent: [NH4+]
Product: C#CC(C)(O)CCC=C(C)CCC=C(C)COCOC
Temperature: 25 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
A solution of 6,10-dimethyl-11-(methoxymethyl)oxy-5,9-undecadien-2-one (67 mg, 0.26 mmol) in tetrahydrofuran (2 ml) was stirred on an ice bath under argon atmosphere. To the solution was added lithium acetylide ethylenediamine complex (30 mg, 0.33 mmol), and the mixture was warmed to room temperature and stirred for 3 hours. After addition of saturated aqueous ammonium chloride (2 ml), the reaction mixture was extracted with ether. The extract was dried over Na2SO4 and evaporated in vacuo to remove the solvent to give a crude product, which was purified with silica gel column chromatography to obtain 3,7,11-trimethyl-12-(methoxymethyl)oxy-6,10-dodecadien-1-in-3-ol (61 mg, 83%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[N:4][C:3]=1[NH:9][NH2:10].[OH-].[Na+].[H][H]>CO.[Pd]>[NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[N:4][C:3]=1[NH:9][NH2:10]
Reactant: NNc1nnc(Cl)cc1N
Reactant: [H][H]
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: NNc1nnccc1N
Reaction time: 4 h

Procedure:
A solution of 4 g of 4-amino-6-chloro-3-hydrazinopyridazine in 240 ml. of methanol and 60 ml. of 0.5 N sodium hydroxide in methanol are charged into a Paar shaker. To this solutionn, 2 g. of 10% palladium on carbon catalyst is added. The Paar shaker is charged at room temperature with hydrogen to an initial pressure of 50 psi and shaken. After about 4 hours, the reaction mixture is filtered, the solvent evaporated, and the residue extracted with chloroform. The chloroform solution is evaporated to dryness, and the 4-amino-3-hydrazino pyridazine obtained is dissolved in methanol. Hydrogen chloride gas is bubbled in, and the 4-amino-3-hydrazinopyridazine dihydrochloride (m.p. 281°-283°C.) which precipitates is separated by filtration.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1.Cl[C:21]([O:23][CH2:24][CH:25]1[C:37]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22]>ClCCl>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:21](=[O:22])[O:23][CH2:24][CH:25]3[C:37]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[C:31]4[C:26]3=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Solvent: ClCCl
Product: Nc1nc2ccccc2c2c1ncn2CCCCNC(=O)OCC1c2ccccc2-c2ccccc21
Reaction time: 0.02 h

Procedure:
To a solution of 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine (9.3 mg, 36 μmol) in 10 mL of dichloromethane at ambient temperature was added 9-fluorenylmethyl chloroformate (8 mg, 30 μmol) as a solid. The mixture was vortexed at room temperature for about 1 min., becoming slightly cloudy. Aminomethylpolystyrene (ca. 90 mg, 0.64 meq/g, 100-200 mesh, Bachem) was added to quench excess chloroformate, and after a few minutes the mixture was filtered through a short plug of silica gel, eluting with 10:1 dichloromethane-methanol to isolate the product as a solid. 1H NMR (500 MHz, DMSOd6) δ 8.27 (s, 1H), 8.08 (d, J=8.1 Hz, 1H), 7.87 (d, J=7.6 Hz, 2H), 7.65 (m, 3H), 7.50 (t, J=7.6 Hz, 1H), 7.40 (t, J=7.3 Hz, 2H), 7.3 (m, 4H), 7.15 (bs, 2H), 4.62 (t, J=7 Hz, 2H), 4.27 (d, J=7 Hz, 2H), 4.17 (t, J=7 Hz, 1H), 3.03 (q, J=7 Hz, 2H), 1.84 (quintet, J=7 Hz, 2H), 1.45 (quintet, J=7 Hz, 2H). MS (APCI) m/e 478.28 (M+H).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[O:14]C.C(O)C>C(Cl)Cl>[OH:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[OH:14]
Reactant: COc1ccc(F)cc1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCO
Product: Oc1ccc(F)cc1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 104.1 %

Procedure:
A 1 M solution of boron tribromide in methylene chloride (500 mL, 0.50 mole) was cooled to -78 ° C. To this solution was added in a dropwise manner a solution of 46 g (0.30 mole) of 1,2-dimethoxy-4-fluorobenzene in 100 mL of methylene chloride. Upon completion of addition, the mixture was allowed to warm to ambient temperature at which it stirred for about 16 hours. At the conclusion of this period the reaction mixture was cooled to 0° C., and ethanol was added to the reaction mixture. The solvents were evaporated under reduced pressure, leaving 40 g of 1,2-dihydroxy-4-fluorobenzene as a residue. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[S:34](=[O:37])(=[O:36])[NH2:35])=[CH:24][CH:23]=2)[C:7](=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])[N:9]=1)[CH2:2][CH2:3][CH3:4].[C:38]1([CH:44]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C:45](Cl)=[O:46])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.CO>C(Cl)Cl>[CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[S:34](=[O:37])(=[O:36])[NH:35][C:45](=[O:46])[CH:44]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[CH:24][CH:23]=2)[C:7](=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nn(-c2ccccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CO
Product: CCCCc1nn(-c2ccccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)C(c2ccccc2)c2ccccc2)cc1
Yield: 73 %

Procedure:
By the procedure of Example 13, Step C, 5-n-butyl-2,4-dihydro-4-[(2'-sulfamoylbiphenyl-4-yl)methyl]-2-[2-(trifluoromethyl)phenyl]-3H-1,2,4-triazol-3-one (from Example 16, Step C) was reacted with diphenylacetyl chloride. The crude product was evaporated twice from toluene and flash chromatographed twice on silica gel (gradient elution with 0.1-1% MeOH in CH2Cl2 and then approx. 0.01-1% MeOH in CH2Cl2) to give a 73% yield of the title compound as off-white crystals, mp 144°-146° C.; homogeneous by TLC in 19:1 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 725 (M+1)+.
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][C:9]([NH:11][CH:12]([CH:19]([CH3:21])[CH3:20])[CH:13]([OH:18])[C:14]([F:17])([F:16])[F:15])=[O:10])[C:6]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:5][CH:4]=[C:3]1[NH:28][C:29]([NH:31][CH2:32][C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1)=[O:30].CO>ClCCl>[O:1]=[C:2]1[N:7]([CH2:8][C:9]([NH:11][CH:12]([CH:19]([CH3:21])[CH3:20])[C:13](=[O:18])[C:14]([F:15])([F:17])[F:16])=[O:10])[C:6]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:5][CH:4]=[C:3]1[NH:28][C:29]([NH:31][CH2:32][C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1)=[O:30]
Reactant: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ncc(NC(=O)NCc2cccnc2)c1=O)C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ncc(NC(=O)NCc2cccnc2)c1=O)C(=O)C(F)(F)F

Procedure:
2-[6-Oxo-2-phenyl-5-[3-(3-pyridylmethyl)ureido]-1,6-dihydro-1-pyrimidinyl]-N-(3,3,3-trifluoro-2-hydroxy-1-isopropylpropyl)acetamide was subjected to conditions similar to those described in Example 1. Chromatography, with methanol:dichloromethane (5.95) as the eluent, gave 2-[6-oxo-2-phenyl-5-[3-(3-pyridylmethyl)ureido]-1,6-dihydro-1-pyrimidinyl]-N-(3,3,3-trifluoro-1-isopropyl-2-oxopropyl)acetamide as a white solid; NMR (DMSO/D2O): 8.60 (s,1), 8.42 (m,3), 7.71 (m,1), 7.47 (m,5), 4.58 (d,1), 4.39 (d,1), 4.31 (s,2), 2.20 (m,1), 0.83 (d,3), 0.77 (d,3).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C([O:14][C:15](=O)[NH:16][C:17]1[S:21][C:20]2[C:22]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:23][CH:24]=[C:25]([O:26][CH3:27])[C:19]=2[CH:18]=1)C1C=CC=CC=1>>[CH3:27][O:26][C:25]1[C:19]2[CH:18]=[C:17]([NH:16][C:15]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:14])[S:21][C:20]=2[C:22]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:23][CH:24]=1
Reactant: COc1ccc(-c2ccccc2)c2sc(NC(=O)OCc3ccccc3)cc12
Reactant: C1COCCN1
Product: COc1ccc(-c2ccccc2)c2sc(NC(=O)N3CCOCC3)cc12

Procedure:
The title compound MS: mi/e=369.3 (M+H+) was obtained as a light brown solid (58% yield) by the reaction of morpholine with (4-methoxy-7-phenyl-benzo[b]thiophen-2-yl)-carbamic acid benzyl ester according to the method described above for example 1.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([C:14]([O:16]CC)=[O:15])[C:8]([OH:19])=[N:7]2>CC(O)C.O>[Cl:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([C:14]([OH:16])=[O:15])[C:8]([OH:19])=[N:7]2
Reactant: CCOC(=O)c1nc2ccc(Cl)cc2nc1O
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: O=C(O)c1nc2ccc(Cl)cc2nc1O

Procedure:
Potassium hydroxide (1.25 g, 22.2 mmol) was added to a suspension of 6-chloro-2-(ethoxycarbonyl)-3-hydroxyquinoxaline (0.56 g, 2.22 mmol) in 2-propanol (5 mL) and water (7.5 mL) and the resulting solution were heated at reflux for 12 h. The cooled mixture was acidified to pH 2 and the solvents were removed under reduced pressure, after which the residue was taken up in water (50 mL) and extracted with ethyl acetate (2×40 mL). The organic extracts were combined and the solvents were removed under reduced pressure, producing a residue that was purified by flash column chromatography on silica gel, eluting with methanol/methylene chloride (1:9), to provide 6-chloro-3-hydroxyquinoxaline-2-carboxylic acid as a light yellow solid: 1H NMR (400 MHz, CD3OD) δ 7.91 (d, 1H), 7.45 (d, 1H), 7.37 (dd, 1H) ppm; ESI MS m/z 223 [M−H]−.
Reaction SMILES: [NH2:1][C:2]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[N:14][NH:15]3)=[CH:11][CH:10]=2)=[O:7])=[C:4](Cl)[CH:3]=1.[CH2:24]([NH:28][CH2:29][CH:30]([CH3:32])[CH3:31])[CH:25]([CH3:27])[CH3:26]>CN1C(=O)CCC1.O>[NH2:1][C:2]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[N:14][NH:15]3)=[CH:11][CH:10]=2)=[O:7])=[C:4]([N:28]([CH2:29][CH:30]([CH3:32])[CH3:31])[CH2:24][CH:25]([CH3:27])[CH3:26])[CH:3]=1
Reactant: CC(C)CNCC(C)C
Reactant: Nc1cc(Cl)c(C(=O)Nc2ccc3cn[nH]c3c2)cc1[N+](=O)[O-]
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)CN(CC(C)C)c1cc(N)c([N+](=O)[O-])cc1C(=O)Nc1ccc2cn[nH]c2c1
Temperature: 25 °C

Procedure:
A solution 4-amino-2-chloro-N-(1H-indazol-6-yl)-5-nitrobenzamide (1 mmol; see Example 48) in NMP (2 mL) was added with diisobutylamine (0.5 mL), and the resulting mixture was subjected to microwave irradiation at 140° C. for 1 h. The reaction mixture was cooled to room temperature, diluted with water (20 mL). The solid formed was collected by filtration, washed with water, and dried in vacuo to provide 4-amino-2-diisobutylamino-N-(1H-indazol-6-yl)-5-nitrobenzamide.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[C:12]([C:15]1[N:19]2[N:20]=[C:21]([C:24](=O)[CH3:25])[CH:22]=[CH:23][C:18]2=[N:17][CH:16]=1)([OH:14])[CH3:13].Cl.[NH2:28][NH:29][C:30]([NH2:32])=[O:31].C(N(CC)CC)C>CO>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[C:12]([C:15]1[N:19]2[N:20]=[C:21](/[C:24](=[N:28]/[NH:29][C:30]([NH2:32])=[O:31])/[CH3:25])[CH:22]=[CH:23][C:18]2=[N:17][CH:16]=1)([OH:14])[CH3:13]
Reactant: NNC(N)=O
Reactant: CC(=O)c1ccc2ncc(C(C)(O)c3cc4cccnc4cc3F)n2n1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: C/C(=N\NC(N)=O)c1ccc2ncc(C(C)(O)c3cc4cccnc4cc3F)n2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.7 %

Procedure:
To a solution of 1-(3-(1-(7-fluoroquinolin-6-yl)-1-hydroxyethyl)imidazo[1,2-b]pyridazin-6-yl)ethanone (35 mg, 0.09 mmol) in methanol (20 mL) was added semicarbazide hydrochloride (20 mg, 0.18 mmol). Triethyl amine was added dropwise to adjust the pH to 5-6. The reaction mixture was stirred at room temperature overnight. The solution was concentrated in reduced pressure and the residue was purified by column chromatography (3%-50% MeOH in CH2Cl2) to afford 23 mg (yield: 62%) title compound. 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.47 (s, 1H), 8.87 (d, 1H), 8.52 (m, 2H), 8.06 (d, 1H), 7.92 (d, 1H), 7.85 (s, 1H), 7.54 (m, 2H), 6.62 (b, 2H), 6.24 (s, 1H), 2.13 (s, 3H), 1.53 (s, 3H). LCMS (method A): [MH]+=408, tR=4.03 min.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][C:7]([CH3:37])([CH3:36])[CH2:8][C@@:9]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:14][C:13](=[O:15])[N:12]([C@H:16]([C:18]2[CH:23]=[CH:22][C:21]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[CH3:17])[CH2:11][CH2:10]1.C(N(CC)CC)C>ClCCl>[OH:6][C:7]([CH3:36])([CH3:37])[CH2:8][C@@:9]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:14][C:13](=[O:15])[N:12]([C@H:16]([C:18]2[CH:23]=[CH:22][C:21]([CH:24]3[CH2:29][CH2:28][N:27]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[CH3:17])[CH2:11][CH2:10]1
Reactant: C[C@@H](c1ccc(C2CCNCC2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](c1ccc(C2CCN(S(C)(=O)=O)CC2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
MeSO2Cl (29 μL) was added to a solution of (S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-3-[(S)-1-(4-piperidin-4-yl-phenyl)-ethyl]-[1,3]oxazinan-2-one (150 mg) and triethylamine (100 μL) in dichloromethane (3 mL) at room temperature. After stirring the solution at room temperature overnight, more dichloromethane was added and the resulting solution was washed with aqueous NaHCO3 solution, water, and brine. The organic solution was then dried (MgSO4) and concentrated. The residue was purified by HPLC on reversed phase (MeCN/H2O/NH3) to afford the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:10][CH2:11][C@H:12]([O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[CH2:13][N:14]1[CH2:18][CH2:17][CH2:16][C@H:15]1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[C:22]([F:27])[CH:21]=1)[CH3:9].[CH2:36]([Sn](CCCC)(CCCC)C=C)[CH2:37]CC>O1CCOCC1>[Si:29]([O:28][C@@H:12]([CH2:11][O:10][C@@H:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH:36]=[CH2:37])[CH3:9])[CH2:13][N:14]1[CH2:18][CH2:17][CH2:16][C@H:15]1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[C:22]([F:27])[CH:21]=1)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1ccc(C[C@@H]2CCCN2C[C@H](CO[C@H](C)c2ccccc2Br)O[Si](C)(C)C(C)(C)C)cc1F
Solvent: C1COCCO1
Product: C=Cc1ccccc1[C@@H](C)OC[C@@H](CN1CCC[C@H]1Cc1ccc(C)c(F)c1)O[Si](C)(C)C(C)(C)C
Temperature: 100 °C
Reaction time: 16 h
Yield: 78 %

Procedure:
(2S)-1-[(2R)-3-[(1R)-1-(2-Bromophenyl)ethoxy]-2-{[tert-butyl(dimethyl)silyl]oxy}propyl]-2-(3-fluoro-4-methylbenzyl)pyrrolidine (1712 mg, 3.03 mmol), which had been obtained in Example 180 (180b), was dissolved in 1,4-dioxane (30 mL), added with tributyl(vinyl) tin (1.33 mL, 4.55 mL) and tetrakistriphenyl phosphine palladium (347 mg, 0.30 mmol), and stirred for 16 hours at 100° C. After cooling the reaction solution to room temperature, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (n-hexane/ethyl acetate=4/1) and basic silica gel column chromatography (n-hexane/ethyl acetate=4/1) to give the title compound as a colorless oily substance (1210 mg, yield 78%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[NH:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14].[H-].[Na+].I[CH3:28]>CN(C=O)C.CCOCC>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[N:12]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH3:28]
Reactant: COC(=O)c1cc(Br)cc(C)c1NS(=O)(=O)c1ccc(OC)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)cc(C)c1N(C)S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.6 %

Procedure:
To a solution of 5.00 g (0.012 mol) of 5-bromo-2-(4-methoxy-benzenesulfonylamino)-3-methyl-benzoic acid methyl ester (U.S. Pat. No. 5,776,961) in 40 mL of DMF was added 0.604 g (0.015 mol) of 60% sodium hydride. The resulting mixture was stirred at room temperature foe 0.5 h and then 1.2 ml (0.018 mol) of iodomethane was added. The reaction was then stirred for 15 h and then diluted with ether. The organics were washed with water, dried over MgSO4, filtered and concentrated in vacuo. The residue was triturated with ether and the resulting white solid was collected by filtration and dried in vacuo to provide 4.45 g (86%) of the N-methyl sulfonamide. Electrospray Mass Spec 429.8 (M+H)+
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:15])[CH2:7]2.[Cl:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8]3[C:3]=2[CH2:4][CH2:5][N:6]([CH3:15])[CH2:7]3)=[CH:19][CH:18]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CN1CCc2c(Br)ccc([N+](=O)[O-])c2C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CN1CCc2c(-c3ccc(Cl)cc3)ccc([N+](=O)[O-])c2C1

Procedure:
A mixture of 5-bromo-N-methyl-8-nitro-1,2,3,4-tetrahydroisoquinoline (4.07 g, 15 mmol), 4-chlorophenylboronic acid (3.5 g, 22.5 mmol), sodium carbonate (8.0 g, 75.5 mmol), 1,2-dimethoxyethane (60 ml), water (30 ml) and tetrakis(triphenyl-phosphine)palladium(0) (0.20 g, 0.17 mmol) was stirred at reflux for 3.5 h. Water (50 ml) was added and the mixture was extracted with ethyl acetate (100 ml). The crude mixture was recrystallized from ethanol (96%). Yield 3.62 g (80%). Mp 162-163° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:17]2[CH2:21][N:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-])=O)[CH:23]=3)[C:19](=[O:31])[CH2:18]2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCOC(C)=O.CCO.[Ni]>[NH2:28][C:24]1[CH:23]=[C:22]([N:20]2[CH2:21][CH:17]([C:11]3[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:10]=3)[CH2:18][C:19]2=[O:31])[CH:27]=[CH:26][CH:25]=1
Reactant: COc1ccc(C2CC(=O)N(c3cccc([N+](=O)[O-])c3)C2)cc1OCc1ccccc1
Agent: [Ni]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(C2CC(=O)N(c3cccc(N)c3)C2)cc1OCc1ccccc1
Reaction time: 10 h

Procedure:
To a solution of 4-(3-benzyloxy-4-methoxyphenyl)-1-(3-nitrophenyl)-pyrrolidin-2-one (100 mg) in EtOAc/EtOH (2 mL, 1:1) was added Raney Ni. The mixture was then put under vacuum and recharged with H2. The mixture was stirred under H2 for 10 h. After filtration, concentration gave crude product.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]3[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=3[N:9]=[CH:10][N:11]=2)[CH:3]=[N:2]1.[C:23]([CH:25]=[C:26]1[CH2:29][CH:28]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:27]1)#[N:24].N12CCCN=C1CCCCC2>C(#N)C>[C:23]([CH2:25][C:26]1([N:1]2[CH:5]=[C:4]([C:6]3[C:7]4[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=4[N:9]=[CH:10][N:11]=3)[CH:3]=[N:2]2)[CH2:29][CH:28]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:27]1)#[N:24]
Reactant: CCOC(=O)C1CC(=CC#N)C1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)C1CC(CC#N)(n2cc(-c3ncnc4c3ccn4COCC[Si](C)(C)C)cn2)C1
Temperature: 25 °C
Reaction time: 136 h

Procedure:
To a solution of 4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (5.23 g, 16.6 mmol) and ethyl 3-(cyanomethylene)cyclobutanecarboxylate (prepared in Step 4) in acetonitrile (40 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (2.48 mL, 16.6 mmol). The mixture was stirred for 136 hours at room temperature. The solvent was removed in vacuo. Flash column chromatography, eluting with a gradient of 50-90% ethyl acetate in hexanes afforded product as a mixture of cis- and trans-isomers (4.53 g, 52% over the two steps).
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:8][C:9]([CH3:13])([CH3:12])[CH2:10]O>C1(C)C=CC=CC=1>[CH3:10][C:9]1([CH3:13])[NH:8][C:1]2([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[O:7][CH2:12]1
Reactant: CC(C)(N)CO
Reactant: O=C1CCCCC1
Solvent: Cc1ccccc1
Product: CC1(C)COC2(CCCCC2)N1
Temperature: 25 °C
Yield: 81.2 %

Procedure:
Into a solution of 45 g (460 mmol) of cyclohexanone in 300 mL of toluene is added 35.6 g (400 mmol) of 2-amino-2,2-dimethylethanol. The reaction mixture is then heated to reflux and the by-product water is collected by a Dean-Stark trap. After 16 hours of heating at reflux, the reaction mixture is allowed to cool to ambient temperature and is then concentrated under vacuum to give 55 g of a yellow liquid. The product, identified by mass spectroscopy (m/z=169) is obtained in an 81.4% yield. The structure is confirmed by 1Hnmr.