Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH:8]([N:9]2C(=O)C3=CC=CC=C3C2=O)[CH2:7][CH2:6][C:5]2[CH:20]=[CH:21][CH:22]=[CH:23][C:4]=2[N:3]1[CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].O.NN>C(O)C>[NH2:9][CH:8]1[CH2:7][CH2:6][C:5]2[CH:20]=[CH:21][CH:22]=[CH:23][C:4]=2[N:3]([CH2:24][C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])[C:2]1=[O:1]
Reactant: CC(C)(C)OC(=O)CN1C(=O)C(N2C(=O)c3ccccc3C2=O)CCc2ccccc21
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)CN1C(=O)C(N)CCc2ccccc21
Yield: 86.9 %

Procedure:
To 100 ml of ethanol is added 10 g of tert-butyl 2-oxo-3-phthalimido-2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetate, and 5 g of hydrazine hydrate is added to the mixture, followed by refluxing for 2 hours. The reaction mixture is concentrated under reduced pressure, and 300 ml of water is added to the residue, followed by extraction with 200 ml of ethyl acetate. The extract is washed with 1N aqueous sodium hydroxide and water, successively, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crystals, which separate out, are treated with a mixture of ether and petroleum ether and collected by filtration to give 6 g of tert-butyl 3-amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetate as colorless prisms. m.p. 121°-122° C.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([CH:10](O)[CH2:11][C:12]2[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:13]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CS(Cl)(=O)=O.N12CCCN=C1CCCCC2>O1CCCC1>[C:1]([C:5]1[N:6]=[C:7](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:13]=2)[S:8][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(CC(O)c2nc(C(C)(C)C)cs2)ccn1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cc(/C=C/c2nc(C(C)(C)C)cs2)ccn1
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 71.7 %

Procedure:
The tert-butyl N-(4-{2-[4-(tert-butyl)-1,3-thiazol-2-yl]-2-hydroxyethyl}-2-pyridyl)carbamate (1.80 g, 4.77 mmol) obtained in (C) was dissolved in anhydrous tetrahydrofuran (20 ml), added with triethylamine (2.33 ml, 16.7 mmol) and methanesulfonyl chloride (738 μl, 9.54 mmol), and stirred at 0° C. for 3.5 hours. After insoluble solids were removed, the reaction mixture was washed with tetrahydrofuran, and the solvent was evaporated under reduced pressure. The residue was dissolved in toluene (30 ml), added with 1,8-diazabicyclo[5.4.0]undec-7-ene (1.07 ml, 7.15 mmol), and refluxed by heating for 1 hour. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1→2:1, v/v) to obtain the title compound (1.23 g, 72%).
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[C:9]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=4)=[CH:15][C:14]=3[O:25][CH3:26])[N:10]=[CH:11][C:6]=2[CH:5]=[CH:4][N:3]=1.[O:27]1[CH2:32][CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH2:29][CH2:28]1>>[O:27]1[CH2:28][CH:29]=[C:30]([C:2]2[C:7]3[N:8]=[C:9]([NH:12][C:13]4[CH:18]=[CH:17][C:16]([C:19]5[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=5)=[CH:15][C:14]=4[O:25][CH3:26])[N:10]=[CH:11][C:6]=3[CH:5]=[CH:4][N:3]=2)[CH2:31][CH2:32]1
Reactant: COc1cc(-c2cnn(C)c2)ccc1Nc1ncc2ccnc(Cl)c2n1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Product: COc1cc(-c2cnn(C)c2)ccc1Nc1ncc2ccnc(C3=CCOCC3)c2n1

Procedure:
The title compound was prepared according to the method described for Example 91 using 8-chloro-N-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidin-2-amine (Example 94) and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH:12]2[C:10]([C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=3)([CH2:11]2)[C:9]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.[Pd]>[NH2:21][C:18]1[CH:19]=[CH:20][C:15]([C:10]23[CH2:11][CH:12]2[C:13](=[O:14])[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9]3=[O:24])=[CH:16][CH:17]=1
Reactant: O=C1C2CC2(c2ccc([N+](=O)[O-])cc2)C(=O)N1Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(C23CC2C(=O)N(Cc2ccccc2)C3=O)cc1

Procedure:
Following the procedure of Example 3, a solution of 2.0 g of 3-benzyl-1-(4-nitrophenyl)-3-azabicyclo[3.1.0]hexane-2,4-dione in 100 ml of ethanol is hydrogenated in the presence of 0.2 g of 5% palladium on carbon and worked up, affording the title compound which melts at 154°-155° C. after recrystallsation from ethanol.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:50]=[CH:49][C:9]2[N:10]([CH:43]3[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]3)[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]=[C:18]([C:23]3[C:28]([C:29]5[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=5)=[CH:27][CH:26]=[C:25]([C:36]([N:38]5[CH2:42][CH2:41][CH2:40][CH2:39]5)=[O:37])[CH:24]=3)[CH:17]=[CH:16]4)=[N:12][C:8]=2[CH:7]=1)=[O:5])C.Cl>C1COCC1.CO.[OH-].[Na+]>[CH:43]1([N:10]2[C:9]3[CH:49]=[CH:50][C:6]([C:4]([OH:5])=[O:3])=[CH:7][C:8]=3[N:12]=[C:11]2[C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]=[C:18]([C:23]2[C:28]([C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=4)=[CH:27][CH:26]=[C:25]([C:36]([N:38]4[CH2:42][CH2:41][CH2:40][CH2:39]4)=[O:37])[CH:24]=2)[CH:17]=[CH:16]3)[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48]1
Reactant: CCOC(=O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(C(=O)N5CCCC5)ccc4-c4ccc(F)cc4)ccc3c1)n2C1CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(C(=O)N5CCCC5)ccc4-c4ccc(F)cc4)ccc3c1)n2C1CCCCC1
Temperature: 50 °C
Yield: 34.4 %

Procedure:
A solution of 197 mg (0.30 mmol) Compound 549a in 3.75 mL THF, 3 mL MeOH and 0.75 mL 2 N NaOH was stirred at room temperature overnight and then heated at 50° C. for 1.5 h. After the addition of 1.5 mL 1 M HCl, the solution was evaporated to dryness and the residue was purified on HPLC to yield 66 mg yellow solid.
Reaction SMILES: C(O[C:6](=O)[NH:7][CH2:8][CH2:9][C:10](=[O:19])[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=1)(C)(C)C.[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24].[O:28]=[C:29]1[NH:38][CH:37]=[CH:36][C:35]2[N:34]=[C:33]([C:39]3[CH:46]=[CH:45][C:42](C=O)=[CH:41][CH:40]=3)[C:32]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)=[CH:31][C:30]1=2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[F:21][C:22]([F:27])([F:26])[C:23]([O-:25])=[O:24].[OH:18][C:14]1[CH:13]=[C:12]([NH:11][C:10](=[O:19])[CH2:9][CH2:8][NH2+:7][CH2:6][C:42]2[CH:41]=[CH:40][C:39]([C:33]3[C:32]([C:47]4[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=4)=[CH:31][C:30]4[C:29](=[O:28])[NH:38][CH:37]=[CH:36][C:35]=4[N:34]=3)=[CH:46][CH:45]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)NCCC(=O)Nc1cccc(O)c1
Reactant: O=Cc1ccc(-c2nc3cc[nH]c(=O)c3cc2-c2ccccc2)cc1
Reactant: O=C(O)C(F)(F)F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(CC[NH2+]Cc1ccc(-c2nc3cc[nH]c(=O)c3cc2-c2ccccc2)cc1)Nc1cccc(O)c1
Product: O=C([O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of [2-(3-hydroxy-phenylcarbamoyl)-ethyl]-carbamic acid tert-butyl ester (4-3) (100 mg, 0.36 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (1 mL). The suspension immediately turned into clear solution and was stirred at room temperature for 1 hr. The volatile solvents were removed by rotovap evaporation and the oil residue was further dried by vacuum pump over night. The oil residue was re-solubilized in dichloromethane (1 mL) and de-salted with triethylamine (1 mL). After the resulting solution was stirred at room temperature for 1 hr, 4-(5-oxo-3-phenyl-5,6-dihydro-1,6-naphthyridin-2-yl)benzaldehyde (4-5; synthesis shown and described in Reaction Scheme V) (80 mg, 0.25 mmol) was added followed by sodium triacetoxyborohydride (159 mg, 0.75 mmol) after an additional 0.5 hr of stirring at room temperature. The final reaction mixture was stirred at room temperature overnight and then directly purified by HPLC (Phenomenx Synergi column; 20-85% acetonitrile/water+0.1% TFA) to afford the product (4-6) as bright yellow oil: 1H-NMR (500 MHz, d4-CD3OD) δ 8.64 (s, 1H), 7.53-7.48 (m, 5H), 7.30-7.28 (m, 3H), 7.24-7.23 (m, 2H), 7.17 (m, 1H), 7.12 (m, 1H), 6.96 (m, 1H), 6.87 (m, 1H), 6.55 (m, 1H), 4.28 (s, 2H), 3.34 (m, 2H), 2.83 (m, 2H); LRMS, calc'd for C30H26N4O3 (M+1), 491.57; found 491.59.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:26][O:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)C>[Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:32]([C:31]3[CH:34]=[CH:35][C:28]([O:27][CH3:26])=[CH:29][CH:30]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COc1ccc(C=O)cc1
Reactant: Nc1ncc(Cl)c(N2CCN(Cc3ccc(Cl)cc3)CC2)c1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(-c2nc3c(N4CCN(Cc5ccc(Cl)cc5)CC4)c(Cl)cnc3[nH]2)cc1
Temperature: 70 °C

Procedure:
To a mixture of 5-chloro-4-(4-(4-chlorobenzyl)piperazin-1-yl)-3-nitropyridin-2-amine (0.027 g, 0.07 mmol), and ethanol (3.0 ml) was added 4-methoxybenzaldehyde (0.014 g, 0.10 mmol) with the aid of ethanol (1 ml) followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.3 ml, 0.3 mmol). The reaction mixture was heated at 70° C. for 4.5 h, then allowed to cool to room temperature and the solvents were removed in vacuo. The residue was absorbed on silica gel and the free running powder was placed on a 10 g isolute silica column which was eluted with 30% ethyl acetate in dichloromethane, and then 2% methanol in ethyl acetate/dichloromethane (v/v; 1:1). The title compound was obtained as a white solid (0.009 g, 28%); 1H-NMR (500 MHz, DMSO-d6) 2.59 (br s, 4H, piperazine N(CH2)2), 3.56 (s, 2H, NCH2), 3.69 (br s, 4H, piperazine N(CH2)2), 3.84 (s, 3H, OCH3), 7.10 (d, J=8.86 Hz, 2H) and 8.12 (d, J=8.82 Hz, 2H) (3,5-C6H4OMe and 2,6-C6H4-Ome), 7.41 (s, 4H) (3,5-ArH and 2,6-ArH), 8.07 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.35 (s, 1H, imidazo[4,5-b]pyridine N—H);
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[NH:31][C:32]([CH:35]5[CH2:39][CH2:38][CH2:37][N:36]5[C:40](=[O:53])[CH:41]([NH:48][C:49]([O:51][CH3:52])=[O:50])[CH2:42][CH2:43][C:44]([F:47])([F:46])[F:45])=[N:33][CH:34]=4)=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)=[CH:16][N:17]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:52][O:51][C:49](=[O:50])[NH:48][CH:41]([C:40]([N:36]1[CH2:37][CH2:38][CH2:39][CH:35]1[C:32]1[NH:31][C:30]([C:27]2[CH:26]=[CH:25][C:24]([C:21]3[CH:22]=[CH:23][C:18]([C:15]4[NH:14][C:13]([CH:9]5[CH2:10][CH2:11][CH2:12][NH:8]5)=[N:17][CH:16]=4)=[CH:19][CH:20]=3)=[CH:29][CH:28]=2)=[CH:34][N:33]=1)=[O:53])[CH2:42][CH2:43][C:44]([F:46])([F:45])[F:47]
Reactant: COC(=O)NC(CCC(F)(F)F)C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(C5CCCN5C(=O)OC(C)(C)C)[nH]4)cc3)cc2)[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)NC(CCC(F)(F)F)C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(C5CCCN5)[nH]4)cc3)cc2)[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.3 %

Procedure:
To a solution of 2-[5-(4′-{2-[1-(5,5,5-trifluoro-2-methoxycarbonylamino-pentanoyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (340 mg, 0.46 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (1 mL) The reaction was stirred at room temperature for 3 hours and then thoroughly concentrated. The resulting residue was dissolved in dichloromethane and washed three times with saturated aqueous NaHCO3 solution. The organic layer was dried (MgSO4), and concentrated to give the crude free pyrrolidine (270 mg, 92%), which was clean enough to use without further purification. LCMS-ESI+: calculated for C33H36F3N7O3: 635.28; observed [M+1]+: 636.17.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[C:18]2[C:13](=[N:14][C:15](S(C)(=O)=O)=[N:16][C:17]=2[O:19][CH2:20][C@H:21]2[CH2:25][O:24][C:23]([CH3:27])([CH3:26])[O:22]2)[NH:12][N:11]=1.[F:32][C:33]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=1[OH:40]>>[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[C:18]2[C:13](=[N:14][C:15]([O:40][C:34]3[CH:35]=[CH:36][C:37]([F:39])=[CH:38][C:33]=3[F:32])=[N:16][C:17]=2[O:19][CH2:20][C@H:21]2[CH2:25][O:24][C:23]([CH3:27])([CH3:26])[O:22]2)[NH:12][N:11]=1
Reactant: CC1(C)OC[C@H](COc2nc(S(C)(=O)=O)nc3[nH]nc(-c4ccccc4Cl)c23)O1
Reactant: Oc1ccc(F)cc1F
Agent: [K+]
Agent: [OH-]
Product: CC1(C)OC[C@H](COc2nc(Oc3ccc(F)cc3F)nc3[nH]nc(-c4ccccc4Cl)c23)O1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
Powdered KOH (1.0 g) was taken up in 4 mL of 2,4-difluorophenol, and the resulting mixture was heated at 120° C. for 15 minutes. (S)-3-(2-Chloro-phenyl)-4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-6-methylsulfonyl-1H-pyrazolo[3,4-d]pyrimidine (1.34 g, 0.305 mmol) was added, and the reaction mixture was stirred for one hour at 120° C. The reaction mixture was cooled to room temperature, partitioned between water (100 mL) and EtOAc (300 ML0, and the layers were separated. The organic layer was washed three times with 2N aqueous NaOH, once with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative scale TLC (50% MeOH in methylene chloride to provide 1.395 mg of (S)-3-(2-Chloro-phenyl)-6-(2,4-difluoro-phenoxy)-4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-1H-pyrazolo[3,4-d]pyrimidine. Mass Spec. M+H=489. Mp.=70.1-75.9° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]12[CH2:15][CH:14]1[CH2:13][CH2:12][NH:11][CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:17]1[N:26]=[C:25]2[C:20]([C:21](=[O:38])[C:22]([C:35]([OH:37])=[O:36])=[CH:23][N:24]2[C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=2[F:34])=[CH:19][C:18]=1[F:39].[C:40](#N)[CH3:41]>>[C:1]([O:5][C:6]([NH:8][C:9]12[CH2:15][CH:14]1[CH2:13][CH2:12][N:11]([C:17]1[N:26]=[C:25]3[C:20]([C:21](=[O:38])[C:22]([C:35]([O:37][CH2:40][CH3:41])=[O:36])=[CH:23][N:24]3[C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=3[F:34])=[CH:19][C:18]=1[F:39])[CH2:10]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1cn(-c2ccc(F)cc2F)c2nc(Cl)c(F)cc2c1=O
Reactant: CC#N
Reactant: CC(C)(C)OC(=O)NC12CNCCC1C2
Product: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc(N3CCC4CC4(NC(=O)OC(C)(C)C)C3)c(F)cc2c1=O
Yield: 88 %

Procedure:
A solution of 1-tert-butoxycarbonylamino-3-azabicyclo[4.1.0]heptane (200 mg, 0.94 mmol) and the ethyl ester of 7-chloro-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (327 mg, 0.85 mmol) in acetonitrile (12 ml) was heated at reflux for 3 hours. Solvent was removed in vacuo, and the residue was chromatographed on silica gel (eluant: 50% ethyl acetate/hexane) to afford the title product as an off-white solid (423 mg, 0.758 mmol, 88% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[NH:14][CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1.[H-].[Na+].[CH3:21][SiH2:22][CH3:23].P([O-])([O-])([O-])=O.CN([CH:32]=[O:33])C>>[Si:22]([O:3][CH2:2][CH2:1][O:33][CH2:32][CH2:8][CH2:9][CH2:10][CH2:12][CH2:13][N:14]1[CH2:13][C@@H:12]([C:10]2[CH:9]=[CH:8][C:6]3[O:7][C:2]([CH3:18])([CH3:1])[O:3][CH2:4][C:5]=3[CH:11]=2)[O:16][C:15]1=[O:17])([C:5]([CH3:6])([CH3:4])[CH3:11])([CH3:23])[CH3:21]
Reactant: CN(C)C=O
Reactant: C[SiH2]C
Reactant: CC1(C)OCc2cc([C@@H]3CNC(=O)O3)ccc2O1
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Na+]
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCO[Si](C)(C)C(C)(C)C)C(=O)O3)ccc2O1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
A solution of (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (0.83 g) in DMF (20 ml) was treated with sodium hydride (60% dispersion in mineral oil, 0.20 g) and the mixture stirred under nitrogen at 20° C. for 30 min. A solution of {2-[(6-bromohexyl)oxy]ethoxy}tert-butyl)dimethylsilane (1.47 g) in DMF (4 ml) was added and the mixture stirred at 20° C. for 90 min. Phosphate buffer (20 ml, pH6.5) was added, before partitioning between EtOAc (50 ml) and water (50 ml). The layers were separated and the aqueous layer re-extracted with EtOAc (3×30 ml). The combined organic layer was washed with water (3×50 ml) and dried over Na2SO4 before filtering. Solvent evaporation in vacuo gave a residue which was purified by flash chromatography on silica. Elution with EtOAc-cyclohexane (1:1) followed by solvent evaporation in vacuo gave the title compound (0.84 g). LCMS RT=4.11 min, ES+ve 507 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([F:11])[C:3]=1[OH:12].[CH3:13]N=NNC1C=CC(C)=CC=1>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([F:11])[C:3]=1[O:12][CH3:13]
Reactant: O=[N+]([O-])c1cc(F)c(O)c(F)c1
Reactant: CN=NNc1ccc(C)cc1
Solvent: c1ccccc1
Product: COc1c(F)cc([N+](=O)[O-])cc1F

Procedure:
Dissolve 2,6-difluoro-4-nitrophenol (J. Heterocyclic. Chem. 1976, 13, 1253; 10 g, 57.11 mmol) in 300 mL of benzene. Add dropwise a solution of 1-methyl-3-p-tolyltriazene (9.37 g, 62.82 mmol, 1.1 eq.) in benzene (150 mL). After TLC indicates absence of starting material, transfer the reaction mixture to a separator funnel and wash with 1N HCl, then saturated NaHCO3, and then water. Dry the organic layer over MgSO4, filter, and remove the solvent to give a residue. Crystallize the residue from MeOH/water to give 1,3-difluoro-2-methoxy-5-nitrobenzene as white needles: 1H NMR (300 MHz, CDCl3): 4.25 (t, 3H), 7.80 (d, 2H).
Reaction SMILES: [CH3:1][N:2]([CH3:22])[S:3]([C:6]1[CH:7]=[CH:8][C:9]2[O:15][C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[NH:12][C:11](=O)[C:10]=2[CH:21]=1)(=[O:5])=[O:4].B.CSC>O1CCCC1.CO>[CH3:1][N:2]([CH3:22])[S:3]([C:6]1[CH:7]=[CH:8][C:9]2[O:15][C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[NH:12][CH2:11][C:10]=2[CH:21]=1)(=[O:4])=[O:5]
Reactant: CN(C)S(=O)(=O)c1ccc2c(c1)C(=O)Nc1ccccc1O2
Agent: B
Solvent: CO
Solvent: CSC
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)c1ccc2c(c1)CNc1ccccc1O2
Reaction time: 8 h
Yield: 85.4 %

Procedure:
To 5.88 g of 10,11-dihydro-N,N-dimethyl-11-oxodibenz[b,f][1,4]oxazepine-2-sulfonamide in 5 ml of tetrahydrofuran is added 20 ml of a molar solution of borane-dimethylsulfide in tetrahydrofuran. The mixture is stirred overnight and then refluxed for 2 hours. The mixture is chilled, diluted with 10 ml of methanol and then concentrated, methanol added again and the mixture concentrated. To the mixture is added 20 ml of 2N NaOH and the mixture refluxed for 2 hours. The mixture is extracted with dichloromethane, the extract dried (MgSO4) and filtered. The filtrate is passed through a thin pad of hydrous magnesium silicate and the pad washed with dichloromethane. The filtrate is concentrated to give 4.8 g of crystals, m.p. 99°-102° C. Recrystallization from diisopropylether-dichloromethane gives 3.96 g of crystals, m.p. 109°-110° C. Mass Spectrum (FAB) 305(M+H). Anal. Calc'd for C15H16N2O3S: C,59.2; H,5.3; N,9.2; S,10.6. Found: C,57.6; H,5.2; N,8.9; S,10.1.
Reaction SMILES: C(O)(C)C.[Cl:5][C:6]1[N:11]=[C:10]([C:12]([O:14]C)=O)[C:9]([O:16][CH3:17])=[N:8][C:7]=1[NH:18][CH2:19][CH3:20].[CH2:21]([N:23]([CH2:27][CH3:28])[CH2:24][CH2:25][NH2:26])[CH3:22]>CCOCC>[CH2:21]([N:23]([CH2:27][CH3:28])[CH2:24][CH2:25][NH:26][C:12]([C:10]1[C:9]([O:16][CH3:17])=[N:8][C:7]([NH:18][CH2:19][CH3:20])=[C:6]([Cl:5])[N:11]=1)=[O:14])[CH3:22]
Reactant: CCNc1nc(OC)c(C(=O)OC)nc1Cl
Reactant: CCN(CC)CCN
Solvent: CCOCC
Solvent: CC(C)O
Product: CCNc1nc(OC)c(C(=O)NCCN(CC)CC)nc1Cl

Procedure:
In 14 ml. of isopropyl alcohol were dissolved 1.4 g. of methyl 6-chloro-5-ethylamino-3-methoxypyrazine-2-carboxylate and 1.4 g. of N,N-diethylethylenediamine and the solution was refluxed for 4 days. After the reaction was over, the solvent was distilled off under reduced pressure from the reaction mixture and the residue obtained was applied to a silica gel column chromatography. The column was then developed using a mixture of ether and N-hexane of 1:1 volume ratio as an eluting solution. From the 1st fraction 0.7 g. of methyl 5-ethylamino-6-chloro-3-methoxypyrazine-2-carboxylate used as the starting material was recovered and from the 2nd fraction 0.7 g. of colorless plate crystals of N-(2-diethylaminoethyl)-6-chloro-5-ethylamino-3-methoxypyrazine-2-carboxamide a melting at 142° C. were obtained. The product obtained by recrystallizing the crystals from a mixture of benzene and n-hexane melted at 142° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](Cl)=[O:10])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:15][CH:14]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:19]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:16]2[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][CH:15]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Reactant: CCOC(=O)CCNc1ccc(Cl)cc1
Product: CCOC(=O)CCN(C(=O)Cc1ccc(Cl)cc1)c1ccc(Cl)cc1

Procedure:
By a procedure similar to that of example 1.115.1, starting from 4-chlorophenylacetyl chloride and ethyl N-(4-chlorophenyl)-3-aminopropionate, ethyl 3-[2-(4-chloro-phenyl)-N-(4-chlorophenyl)acetamido]-propanoate was obtained as yellowish oil.
Reaction SMILES: [Li]CCCC.CCCCCC.[CH3:12][C:13]1[CH2:14][C:15]2[C:16]([CH:25]=1)=[C:17]1[C:22](=[CH:23][CH:24]=2)[CH:21]=[CH:20][CH:19]=[CH:18]1.[Li].[Cl:27][Si:28](Cl)([CH3:30])[CH3:29]>CCOCC>[Cl:27][Si:28]([CH:14]1[C:15]2=[CH:24][CH:23]=[C:22]3[C:17]([CH:18]=[CH:19][CH:20]=[CH:21]3)=[C:16]2[CH:25]=[C:13]1[CH3:12])([CH3:30])[CH3:29]
Reactant: CC1=Cc2c(ccc3ccccc23)C1
Reactant: C[Si](C)(Cl)Cl
Agent: [Li]
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CC1=Cc2c(ccc3ccccc23)C1[Si](C)(C)Cl
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A 1.6 M n-BuLi solution in hexane (7.5 mL, 12 mmol) was added at −50° C. to a solution of 2-methyl-3H-cyclopenta[a]naphthalene (2.14 g, MW=180.25, 11.9 mmol) in 50 mL of ether. The resulting suspension was allowed to warm to room temperature and stirred for 45 min at the same temperature. Then the lithium suspension was cooled again to −70° C. and added of dichlorodimethylsilane (18 mmol, 2.2 mL). The reaction mixture was allowed to warm to room temperature and stirred overnight. The precipitate of lithium chloride was filtered, the filtrate was evaporated off to dryness and dried in vacuo. Yield 3.14 g (97%).
Reaction SMILES: [CH3:1][C:2]1[C:10]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5]>C1COCC1>[CH3:1][C:2]1[C:10]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: Cc1c(C(=O)O)cccc1N1CCOCC1
Solvent: C1CCOC1
Product: Cc1c(CO)cccc1N1CCOCC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
2-methyl-3-morpholinobenzoic acid (0.5 g, 2.26 mmol) was dissolved in dry THF (12 mL) under Nitrogen and the solution was cooled at 0° C. with an ice bath. A solution of BH3 (1M in THF, 3.39 mL, 3.39 mmol) was added dropwise and the reaction was allowed to reach rt overnight. The mixture was quenched with NH4Cl (sat. solution, 2 mL) and diluted with ethyl acetate (20 mL). The organics were separated, washed with water (10 mL) and brine (10 mL) and dried over Na2SO4. The filtered solution was evaporated under vacuum to give (2-methyl-3-morpholinophenyl)methanol as a crude oil which crystallized over 2 h (0.5 g, quantitative).