Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][S:8]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])[C:14]2=O)(=[O:10])=[O:9].[N+:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][NH2:32])([O-:24])=[O:23]>Cl.C(O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][S:8]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])[C:14]2=[N:32][NH:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[N+:22]([O-:24])=[O:23])(=[O:10])=[O:9]
Reactant: NNc1ccccc1[N+](=O)[O-]
Reactant: O=C1Nc2ccc(S(=O)(=O)NCc3ccco3)cc2C1=O
Agent: Cl
Solvent: CCO
Product: O=C1Nc2ccc(S(=O)(=O)NCc3ccco3)cc2C1=NNc1ccccc1[N+](=O)[O-]
Temperature: 120 °C

Procedure:
A mixture of rpm161 (0.040 g, 0.114 mmol) 2-nitrophenylhydrazine (0.021 g, 0.126 mmol, 1.1 eq) and HCl (aq 4 M, 2 drops) in ethanol (3 mL) was heated in the CEM microwave at 120° C. for 15 min. After cooling to room temperature, pure product rpm168 was collected as an orange precipitate by filtration and dried in vacuo. The pure compound rpm168 was obtained without further purification (0.048 g, 0.099 mmol, 86%). MS (API-ES): m/z 459 (M+NH4)+; HRMS (API-ES) m/z Found: 459.1082 (M+NH4)+.
Reaction SMILES: [N+:1]([CH:4](Br)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([O-])=O.[N+:12](C1C=CC=CC=1C=O)([O-:14])=[O:13].[C:23]1(=[O:33])N[C:26](=[O:28])[C:25]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:24]12.[K]>>[N+:12]([C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=1)[CH2:4][N:1]1[C:26](=[O:28])[C:25]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:24]2[C:23]1=[O:33])([O-:14])=[O:13]
Reactant: O=[N+]([O-])C(Br)c1ccccc1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Agent: [K]
Product: O=C1c2ccccc2C(=O)N1Cc1cccc([N+](=O)[O-])c1

Procedure:
Nitrobenzylbromide is derived from nitrobenzaldehyde, which is then reacted with potassium phthalimide to obtain N-(m-nitrobenzyl)-phthalimide, and m-aminobenzylamine is produced with an yield of about 20% by a two-step reduction reaction (N. Kornblum et al, J. Am. Chem. Soc., 71, 2137 (1949)).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[CH:9]=[CH:10][C:11]3[C:12]4[N:26](COCC[Si](C)(C)C)[N:25]=[CH:24][C:13]=4[C:14](=[O:23])[N:15]([CH2:18][C:19]([F:22])([F:21])[F:20])[C:16]=3[CH:17]=2)[CH:2]=1.FC(F)(F)CN1C2C3C=CC=CC=3NC(=O)C=2CN1COCC[Si](C)(C)C.[ClH:62]>O1CCOCC1>[ClH:62].[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[CH:9]=[CH:10][C:11]3[C:12]4[C:13](=[CH:24][NH:25][N:26]=4)[C:14](=[O:23])[N:15]([CH2:18][C:19]([F:20])([F:21])[F:22])[C:16]=3[CH:17]=2)[CH:2]=1
Reactant: C[Si](C)(C)CCOCn1ncc2c(=O)n(CC(F)(F)F)c3cc(Oc4cccnc4)ccc3c21
Agent: C[Si](C)(C)CCOCN1Cc2c(c3ccccc3[nH]c2=O)N1CC(F)(F)F
Agent: Cl
Solvent: C1COCCO1
Product: O=c1c2c[nH]nc2c2ccc(Oc3cccnc3)cc2n1CC(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 58 %

Procedure:
A suspension of 7-(pyrid-3-yloxy)-5-(2,2,2-trifluoroethyl)-1-{[2-(trimethylsilyl)ethoxy]-methyl}-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one and (2,2,2-trifluoroethyl)-2-{[2-(trimethylsilyl)ethoxy]methyl}-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one (0.19 g, 0.39 mmol) in 10 mL of anhydrous hydrogen chloride dissolved in dioxane (4M) is stirred at room temperature for 18 hours. The suspension is filtered and the solid is washed with DCM and then purified by flash chromatography on a C18 reverse phase (H2O/MeCN: 100/0 to 0/100). The gum obtained is dissolved in molar hydrochloric acid solution and then concentrated to dryness to give 78 mg of a white powder (1.2 hydrochloride, 1.15 H2O; yield: 58%).
Reaction SMILES: Cl.[F:2][C:3]([F:25])([F:24])[C:4]1[CH:23]=[CH:22][CH:21]=[CH:20][C:5]=1[CH:6]([O:15][CH:16]1[CH2:19][NH:18][CH2:17]1)[C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=1.[N-:26]=[C:27]=[O:28]>>[F:25][C:3]([F:2])([F:24])[C:4]1[CH:23]=[CH:22][CH:21]=[CH:20][C:5]=1[CH:6]([O:15][CH:16]1[CH2:19][N:18]([C:27]([NH:26][CH2:3][C:4]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:5]=2)=[O:28])[CH2:17]1)[C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=1
Reactant: CSc1ccc(C(OC2CNC2)c2ccccc2C(F)(F)F)cc1
Reactant: [N-]=C=O
Agent: Cl
Product: CSc1ccc(C(OC2CN(C(=O)NCc3ccccc3)C2)c2ccccc2C(F)(F)F)cc1

Procedure:
This material was prepared from 3-[2-trifluoromethyl-4′-(methylthio)benzhydryloxy]azetidine hydrochloride (118) and the corresponding isocyanate using the procedure described for compound (10).
Reaction SMILES: [Li+].[CH3:2]C([N-]C(C)C)C.[Si:9]([O:16][C@@H:17]1[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@H:19]([C:29]([O:31][CH3:32])=[O:30])[CH2:18]1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].CI>C1COCC1.CCOCC>[Si:9]([O:16][C@@H:17]1[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[C:19]([CH3:2])([C:29]([O:31][CH3:32])=[O:30])[CH2:18]1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:10])[CH3:11]
Reactant: COC(=O)[C@@H]1C[C@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOCC
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C1(C)C[C@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Reaction time: 0.08 h
Yield: 127.2 %

Procedure:
LDA (2M in Heptane/THF/ethylbenzene, 48.5 ml, 97 mmol) was mixed with 100 ml THF at −78° C. and stirred for 5 mins. (2S,4S)-1-tert-butyl 2-methyl 4-(tert-butyldimethylsilyloxy)pyrrolidine-1,2-dicarboxylate (14 g, 38.92 mmol) in 80 ml THF was added dropwise at −78° C. The mixture was stirred at −40° C. for 1 hr. Then the mixture was stirred at −78° C. for 10 mins. MeI (4.85 ml, 77.8 mmol) was slowly added and the mixture was stirred from −78° C. to r.t. overnight. The mixture was diluted with ether and quenched with 5% HCl. The organic layer was separated and washed with NaHCO3, brine, dried over MgSO4 and concentrated. 18.5 g of crude product as a diastereomeric mixture at C-2 was obtained.
Reaction SMILES: C([O:8][C:9]1[C:10](=[O:34])[C:11]([C:29]2[S:30][CH:31]=[CH:32][N:33]=2)=[CH:12][N:13]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[C:22]([F:27])[CH:21]=3)[C:15](=[O:28])[C:14]=12)C1C=CC=CC=1>FC(F)(F)C(O)=O>[F:27][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][C:23]=1[F:26])[CH2:19][N:16]1[CH2:17][CH2:18][N:13]2[CH:12]=[C:11]([C:29]3[S:30][CH:31]=[CH:32][N:33]=3)[C:10](=[O:34])[C:9]([OH:8])=[C:14]2[C:15]1=[O:28]
Reactant: O=C1c2c(OCc3ccccc3)c(=O)c(-c3nccs3)cn2CCN1Cc1ccc(F)c(F)c1
Solvent: O=C(O)C(F)(F)F
Product: O=C1c2c(O)c(=O)c(-c3nccs3)cn2CCN1Cc1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.3 %

Procedure:
9-Benzyloxy-2-(3,4-difluorobenzyl)-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione (35 mg) was dissolved in trifluoroacetic acid (1 ml) and the mixture was stirred at room temperature for 3 hr. Trifluoroacetic acid was evaporated under reduced pressure, toluene was added to the obtained residue and the mixture was concentrated, which operations were performed twice. Ethyl acetate was further added and the obtained solid was collected by filtration to give 2-(3,4-difluorobenzyl)-9-hydroxy-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione (14 mg).
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]2[N:13]([S:14]([C:17]3[CH:21]=[CH:20][S:19][CH:18]=3)(=[O:16])=[O:15])[CH:12]=[C:11]([CH2:22][N:23](C)[C:24](=O)OC(C)(C)C)[CH:10]=2)=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].C(OCC)(=O)C.[ClH:38]>C(OCC)(=O)C.CC(O)C>[ClH:38].[CH3:24][NH:23][CH2:22][C:11]1[CH:10]=[C:9]([C:8]2[C:3]([C:1]#[N:2])=[N:4][CH:5]=[CH:6][CH:7]=2)[N:13]([S:14]([C:17]2[CH:21]=[CH:20][S:19][CH:18]=2)(=[O:16])=[O:15])[CH:12]=1
Reactant: CN(Cc1cc(-c2cccnc2C#N)n(S(=O)(=O)c2ccsc2)c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CNCc1cc(-c2cccnc2C#N)n(S(=O)(=O)c2ccsc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
To a solution of tert-butyl {[5-(2-cyanopyridin-3-yl)-1-(3-thienylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (201 mg) in ethyl acetate (2 mL) and 2-propanol (1 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (3 mL), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from a mixed solvent of ethanol-water to give the title compound as a white solid (yield 134 mg, 78%).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:10]([N:13]2[C:18](=[O:19])[C:17]3[CH2:20][CH2:21][CH2:22][C:16]=3[NH:15][C:14]2=[O:23])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[H-].[Na+].[CH:26](Br)([CH3:28])[CH3:27]>CN(C)P(=O)(N(C)C)N(C)C>[Cl:1][C:2]1[CH:12]=[CH:11][C:10]([N:13]2[C:18](=[O:19])[C:17]3[CH2:20][CH2:21][CH2:22][C:16]=3[N:15]=[C:14]2[O:23][CH:26]([CH3:28])[CH3:27])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)c1cc(-n2c(=O)[nH]c3c(c2=O)CCC3)ccc1Cl
Reactant: CC(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)c1cc(-n2c(OC(C)C)nc3c(c2=O)CCC3)ccc1Cl

Procedure:
using ethyl 2-chloro-5-(1,2,4,5,6,7-hexahydro-2,4-dioxo-3H-cyclopenta[d]pyrimidin-3-yl)-benzoate with sodium hydride and isopropyl bromide in hexamethyl-phosphoric acid triamide there is obtained ethyl 2-chloro-5-(4,5,6,7-tetrahydro-2-isopropoxy-4-oxo-3H -cyclopenta[d]pyrimidin-3-yl)-benzoate. 1H-NMR (CDCl3, 400 MHz): 7.69 ppm (d,1H), 7.54 ppm (d,1H), 7.23 ppm (q,1H), 5.30 ppm (m,1H), 4.38 ppm (q,2H), 2.79 ppm (m,4H). 2.09 ppm (m,2H), 1.38 ppm (t,3H), 1.22 ppm (d,6H).
Reaction SMILES: O[CH:2]([C:4]1[O:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:5]=1)[CH3:3].C(Br)(Br)(Br)[Br:16]>ClCCl>[Br:16][CH:2]([C:4]1[O:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:5]=1)[CH3:3]
Reactant: CC(O)c1cc(-c2ccccn2)no1
Reactant: BrC(Br)(Br)Br
Solvent: ClCCl
Product: CC(Br)c1cc(-c2ccccn2)no1
Temperature: 30 °C
Reaction time: 2.5 h

Procedure:
To a mixture of (RS)-2-(5-(1-hydroxy-ethyl)-isoxazol-3-yl)-pyridine (0.9 gm), and triphenylphosphene (1.77 gm) in dichloromethane (20 ml) was added carbontetrabromide (6 gm) at 0° C. The reaction mixture was stirred at 30° C. over a period of 2.5 h. The reaction was monitored by TLC. The reaction was quenched by addition of water and layers were separated. Combined organic extract was washed with brine and evaporated under vacuum to provide the 1.7 gm crude mass which was purified by using silica gel column chromatography to provide title compound in 0.8 gm quantity (65%).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=O)=[N:7][CH:8]=1.[CH2:20]([O:22][C:23]([C:25]1[CH:26]=[N:27][C:28]2[C:33]([CH:34]=1)=[CH:32][CH:31]=[C:30]([NH2:35])[CH:29]=2)=[O:24])[CH3:21].C(N(C(C)C)CC)(C)C>S(Cl)(Cl)=O.ClCCCl>[CH2:20]([O:22][C:23]([C:25]1[CH:26]=[N:27][C:28]2[C:33]([CH:34]=1)=[CH:32][CH:31]=[C:30]([NH:35][C:11](=[O:13])[C:10]1[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=1[C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:19])[F:18])=[CH:8][N:7]=1)[CH:29]=2)=[O:24])[CH3:21]
Reactant: O=C(O)c1ccccc1-c1ccc(C(F)(F)F)cn1
Reactant: CCOC(=O)c1cnc2cc(N)ccc2c1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cn3)ccc2c1
Reaction time: 4 h
Yield: 84.1 %

Procedure:
2-(5-Trifluoromethyl-pyridin-2-yl)-benzoic acid (325 mg, 1.05 mmol) was dissolved in 15 ml of thionyl chloride, and the mixture heated at 60 C. After 4 h, the volatiles were removed under vacuum, the residue combined with 7-amino-quinoline-3-carboxylic acid ethyl ester (100 mg, 0.46 mmol), dissolved in 1,2-dichloroethane (15 ml), and diisopropylethylamine (300 mg, 2.31 mmol) added. After heating at reflux for 48 h, the reaction mixture was washed with 1N HCl, dried (magnesium sulfate), filtered, and concentrated under vacuum. The resulting residue was purified by silica gel chromatography eluting with 50% ethyl acetate in hexanes to provide 180 mg (85%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:11]([OH:12])=[C:10]([OH:13])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:19])[C:5]([C:16]([OH:18])=[O:17])=[CH:6][N:7]2[CH2:14][CH3:15].[C:20]([O-:23])([O-])=O.[K+].[K+].Cl[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1>CN(C)C=O>[Cl:1][C:2]1[C:11]([O:12][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)=[C:10]([O:13][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[CH:9]=[C:8]2[C:3]=1[C:4](=[O:19])[C:5]([C:16]([O:18][CH2:4][C:3]1[CH:8]=[CH:9][C:10]([O:23][CH3:20])=[CH:11][CH:2]=1)=[O:17])=[CH:6][N:7]2[CH2:14][CH3:15]
Reactant: COc1ccc(CCl)cc1
Reactant: O=C([O-])[O-]
Reactant: CCn1cc(C(=O)O)c(=O)c2c(Cl)c(O)c(O)cc21
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1cc(C(=O)OCc2ccc(OC)cc2)c(=O)c2c(Cl)c(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)cc21
Temperature: 90 °C
Yield: 96 %

Procedure:
To a red suspension of 5-chloro-1-ethyl-6,7-dihydroxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (12.2 g, 43.0 mmol), K2CO3 (23.78 g, 172 mmol) and KI (0.714 g, 4.30 mmol) in N,N-Dimethylformamide (DMF) (200 mL) at r.t. was added 1-(chloromethyl)-4-methoxybenzene (19.26 mL, 142 mmol). The mixture was heated at 90° C. for 4 h. After cooling, the mixture was concentrated and partitioned between water (200 mL) and DCM (200 mL), and extracted with DCM (150 mL) twice. The organic layers were combined, dried and concentrated. The crude product was purified twice through column chromatography eluting with EtOAc/hexanes (0-100%) to afford pure 4-methoxybenzyl 5-chloro-1-ethyl-6,7-bis((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydroquinoline-3-carboxylate (14 g, 20.65 mmol, 48.0% yield) as a white solid. LCMS: (M+H)+: 644.1.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:13]=[C:9]2[O:10][CH2:11][CH2:12][N:8]2[N:7]=1)=O)C.[BH4-].[Li+].CO>C1COCC1>[O:10]1[CH2:11][CH2:12][N:8]2[N:7]=[C:6]([CH2:4][OH:3])[CH:13]=[C:9]12
Reactant: CCOC(=O)c1cc2n(n1)CCO2
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: OCc1cc2n(n1)CCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.6 %

Procedure:
To the stirred solution of ethyl2,3-dihydropyrazolo[5,1-b][1,3]oxazole-6-carboxylate (5.47 g, 35 mmol) of in 100 ml of THF was added 1.05 g of lithium borohydride and 1.54 g of methanol. The solution was heated at 40 C for 2.5 hour. The reaction was quenched by 1N HCl, and adjusted to pH 1.3 and stirred at room temperature for 1 hour. The reaction mixture was adjusted pH to 8 with k2CO3. The reaction mixture was extracted with ethyl acetate. The organic layer was dried over MgSO4, and concentrated to an oil and column chromatographed to give 2.68 g of the desired product (65%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([CH3:25])([CH3:24])[O:18][SiH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:26]1[C:27](=[O:41])[N:28]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[CH:29]=[C:30]([NH2:32])[CH:31]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:42](N(CC)CC)C.[CH2:49]([N:56]1[CH:60]=[C:59]([C:61](Cl)=[O:62])[CH:58]=[N:57]1)[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>ClCCl>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([CH3:25])([CH3:24])[O:18][SiH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:26]1[C:27](=[O:41])[N:28]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[CH:29]=[C:30]([NH:32][C:61]([C:59]2[CH:58]=[N:57][N:56]([CH2:49][C:50]3[CH:55]=[CH:54][C:53]([CH3:42])=[CH:52][CH:51]=3)[CH:60]=2)=[O:62])[CH:31]=1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1c(-c2cc(N)cn(COCC[Si](C)(C)C)c2=O)cc2cc(C(C)(C)O[SiH2]C(C)(C)C)ccc21
Reactant: O=C(Cl)c1cnn(Cc2ccccc2)c1
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(Cn2cc(C(=O)Nc3cc(-c4cc5cc(C(C)(C)O[SiH2]C(C)(C)C)ccc5n4C(=O)OC(C)(C)C)c(=O)n(COCC[Si](C)(C)C)c3)cn2)cc1
Temperature: 5 °C
Reaction time: 18 h

Procedure:
Intermediate (8d), 2-[5-amino-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-5-(tert-butyl-dimethyl-silanyloxymethyl)-indole-1-carboxylic acid tert-butyl ester, (600 mg, 1 mmol) was stirred in dichloromethane (50 mL) at RT with triethylamine (202 mg, 0.278 mL, 2 mmol). The reaction mixture was cooled to 5° C. and then a solution of 1-Benzyl-1H-pyrazole-4-carbonyl chloride (265 mg, 1.2 mmol), which had been prepared according to the protocol below, in dichloromethane (10 ml), was added drop wise. After addition the reaction was stirred at RT for 18 hrs and then the reaction mixture was washed with saturated sodium hydrogen carbonate solution (2×50 mL), brine (50 ml), dried (Na2SO4) and concentrated in vacuo. The resultant crude product was purified by flash chromatography on SiO2 eluting with hexane—50% ethyl acetate/hexane (gradient) to afford the desired compound as a pale green foam, 750 mg, 96%.
Reaction SMILES: CS[C:3]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[CH:4][N+:5]([O-:7])=[O:6].[NH2:14][NH2:15]>CCO>[N+:5]([CH:4]=[C:3]([NH:14][NH2:15])[N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)([O-:7])=[O:6]
Reactant: CSC(=C[N+](=O)[O-])N1CCCCC1
Reactant: NN
Solvent: CCO
Product: NNC(=C[N+](=O)[O-])N1CCCCC1

Procedure:
1-(1-Methylsulfanyl-2-nitro-vinyl)-piperidine (WO 2000016766, 202 mg, 1.00 mmol) was reacted with hydrazine (30 μL, 1.0 mmol) in EtOH to afford (2-nitro-1-piperidin-1-yl-vinyl)-hydrazine and which was converted to 4-nitro-3-piperidin-1-yl-pyridazine following procedures analogous to literature methods (Tett. Lett. 41, 3619, (1977)).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.[CH3:9][N:10]([CH2:15][C:16]1[C:24]2[C:19](=[N:20][CH:21]=[CH:22][CH:23]=2)[N:18]([CH3:25])[CH:17]=1)[C:11](=[O:14])[CH:12]=[CH2:13].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CCN(C(C)C)C(C)C>C(#N)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[NH2:1][C:2]1[N:7]=[CH:6][C:5](/[CH:13]=[CH:12]/[C:11]([N:10]([CH3:9])[CH2:15][C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH3:25])[CH:17]=2)=[O:14])=[CH:4][N:3]=1
Reactant: C=CC(=O)N(C)Cc1cn(C)c2ncccc12
Reactant: Nc1ncc(Br)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: CN(Cc1cn(C)c2ncccc12)C(=O)/C=C/c1cnc(N)nc1
Temperature: 25 °C
Yield: 20 %

Procedure:
A solution of 2-amino-5-bromopyrimidine (0.27 g, 1.55 mmole), N-methyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)acrylamide (0.5 g, 2.33 mmole), Pd(OAc)2 (0.037 g, 0.163 mmole), P(o-tolyl)3 (0.085 g, 0.28 mmole), and (i-Pr)2NEt (0.42 mL, 2.33 mmole) in propionitrile (20 mL) was degassed then heated to reflux. After 18 hr the mixture was cooled to RT and concentrated. Flash chromatography on silica gel (10% MeOH/CH2Cl2) gave the title compound (0.100 g, 18%): MS (ES) m/e 363 (M+H)+.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[O:24][C:25](=[O:27])[CH3:26])[CH2:6]1)(=[O:3])[CH3:2].CO.CC[O:32]CC>C(O)(=O)C.O.[O-2].[Cr+6].[O-2].[O-2]>[C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][C:9](=[O:32])[C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[O:24][C:25](=[O:27])[CH3:26])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CCOCC
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H](OC(C)=O)[C@@]4(C)CC[C@@H]32)C1
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC(=O)[C@H]3[C@@H]4CC[C@H](OC(C)=O)[C@@]4(C)CC[C@@H]32)C1
Temperature: 55 °C
Yield: 20 %

Procedure:
37.4 g (0.1 mol) 3β,17β-diacetoxyandrost-5-ene (Steraloids A7850) in 400 ml glacial acetic acid was reacted with 30.06 g (0.3 mol) chromium(VI) oxide (Aldrich 23,265-3) dissolved in 20 ml H2O and 20 ml glacial acetic acid by the method of Butenandt (op. cit.). The CrO3 solution was added dropwise over 4 hours to the 3β,17β-diacetoxyandrost-5-ene solution while maintaining the temperature at 55° C. At the end of that time methanol was added to the reaction mixture in order to decompose any unreacted CrO3, followed by aqueous salt solution and ether. Evaporation of the ether yielded 7.8 g (20% yield) of crude III. Crystallization from 95% EtOH yielded (III) m.p. 214°-215° C. [218°-219° C., Butenandt, op. cit.; 224°-225° C. (from methanol), Pearson et al., J. Chem. Soc. Perkin Trans., I, 267-273 (1985 )] DSC peak 191°-224° C., max at 220° C. Normal phase tlc: EtOAC-cyclohexane-EtOH (45:45:10), Rf=0.86. IR bands: 1737, 1666 cm-1, (Pearson, op. cit. 1728, 1668).
Reaction SMILES: [CH2:1]([O:16][C:17]1[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=1)[C:20]([O:22]C)=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[OH-].[Na+].Cl.O>O1CCCC1.C(O)C>[CH2:1]([O:16][C:17]1[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=1)[C:20]([OH:22])=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCCCCCCCCCOc1cccc(C(=O)OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCCCCCCOc1cccc(C(=O)O)c1
Temperature: 70 °C
Reaction time: 14 h
Yield: 98.8 %

Procedure:
Compound 1 (2.0 g) was dissolved in tetrahydrofuran (9.0 mL) and ethanol (9.0 mL). Thereto, 5 N aqueous sodium hydroxide solution (2.2 mL) was added, followed by stirring at 70° C. for 14 hours. To the reaction solution, 5 N hydrochloric acid (2.2 mL) and water (18 mL) were added and cooled to 40° C. The obtained solid was filtered and dried under reduced pressure to obtain the title compound (1.9 g) having the following physical property values.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1)=[O:6].C(N(CC)CC)C.[F:29][C:30]1[CH:31]=[C:32]([S:37](Cl)(=[O:39])=[O:38])[CH:33]=[CH:34][C:35]=1[F:36]>C(Cl)Cl>[F:29][C:30]1[CH:31]=[C:32]([S:37]([NH:3][CH:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:5]([O:7][C@@H:8]2[CH:13]3[CH2:12][CH2:11][N:10]([CH2:15][CH2:14]3)[CH2:9]2)=[O:6])(=[O:38])=[O:39])[CH:33]=[CH:34][C:35]=1[F:36]
Reactant: NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Reactant: O=S(=O)(Cl)c1ccc(F)c(F)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O[C@H]1CN2CCC1CC2)C(NS(=O)(=O)c1ccc(F)c(F)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 27.8 %

Procedure:
(R)-quinuclidin-3-yl 2-amino-2-phenylacetate dihydrochloride (I25) (110 mg, 0.33 mmol) was suspended in DCM (4 ml), and triethylamine (121 μl, 1.65 mmol) was added obtaining a solution. 3,4-difluorobenzene-1-sulfonyl chloride (53.1 μl, 0.40 mmol) was added, and the reaction was stirred at RT for 3 hours. The reaction was diluted with DCM and washed with water and brine. The organic phase was dried over Na2SO4, filtered and evaporated to dryness. The residue was triturated with Et2O to obtain (R)-quinuclidin-3-yl 2-(3,4-difluorophenylsulfonamido)-2-phenylacetate (40 mg; 28% yield), which was used as such in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][C:9]=1[NH2:10])=[O:4].[CH:17]([CH:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH2:21][CH2:20]1)=O.C([Sn](Cl)(Cl)CCCC)CCC.C1([SiH3])C=CC=CC=1>C1COCC1.CCOC(C)=O>[CH2:28]([O:27][C:25]([N:22]1[CH2:23][CH2:24][CH:19]([CH2:17][NH:10][C:9]2[CH:8]=[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:6][C:5]=2[C:3]([O:2][CH3:1])=[O:4])[CH2:20][CH2:21]1)=[O:26])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N
Reactant: O=CC1CCN(C(=O)OCc2ccccc2)CC1
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1sc(-c2ccccc2)cc1NCC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 49.6 %

Procedure:
A suspension of 3-amino-5-phenyl-thiophene-2-carboxylic acid methyl ester (0.70 g, 3 mmol) and 4-formyl N-Cbz-piperidine (0.74 g, 3 mmol) in THF (1.2 mL) was treated with dibutyltin dichloride (46 mg, 0.15 mol) followed by phenylsilane (0.41 mL, 3.3 mmol). The mixture was stirred for 2 days at room temperature. The solvent was then evaporated and the residue was purified by silica gel column chromatography using CH2Cl2:hexanes:EtOAc as eluent to provide 4-[(2-Methoxycarbonyl-5-phenyl-thiophen-3-ylamino)-methyl]-piperidine-1-carboxylic acid-benzyl ester (0.6906 g, 50% yield).