Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH:13]([CH2:15][N:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24]([O:26]CC)=[O:25])[CH2:18][CH2:17]3)[O:12][C:11]2=[O:29])=[CH:6][CH:5]=1)(=[NH:3])[NH2:2].[OH-].[Na+].O1CCOCC1>O>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:14][CH:13]([CH2:15][N:16]3[CH2:17][CH2:18][N:19]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])[CH2:20][CH2:21]3)[O:12][C:11]2=[O:29])=[CH:8][CH:9]=1)(=[NH:2])[NH2:3]
Reactant: CCOC(=O)CCN1CCN(CC2CN(c3ccc(C(=N)N)cc3)C(=O)O2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: N=C(N)c1ccc(N2CC(CN3CCN(CCC(=O)O)CC3)OC2=O)cc1
Reaction time: 5 h

Procedure:
A mixture of 1 g of ethyl 3-(4-(3-(4-amidinophenyl)-2-oxo-5-oxazolidinylmethyl)-1-piperazinyl)propionate, 0.2 g of NaOH, 8 ml of dioxane and 2 ml of water is stirred at 20° for 5 hours. After acidification and conventional work-up, 3-(4-(3-(4-amidinophenyl)-2-oxo-5oxazolidinylmethyl)-1-piperazinyl)propionic acid m.p. 269°, is obtained
Reaction SMILES: [CH:1]12[O:7][CH:6]1[CH2:5][CH2:4][N:3]([C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[CH2:2]2.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.Cl([O-])(=O)(=O)=O.[Li+].N1C=CN=C1.[C:35]([Si:39]([CH3:42])([CH3:41])Cl)([CH3:38])([CH3:37])[CH3:36]>C(#N)C.ClCCl>[Si:39]([O:7][C@@H:6]1[CH2:5][CH2:4][N:3]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:2][C@H:1]1[N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:42])[CH3:41].[Si:39]([O:7][C@H:1]1[C@H:6]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[CH2:5][CH2:4][N:3]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:2]1)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:42])[CH3:41]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C1COCCN1
Reactant: O=C(OCc1ccccc1)N1CCC2OC2C1
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CC#N
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CCN(C(=O)OCc2ccccc2)C[C@H]1N1CCOCC1
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CN(C(=O)OCc2ccccc2)CC[C@H]1N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of benzyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (prepared according to a published literature procedure: Fink, Brian, et al., WO 2005/066176, 700 mg, 3.00 mmol), morpholine (0.581 mL, 6.00 mmol), and lithium perchlorate (639 mg, 6.00 mmol) in acetonitrile (10 mL) was heated at 80° C. for 4 h. Solvent was evaporated and the crude intermediate was dissolved in dichloromethane (10 mL), imidazole (654 mg, 9.60 mmol) and tert-butyldimethylchlorosilane (1357 mg, 9.00 mmol) were added. The reaction mixture was stirred at room temperature overnight. The reaction was diluted with dichloromethane and washed with water and brine, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel using an automated ISCO system (220 g gold column, eluting with 5-30% ethyl acetate/hexanes) to give (+/−)-(3R,4R)-benzyl 4-((tert-butyldimethylsilyl)oxy)-3-morpholinopiperidine-1-carboxylate (Isomer A, 0.39 g) as a colorless oil and (+/−)-(3R,4R)-benzyl 3-((tert-butyldimethylsilyl)oxy)-4-morpholinopiperidine-1-carboxylate (Isomer B, 0.43 g) as a colorless oil. The structures were confirmed by NMR studies (1H-1D, 13C-1D, COSY, NOESY, dept-1H-13C-HSQC, 1H-13C-HMBC).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=4)[CH2:15][CH2:14]3)[CH:10]=[N:11][C:5]=2[N:4]2[CH2:28][CH2:29][CH2:30][C@@H:3]12.Cl.[CH3:32][NH:33][CH3:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[CH3:32][N:33]([CH3:34])[C:23](=[O:24])[C:22]1[CH:26]=[CH:27][C:19]([N:16]2[CH2:15][CH2:14][N:13]([CH2:12][C:9]3[CH:10]=[N:11][C:5]4[N:4]5[CH2:28][CH2:29][CH2:30][C@H:3]5[C:2](=[O:1])[NH:7][C:6]=4[CH:8]=3)[CH2:18][CH2:17]2)=[CH:20][CH:21]=1
Reactant: CNC
Reactant: O=C(O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CN(C)C(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.7 %

Procedure:
In a 1 dram vial, (S)-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzoic acid (100 mg, 0.245 mmol) was suspended in DMF (Volume: 1.227 mL) then added dimethylamine hydrochloride (24.02 mg, 0.295 mmol), HATU (140 mg, 0.368 mmol) and N-methylmorpholine (0.108 mL, 0.982 mmol). The reaction was stirred at RT overnight. The mixture was purified by prep HPLC-MS (acidic mode, 15-35%). The pH of the combined fractions was adjusted to pH=8-9 and extracted with EtOAc (3×30 ml), washed with brine, dried with MgSO4, filtered and concentrated to dryness. The residue was taken up with water/ACN (1:1), and concentrated in vacuo to provide the title compound as a fluffy white solid (21 mg, 19% yield). m.p.=99.2° C. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.85-2.04 (m, 3 H) 2.12-2.21 (m, 1 H) 2.43-2.49 (m, 4 H) 2.94 (s, 6 H) 3.14-3.23 (m, 4 H) 3.35-3.43 (m, 3 H) 3.54-3.64 (m, 1 H) 3.94-4.03 (m, 1 H) 6.92 (d, J=9.09 Hz, 2 H) 6.99 (d, J=1.77 Hz, 1 H) 7.29 (d, J=8.84 Hz, 2 H) 7.62 (d, J=1.52 Hz, 1 H) 10.44 (s, 1 H). [M+H] calc'd for C24H30N6O2, 435; found, 435.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[NH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]([CH2:16][N:17]([CH3:19])[CH3:18])[CH:13]=[CH:14][CH:15]=1>C(#N)C>[CH3:1][NH:2][C:3]([NH:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][N:17]([CH3:18])[CH3:19])[CH:11]=1)=[O:4]
Reactant: CN(C)Cc1cccc(OCCCN)c1
Reactant: CN=C=O
Solvent: CC#N
Product: CNC(=O)NCCCOc1cccc(CN(C)C)c1

Procedure:
Methyl isocyanate (0.27 ml) and 3-(3-aminopropoxy)-N,N-dimethylbenzenemethanamine (0.97 g) were stirred at room temperature in acetonitrile for 2 hours. The title compound was filtered off, washed with acetonitrile and recrystallised from ethyl acetate as colourless prisms (0.49 g) m.p. 79.5°-80°. TLC silica; methanol:0.88 ammonia (80:1) Rf 0.45.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[N:6][CH:7]=1.[N+:9]([C:12]1[N:13]=[C:14]2[N:19]([CH:20]=1)[CH2:18][CH2:17][CH:16]([CH2:21][OH:22])[O:15]2)([O-:11])=[O:10].[H-].[Na+].C(=O)=O.CC(C)=O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH2:21][CH:16]2[O:15][C:14]3=[N:13][C:12]([N+:9]([O-:11])=[O:10])=[CH:20][N:19]3[CH2:18][CH2:17]2)=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1cn2c(n1)OC(CO)CC2
Reactant: Fc1ccc(Br)cn1
Agent: O=C=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: O=[N+]([O-])c1cn2c(n1)OC(COc1ccc(Br)cn1)CC2
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 87.3 %

Procedure:
5-Bromo-2-fluoropyridine (91) (0.52 mL, 5.05 mmol) was added to a solution of oxazine alcohol 134 (see Example 2BB) (500 mg, 2.51 mmol) in anhydrous DMF (10 mL) under N2 at 0° C. The resulting mixture was treated with 60% NaH (151 mg, 3.78 mmol), then quickly degassed and resealed under N2. Further 5-bromo-2-fluoropyridine (91) (0.52 mL, 5.05 mmol) was added and the mixture was stirred at room temperature for 2.5 h, and then cooled (CO2/acetone), quenched with ice/aqueous NaHCO3 (30 mL), added to brine (100 mL) and extracted with CH2Cl2 (8×100 mL). The combined extracts were evaporated to dryness and the residue was chromatographed on silica gel. Elution with 0-1% EtOAc/CH2Cl2 firstly gave foreruns, and then further elution with 2-4% EtOAc/CH2Cl2 gave 7-{[(5-bromo-2-pyridinyl)oxy]methyl}-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (136) (778 mg, 87%) as a white solid: mp (MeOH/CH2Cl2/hexane) 182-184° C.; 1H NMR [(CD3)2SO] δ 8.30 (dd, J=2.6, 0.5 Hz, 1H), 8.07 (s, 1H), 7.95 (dd, J=8.8, 2.6 Hz, 1H), 6.91 (dd, J=8.8, 0.6 Hz, 1H), 4.90 (m, 1H), 4.58 (dd, J=12.0, 3.3 Hz, 1H), 4.52 (dd, J=12.0, 6.0 Hz, 1H), 4.17 (ddd, J=12.6, 5.8, 2.8 Hz, 1H), 4.09 (ddd, J=12.5, 11.0, 5.2 Hz, 1H), 2.34-2.26 (m, 1H), 2.23-2.11 (m, 1H). Anal. (C12H11BrN4O4) C, H, N.
Reaction SMILES: [C:1]([NH:6][N:7]=[C:8]([CH3:18])[CH2:9][CH2:10][C:11]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:12])([CH2:4][CH3:5])([CH3:3])[CH3:2].[Cl:19]Cl>>[C:1]([N:6]=[N:7][C:8]([Cl:19])([CH3:18])[CH2:9][CH2:10][C:11]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:12])([CH2:4][CH3:5])([CH3:3])[CH3:2]
Reactant: CCCCOC(=O)CCC(C)=NNC(C)(C)CC
Reactant: ClCl
Product: CCCCOC(=O)CCC(C)(Cl)N=NC(C)(C)CC
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 104 %

Procedure:
To a solution of 90 grams (0.316 moles) of butyl levulinate t-amylhydrazone in 150 mls. of petane in a 500 ml. round bottom flask was passed 10.9 grams (.154 moles) of chlorine holding the temperature at -20°C with a dry ice- isopropanol bath. The chlorine was added over 30 minutes and then the reaction was stirred an additional 15 minutes at -20°C and filtered. The filtrate was dried and the pentane evaporated leaving 46.6 grams of crude butyl 4-t-amylazo-4-chlorovalerate.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH:12]1([NH:15][C:16]([C:18]2[CH:19]=[C:20]([F:39])[C:21]([CH3:38])=[C:22]([C:24]3[CH:37]=[CH:36][C:27]([C:28]([NH:30][C:31]([CH2:34][CH3:35])([CH3:33])[CH3:32])=[O:29])=[CH:26][N:25]=3)[CH:23]=2)=[O:17])[CH2:14][CH2:13]1>C(Cl)(Cl)Cl.CO>[CH:12]1([NH:15][C:16]([C:18]2[CH:19]=[C:20]([F:39])[C:21]([CH3:38])=[C:22]([C:24]3[N+:25]([O-:9])=[CH:26][C:27]([C:28]([NH:30][C:31]([CH3:33])([CH3:32])[CH2:34][CH3:35])=[O:29])=[CH:36][CH:37]=3)[CH:23]=2)=[O:17])[CH2:14][CH2:13]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCC(C)(C)NC(=O)c1ccc(-c2cc(C(=O)NC3CC3)cc(F)c2C)nc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCC(C)(C)NC(=O)c1ccc(-c2cc(C(=O)NC3CC3)cc(F)c2C)[n+]([O-])c1
Temperature: 60 °C

Procedure:
mCPBA (57-86%, 15 mg) was added to a solution of 6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-(tert-pentyl)nicotinamide (Intermediate 32, 20 mg) in chloroform (3 ml) at 60° C. and the reaction maintained at 60° C. for 7 hrs. The reaction was allowed to cool, diluted with methanol, and passed through an aminopropyl SPE (2 g) and an SCX SPE (1.0 g). The filtrate was reduced to dryness under vacuum and the residue triturated with ether to give 6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-(1,1-dimethylpropyl)-3-pyridinecarboxamide 1-oxide as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C@@H:6]([NH2:11])[CH2:5]2.C(N(C(C)C)CC)(C)C.Cl[CH2:22][CH2:23][C:24]1[CH:32]=[C:31]([O:33][CH2:34][C@@H:35]2[CH2:39][CH2:38][CH2:37][O:36]2)[CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27].CC(C)([O-])C.[K+]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C@@H:6]([N:11]1[CH2:22][CH2:23][C:24]3[C:25](=[CH:29][CH:30]=[C:31]([O:33][CH2:34][C@@H:35]4[CH2:39][CH2:38][CH2:37][O:36]4)[CH:32]=3)[C:26]1=[O:27])[CH2:5]2
Reactant: O=C(Cl)c1ccc(OC[C@@H]2CCCO2)cc1CCCl
Reactant: N[C@@H]1Cc2ccc(Br)cc2C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C1c2ccc(OC[C@@H]3CCCO3)cc2CCN1[C@@H]1Cc2ccc(Br)cc2C1
Reaction time: 0.08 h

Procedure:
A mixture of (R)-5-bromoindan-2-ylamine (hydrochloride, 1.05 g), THF (20 ml) and diisopropylethylamine (1.0 g) was admixed with 2-(2-chloroethyl)-4-[(S)-1-(tetrahydrofuran-2-yl)methoxy]benzoyl chloride (1.28 g; from 6-[(S)-1-(tetrahydrofuran-2-yl)methoxy]-isochroman-1-one by boiling with thionyl chloride). After 5 minutes, potassium tert-butoxide (1.42 g) was added. After 12 hours, the reaction mixture was partitioned between water and ethyl acetate. The organic phase was dried over sodium sulfate and concentrated. The residue was chromatographed on silica gel (eluent: 1:1 ethyl acetate/heptane). This afforded the product with the molecular weight of 442.36 (C23H24BrNO3); MS (ESI): 442 (M+H+).
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C:2]([CH3:4])=[O:3].C(OC)(OC)OC.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:26][O:27][C:28](OC)([CH3:33])[C:29]([O:31][CH3:32])=[O:30].C1(C=CC(O)=CC=1)O>CO>[C:1]([O:6][CH3:7])(=[O:5])[C:2]([CH3:4])=[O:3].[CH3:26][O:27][C:28](=[CH2:33])[C:29]([O:31][CH3:32])=[O:30]
Reactant: COC(=O)C(C)(OC)OC
Agent: COC(=O)C(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Oc1ccc(O)cc1
Solvent: CO
Solvent: COC(OC)OC
Product: C=C(OC)C(=O)OC

Procedure:
The dimethyl acetal of methyl pyruvate was prepared using methyl pyruvate, trimethyl orthoformate, MeOH and p-toluenesulfonic acid according to the method of Wermuth (Bull. Soc. Chim. France, 732 (1964)). Methyl pyruvate dimethylacetal (50 g) p-toluenesulfonic acid (1.34 g) and hydroquinone (1.90 g) were heated in an oil bath (approx. 150° C.) and MeOH was allowed to distill off slowly (approx. 10 mL). The residue was then distilled to afford the title ester, bp approx. 50° C./20 mmHg.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([OH:17])=[CH:9][CH:8]=1)[CH3:2].[CH3:19][C:20]1[C:25]([CH2:26][CH2:27]O)=[CH:24][CH:23]=[C:22]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=2)[N:21]=1>>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([O:17][CH2:27][CH2:26][C:25]2[C:20]([CH3:19])=[N:21][C:22]([C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:36])[F:37])=[CH:31][CH:30]=3)=[CH:23][CH:24]=2)=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)CCc1ccc(O)c2ccccc12
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CCO
Product: CCOC(=O)CCc1ccc(OCCc2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)c2ccccc12

Procedure:
In analogy to the procedures described in example 4D] and 4E], 3-(4-hydroxy-naphthalen-1-yl)-propionic acid ethyl ester [Helvetica Chimica Acta (2001), 84(8), 2198-2211] was reacted with 2-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-ethanol (example 4K]) to give 3-(4-{2-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-ethoxy}-naphthalen-1-yl)-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless solid.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].C1OC1.[OH-].[K+].[CH2:17](Cl)/[CH:18]=[CH:19]/[CH2:20]Cl>C(Cl)Cl>[CH:18]([CH:19]1[CH2:20][C:2]1([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])=[CH2:17]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: ClC/C=C/CCl
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CO1
Product: C=CC1CC1(C(=O)OCC)C(=O)OCC

Procedure:
To demonstrate the versatility of the process, 16 g (0.1 mol) diethyl malonate and 62.55 g of a block copolymer of ethylene oxide and polypropylene oxide having an average molecular weight of about 13,300 (Pluronic® 127) were charged to a reactor. Methylene dichloride (100 mls.) and 11.2 g solid potassium hydroxide (90%) were added and the mixture vigorously agitated while maintaining the temperature at or below 35° C. The 1,4-dichlorobutene-2 (12.4 g; 0.1 mol) was then added over a 5 minute period. About 22% conversion to diethyl 2-vinylcyclopropane-1,1-dicarboxylate was obtained after one hour of reaction. The reaction was continued to obtain essentially complete conversion of the reactants to the desired vinylcyclopropane product.
Reaction SMILES: [CH3:1][NH:2][C:3](=O)[CH2:4][C:5]1([NH:18][CH3:19])[S:17][CH:8]2[C:9]3[N:14]([CH2:15][CH2:16][CH:7]2[CH2:6]1)[CH2:13][CH:12]=[CH:11][CH:10]=3.[H-].COCCO[Al+]OCCOC.[Na+].[H-]>>[CH3:19][NH:18][C:5]1([CH2:4][CH2:3][NH:2][CH3:1])[S:17][CH:8]2[C:9]3[N:14]([CH2:15][CH2:16][CH:7]2[CH2:6]1)[CH2:13][CH:12]=[CH:11][CH:10]=3
Reactant: CNC(=O)CC1(NC)CC2CCN3CC=CC=C3C2S1
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Product: CNCCC1(NC)CC2CCN3CC=CC=C3C2S1
Yield: 58.3 %

Procedure:
A mixture of 0.125 g (0.43 mmol) of (2RS,10bSR)-N-methyl-2-(2-methylamino-1,3,4,6,7,10b-hexahydrothieno[2,3-a]quinolizin-2-yl)acetamide and 0.51 ml (1.72 mmol) of 3.4M sodium bis(2-methoxyethoxy)aluminum hydride were reacted employing the procedure substantially described in Example 27 Step B to give 0.07 g (59%) of (2RS,10bSR)-2-methylamino-2-(2-methylaminoethyl)-1,3,4,6,7,10b-hexahydrothieno[2,3-a]quinolizine as a brown oil.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([N:12]3[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]3)[O:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>O1CCCC1.CO.C(OCC)(=O)C>[C:1]1([C:7]2[N:8]=[C:9]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[O:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(-c3ccccc3)co2)CC1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: c1ccc(-c2coc(N3CCNCC3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.2 %

Procedure:
To a solution of tert-butyl 4-(4-phenyl-1,3-oxazol-2-yl)piperazine-1-carboxylate (590 mg, 1.79 mmol) in tetrahydrofuran (4 ml) and methanol (4 ml) was added a solution of 4 N hydrogen chloride in ethyl acetate (4 ml), and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure. The residue was poured to an aqueous 1 N sodium hydroxide solution (10 ml) and extracted with chloroform. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give 370 mg (90.0%) of the desired product as an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1.II.CO[C:13](=[O:26])[CH2:14][NH:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>C(OCC)C>[OH:26][C:13]([C:2]1[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1)([C:2]1[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1)[CH2:14][NH:15][C:16](=[O:17])[O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)CNC(=O)OCc1ccccc1
Reactant: Cc1cccc(Br)c1
Agent: II
Solvent: CCOCC
Product: Cc1cccc(C(O)(CNC(=O)OCc2ccccc2)c2cccc(C)c2)c1
Reaction time: 0.5 h
Yield: 62.3 %

Procedure:
3-Bromotoluene (0.8 mL, 6.6 mmol) was added to Mg turnings (0.312 g, 13 mmol) in diethyl ether (5 mL) and an iodine crystal was also added. The reaction was stirred for 30 minutes. The solution was then transferred to another flask (via a pipet) to separate from the excess Mg. A solution of carbobenzyloxyglycine methyl ester (0.294 g, 1.32 mmol) in diethyl ether (3 mL) was then added to the solution of the Grignard reagent and the reaction was stirred for 1 hour. The reaction was then quenched with sat. aq ammonium chloride and the aqueous phase was extracted with ethyl acetate (3×). The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified on Biotage chromatography (10% to 10% ethyl acetate/hexane) to give the title material (0.309 g, 62%) as an oil. 1H NMR (400 MHz, DMSO-d6) δ: 2.26 (6H, s), 3.82 (2H, d, J=5.81 Hz), 4.99 (2H, s), 5.76 (1H, s), 6.79 (1H, t, J=5.56 Hz), 7.01 (2H, d, J=7.07 Hz), 7.09-7.40 (11H, m). LC/MS (M−H)−: 374. HPLC ret. time (Condition B): 2.133 min.
Reaction SMILES: C(O[CH2:5][CH2:6][SH:7])(=O)C.O.[CH3:9][Sn:10](Cl)(Cl)Cl.[C:14](=[O:17])(O)[O-:15].[Na+]>CCCCCCC>[SH:7][CH2:6][CH2:5][CH2:9][C:14]([O-:15])=[O:17].[SH:7][CH2:6][CH2:5][CH2:9][C:14]([O-:15])=[O:17].[SH:7][CH2:6][CH2:5][CH2:9][C:14]([O-:15])=[O:17].[CH3:9][Sn+3:10]
Reactant: CC(=O)OCCS
Reactant: C[Sn](Cl)(Cl)Cl
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCCCCCC
Product: C[Sn+3]
Product: O=C([O-])CCCS
Reaction time: 1 h

Procedure:
Into a 2 liter flask placed 182 gm (1.5 mole) 2-mercaptoethyl acetate, 200 ml water, 300 ml heptane and 120 gm (0.5 mole) monomethyltin trichloride. To the above stirred mixture is added portionwise 126 gm (1.5 mole) sodium bicarbonate maintaining a pot temperature of 25°-40° C. by the addition rate. When addition is complete, allow to stir 1 hour at 25°-40° C. The layers are separated and the organic plase washed with 200 ml water. The heptane is removed under vacuum. A yield of 240 gm, monomethyltin tris(2-mercaptoethylacetate) is obtained as a colorless oil. nD25 1.5575.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][C:11]2=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[BH4-].[Na+].C1(C)C=CC=CC=1.O>CO.C1(C)C=CC(S(O)(=O)=O)=CC=1>[N+:1]([C:4]1[CH:13]=[C:12]2[C:7](=[CH:6][CH:5]=1)[CH2:8][CH2:9][CH:10]=[CH:11]2)([O-:3])=[O:2]
Reactant: O=C1CCCc2ccc([N+](=O)[O-])cc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CO
Product: O=[N+]([O-])c1ccc2c(c1)C=CCC2
Yield: 84.8 %

Procedure:
A suspension of 7-nitrotetralone (20 g, 0.105 mol) in MeOH (300 mL) was treated with NaBH4 (4.1 g) with intermitent cooling. After the addition, cooling was removed and the reaction stirred over night. The reaction was cooled in ice-water and quenched with a solution of MeOH (200 mL) and concentrated HCl (35 mL). The solvent was evaporated, the residue was suspended in H2O, and the mixture was extracted with CHCl. The extracts were dried and the solvent evaporated to give a tan solid. A mixture of the solid, p-toluenesulfonic acid (0.4 g), and toluene (300 mL) was heated to reflux for over night with water being collected in a Dean-Stark trap. The reaction was cooled, washed with H2O, aqueous NaHCO3, and brine, then the solvent was dried and evaporated to give a dark liquid (15.6 g) that had an nmr consistent with the desired material.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([CH2:10][C:11]1([N:22]2[CH:26]=[C:25]([C:27]3[CH:32]=[CH:31][N:30]=[C:29]4[NH:33][CH:34]=[CH:35][C:28]=34)[CH:24]=[N:23]2)[CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12]1)#[N:9]>C(Cl)Cl>[NH:33]1[C:29]2=[N:30][CH:31]=[CH:32][C:27]([C:25]3[CH:24]=[N:23][N:22]([C:11]4([CH2:10][C:8]#[N:9])[CH2:12][NH:13][CH2:14]4)[CH:26]=3)=[C:28]2[CH:35]=[CH:34]1.[C:3]([OH:5])([C:2]([F:7])([F:6])[F:1])=[O:4]
Reactant: CC(C)(C)OC(=O)N1CC(CC#N)(n2cc(-c3ccnc4[nH]ccc34)cn2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CCC1(n2cc(-c3ccnc4[nH]ccc34)cn2)CNC1
Temperature: 30 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (7.0 mL) was added to tert-butyl 3-(cyanomethyl)-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidine-1-carboxylate (0.90 g, 2.4 mmol) in methylene chloride (7.0 mL). The reaction mixture was stirred at 30° C. for 2 h. The volatiles were removed under reduced pressure to afford the desired product (quantitative) as TFA salt which was directly used in the next step reaction without further purification. LCMS (M+H)+: m/z 279.1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[Br:30][C:31]1[CH:36]=[CH:35][C:34](O)=[CH:33][CH:32]=1>>[Br:30][C:31]1[CH:36]=[CH:35][C:34]([O:29][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:26])[CH3:27])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:33][CH:32]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCC(O)c3ccc(Br)cc3)CC2)c1
Reactant: Oc1ccc(Br)cc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCC(Oc3ccc(Br)cc3)c3ccc(Br)cc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-(4-bromophenyl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-bromophenol: ESMS m/e: 612.7 (M+H)+.