Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:18]=[C:17]([Cl:19])[S:16][C:15]=2[CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30](OCC)=[O:31])=[C:24]([CH3:35])[C:23]=2[CH3:36])=[CH:10][CH:9]=1>>[Cl:19][C:17]1[S:16][C:15]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][CH2:30][OH:31])=[C:24]([CH3:35])[C:23]=2[CH3:36])=[C:14]([C:11]2[CH:10]=[CH:9][C:8]([Cl:7])=[CH:13][CH:12]=2)[CH:18]=1
Reactant: CCOC(=O)CCc1ccc(OCc2sc(Cl)cc2-c2ccc(Cl)cc2)c(C)c1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: Cc1c(CCCO)ccc(OCc2sc(Cl)cc2-c2ccc(Cl)cc2)c1C

Procedure:
The title compound was prepared according to the procedure described in Example 223 by LAH reduction of ethyl 3-(4-((3-(4-chlorophenyl)-5-chlorothiophen-2-yl)methoxy)-2,3-dimethyl phenyl)propanoate to give the desired product as off-white oil. 1H NMR (300 MHz, CD3OD) δ 7.38 (s, 4H), 7.06 (s, 1H), 6.89 (d, J=8.4 Hz, 1H), 6.62 (d, J=8.4 Hz, 1H), 5.05 (s, 2H), 3.58 (t, J=6.3 Hz, 2H), 2.64 (t, J=7.5 Hz, 2H), 2.21 (s, 3H), 2.14 (s, 3H), 1.76 (t, J=7.5 Hz, 2H). Mass spectrum (ESI, m/z): Calcd. for C22H22Cl2O2S, 385.1 (M-Cl). found 385.1.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH2:7][C:8]([OH:10])=[O:9])[NH:4][N:3]=1.Cl.[CH3:12]O>>[CH3:12][O:9][C:8](=[O:10])[CH2:7][C:5]1[NH:4][N:3]=[C:2]([CH3:1])[CH:6]=1
Reactant: CO
Reactant: Cc1cc(CC(=O)O)[nH]n1
Agent: Cl
Product: COC(=O)Cc1cc(C)n[nH]1
Yield: 70 %

Procedure:
A solution of 3-methyl-5-pyrazoleacetic acid (5.0 g, 35.7 mmol) [see C. Ainsworth, J. Amer. Chem. Soc., 76, 3172 (1954)] in methanol (50 mL) is saturated with HCl gas. The mixture is warmed to reflux for 5 hours, after which the solution is concentrated. The solid residue is taken up in chloroform and washed with 0.5N aqueous sodium bicarbonate, dried over MgSO4, and evaporated to afford 3-methyl-5-pyrazoleacetic acid methyl ester (3.9 g, 70%) sufficiently pure for further use.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][CH:23](C(OC(C)(C)C)=O)[CH2:24][CH3:25])=[CH:16][CH:15]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][NH:22][CH2:23][CH2:24][CH3:25])=[CH:18][CH:19]=1)(=[O:11])=[O:10]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1Cl
Reactant: CCC(NCCc1ccc(N)cc1)C(=O)OC(C)(C)C
Product: CCCNCCc1ccc(NS(=O)(=O)c2ccc(F)cc2Cl)cc1

Procedure:
Using procedure 4, 2-chloro-4-fluorobenzenesulfonyl chloride was added to 2-(4-aminophenyl)ethyl-1-(tert-butoxycarbonyl)propylamine to give the title compound as a solid, m.p. 165-167° C.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]([C:10]2[C:11]([Cl:17])=[N:12][C:13]([Cl:16])=[N:14][CH:15]=2)[OH:9])[CH:5]=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].CC1(C)N([O])C(C)(C)CCC1.[O-]Cl.[Na+]>ClCCl.O.CCCC[N+](CCCC)(CCCC)CCCC.[Br-]>[Br:1][C:2]1[N:7]=[C:6]([C:8]([C:10]2[C:11]([Cl:17])=[N:12][C:13]([Cl:16])=[N:14][CH:15]=2)=[O:9])[CH:5]=[CH:4][CH:3]=1
Reactant: OC(c1cccc(Br)n1)c1cnc(Cl)nc1Cl
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: O
Product: O=C(c1cccc(Br)n1)c1cnc(Cl)nc1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of crude (6-bromo-pyridin-2-yl)-(2,4-dichloro-pyrimidin-5-yl)-methanol (from Example 28 supra) (16.1 g, crude) in dichloromethane (200 mL), water (20 mL) was added followed by NaHCO3 (2.1 g, 25 mmol), TBAB (485 mg, 1.5 mmol) and TEMPO (90 mg, 0.5 mmol). The mixture was then cooled to 0° C. and NaClO (70 mL, active chloride >6.0%) was added slowly and the resulting mixture was stirred for 30 minutes. The mixture was poured into water and extracted with dichloromethane. The organic phase was dried over anhydrous MgSO4, filtered and concentrated. The residue was purified by column chromatography (silica gel, eluting with ethyl acetate:petroleum ether, 1:20) to give (6-bromo-pyridin-2-yl)-(2,4-dichloro-pyrimidin-5-yl)-methanone as a white solid. (Yield 12.7 g, 76% over two steps).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([N+:10]([O-])=O)[CH:3]=1.[N:13]1([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(P(C1C=CC=CC=1C1C=CC=CC=1)C(C)(C)C)(C)(C)C>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:13]1([CH:19]2[CH2:24][CH2:23][N:22]([C:2]3[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([CH:3]=3)[NH2:10])[CH2:21][CH2:20]2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: COc1ccc(Br)cc1[N+](=O)[O-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: C1COCCO1
Product: COc1ccc(N2CCC(N3CCCCC3)CC2)cc1N
Temperature: 100 °C
Yield: 26.5 %

Procedure:
To 4-bromo-2-nitroanisole (2.02 g, 8.72 mmol) and 1,4′-bipiperidine (3.49 g, 20.7 mmol) in dioxane (80 mL) was added sequentially, cesium carbonate (6.74 g, 20.7 mmol), palladium (II) acetate (0.196 g, 0.870 mmol) and di-tert-butylphosphino-biphenyl (0.527 g, 1.77 mmol). The reaction was heated at 100° C. for 24 hours, filtered through Celite®, concentrated and purified by flash chromatography. The residue was taken up in EtOAc (100 mL) and Pd on carbon was added in one portion. The mixture was stirred at rt under H2 (1 atm.) until complete by TLC. The reaction was filtered through Celite® and concentrated to provide the title compound of step A (0.667 g, 2.31 mmol, 26% over two steps). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.32-1.40 (m, 2H), 1.43-1.54 (m, 6H), 1.73 (d, J=12.1 Hz, 2H), 2.18-2.28 (m, 1H), 2.41-2.47 (m, 6H), 3.43 (d, J=12.5 Hz, 2H), 3.65 (s, 3H), 4.52 (s, 2H), 6.06 (dd, J=8.6, 2.7 Hz, 1H), 6.28 (d, J=2.9 Hz, 1H), 6.60 (d, J=8.8 Hz, 1H).
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[F:14])([CH3:6])([CH3:5])[CH3:4].Br[CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>>[C:3]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:9][C:8]=1[F:14])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)c1ccc(O)cc1F
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)COc1ccc(C(C)(C)C)c(F)c1
Yield: 83.2 %

Procedure:
Sixty % sodium hydride (128 mg, 3.2 mmol), 4-tert-butyl-3-fluorophenol (450 mg, 2.7 mmol), tert-butyl bromoacetate (632 mg, 3.2 mmol) were treated in the same procedure described in Example 3(b) to furnish 634 mg (82% yield) of the title compound as a white solid.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([CH:12]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13]1)=[N:10][OH:11].[OH-].[K+].O.[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31]>C(O)C>[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31].[F:8][C:6]1[CH:5]=[CH:4][C:3]2[C:9]([CH:12]3[CH2:16][CH2:15][N:14]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH2:13]3)=[N:10][O:11][C:2]=2[CH:7]=1
Reactant: ON=C(c1ccc(F)cc1F)C1CCN(Cc2ccccc2)C1
Agent: O=C(O)/C=C/C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Fc1ccc2c(C3CCN(Cc4ccccc4)C3)noc2c1
Yield: 74.8 %

Procedure:
A mixture of (2,4-difluorophenyl)[1-(phenylmethyl)-3-pyrrolidinyl]methanone oxime (10.8 g, 34.2 mmol), potassium hydroxide (10 g), water (100 ml), and ethanol (100 ml) was heated at reflux for 2 hours. At the end of the reaction, the solution was cooled and ethanol was removed on a rotary evaporator. The aqueous mixture was diluted with water (100 ml) then extracted with dichloromethane (500 ml). The organic solution was washed with brine and dried over anhydrous MgSO4. The solution was concentrated to an oil (9.8 g). The crude product was purified by flash chromatography over a silica gel column. The product thus obtained weighed 4.46 g (44%) as a light yellow oil. The oily product was dissolved in ethanol, and then treated with a solution of fumaric acid (1.73 g, 1.0 eq) in ethanol. Crystallization took place slowly with the addition of isopropyl ether. Recrystallization from ethanol (15 ml) gave 4.6 g of 6-fluoro-3-[1-(phenylmethyl)-3-pyrrolidinyl]-1,2-benzisoxazole fumarate as white crystals, m.p. =142°-144° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]([NH:16][C:17]3[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[CH:19][CH:18]=3)=[O:15])[CH:5]=[CH:4][C:3]1=2.[OH-].[K+]>CO>[CH3:1][C:2]1([CH3:27])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([C:21]([OH:23])=[O:22])=[CH:25][CH:26]=3)=[O:15])[CH:5]=[CH:4][C:3]1=2
Reactant: COC(=O)c1ccc(NC(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)CCC(C)(C)c2cc(C(=O)Nc3ccc(C(=O)O)cc3)ccc21
Reaction time: 16 h
Yield: 78.5 %

Procedure:
A 25 mL round bottom flask equipped with a reflux condenser was charged with methyl methyl 4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-carboxamido)benzoate 3 (0.200 g, 0.547 mmol), MeOH (10 mL) and KOH (0.122 g, 2.18 mmol). The reaction mixture was stirred for 16 h at reflux, evaporated to dryness and partitioned between EtOAc and H2O. 6N HCl was added until pH became acidic and the organic layer was separated, washed with water, brine, dried with Na2SO4, filtered and concentrated on a rotary evaporator to give 4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-carboxamido)benzoic acid 4 as a white solid (0.151 g, 78%).
Reaction SMILES: [Br:1][C:2]1[C:9]([OH:10])=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([F:11])[CH:3]=1.[CH2:12](Cl)[O:13][CH3:14].[H-].[Na+].CCOCC>CN(C)C=O>[Br:1][C:2]1[C:9]([O:10][CH2:12][O:13][CH3:14])=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([F:11])[CH:3]=1
Reactant: O=Cc1cc(O)c(Br)cc1F
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COCOc1cc(C=O)c(F)cc1Br
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4-Bromo-2-fluoro-5-hydroxy-benzaldehyde (750 mg, 3.41 mmol) and MOMCl (545 mg, 6.82 mmol) were dissolved in anhydrous N,N-dimethylformamide (5 mL) and cooled to 0° C. NaH (160 mg, 60% suspension in mineral oil, 4 mmol) is then added. The resulting mixture is allowed to stir at room temperature for 1 h. Ether is then added and washed with H2O (3×20 mL) and brine. After dried over Na2SO4, the ether is removed and the residue is purified through chromatography to afford the desired MOM ether (700 mg, 78%).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH2:11][CH:10]([NH2:15])[CH2:9][CH2:8]2.[C:16]1(=O)[O:21][C:19](=[O:20])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12>CN(C=O)C.O>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH2:11][CH:10]([N:15]1[C:19](=[O:20])[C:18]3[C:17](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:16]1=[O:21])[CH2:9][CH2:8]2
Reactant: O=C1OC(=O)c2ccccc21
Reactant: COc1ccc2c(c1)CCC(N)C2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCC(N1C(=O)c3ccccc3C1=O)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.1 %

Procedure:
To a stirred suspension of 60% NaH (6 g; 0.182 mmol) in DMF (400 mL) is added 6-methoxy-1,2,3,4-tetrahydronaphthalen-2-ylamine (30 g; 0.140 mol), portionwise at 0° C. The reaction mixture is warmed to RT and stirred for an additional 1 h. Phthalic anhydride (20.7 g; 0.139 mol) is added in 1-portion at RT, upon which the reaction mixture is stirred for an additional 1 h followed by 18 h at 120° C. The reaction was allowed to cool to RT, diluted with H2O and extracted several times with EtOAc. The combined organic extracts are washed with water, brine, dried over Na2SO4, and the solvent removed under reduced pressure. The crude solid was triturated with MeOH, filtered, and dried under vacuo to afford 29.1 g (67%) of 2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)isoindole-1,3-dione as an off-white solid.
Reaction SMILES: [CH2:1]1[NH:13][CH2:12][C:11]2[NH:10][C:9]3[CH:8]=[CH:7][CH:6]=[C:5]4[C:14](=[O:17])[NH:15][N:16]=[C:2]1[C:3]=2[C:4]=34.[C:18]([O:22][C:23]([NH:25][C@@H:26]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:27](O)=[O:28])=[O:24])([CH3:21])([CH3:20])[CH3:19].NC(C)(C)C(N1CC2NC3C=CC=C4C(=O)NN=C(C=2C=34)C1)=O>>[C:18]([O:22][C:23](=[O:24])[NH:25][C@@H:26]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:27](=[O:28])[N:13]1[CH2:12][C:11]2[NH:10][C:9]3[CH:8]=[CH:7][CH:6]=[C:5]4[C:14](=[O:17])[NH:15][N:16]=[C:2]([C:3]=2[C:4]=34)[CH2:1]1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: O=C1NN=C2CNCc3[nH]c4cccc1c4c32
Agent: CC(C)(N)C(=O)N1CC2=NNC(=O)c3cccc4[nH]c(c2c34)C1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N1CC2=NNC(=O)c3cccc4[nH]c(c2c34)C1

Procedure:
Compound 63 was prepared from 2,3,4,9-tetrahydro-2,4,9,10-tetraazacyclohepta[def]fluoren-8(1H)-one and (S)-2-((tert-butoxycarbonyl)amino)-3-phenylpropanoic acid to the procedure similar to that for Compound 62. 1H NMR (DMSO-d6) δ 11.8 (s, 1H), 10.0 (s, 1H), 7.51 (d, 1H, J=8.0 Hz), 7.05-7.47 (m, 7H), 4.96-5.02 (m, 1H), 4.25-4.81 (m, 4H), 2.62-2.88 (m, 2H), 1.27 (s, 6H), and 1.16 (s, 3H). MS (ESI) m/e [M+1]+ 474.
Reaction SMILES: Br[C:2]1[C:3]([NH:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.[CH3:16][O:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:19]=1[CH2:26][NH2:27].C(N(CC)C(C)C)(C)C>CS(C)=O>[Br:8][C:6]1[N:7]=[C:2]([NH:27][CH2:26][C:19]2[CH:20]=[CH:21][C:22]([O:24][CH3:25])=[CH:23][C:18]=2[O:17][CH3:16])[C:3]([NH:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:4][CH:5]=1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: CCOC(=O)CNc1ncc(Br)nc1Br
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CNc1ncc(Br)nc1NCc1ccc(OC)cc1OC
Temperature: 150 °C
Yield: 47.8 %

Procedure:
Ethyl 2-(3,5-dibromopyrazin-2-ylamino)acetate (See Example 1.C) (1.06 g, 3.13 mmol), (2,4-dimethoxyphenyl)methanamine (0.601 g, 3.60 mmol), N,N-diisopropylethylamine (1.63 mL, 9.38 mmol) and dimethylsulfoxide (1.6 mL) were combined in a microwave vial with a stirbar and heated in a microwave reactor at 150° C. for 2 h. The resulting mixture was purified using flash chromatography (5-60% ethyl acetate in hexane). Fractions containing the desired product were combined and concentrated nearly to dryness under reduced pressure. Ethyl acetate (2 mL) and hexane (18 mL) was added. The resulting solids were collected by vacuum filtration, washed with hexane and dried under high vacuum to give the desired product (0.636 g, 1.495 mmol, 48% yield) as a light pink solid. 1H NMR (300 MHz, DMSO-d6) δ (ppm) 7.24 (s, 1H), 7.19 (d, J=8.52 Hz, 1H), 7.11 (t, J=5.63 Hz, 1H), 6.84 (t, J=4.81 Hz, 1H), 6.59 (d, J=2.47 Hz, 1H), 6.50 (dd, J=2.20, 8.24 Hz, 1H), 4.37 (d, J=4.67 Hz, 2H), 3.96-4.15 (m, 4H), 3.81 (s, 3H), 3.75 (s, 3H), 1.17 (t, 3H); MS (ESI) m/z 425.3 [M]+, 426.9 [M+2]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([C:10]([OH:12])=O)=[CH:7][C:6]=2[CH:13]=1.[ClH:14].Cl.[NH2:16][C@@H:17]1[CH:22]2[CH2:23][CH2:24][N:19]([CH2:20][CH2:21]2)[CH2:18]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[ClH:14].[N:19]12[CH2:24][CH2:23][CH:22]([CH2:21][CH2:20]1)[C@@H:17]([NH:16][C:10]([C:8]1[S:9][C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:13][C:6]=3[CH:7]=1)=[O:12])[CH2:18]2
Reactant: N[C@H]1CN2CCC1CC2
Reactant: O=C(O)c1cc2cc(Br)ccc2s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2cc(Br)ccc2s1

Procedure:
133.7 mg (0.52 mmol) of 5-bromo-1-benzothiophene-2-carboxylic acid, 155.4 mg (0.78 mmol) of (R)-3-aminoquinuclidine dihydrochloride, 296.7 mg (0.78 mmol) of HATU, 369.8 mg (2.86 mmol) of N,N-diisopropylethylamine and 1.5 ml of DMF are reacted according to the general procedure (variant A). The reaction mixture is purified by preparative HPLC. The product is dissolved in acetonitrile, and an excess of 1N hydrochloric acid is added. The solvent is then removed. 175 mg (84% of theory) of the title compound are isolated.
Reaction SMILES: [CH3:1][CH:2]1[C:6]2([CH2:11][CH:10]([CH3:12])[CH2:9][C:8]([CH3:14])([CH3:13])[CH2:7]2)[C:5](=[CH2:15])[C:4](=[O:16])[CH2:3]1.ClC1C=CC=C(C(OO)=[O:25])C=1>C(Cl)Cl>[CH3:13][C:8]1([CH3:14])[CH2:9][CH:10]([CH3:12])[CH2:11][C:6]2([CH:2]([CH3:1])[CH2:3][C:4](=[O:16])[C:5]32[O:25][CH2:15]3)[CH2:7]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C1C(=O)CC(C)C12CC(C)CC(C)(C)C2
Solvent: ClCCl
Product: CC1CC(C)(C)CC2(C1)C(C)CC(=O)C21CO1
Temperature: 0 °C
Reaction time: 1 h
Yield: 60.6 %

Procedure:
At 0° C., a solution of 4,7,7,9-tetramethyl-1-methylenespiro[4.5]decan-2-one (1.43 g, 6.49 mmol), in CH2Cl2 (10 mL) was added dropwise within 45 min. to a stirred solution of 70% 3-chloroperbenzoic acid (1.76 g, 7.14 mmol) in CH2Cl2 (20 mL). After further stirring at 0° C. for 1 h, the cooling bath was removed, and the reaction mixture stirred for 3 d, with an additional portion of 70% 3-chloroperbenzoic acid (1.76 g, 7.14 mmol) being added after the first and second day. The insoluble material was removed by vacuum filtration and washed with CH2Cl2. The combined organic solutions were washed with 20% aq. NaHSO3, halfconc. NaHCO3, and water (50 mL), the aqueous washings again extracted with CH2Cl2 (50 mL). The combined organic extracts were dried (Na2SO4) and concentrated in a rotary evaporator. The resulting residue was purified by silica-gel FC (pentane/Et2O, 19:1, Rf=0.11) to provide 6,6,8,10-tetramethyl-1-oxadispiro[2.0.5.3]dodecan-12-one (930 mg, 61%).
Reaction SMILES: [CH3:1][C:2]([CH:4]=[P:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[CH2:24]([Li])[CH2:25][CH2:26]C.C(Br)C#C>O1CCCC1>[CH2:1]([C:2]([CH:4]=[P:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:3])[CH2:26][C:25]#[CH:24]
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: [Li]CCCC
Agent: C#CCBr
Solvent: C1CCOC1
Product: C#CCCC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
20.0 g of methylcarbonylmethylenetriphenyl phosphorane is dissolved in 628 ml of tetrahydrofuran and mixed by instillation at -78° C. with 41.3 ml of butyllithium (1.6 molar solution in hexane). Then,5.0 ml of propargyl bromide is instilled. The reaction mixture is added to an ice/common salt solution after heating to room temperature, and the mixture is extracted with ethyl acetate. After drying the organic phase with sodium sulfate,23.4 g of solid is obtained. Column chromatographic purification (silica gel/ethyl acetate) yields 15.4 g of the title compound with a melting point of 135°-136° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][N:10]=[C:9]([NH:12][CH2:13][CH2:14][NH:15][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[C:8]=2[CH:24]=1)([O-])=O.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[S:11][N:10]=[C:9]([NH:12][CH2:13][CH2:14][NH:15][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[C:8]=2[CH:24]=1
Reactant: O=C(NCCNc1nsc2ccc([N+](=O)[O-])cc12)c1ccccn1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1ccc2snc(NCCNC(=O)c3ccccn3)c2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 104.5 %

Procedure:
A mixture of N-(2-(5-nitrobenzo[d]isothiazol-3-ylamino)ethyl)picolinamide (100 mg, 0.29 mmol), iron powder (100 mg, 1.75 mmol) and ammonium chloride (31 mg, 0.29 mmol) in ethanol (5 mL) and water (2.5 mL) was allowed to stir at room temperature for 15 min. The mixture was then heated at 80° C. for 20 min. The reaction mixture was cooled to room temperature and passed through a plug of Celite. The filtrate was concentrated under reduced pressure and the resulting residue was diluted with water. The aqueous solution was extracted several times with ethyl acetate and then concentrated under reduced pressure. Purification by column chromatography, on silica gel, eluting with a mixture of 2% methanol in dichloromethane, and selected fractions were combined and concentrated under reduced pressure to yield N-(2-(5-aminobenzo[d]isothiazol-3-ylamino)ethyl)picolinamide (95 mg) as a pale yellow solid. 1H NMR (300 MHz, CDCl3): 8.56 (d, 1H), 8.25 (d, 1H), 8.20 (d, 2H), 7.80 (t, 1H), 7.40 (m, 1H), 7.18 (d, 1H), 6.01 (s, 1H), 5.98 (d, 1H), 4.80 (broad s, 1H), 3.70 (m, 2H), 3.40 (m, 2H). MW=313 confirmed by LC-MS, tr=9.21 min (Method Y) MH+=314.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH2:20][CH2:21][CH3:22])=[C:6]([C:8]2[NH:13][C:12](=[O:14])[C:11]([CH2:15][CH3:16])=[C:10]([CH2:17][CH3:18])[N:9]=2)[CH:7]=1.O.CS[C:26](=[NH:28])[NH2:27]>C(O)(=O)C>[CH2:17]([C:10]1[N:9]=[C:8]([C:6]2[CH:7]=[C:2]([NH:1][C:26]([NH2:28])=[NH:27])[CH:3]=[CH:4][C:5]=2[O:19][CH2:20][CH2:21][CH3:22])[NH:13][C:12](=[O:14])[C:11]=1[CH2:15][CH3:16])[CH3:18]
Reactant: CSC(=N)N
Reactant: CCCOc1ccc(N)cc1-c1nc(CC)c(CC)c(=O)[nH]1
Solvent: O
Solvent: CC(=O)O
Product: CCCOc1ccc(NC(=N)N)cc1-c1nc(CC)c(CC)c(=O)[nH]1
Reaction time: 10 h
Yield: 24.9 %

Procedure:
The compound (140 mg, 0.41 mmol) of example 42 was suspended in a mixed solution of water (2.5 ml) and acetic acid (2.5 ml), added with S-methylisothiourea (64 mg, 0.45 mmol), and heated to reflux under stirring for 10 h. The reaction mixture was concentrated to dryness, dissolved in dichloromethane (20 ml), and washed orderly with 1N NaOH (5 ml), water (10 ml) and saturated saline. The organic phase was dried with anhydrous Na2SO4 and concentrated under reduced pressure to give an oil, which was passed through a silica gel column using ethyl acetate-petroleum ether as an eluant to obtain the title compound (35 mg, yield: 25%). 1H NMR (CDCl3) δ: 8.26 (1H, d), 8.00 (1H, dd), 7.50 (1H, br), 6.99 (1H, d), 4.14 (2H, t), 2.67 (2H, q), 2.59 (2H, q), 1.97 (2H, m), 1.29 (3H, t), 1.15 (3H, t), 1.13 (3H, t).
Reaction SMILES: [CH3:1][CH:2]([CH3:38])[C@H:3]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24](C4SC(C5C=CC=CC=5)=CN=4)=[O:25])=[CH:19][CH:18]=3)=[CH:13][CH:14]=2)[C:9]1=[O:37])[C:4]([O:6][CH3:7])=[O:5].NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1.[O:64]1[C:68]([C:69]2[CH:78]=[CH:77][C:72](C(OC)=O)=[CH:71][CH:70]=2)=[CH:67][N:66]=[CH:65]1>>[CH3:38][CH:2]([CH3:1])[C@H:3]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:17]3[CH:18]=[CH:19][C:20]([NH:23][C:24](=[O:25])[C:72]4[CH:71]=[CH:70][C:69]([C:68]5[O:64][CH:65]=[N:66][CH:67]=5)=[CH:78][CH:77]=4)=[CH:21][CH:22]=3)=[CH:13][CH:14]=2)[C:9]1=[O:37])[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(-c2cnco2)cc1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ncc(-c5ccccc5)s4)cc3)cc2C1=O
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(-c5cnco5)cc4)cc3)cc2C1=O
Yield: 58 %

Procedure:
The compound of example 621 was prepared analogous to the compound of example 611 by reaction of compound of example 6 with commercially available methyl 4-(oxazol-5-yl)benzoate (Ryan Scientific, USA).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]3[CH2:13][CH2:14][CH2:15][CH:16]([C:18]([O:20]C)=[O:19])[CH2:17][C:11]3(N3CCCC3)[O:10][N:9]=2)=[CH:4][CH:3]=1.O>S(=O)(=O)(O)O.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[CH2:13][CH2:14][CH2:15][CH:16]([C:18]([OH:20])=[O:19])[CH2:17][C:11]=3[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)C1CCCC2C(c3ccc(Cl)cc3)=NOC2(N2CCCC2)C1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)C1CCCc2c(-c3ccc(Cl)cc3)noc2C1

Procedure:
5 g of methyl 3-(4-chlorophenyl)-3a,5,6,7,8,8a-hexahydro-8a-pyrrolidino-4H-cyclohept[d]isoxazole-7-carboxylate in 5 ml of concentrated sulfuric acid, 5 ml of acetic acid and ml of water were heated at 120° C. for 5 hours. The separated product was filtered off, washed with water and dried in vacuo to give 3.1 of 3-(4-chlorophenyl)-5,6,7,8-tetrahydro-4H-cyclohept[d]isoxazole-7-carboxylic acid of melting point 215°-217° C.