Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH:5]([NH:13][CH:14]=[O:15])[CH:6]=[C:7]([CH2:11]Br)[CH2:8][CH2:9][F:10])[CH3:2].[P:17]([O:26]C(C)C)([O:22][CH:23]([CH3:25])[CH3:24])[O:18][CH:19]([CH3:21])[CH3:20]>>[CH2:1]([O:3][C:4](=[O:16])[CH:5]([NH:13][CH:14]=[O:15])[CH:6]=[C:7]([CH2:11][P:17]([O:22][CH:23]([CH3:25])[CH3:24])([O:18][CH:19]([CH3:21])[CH3:20])=[O:26])[CH2:8][CH2:9][F:10])[CH3:2]
Reactant: CCOC(=O)C(C=C(CBr)CCF)NC=O
Reactant: CC(C)OP(OC(C)C)OC(C)C
Product: CCOC(=O)C(C=C(CCF)CP(=O)(OC(C)C)OC(C)C)NC=O
Reaction time: 18 h

Procedure:
1.43 g (4.82 mmol) of 4-bromomethyl-6-fluoro-2-formylamino-hex-3-enoic acid ethyl ester and 5.3 ml (19 mmol) of triisopropyl phosphite (96% ) are heated to 80° and stirred under a pressure of approximately 130 mbar for 18 hours. The excess triisopropyl phosphite is distilled off under reduced pressure and the evaporation residue is purified by chromatography on silica gel with ethyl acetate. 4-diisopropylphosphonomethyl-6-fluoro-2-formylamino-hex-3-enoic acid ethyl ester is obtained in the form of a yellowish oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11](=[O:16])[CH2:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17]([Mg]Br)#[CH:18]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11]([C:17]#[CH:18])([OH:16])[CH2:12]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C#C[Mg]Br
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(=O)C2
Solvent: C1CCOC1
Product: C#CC1(O)CC2CCC(C1)N2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.8 %

Procedure:
This compound was prepared according to a procedure similar to that described in Procedure A. I In a solution of 3-Oxo-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (2.25 g, 10 mmol) in tetrahydrofuran (20 mL) was dropped in ethynyl magnesium bromide (60 mL, 30 mmol) at −0° C. Then the solution was stirred overnight at room temperature. Then the reaction mixture was quenched with saturated NH4Cl and extracted with dichloromethane, dried with anhydrous sodium sulfate to afford 3-Ethynyl-3-hydroxy-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (0.8 g, 32%). 1H NMR: (DMSO-d6, 400 MHz) δ 5.43 (s, 1H), 3.98 (s, 2H), 3.24 (s, 1H), 2.08-1.91 (m, 8H), 1.37 (s, 9H).
Reaction SMILES: [F:1][C:2]([N:5]=[C:6]=[O:7])([F:4])[F:3].[C:8]1([NH:14][OH:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CCCCC>C(OCC)C>[F:1][C:2]([F:4])([F:3])[NH:5][C:6]([N:14]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[OH:15])=[O:7]
Reactant: O=C=NC(F)(F)F
Reactant: ONc1ccccc1
Solvent: CCCCC
Solvent: CCOCC
Product: O=C(NC(F)(F)F)N(O)c1ccccc1
Reaction time: 1 h

Procedure:
A solution of trifluoromethyl isocyanate (11.1 grams, 0.1 mol) in diethyl ether (35 ml) is added dropwise, with stirring to a solution of N-phenyl hydroxylamine (10.9 grams; 0.1 mol) in ether (60 ml) at room temperature. Stirring is continued for a period of about 1 hour resulting in a precipitate. Pentane is added to the mixture to form additional precipitate. The precipitate is then recovered by filtration, is washed and dried to yield 1-trifluoromethyl-3-phenyl-3-hydroxyurea.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C@H:10]2[CH2:13][C@H:12]([OH:14])[CH2:11]2)=[CH:6][CH:5]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C@H:10]2[CH2:11][C@H:12]([OH:14])[CH2:13]2)=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccc([C@H]2C[C@H](O)C2)cc1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc([C@H]2C[C@H](O)C2)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a stirred solution of trans-3-(4-nitrophenyl)cyclobutanol (step 3, 1.0 g, 4.9 mmol) in methanol (20 mL) was added 10% Pd—C (50 mg). The mixture was stirred at room temperature under hydrogen atmosphere for 2.5 h. The palladium catalyst was removed by filtration and washed with methanol (100 mL) and ethyl acetate (100 mL). The filtrate was concentrated under reduced pressure to afford 0.9 g (quant.) of the title compound as pale yellow solids: MS (EI) m/z 163 (M+); 1H-NMR (CDCl3) δ 7.03 (2H, d, J=8.3 Hz), 6.66 (2H, d, J=8.3 Hz), 4.56–4.47 (1H, m), 3.58–3.48 (3H, m), 2.48–2.31 (2H, m), 1.73 (1H, d, J=5.1 Hz).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([CH3:11])=[CH:4][N:3]=1.[NH:12]1[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:14][CH2:13]1>C(#N)C.[Pd]>[CH3:11][C:5]1[CH:6]=[C:7]([NH2:8])[C:2]([N:12]2[CH2:13][CH2:14][CH:15]([CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH2:16][CH2:17]2)=[N:3][CH:4]=1
Reactant: Cc1cnc(Cl)c([N+](=O)[O-])c1
Reactant: C1CCN(CCC2CCNCC2)CC1
Agent: [Pd]
Solvent: CC#N
Product: Cc1cnc(N2CCC(CCN3CCCCC3)CC2)c(N)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 99.8 %

Procedure:
To a stirred solution of 0.086 g (0.50 mmol) of 2-chloro-5-methyl-3-nitro-pyridine in acetonitrile (5 mL) is added 0.098 g (0.50 mmol) of 1-(2-piperidin-4-yl-ethyl)-piperidine. The mixture is heated in a microwave reactor at 100° C. for 10 minutes then cooled to room temperature. To this solution is added 0.010 g (0.009 mmol) of 10% palladium on carbon. The mixture is placed under an atmosphere of hydrogen and stirred overnight at room temperature. The mixture is filtered and concentrated under reduced pressure to give 0.151 g (quant.) of 5′-methyl-4-(2-piperidin-1-yl-ethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-ylamine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:11]=3[N:12]=2)[CH:5]=[CH:6][CH:7]=1.[CH:18]1[C:23]([C:24]([OH:26])=[O:25])=[CH:22][C:21]2[C:27]([O:29][C:30](=O)[C:20]=2[CH:19]=1)=[O:28]>>[Cl:17][C:14]1[CH:15]=[CH:16][C:10]2[O:9][C:8]([C:4]3[CH:3]=[C:2]([N:1]4[C:27](=[O:28])[C:21]5[C:20](=[CH:19][CH:18]=[C:23]([C:24]([OH:26])=[O:25])[CH:22]=5)[C:30]4=[O:29])[CH:7]=[CH:6][CH:5]=3)=[N:12][C:11]=2[CH:13]=1
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Reactant: Nc1cccc(-c2nc3cc(Cl)ccc3o2)c1
Product: O=C(O)c1ccc2c(c1)C(=O)N(c1cccc(-c3nc4cc(Cl)ccc4o3)c1)C2=O

Procedure:
Prepared by the method of Example 1b), from 2-(3-aminophenyl)-5-chlorobenzoxazole (34 mg, 0.14 mmol) and 1,2,4-benzenetricarboxylic anhydride (30 mg, 0.16 mmol) the title compound was obtained, 38 mg (64%). 1H NMR (DMSO) δ 8.48(dd, 1H), 8.39(bd, 2H), 8.30(dt, 1H), 8.16(d, 1H), 8.00(d, 1H), 7.88(m, 4H), 7.54(dd, 1H). MS 417 m/z (M−H)−.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:38]=[CH:39][CH:40]=1)[NH:18][C:19]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:20]=1[C:21]([NH:23][O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:22]>>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([N:18]2[C:19]3[C:20](=[CH:32][C:33]([F:37])=[C:34]([F:36])[CH:35]=3)[C:21](=[O:22])[N:23]([O:24][CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:1]2=[O:2])[CH:38]=[CH:39][CH:40]=1
Reactant: COc1cccc(Nc2cc(F)c(F)cc2C(=O)NOCc2ccccc2)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Product: COc1cccc(-n2c(=O)n(OCc3ccccc3)c(=O)c3cc(F)c(F)cc32)c1
Yield: 18.7 %

Procedure:
Using General Method 3, the reaction of carbonyldiimidazole (5.5 g, 33.8 mmol) and crude 2-(3-methoxy-anilino)-N-benzyloxy-4,5-difluoro-benzamide (Example X, 6.5 g, 16.9 mmol) provided 1.3 g of the title compound as a solid, mp 157-158° C.
Reaction SMILES: C1(N[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)CCCC1.[F:23][C:24]1[CH:25]=[C:26]([NH2:31])[CH:27]=[C:28]([F:30])[CH:29]=1>>[F:23][C:24]1[CH:25]=[C:26]([NH:31][C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)[CH:27]=[C:28]([F:30])[CH:29]=1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Reactant: Nc1cc(F)cc(F)c1
Product: Cc1nc(NCc2ccccn2)nc(Nc2cc(F)cc(F)c2)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using (3,5-difluorophenyl)amine instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (300 MHz, CDCl3) δ ppm 2.07 (s, 3H), 2.34 (s, 3H), 4.73 (d, J=3.1 Hz, 2H), 5.93 (bs, 1H), 6.39-6.49 (m, 2H), 7.13-7.22 (m, 3H), 7.34 (d, J=7.8 Hz, 1H), 7.63 (t, J=5.9 Hz, 1H), 8.59 (d, J=3.8 Hz, 1H); MS (ESI) m/z 342.7 (M+1)+.
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.CN(C)C1C=CC=CC=1.[Cl:16][C:17]1[CH:26]=[CH:25][C:24]2[NH:23][CH2:22][C:21]3[CH:27]=[N:28][N:29]([CH3:30])[C:20]=3[C:19]=2[CH:18]=1>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[Cl:16][C:17]1[CH:26]=[CH:25][C:24]2[N:23]([C:4]([CH:1]3[CH2:3][CH2:2]3)=[O:5])[CH2:22][C:21]3[CH:27]=[N:28][N:29]([CH3:30])[C:20]=3[C:19]=2[CH:18]=1
Reactant: O=C(Cl)C1CC1
Reactant: Cn1ncc2c1-c1cc(Cl)ccc1NC2
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: Cn1ncc2c1-c1cc(Cl)ccc1N(C(=O)C1CC1)C2
Reaction time: 2 h

Procedure:
Cyclopropanecarbonyl chloride (1.5 ml) was addded dropwise to a mixture of N,N-dimethylaniline (2.4 ml), 4-dimethylaminopyridine (5.0 mg) and 8-chloro-4,5-dihydro-1-methyl-1H -pyrazolo[4,3-c]quinoline (2.0 g) in chloroform (20 ml) at 0° C. and the mixture was allowed to stir at that temperature for 2 hours. After the solvent was evaporated in vacuo, the residue was mixed with 5% hydrochloric acid and extracted with ethyl acetate. The extract was washed with 5% hydrochloric acid, saturated aqueous sodium hydrogen carbonate and water and then dried over magnesium sulfate. The solvent was evaported in vacuo to give light brown powder (2. 0 g), which was recrystallized from a mixture of n-hexane and ethyl acetate to afford 8-chloro-5-cyclopropylcarbonyl-4,5-dihydro-1-methyl-1H-pyrazolo[4,3-c]quinoline as colourless prisms.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH:13]([C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[C:21](=[O:25])[CH2:20][CH2:19][CH2:18]2)=[CH2:14].[C:26]1([C:32]2[O:36][N:35]=[C:34]([C:37](F)=[O:38])[C:33]=2[C:40]([F:43])([F:42])[F:41])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1>[C:26]1([C:32]2[O:36][N:35]=[C:34]([C:37]([CH:20]3[CH2:19][CH2:18][C:17]4[C:22](=[CH:23][CH:24]=[C:15]([CH:13]=[CH2:14])[CH:16]=4)[C:21]3=[O:25])=[O:38])[C:33]=2[C:40]([F:42])([F:43])[F:41])[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: C=Cc1ccc2c(c1)CCCC2=O
Reactant: O=C(F)c1noc(-c2ccccc2)c1C(F)(F)F
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C=Cc1ccc2c(c1)CCC(C(=O)c1noc(-c3ccccc3)c1C(F)(F)F)C2=O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 64.9 %

Procedure:
To a heat gun dried 100 mL 2-necked flask was added diisopropylamine (0.910 mL, 6.39 mmol) under a nitrogen atmosphere followed by THF (5 mL). The flask was cooled to 0° C. and n-BuLi (2.55 mL, 6.39 mmol) was added dropwise over a period of 2 min. The contents were stirred at 0° C. for 20 min., cooled to −78° C. and 6-vinyl-3,4-dihydronaphthalen-1(2H)-one (I-1B, 1 g, 5.81 mmol) dissolved in 2 mL of THF was added dropwise over a period of 3 min. The pale yellow reaction mixture was stirred at −78° C. for 20 min. Then 5-phenyl-4-(trifluoromethyl)isoxazole-3-carbonyl fluoride (I-14, 1.505 g, 5.81 mmol) dissolved in 2 mL of THF was added dropwise over a period of 2 min. The reaction mixture was stirred at −78° C. for 20 min, bought to room temperature and stirred at room temperature for 10 min. The reaction mixture was quenched with 1N HCl (5 mL) and extracted into EtOAc (20 mL). The aqueous layer was re-extracted with EtOAc (10 mL). The combined organic layers were dried over sodium sulfate concentrated and purified by column chromatography using an ISCO setup (80 g, RediSep® silica gel column). The desired fractions were collected and concentrated to yield 2-(5-phenyl-4-(trifluoromethyl)isoxazole-3-carbonyl)-6-vinyl-3,4-dihydronaphthalen-1(2H)-one (1.55 g, 3.77 mmol, 64.9% yield) as a yellow solid. LC/MS M+1=412.12.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][N:17](C(OC(C)(C)C)=O)[CH2:18][CH2:19][C:20]=4[C:11]=3[CH:10]=[N:9]2)=[CH:5][CH:4]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][NH:17][CH2:18][CH2:19][C:20]=4[C:11]=3[CH:10]=[N:9]2)=[CH:28][CH:29]=1
Reactant: COc1ccc(Cn2ncc3c4c(cnc32)CN(C(=O)OC(C)(C)C)CC4)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(Cn2ncc3c4c(cnc32)CNCC4)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 81.1 %

Procedure:
To a solution of tert-butyl 3-(4-methoxybenzyl)-8,9-dihydro-3H-pyrazolo[3,4-c][2,7]naphthyridine-7(6H)-carboxylate (3.5 g, 8.8 mmol) in dichloromethane (35 mL) at room temperature was added trifluoroacetic acid (5.04 g, 44.4 mmol) in a drop wise manner. The reaction mixture was stirred at room temperature for 5 hours. Once the reaction was complete the solvent was removed under reduced pressure and the resulting residue was triturated with diethyl ether to give a solid. The solid was filtered, washed with diethyl ether and dried under reduce pressure. The dried solid was then dissolved in water and basified with saturated Na2CO3 solution. The aqueous layer was extracted with 10% methanol in CH2Cl2 (3×150 mL). The organic extracts were combined, dried using sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was triturated with hexane to afford the pure desired product 3-(4-methoxy-benzyl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c][2,7]naphthyridine as a white solid (2.1 g, 80%). M.p.=96-102° C. 1H NMR (400 MHz, CDCl3) δ 8.22 (s, 1H), 7.93 (s, 1H), 7.26 (d, J=8.4 Hz, 2H), 6.80 (d, J=8.4 Hz, 2H), 5.61 (s, 2H), 4.11 (s, 2H), 3.73 (s, 3H), 3.219 (t, J=6 Hz, 2H), 3.016 (t, J=6 Hz, 2H) LCMS [M+H]: 295.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.[C:11]1(=O)[CH2:16][CH2:15][CH2:14][C:13](=[O:17])[CH2:12]1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[NH:9][C:11]1[CH2:16][CH2:15][CH2:14][C:13](=[O:17])[C:12]2=1
Reactant: COc1ccc(NN)cc1
Reactant: O=C1CCCC(=O)C1
Solvent: Cc1ccccc1
Product: COc1ccc2[nH]c3c(c2c1)C(=O)CCC3
Yield: 65.5 %

Procedure:
To a mixture of 4-methoxyphenyl hydrazine (0.359 g, 2.06 mmol) in toluene (30 mL) is added 1,3 cyclohexanedione (0.231 g, 2.06 mmol). The mixture is refluxed for 30 minutes. The toluene is removed under reduced pressure and the residue triturated in CH2Cl2: CH3OH (95:5). A white solid is filtered to give 0.2903 g (65%) of the title compound; IR (drift) 3160, 3141, 3114, 3064, 1619, 1588, 1474, 1434, 1277, 1215, 1140, 1015, 844, 802, 791 cm−1. MS (ESI+) for C13H13N1O2 m/z 216 (M+H)+. 1H NMR (DMSO-d6) δ2.08, 2.39, 2., 3.74, 6.74, 7.25, 7.43; Anal Calcd for C13H13NO2: C, 72.54; H, 6.09; N, 6.51. Found: C, 71.48; H, 6.06; N, 6.45.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=1[Cl:11].[Br-:13].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl.CO>[CH3:1][O:2][C:3](=[O:12])[C:4]1[C:9]([Br:13])=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=1[Cl:11]
Reactant: [Br-]
Reactant: COC(=O)c1cc(N)ccc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1c(Cl)ccc(N)c1Br
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 28 %

Procedure:
To a solution of 5-amino-2-chloro-benzoic acid methyl ester (6.76 g, 36.4 mmol) in dichloromethane (100 mL) and methanol (50 mL) was added tetra-n-butylammonium tribromide (17.7 g, 36.4 mmol). The mixture was stirred at 25° C. for 90 minutes. Sodium thiosulfate (10% aqueous solution) was added and the mixture was extracted with dichloromethane. The combined extracts were washed with water, dried (Na2SO4), filtered, and concentrated to dryness under reduced pressure. The crude material was purified by flash column chromatography (hexane/acetone 8:2). Fractions with the desired product were concentrated to small volume. The resulting suspension was allowed to stand for two hours and was then filtered to obtain 5-amino-6-bromo-2-chloro-benzoic acid methyl ester as a white solid (2.7 g, 28%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:17][CH2:16][C:11]3(OCC[O:12]3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.O.[OH-].[Na+]>FC(F)(F)C(O)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:9][CH2:10][C:11](=[O:12])[CH2:16][CH2:17]2)=[N:6][CH:7]=1
Reactant: Brc1ccc(C2CCC3(CC2)OCCO3)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C1CCC(c2ccc(Br)cn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103 %

Procedure:
5-Bromo-2-(1,4-dioxaspiro[4,5]decane-8-yl)pyridine (9.0 g) described in Reference Example 102(2) was dissolved in trifluoroacetic acid (15 ml) and stirred at room temperature overnight. After completion of the reaction, water was added under ice cooling, neutralized by the addition of 4N aqueous solution of sodium hydroxide and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to give 4-(5-bromopyridin-2-yl)cyclohexanone (7.9 g) as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH:4]([CH3:21])[CH2:5][C:6]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:9]([OH:16])=[C:8]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:7]=1.[CH2:23](O)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]C.C([Sn](=O)CCCC)CCC>>[CH2:1]([O:2][C:3](=[O:22])[CH:4]([CH3:21])[CH2:5][C:6]1[CH:7]=[C:8]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:9]([OH:16])=[C:10]([C:12]([CH3:14])([CH3:13])[CH3:15])[CH:11]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: COC(=O)C(C)Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: CCCCCCCCCO
Agent: CCCC[Sn](=O)CCCC
Product: CCCCCCCCCOC(=O)C(C)Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 100 °C

Procedure:
30.6 g of methyl-2-methyl-3-(3',5'-di-tert.-butyl-4'-hydroxyphenyl)-propionate and 14.4 g of n-nonyl alcohol are placed in a 100 ml sulfonating flask and heated to 100° C. 0.2 g of dibutyltin oxide is added and the temperature is increased to 150° C. Methyl alcohol is split off from a temperature of 125° C. The reaction is maintained at 150° C. for 6 hours.
Reaction SMILES: [C:1]1([CH3:20])[CH:6]=[CH:5][C:4]([CH:7]2[C:11]3[NH:12][C:13]([C:15]([O:17]CC)=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[OH-].[Na+].CO>C1COCC1>[C:1]1([CH3:20])[CH:2]=[CH:3][C:4]([CH:7]2[C:11]3[NH:12][C:13]([C:15]([OH:17])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8]2)=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1cc2c([nH]1)C(c1ccc(C)cc1)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(C2CCc3cc(C(=O)O)[nH]c32)cc1
Yield: 51 %

Procedure:
The title compound was synthesized from ethyl 6-p-tolyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.1423 g, 0.56 mmol, 1 equiv) and sodium hydroxide (1.4 mL, 14 mmol, 10M, 25 equiv), according to General Procedure 7. A 4-5:1 mixture of methanol (MeOH) and THF (5-6 mL) was used. The resulting product was purified by preparative HPLC using the Chromeleon purification system. A 0.1% formic acid/1% acetonitrile mixture in water (aqueous phase) and methanol (no modifier added—organic phase) using a 50 mm Dynamax HPLC C-18 column at 28 mL/min (initial gradient of 40% methanol and increasing to 100% over 7 minutes) afforded the title compound (68.9 mg, 51%) with purity by HPLC of 97.9% (UV). LCMS m/e 240.2 (M−H). 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.17-2.26 (m, 1H), 2.29 (s, 3H), 2.62 (ddd, J=14.43, 6.06, 5.84 Hz, 1H), 2.68-2.77 (m, 1H), 2.85-2.96 (m, J=8.63, 8.49, 8.49, 4.20 Hz, 1H), 4.21 (dd, J=8.47, 5.42 Hz, 1H), 6.66 (s, 1H), 6.94-7.03 (m, 2H), 7.09 (d, J=7.91 Hz, 2H).
Reaction SMILES: C(OC([N:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][N:12]([CH2:16][C:17]3[S:18][C:19]4[C:24]([N:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[N:23][C:22]([Cl:31])=[N:21][C:20]=4[N:32]=3)[CH2:13]2)[CH2:9]1)=O)(C)(C)C.N1CCC(N2C[CH2:43][O:42][CH2:41][CH2:40]2)CC1>>[Cl:31][C:22]1[N:23]=[C:24]([N:25]2[CH2:26][CH2:27][O:28][CH2:29][CH2:30]2)[C:19]2[S:18][C:17]([CH2:16][N:12]3[CH2:13][CH2:14][CH:9]([N:8]4[CH2:40][CH2:41][O:42][CH2:43][CH2:15]4)[CH2:10][CH2:11]3)=[N:32][C:20]=2[N:21]=1
Reactant: CC(C)(C)OC(=O)N1CC2CN(Cc3nc4nc(Cl)nc(N5CCOCC5)c4s3)CC2C1
Reactant: C1CC(N2CCOCC2)CCN1
Product: Clc1nc(N2CCOCC2)c2sc(CN3CCC(N4CCOCC4)CC3)nc2n1

Procedure:
Prepared according to the method used in the preparation of 5-(5-chloro-7-morpholin-4-ylthiazolo[4,5-d]pyrimidin-2-ylmethyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester using 4-piperidin-4-ylmorpholine in place of hexahydro-pyrrolo[3,4-e]pyrrole-2-carboxylic acid tert-butyl ester. The title compound was obtained as a yellow solid (220 mg, 39%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:14])[CH2:9][CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:15]1([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][C:22]([O:24][CH:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][N:33]([CH3:60])[C:34](=[O:59])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][N:40]([C:51]2[CH:56]=[CH:55][C:54]([NH:57][CH3:58])=[CH:53][CH:52]=2)[C:41](=[O:50])[O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:27][CH2:26]1)=[O:23]>>[C:15]1([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][C:22]([O:24][CH:25]1[CH2:26][CH2:27][N:28]([CH2:31][CH2:32][N:33]([CH3:60])[C:34](=[O:59])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][N:40]([C:51]2[CH:56]=[CH:55][C:54]([N:57]([C:11](=[O:13])[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH3:14])[CH3:58])=[CH:53][CH:52]=2)[C:41](=[O:50])[O:42][CH2:43][C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH2:29][CH2:30]1)=[O:23]
Reactant: CN(CCC(=O)O)C(=O)OC(C)(C)C
Reactant: CNc1ccc(N(CCCCCC(=O)N(C)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)C(=O)OCc2ccccc2)cc1
Product: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCCN(C(=O)OCc1ccccc1)c1ccc(N(C)C(=O)CCN(C)C(=O)OC(C)(C)C)cc1
Yield: 112.2 %

Procedure:
N-(tert-Butoxycarbonyl)-N-methyl-β-alanine (41 mg, 0.19 mmol) and the compound (150 mg, 0.21 mmol) obtained in Example 97c were used to give the title compound (190 mg; yield, 100%) as a white solid according to the method described in Example 41a.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[C:24](O)(=[O:29])[CH2:25][CH2:26][CH2:27][CH3:28]>>[CH3:1][O:2][C:3]([N:5]1[C@H:13]2[C@H:8]([C@:9]([O:23][C:24](=[O:29])[CH2:25][CH2:26][CH2:27][CH3:28])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Reactant: CCCCC(=O)O
Product: CCCCC(=O)O[C@@]1(C#Cc2cccc(C)c2)CCC[C@@H]2[C@H]1CCN2C(=O)OC

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and pentanoic acid to yield (3aR,4S,7aR)-4-pentanoyloxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester. MS [M+Na]=420; RT=8.337 min; LC-MS Method III
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8](=O)[NH:7][C:6]=2[CH:17]=1.[CH3:18][CH:19]1[CH2:24][NH:23][CH2:22][CH:21]([CH3:25])[NH:20]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8]([N:23]3[CH2:22][CH:21]([CH3:25])[NH:20][CH:19]([CH3:18])[CH2:24]3)=[N:7][C:6]=2[CH:17]=1
Reactant: O=C1Nc2cc(Cl)ccc2Nc2ccccc21
Reactant: CC1CNCC(C)N1
Product: CC1CN(C2=Nc3cc(Cl)ccc3Nc3ccccc32)CC(C)N1
Yield: 52.8 %

Procedure:
8-Chloro-5,10-dihydro-dibenzo[b,e][1,4]diazepine-11-one (25 mg, 0.1 mmol) and 2,6-dimethylpiperazine (114 mg, 1.0 mmol) were reacted according to GP4 to give 18 mg of the title compound (160FE33B). MS (ESI) 341 (MH+). Purity for MH+ (UV/MS) 100/100.