Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[N:17]=[CH:16][C:15]([C:21]([CH:23]2[CH2:25][CH2:24]2)=[O:22])=[C:14]3[NH:26][C@H:27]2[CH2:32][CH2:31][C@H:30]([N:33](C)[C:34](=O)OC(C)(C)C)[CH2:29][CH2:28]2)[CH:5]=[C:6]([O:9][CH3:10])[C:7]=1[OH:8].C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[N:17]=[CH:16][C:15]([C:21]([CH:23]2[CH2:24][CH2:25]2)=[O:22])=[C:14]3[NH:26][C@H:27]2[CH2:32][CH2:31][C@H:30]([NH:33][CH3:34])[CH2:29][CH2:28]2)[CH:5]=[C:6]([O:9][CH3:10])[C:7]=1[OH:8]
Reactant: COc1cc(-c2ccc3ncc(C(=O)C4CC4)c(N[C@H]4CC[C@H](N(C)C(=O)OC(C)(C)C)CC4)c3c2)cc(Cl)c1O
Solvent: O=C(O)C(F)(F)F
Product: CN[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(Cl)c(O)c(OC)c4)cc23)CC1

Procedure:
Following general procedure A-2, tert-butyl trans-4-[6-(3-chloro-4-hydroxy-5-methoxyphenyl)-3-(cyclopropanecarbonyl)quinolin-4-ylamino]cyclohexyl(methyl)carbamate (0.135 mmol) was reacted with TFA (2 mL) to afford the desired product (41 mg, 63% over two steps) as a yellow solid: 1H NMR (300 MHz, CD3OD+TFA-d) δ 9.34 (s, 1H), 8.48 (s, 1H), 8.31 (d, J=8.7 Hz, 1H), 7.99 (d, J=8.7 Hz, 1H), 7.35 (s, 1H), 7.27 (s, 1H), 4.50 (s, 1H), 4.00 (s, 3H), 2.88-2.81 (m, 1H), 2.74 (s, 3H), 2.54-2.47 (m, 2H), 2.38-2.27 (m, 2H), 1.88-1.77 (m, 2H), 1.62-1.56 (m, 2H), 1.34-1.16 (m, 4H); ESI MS m/z 480 [C27H30ClN3O3+H]+; HPLC>99% (AUC), tR=9.45 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([C:12]1[CH:13]=[C:14]([CH:28]=[CH:29][CH:30]=1)[O:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]2[CH:22]=[C:23]([C:25]([OH:27])=O)[S:24][C:17]=12)=[O:11].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl.Cl.[NH2:75][CH2:76][CH2:77][CH2:78][NH:79][CH2:80][C:81]([O:83][CH3:84])=[O:82]>CN(C=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([C:12]1[CH:13]=[C:14]([CH:28]=[CH:29][CH:30]=1)[O:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]2[CH:22]=[C:23]([C:25]([NH:75][CH2:76][CH2:77][CH2:78][NH:79][CH2:80][C:81]([O:83][CH3:84])=[O:82])=[O:27])[S:24][C:17]=12)=[O:11]
Reactant: Cc1ccc(F)c(NC(=O)c2cccc(Oc3ccnc4cc(C(=O)O)sc34)c2)c1
Reactant: COC(=O)CNCCCN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CNCCCNC(=O)c1cc2nccc(Oc3cccc(C(=O)Nc4cc(C)ccc4F)c3)c2s1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a stirred, cooled (0° C.) solution of 7-(3-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)thieno[3,2-b]pyridine-2-carboxylic acid (80 mg, 0.19 mmol) in anhydrous DMF (10 ml) were added PyBOP (109 mg, 0.21 mmol) and N,N-diisopropylethylamine (123 mg, 0.95 mmol). The mixture was stirred at 0° C. for 10 minutes, followed by addition of methyl [(3-aminopropyl)amino]acetate dihydrochloride (50 mg, 0.23 mmol). Stirring was continued at 0° C. for 10 minutes then room temperature for 2 hours. The mixture was poured into 100 ml of water with vigorous stirring. The precipitates were filtered, washed with water and dried to give the crude, which was purified by silica gel chromatography eluting with 5-8% methanol in chloroform to give methyl {[3-({[7-(3-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)thieno[3,2-b]pyridin-2-yl]carbonyl}amino)propyl]amino}acetate as light beige solid. Yield: 40 mg, 38%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]=[C:11]([C@@H:13]([N:15]3C(=O)C4C(=CC=CC=4)C3=O)[CH3:14])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.CNN>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]=[C:11]([C@@H:13]([NH2:15])[CH3:14])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H](c1nc(-c2cccc(Cl)c2)no1)N1C(=O)c2ccccc2C1=O
Agent: CNN
Solvent: CCO
Product: C[C@H](N)c1nc(-c2cccc(Cl)c2)no1
Temperature: 80 °C
Reaction time: 13 h
Yield: 79 %

Procedure:
To a stirred solution of (S)-2-(1-(3-(3-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethyl)isoindoline-1,3-dione (100 mg, 0.283 mmol) in ethanol (5 ml) was added methylhydrazine (16 μL, 0.311 mmol). Stir for 13 hours at 80° C. Concentrate in vacuo. Flash column chromatography (silica, 40 g) eluting with dichloromethane afforded 50 mg of desired product. HRMS m/z 224.4 (M+H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[CH2:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][NH:33]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:29])([F:30])[F:31])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([N:33]4[CH2:34][C:35]5[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=5)[CH2:32]4)=[O:23])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Reactant: c1ccc2c(c1)CNC2
Product: O=C(c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1)N1Cc2ccccc2C1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1,3-dihydroisoindole as in General Procedure 10 to give the title compound. LCMS: m/z=548.94 (M+H+); retention time=0.94 minutes.
Reaction SMILES: [NH2:1][CH:2]([C:22]1[CH:31]=[CH:30][C:29]2[C:28]([CH3:33])([CH3:32])[CH2:27][CH2:26][C:25]([CH3:35])([CH3:34])[C:24]=2[CH:23]=1)[C:3]([NH:5][C:6]1[CH:21]=[CH:20][C:9]([C:10]([O:12]CC2C=CC=CC=2)=[O:11])=[CH:8][CH:7]=1)=[O:4].C1C[O:39][CH2:38][CH2:37]1.C(N(CC)CC)C.C(Cl)(=O)C>O>[C:38]([NH:1][CH:2]([C:22]1[CH:31]=[CH:30][C:29]2[C:28]([CH3:33])([CH3:27])[CH2:32][CH2:34][C:25]([CH3:26])([CH3:35])[C:24]=2[CH:23]=1)[C:3]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([OH:12])=[O:11])=[CH:20][CH:21]=1)=[O:4])(=[O:39])[CH3:37]
Reactant: C1CCOC1
Reactant: CC1(C)CCC(C)(C)c2cc(C(N)C(=O)Nc3ccc(C(=O)OCc4ccccc4)cc3)ccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(=O)Cl
Product: CC(=O)NC(C(=O)Nc1ccc(C(=O)O)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
1.5 g (3.2 mmol) of benzyl 4-[α-amino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido]benzoate, 75 ml of THF and 490 μl (3.5 mmol) of triethylamine were introduced into a round-bottomed flask. 250 μl (3.5 mmol) of acetyl chloride were added dropwise and the mixture was stirred at room temperature for 2 hours. The reaction medium was poured into water, extracted with ethyl acetate, the organic phase decanted, dried over magnesium sulfate and evaporated. The residue obtained was triturated in hexane, filtered and dried. 1.6 g (94%) of the expected compound of melting point 258°-259° C. was obtained.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].[H-].[Na+].[I:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Br)=[CH:12][CH:11]=1>CN(C)C=O>[I:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][N:1]2[CH2:5][CH2:4][CH2:3][C:2]2=[O:6])=[CH:12][CH:11]=1
Reactant: O=C1CCCN1
Reactant: BrCc1ccc(I)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCCN1Cc1ccc(I)cc1
Temperature: 25 °C
Yield: 98.6 %

Procedure:
A solution of 2-pyrrolidinone (850 mg, 10 mmol) in dimethylformamide (40 ml) was cooled in an ice/methanol bath with stirring under an atmosphere of argon. Then a solid suspension of sodium hydride (60% in mineral oil, 440 mg, 11 mmol) was added portionwise over 10 minutes. The reaction mix was allowed to stir with cooling for 30 minutes, then 4-iodobenzyl bromide (2.97 g, 10 mmol) was added portionwise over 10 minutes. The whole mix was allowed to warm slowly up to room temperature then stirred for a further 2 hours. The reaction mixture was partitioned between ethyl acetate (100 ml), and water (200 ml), the organic layer was removed and reduced to minimum volume under reduced pressure. The residue was purified by column chromatography on a 20 g pre-packed silica column eluting from 0-100% ethyl acetate in petroleum ether to give the title compound as a yellow solid (2.97 g, 99%).
Reaction SMILES: [O:1]([CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:18][OH:19]>>[O:1]([CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][C:13](=[N:18][OH:19])[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=C1CCN(CCOc2ccccc2)CC1
Agent: Cl
Product: ON=C1CCN(CCOc2ccccc2)CC1

Procedure:
1-(2-Phenoxyethyl)-4-piperidone oxime is prepared from 1-(2-phenoxyethyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.
Reaction SMILES: Cl.Cl.[N:3]1([C:10]2[CH:11]=[C:12]([CH:20]([CH3:22])[CH3:21])[CH:13]=[C:14]3[C:19]=2[N:18]=[CH:17][CH:16]=[CH:15]3)[CH2:9][CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.Cl[CH2:24][C:25]1[N:26]=[C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[S:28][CH:29]=1.C([O-])([O-])=O.[Cs+].[Cs+].CCOC(C)=O>CN(C=O)C>[CH:20]([C:12]1[CH:13]=[C:14]2[C:19](=[C:10]([N:3]3[CH2:9][CH2:8][CH2:7][N:6]([CH2:24][C:25]4[N:26]=[C:27]([C:30]5[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=5)[S:28][CH:29]=4)[CH2:5][CH2:4]3)[CH:11]=1)[N:18]=[CH:17][CH:16]=[CH:15]2)([CH3:22])[CH3:21]
Reactant: ClCc1csc(-c2ccccc2)n1
Reactant: CC(C)c1cc(N2CCCNCC2)c2ncccc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)c1cc(N2CCCN(Cc3csc(-c4ccccc4)n3)CC2)c2ncccc2c1
Temperature: 60 °C
Yield: 49.7 %

Procedure:
A mixture of 8-[1,4]-diazepan-1-yl-6-isopropyl-quinoline dihydrochloride (0.34 g, 1 mmol, 1 equiv), 4-chloromethyl-2-phenyl-thiazole (0.21 g, 1 equiv) and Cs2CO3 (1.63 g, 5 equiv) in 5 mL of DMF was heated to 60° C. for 3 hours and then cooled to room temperature. EtOAc (˜70 mL) was added and the mixture washed with saturated aqueous NaHCO3 (70 mL) and brine (70 mL), dried over magnesium sulfate and concentrated. The residue was purified by silica gel flash column chromatography using 5% to 40% EtOAc in hexanes. Silica gel chromatography was repeated using 5% to 10% MeOH in EtOAc to afford the title compound (0.22 g, 50%) as light tan solid. 1H NMR (400 MHz, d6-CD3OD) δ 8.66 (dd, 1H, J=1.8 and 4 Hz), 8.07 (dd. 1H, J=1.5 and 8.4 Hz), 7.91 (m, 1H), 7.90 (d, 1H, J=2.2 Hz), 7.41 (m, 3H), 7.36 (s, 1H), 7.31 (dd, 1H, J=4.0 and 8.0 Hz), 7.16 (d, 1H, J=1.6 Hz), 7.04 (d, 1H, J=1.6 Hz), 3.90 (s, 2H), 3.71 (m, 2H), 3.59 (t, 2H, J=5.6 Hz), 3.11 (m, 2H), 2.92 (m, 3H), 2.10 (m, 2H), 1.31 (d, 6H, J=7.2 Hz). MS (ES) m/z 443.2 (M+H+).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]2[NH:10][C:11]([CH3:13])=[CH:12][C:5]=12.[CH3:14]I>C1COCC1>[Br:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]2[N:10]([CH3:14])[C:11]([CH3:13])=[CH:12][C:5]=12
Reactant: Cc1cc2c(Br)ccnc2[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc2c(Br)ccnc2n1C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 63.1 %

Procedure:
NaH (60% in oil dispersion) (1.228 g, 30.7 mmol) was suspended in THF (60 mL) and the mixture cooled to 0° C. A solution of 4-bromo-2-methyl-1H-pyrrolo[2,3-b]pyridine (D24) (3.24 g, 15.35 mmol) in THF (30.0 ml) was added dropwise to the mixture and allowed to stir at that temperature for 15 mins, after which MeI (1.440 mL, 23.03 mmol) was added dropwise. The final mixture was stirred at 0° C. for 15 min and then at RT for ca. 3 hours. The reaction mixture was quenched with NH4Cl solution (ca. 100 mL), extracted with ethyl acetate (50 mL×3). The combined organics were dried over MgSO4 and concentrated. The residue was purified by chromatography on silica, eluting with a gradient of 0-50% ethyl acetate in cyclohexane. The corresponding fractions were combined to give the title compound (2.18 g, approx. 47% purity) which was used without further purification in the next stage. LCMS (A): m/z (M+H)+ 225/227, C9H9BrN2 requires 224/226 (acidic).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.Cl.Cl.[CH3:22][N:23]([CH3:28])[CH:24]1[CH2:27][NH:26][CH2:25]1.C(N(CC)CC)C>>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([N:26]4[CH2:27][CH:24]([N:23]([CH3:28])[CH3:22])[CH2:25]4)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Reactant: CN(C)C1CNC1
Agent: Cl
Solvent: CCN(CC)CC
Product: CN(C)C1CN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)C1

Procedure:
A mixture of 0.25 g (1.32 mmoles) of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 0.34 g (12 mmoles) of 3-dimethylaminoazetidine dihydrochloride and 3.3 g (33 mmoles) of triethylamine is heated under reflux in 10 ml of pryidine for 2 hours. The mixture is evaporated under vacuum, water is added and the resulting mixture made alkaline with 1N sodium hydroxide, heated, filtered while hot, acidified with acetic acid and filtered again. After washing with water, 0.4 g (88%) of 1-cyclopropyl-6-fluoro-7-(3-dimethylamino-1-azetidinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are obtained, melting at 255°-61° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:16]=1)[C:5]([NH:7][C:8]1[CH:12]=[CH:11][N:10]([CH3:13])[N:9]=1)=[O:6].CC1C=CC(S(O[C@@H:36]2[CH2:40][CH2:39][O:38][CH2:37]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:13][N:10]1[CH:11]=[CH:12][C:8]([NH:7][C:5](=[O:6])[C:4]2[CH:3]=[C:2]([O:1][C@H:36]3[CH2:40][CH2:39][O:38][CH2:37]3)[CH:16]=[C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:14]=2)=[N:9]1
Reactant: Cn1ccc(NC(=O)c2cc(O)cc(OCc3ccccc3)c2)n1
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2CCOC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cn1ccc(NC(=O)c2cc(OCc3ccccc3)cc(O[C@H]3CCOC3)c2)n1
Temperature: 160 °C
Reaction time: 3 h
Yield: 82.7 %

Procedure:
A suspension of 3-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)-5-[(phenylmethyl)oxy]benzamide (450 mg, 1.39 mmol), (3R)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate (507 mg, 2.09 mmol) and potassium carbonate (481 mg, 3.48 mmol) in acetonitrile (5 mL) was stirred in a Smith Creator microwave at 160° C. for 3 hours. The solvent was removed in vacuo and ethyl acetate added. The organics were washed with water (40 mL), brine (40 mL), dried (MgSO4), filtered and the solvent removed in vacuo to give a yellow foam which was chromatographed on silica, eluting with a gradient of 0-100% ethyl acetate in iso-hexane, to give the title compound as a white foam (452 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:16]O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:16])=[O:10])=[CH:6][CH:7]=1
Reactant: CO
Reactant: O=C(O)Cc1ccc(Br)cc1
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1ccc(Br)cc1
Yield: 94 %

Procedure:
To a solution of 2-(4-bromophenyl)acetic acid (10 g, 47 mmol) in methanol (100 mL) was dropwise thionyl chloride (0.2 mL) at room temperature. The mixture solution was heated to reflux for 3 hours. Then removed the solvent to dry to gave methyl 2-(4-bromophenyl)acetate as a colorless oil (10 g, 94%). 1H NMR (300 MHz, CDCl3): δ 7.45 (d, J=9 Hz, 2H), 7.15 (d, J=9 Hz, 2H), 3.70 (s, 3H), 3.58 (s, 2H).
Reaction SMILES: C([O:3][C:4](=O)[NH:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[C:13]#[N:14])C.[CH3:16][O:17][CH2:18][C:19]([NH:21][NH2:22])=O>>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]2[NH:5][C:4](=[O:3])[N:22]3[N:21]=[C:19]([CH2:18][O:17][CH3:16])[N:14]=[C:13]3[C:7]=2[CH:8]=1
Reactant: COCC(=O)NN
Reactant: CCOC(=O)Nc1ccc(Cl)cc1C#N
Product: COCc1nc2c3cc(Cl)ccc3[nH]c(=O)n2n1
Yield: 88 %

Procedure:
As described for example 1a) (4-chloro-2-cyano-phenyl)-carbamic acid ethyl ester (71.0 g, 316 mmol) using methoxymethyl-carboxylic acid hydrazide instead of cyclopropane-carboxylic acid hydrazide, was converted to the title compound (73.9 g, 88%) which was obtained as a yellow solid. MS: m/e=264.9 [M+H]+.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][CH2:6][CH2:5]1.Cl.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:20]=[CH:21][C:22]=1[O:23][CH3:24].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[C:39]([OH:46])(=[O:45])/[CH:40]=[CH:41]/[C:42]([OH:44])=[O:43]>CC(=O)CC.C(O)(C)C.C(OCC)(=O)C>[C:39]([OH:46])(=[O:45])/[CH:40]=[CH:41]/[C:42]([OH:44])=[O:43].[O:7]1[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH:4]([CH2:3][CH2:2][N:28]2[CH2:27][CH2:26][CH:25]([C:19]3[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:17]([O:16][CH3:15])[CH:18]=3)[CH2:30][CH2:29]2)[CH2:5][CH2:6]1
Reactant: COc1ccc(C2CCNCC2)cc1OC
Reactant: BrCCC1CCOc2ccccc21
Agent: Cl
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])[O-]
Solvent: CCC(C)=O
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: COc1ccc(C2CCN(CCC3CCOc4ccccc43)CC2)cc1OC
Yield: 80.4 %

Procedure:
The procedure of Example 2 is followed, but starting with the A isomer of 4-(2-bromoethyl)-3,4-dihydro-(2H)-benzopyran (1.5 g) and 4-(3,4-dimethoxyphenyl)piperidine hydrochloride (1.78 g), followed by dry potassium carbonate (1.71 g) and by potassium iodide (1.03 g) in 2-butanone (50 cc). The oil obtained is taken up with ethyl acetate (50 cc). The organic phase is washed with a 1N solution of sodium hydroxide (10 cc) and then with water and is then dried over magnesium sulphate. It is then concentrated to dryness under reduced pressure and the residue is chromatographed on a column 3 cm in diameter, containing silica gel (25 g), using a dichloromethane-acetone mixture (70-30 by volume) as eluent and collecting 100-cc fractions. The first five fractions are concentrated to dryness. The oil obtained is dissolved while hot in the minimum quantity of isopropyl alcohol and then this solution is added to a warm solution of fumaric acid (0.696 g) in isopropyl alcohol. After return to a temperature in the region of 20° C., the crystals formed are filtered off and then recrystallized from isopropanol (100 cc). The A isomer of 1-[2-(3,4-dihydro-1(2H)-benzopyran-4-yl)ethyl]-4-(3,4-dimethoxyphenyl)piperidine fumarate (2.4 g) is thus obtained in the form of a white solid melting at 170° C.
Reaction SMILES: C([NH:8][C:9]1[C:10]([CH3:30])=[C:11]([CH3:29])[C:12]2[O:16][C@@H:15]([CH3:17])[C@@H:14]([C:18]3[CH:23]=[CH:22][C:21]([CH:24]([CH3:26])[CH3:25])=[CH:20][CH:19]=3)[C:13]=2[C:27]=1[CH3:28])C1C=CC=CC=1>CCCCCC>[CH:24]([C:21]1[CH:22]=[CH:23][C:18]([C@H:14]2[C:13]3[C:27]([CH3:28])=[C:9]([NH2:8])[C:10]([CH3:30])=[C:11]([CH3:29])[C:12]=3[O:16][C@H:15]2[CH3:17])=[CH:19][CH:20]=1)([CH3:26])[CH3:25]
Reactant: Cc1c(C)c2c(c(C)c1NCc1ccccc1)[C@H](c1ccc(C(C)C)cc1)[C@H](C)O2
Solvent: CCCCCC
Product: Cc1c(C)c2c(c(C)c1N)[C@H](c1ccc(C(C)C)cc1)[C@H](C)O2
Yield: 83 %

Procedure:
Using (cis)-3-(4-isopropylphenyl)-2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran obtained in Reference Example 352, (cis)-5-bromo-3-(4-isopropylphenyl)-2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran was synthesized in the same manner as in Reference Example 23. Using the compound, (cis)-N-benzyl-3-(4-isopropylphenyl)-2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-amine was synthesized in the same manner as in Reference Example 24. Using the compound, the title compound was synthesized in the same manner as in Reference Example 30. Yield: 83%. Melting point: 91-92° C. (hexane).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([C:5]([F:8])([F:7])[F:6])=[O:4].[CH3:11][C:12](=[CH2:14])[CH3:13].C(=O)=O.CC(O)C>>[F:1][C:2]([F:10])([F:9])[C:3]([C:5]([F:8])([F:7])[F:6])([OH:4])[CH2:13][C:12]([CH3:14])=[CH2:11]
Reactant: C=C(C)C
Reactant: O=C(C(F)(F)F)C(F)(F)F
Agent: O=C=O
Solvent: CC(C)O
Product: C=C(C)CC(O)(C(F)(F)F)C(F)(F)F
Temperature: 20 °C
Yield: 82.9 %

Procedure:
Hexafluoroacetone (238 g) and 120 g of isobutylene were condensed into a lecture bottle using Dry Ice/2-propanol cooling. The temperature was raised in the sealed vessel to 20° C. while stirring in a water bath and temperature maintained overnight. The next morning the temperature was raised to 50° C. for 2 hours. After cooling, excess isobutylene was bled off and the product distilled at 100-115° C. to afford 264 g (83%) of a clear liquid. The identity of the product was confirmed using 1H NMR spectroscopy and HRMS.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH:15]([C:21]([O:23]CC)=[O:22])[C:16]([O:18]CC)=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].C1COCC1.O>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][CH:15]([C:16]([OH:18])=[O:17])[C:21]([OH:23])=[O:22])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(CC1CCN(C(=O)OC(C)(C)C)CC1)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(CC(C(=O)O)C(=O)O)CC1
Yield: 82.4 %

Procedure:
1-(tert-Butoxycarbonyl)-4-[2,2-di(ethoxycarbonyl)ethyl]piperidine (12.2 g, 34 mmol), prepared as in Example 1, Step (b), and potassium hydroxide (4.2 g, 75 mmol) were combined in ethanol (10 mL), THF (20 mL), and water (50 mL) and the mixture was heated at reflux for 3 hours. The mixture was cooled and washed with ether, acidified with sulfuric acid, and extracted into ether. The ether was dried over sodium sulfate and evaporated. Crystallization of the residue from ether gave 1-(tert-butoxycarbonyl)-4-[2,2-di(carboxy)ethyl]piperidine (8.5 g, 28 mmol) which was heated in an oil bath to 165° C. until evolution of CO2 ceased (approximately 10 minutes). The residue was cooled and upon crystallization gave 3-[l-(tert-butoxycarbonyl)piperidin-4-yl]propionic acid (7.2 g, 28 mmol), m.p. 81°-83° C.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1.C([O:17][C:18](=O)[C:19]([F:22])([F:21])[F:20])C.OS(O)(=O)=O>C1(C)C=CC=CC=1>[F:20][C:19]([F:22])([F:21])/[C:18](/[OH:17])=[CH:11]/[C:10]([C:7]1[CH:6]=[CH:5][C:4]([O:3][C:2]([F:13])([F:14])[F:1])=[CH:9][CH:8]=1)=[O:12]
Reactant: CCOC(=O)C(F)(F)F
Reactant: CC(=O)c1ccc(OC(F)(F)F)cc1
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: O=C(/C=C(\O)C(F)(F)F)c1ccc(OC(F)(F)F)cc1
Temperature: 2 °C
Reaction time: 14 h
Yield: 83.6 %

Procedure:
25 g (122 mmol) 1-(4-Trifluoromethoxy-phenyl)-ethanone were added to a suspension of 16.5 g (147 mmol) potassium-tert-butylate in 250 ml toluene. The suspension was cooled to 2° C. and 17.5 ml (147 mmol) ethyltrifluoroacetate were added within 15 min. The mixture was stirred at ambient temperature for 14 h, cooled to 2° C. and brought to pH 6 with 10% aqueous H2SO4. Twofold extraction with tert-butyl methylether was followed by washing of the combined extracts with brine/ice water 1/1 and drying of the organic layer over sodium sulfate. The solvent was removed under reduced pressure and the residue purified by flash chromatography (silica gel, dichloromethane) to give 30.5 g (102 mmol, 83%) of the title compound as red oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[O:57]=[C:58]1[CH:62]([C:63](O)=[O:64])[CH2:61][CH2:60][N:59]1[C:66]1[CH:71]=[CH:70][C:69]([CH3:72])=[CH:68][CH:67]=1>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:63]([CH:62]1[CH2:61][CH2:60][N:59]([C:66]2[CH:71]=[CH:70][C:69]([CH3:72])=[CH:68][CH:67]=2)[C:58]1=[O:57])=[O:64]
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: Cc1ccc(N2CCC(C(=O)O)C2=O)cc1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(N2CCC(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)C2=O)cc1
Yield: 42.1 %

Procedure:
This compound was prepared according to method E with 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0200 g; 0.865 mmol), PyBOP (0.450 g; 0.865 mmol), N,N diisopropylethylamine (0.373 mL; 2.16 mmol) and 2-oxo-1-p-tolylpyrrolidine-3-carboxylic acid (0.189 g; 0.865 mmol) in DMF (3 mL). The crude mixture was purified flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.144 g (42%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-oxo-1-p-tolylpyrrolidine-3-carboxamide as a white solid.