Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:21][CH2:20][CH2:19][CH2:18][O:17][C:16]=4[CH:22]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:23].Br[CH2:25][C:26]1[O:27][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=1.BrCC1CCCCO1>>[F:32][C:31]([F:34])([F:33])[C:28]1[O:27][C:26]([CH2:25][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]3([C:13]4=[CH:14][C:15]5[O:21][CH2:20][CH2:19][CH2:18][O:17][C:16]=5[CH:22]=[C:12]4[O:11][CH2:10]3)[C:2]2=[O:23])=[CH:30][CH:29]=1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCCO3
Reactant: FC(F)(F)c1ccc(CBr)o1
Agent: BrCC1CCCCO1
Product: O=C1N(Cc2ccc(C(F)(F)F)o2)c2ccccc2C12COc1cc3c(cc12)OCCCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 3,4-dihydro-2H-spiro[furo[2,3-h][1,5]benzodioxepine-9,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, and 2-(bromomethyl)-5-(trifluoromethyl)furan to replace 2-(bromomethyl)tetrahydro-2H-pyran, 1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-3,4-dihydro-2H-spiro[furo[2,3-h][1,5]benzodioxepine-9,3′-indol]-2′(1′H)-one was obtained (97%) as a colorless solid: mp 162-164° C. (water/methanol); 1H NMR (300 MHz, CDCl3) δ7.30 (ddd, J=7.8, 7.8, 1.2 Hz, 1H), 7.18 (d, J=7.5 Hz, 1H), 7.07 (dd, J=7.5, 7.5 Hz, 1H), 6.98 (d, J=7.8 Hz, 1H), 6.76-6.73 (m, 1H), 6.60 (s, 1H), 6.39 (d, J=3.3 Hz, 1H), 6.32 (s, 1H), 5.07 (d, J=16.4 Hz, 1H), 4.94 (d, J=9.0 Hz, 1H), 4.89 (d, J=16.4 Hz, 1H), 4.68 (d, J=9.0 Hz, 1H), 4.29-4.21 (m, 1H), 4.14-4.02 (m, 2H), 3.99-3.91 (m, 1H), 2.23-2.00 (m, 2H); 13C NMR (75 MHz, CDCl3) δ177.1, 156.8, 153.2, 152.1 (q, J=1.3 Hz), 146.4, 141.8 (q, J=42.9 Hz), 141.4, 132.1, 129.1, 124.2, 124.0, 122.9, 118.9 (q, J=267 Hz), 116.1, 112.8 (q, J=2.7 Hz), 109.4, 109.0, 103.6, 80.4, 70.91, 70.90, 58.0, 37.1, 32.3; MS (ES+) m/z 457.9 (M+1).
Reaction SMILES: C1(O[C:8](=[O:27])[NH:9][C:10]2[S:11][C:12]3[C:18]([CH:19]4[CH2:24][O:23][CH2:22][CH2:21][O:20]4)=[CH:17][CH:16]=[C:15]([O:25][CH3:26])[C:13]=3[N:14]=2)C=CC=CC=1.[OH:28][CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.N1C=CC=CC=1>C(Cl)(Cl)Cl>[O:20]1[CH2:21][CH2:22][O:23][CH2:24][CH:19]1[C:18]1[C:12]2[S:11][C:10]([NH:9][C:8]([N:32]3[CH2:33][CH2:34][CH:29]([OH:28])[CH2:30][CH2:31]3)=[O:27])=[N:14][C:13]=2[C:15]([O:25][CH3:26])=[CH:16][CH:17]=1
Reactant: OC1CCNCC1
Reactant: COc1ccc(C2COCCO2)c2sc(NC(=O)Oc3ccccc3)nc12
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)N3CCC(O)CC3)nc12

Procedure:
From (+)-(7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-yl)-carbamic acid phenyl ester with 4-hydroxypiperidine and pyridine in chloroform. [α]D20=+29.4° (c=1.01, CHCl3), ES-MS m/e (%): 394 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:12]=[N:13][N:14]=[C:7]1[C:6]([O:15]C)=[N:5]2.Cl>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:12]=[N:13][N:14]=[C:7]1[C:6]([OH:15])=[N:5]2
Reactant: COc1nc2cc(Cl)ccc2n2cnnc12
Agent: Cl
Solvent: CC(=O)O
Product: Oc1nc2cc(Cl)ccc2n2cnnc12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture consisting of 3.4 g. (0.014 mole) of 7-chloro-4-methoxy-[1,2,4]triazolo[4,3-a]quinoxaline, 35 ml. of 1N hydrochloric acid and 105 ml. of glacial acetic acid was refluxed for a period of 2.5 hours. Upon completion of this step, the reaction mixture was cooled to room temperature and poured over ice/water. The resulting mixture was then stirred for a period of 20 minutes, filtered and the recovered solid product washed with water and air-dried to constant weight to ultimately afford 2.6 g. (87%) of pure 7-chloro-4-hydroxy[1,2,4]triazolo[4,3-a]quinoxaline, m.p. >300° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[CH3:9][C:10]([CH3:13])([O-])[CH3:11].[K+]>C(O)(C)(C)C>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:10]([CH3:13])([CH3:11])[CH3:9])[N:3]=1
Reactant: CC(C)(C)[O-]
Reactant: Brc1cccc(Br)n1
Agent: [K+]
Solvent: CC(C)(C)O
Product: CC(C)(C)c1cccc(Br)n1
Yield: 47.4 %

Procedure:
2,6-Dibromopyridine (50 g) was added to a solution of potassium tert-butoxide (35.5 g) in tert-butanol (300 ml). The mixture was heated to reflux for 3.5 hours then cooled and concentrated. The residue was quenched with water and extracted into ethyl acetate. The combined organic extracts were washed with brine, dried and concentrated to give 2-bromo-6-tert-butylpyridine (21.4 g, 44% yield ) as a clear oil; 1H NMR (270 MHz): δ 1.55(9H,s), 6.58(1H,d), 6.98(1H,d), 7.33(1H,t)ppm.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH:9]=[CH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:25])C=1.O.S([O-])(O)=O.[Na+]>ClCCl>[C:1]1([CH:7]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:8][CH:9]2[O:25][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCC(c1ccccc1)c1ccccc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: c1ccc(C(CC2CO2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.52 g of 4,4-diphenylbut-1-ene in 25 mL of dichloromethane at 0° C. was added 0.75 g of 50-60% by wt of m-chloroperbenzoic acid. The mixture was stirred at room temperature overnight, then heated at reflux for 1 hr. Water, 1 mL, and 0.25 g of sodium hydrogen sulfite were added to destroy the excess oxidizing agent. The organic layer was washed with water and dilute sodium hydrogen carbonate solution, dried, then concentrated in vacuo to give 0.5 g of 4,4-diphenylbut-1-ene oxide which is characterized by:
Reaction SMILES: Cl.[C:2]1([C:8]2([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C@@H:16]3[C@@H:12]([CH2:13][NH:14][CH2:15]3)[C@@:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])([OH:17])[CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][O:33][C:34]1[CH:35]=[C:36]([CH2:40][C:41](O)=[O:42])[CH:37]=[CH:38][CH:39]=1>>[C:26]1([C:8]2([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C@@H:16]3[C@@H:12]([CH2:13][N:14]([C:41](=[O:42])[CH2:40][C:36]4[CH:37]=[CH:38][CH:39]=[C:34]([O:33][CH3:32])[CH:35]=4)[CH2:15]3)[C@@:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])([OH:17])[CH2:10][CH2:9]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COc1ccccc1[C@]1(O)CCC(c2ccccc2)(c2ccccc2)[C@H]2CNC[C@H]21
Reactant: COc1cccc(CC(=O)O)c1
Agent: Cl
Product: COc1cccc(CC(=O)N2C[C@@H]3[C@H](C2)C(c2ccccc2)(c2ccccc2)CC[C@@]3(O)c2ccccc2OC)c1
Yield: 58.5 %

Procedure:
By working in accordance with Use Example 4, starting from 0.75 g of (3aS,4S,7aS)-7,7-diphenyl-4-(2-methoxyphenyl)-perhydroisoindol-4-ol hydrochloride and 0.28 g of (3-methoxyphenyl)-acetic acid, 0.54 g of (3aS, 4S, 7aS)-7,7-diphenyl-4-(2-methoxyphenyl)-2-[(3-methoxyphenyl)-acetyl]-perhydroisoindol-4-ol is obtained in the form of white crystals which melt at 185° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:15]2[CH:20]=[C:19](O)[CH:18]=[C:17]([O:22][CH2:23][CH3:24])[CH:16]=2)[C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)#[N:2].[NH2:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1>>[NH2:25][C:26]1[CH:31]=[C:30]([C:19]2[CH:18]=[C:17]([O:22][CH2:23][CH3:24])[CH:16]=[C:15]([CH:10]([NH:9][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=3)[C:11]([O:13][CH3:14])=[O:12])[CH:20]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: CCOc1cc(O)cc(C(Nc2ccc(C#N)cc2)C(=O)OC)c1
Product: CCOc1cc(-c2cccc(N)c2)cc(C(Nc2ccc(C#N)cc2)C(=O)OC)c1

Procedure:
Analogously to Example 155, from methyl (RS)-(4-cyano-phenylamino)-(3-ethoxy-5-hydroxy-phenyl)-acetate via methyl (RS)-(4-cyano-phenylamino)-(3-ethoxy-5-trifluoro-methanesulphonyloxy-phenyl)-acetate by reaction with 3-aminophenylboronic acid there was obtained the compound methyl (RS)-(3′-amino-5-ethoxy-biphenyl-3-yl)-(4-cyano-phenylamino)-acetate, which was converted into methyl (RS)-(3′-amino-5-ethoxy-biphenyl-3-yl)-(4-carbamimidoyl-phenylamino)-acetate hydrochloride; MS: 419 ([M+H]+).
Reaction SMILES: C[N:2](/[CH:4]=[C:5](/[C:16](=O)[C:17]([F:20])([F:19])[F:18])\[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])C.Cl.[NH:23]([CH:25]1[CH2:30][CH2:29][C:28]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])([CH3:31])[CH2:27][CH2:26]1)N.CCN(C(C)C)C(C)C>CCO>[CH2:36]([O:35][C:33](=[O:34])[CH2:32][C:28]1([CH3:31])[CH2:27][CH2:26][CH:25]([N:23]2[C:16]([C:17]([F:20])([F:19])[F:18])=[C:5]([C:6]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:7])[CH:4]=[N:2]2)[CH2:30][CH2:29]1)[CH3:37]
Reactant: CCOC(=O)CC1(C)CCC(NN)CC1
Reactant: CN(C)/C=C(\C(=O)OCc1ccccc1)C(=O)C(F)(F)F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOC(=O)CC1(C)CCC(n2ncc(C(=O)OCc3ccccc3)c2C(F)(F)F)CC1
Reaction time: 8 h
Yield: 73.5 %

Procedure:
A solution of (Z)-benzyl 2-((dimethylamino)methylene)-4,4,4-trifluoro-3-oxobutanoate (2.018 g, 6.70 mmol) in EtOH (20 mL) was added dropwise to a solution of ethyl 2-(4-hydrazinyl-1-methylcyclohexyl)acetate hydrochloride (1.6 g, 6.38 mmol) and DIPEA (2.452 ml, 14.04 mmol) in EtOH (31.9 ml) at ambient temperature. The reaction was allowed to stir overnight. The solvent was removed and the residual oil was purified using a 40 g REDISEP™ Gold SiO2 column eluting with 0-25% EtOAc/hexane using the Gold resolution method. Fractions containing the desired product were combined and concentrated in vacuo to provide benzyl 1-(4-(2-ethoxy-2-oxoethyl)-4-methylcyclohexyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (2.12 g, 4.69 mmol, 73.4% yield) as a mixture of isomers (colorless syrup). LCMS=453.4 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[C:12]([C:23]2[N:27]([CH2:28][CH2:29][CH2:30][CH3:31])[N:26]=[N:25][N:24]=2)=[CH:11][C:10]=1[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38](O)=[O:39])[CH:33]=1)C1C=CC=CC=1.[O:41]1[CH2:46][CH2:45][N:44]([CH2:47][CH2:48][CH2:49][N:50]2[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]2)[CH2:43][CH2:42]1>>[CH2:28]([N:27]1[C:23]([C:12]2[C:13]([OH:15])=[CH:14][C:9]([OH:8])=[C:10]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([N:53]4[CH2:52][CH2:51][N:50]([CH2:49][CH2:48][CH2:47][N:44]5[CH2:43][CH2:42][O:41][CH2:46][CH2:45]5)[CH2:55][CH2:54]4)=[O:39])[CH:33]=3)[CH:11]=2)=[N:24][N:25]=[N:26]1)[CH2:29][CH2:30][CH3:31]
Reactant: C(CN1CCNCC1)CN1CCOCC1
Reactant: CCCCn1nnnc1-c1cc(-c2cccc(C(=O)O)c2)c(OCc2ccccc2)cc1OCc1ccccc1
Product: CCCCn1nnnc1-c1cc(-c2cccc(C(=O)N3CCN(CCCN4CCOCC4)CC3)c2)c(O)cc1O

Procedure:
This product was synthesized using 2′,4′-bis-benzyloxy-5′-(1-butyl-1H-tetrazol-5-yl)-biphenyl-3-carboxylic acid and 1-(3-morpholinopropyl)-piperazine as described in general procedure D. LCMS: 550 [M+H].
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:10][OH:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24].C(=O)([O-])O.[Na+]>ClCCl>[S:23]([O:11][CH2:10][CH2:9][C:8]1[CH:12]=[CH:13][CH:14]=[C:6]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:7]=1)(=[O:25])(=[O:24])[CH3:22]
Reactant: OCCc1cccc(N2CCCC2)c1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCc1cccc(N2CCCC2)c1
Reaction time: 8 h

Procedure:
3-Pyrrolidinophenethyl alcohol was dissolved in dichloromethane (20 ml). Triethylamine (3.7 ml, 26.7 ml) and methanesulfonyl chloride (1.9 ml, 24.5 mmol) were added to the obtained solution at 0° C., and they were stirred overnight. The reaction mixture was distributed into 5% aqueous sodium hydrogencarbonate solution and dichloromethane. The organic layer was dried and the solvent was evaporated under reduced pressure. The residue was subjected to the silica gel column chromatography. After the elution with hexane and ethyl acetate (7:3), suitable fractions were collected and the solvent was evaporated under reduced pressure to obtain 3-pyrrolidinophenethyl mesylate in the form of a white solid (5.13 g, 87%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4](Cl)[N:3]=1.C([O-])([O-])=O.[Na+].[Na+].O.CC1(C)C(C)(C)OB([C:28]2[CH:29]=[C:30]([C:50]([F:53])([F:52])[F:51])[C:31]([O:34][CH2:35][CH2:36][CH:37]3[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][CH2:38]3)=[N:32][CH:33]=2)O1>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([C:28]2[CH:29]=[C:30]([C:50]([F:53])([F:51])[F:52])[C:31]([O:34][CH2:35][CH2:36][CH:37]3[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:47])([CH3:48])[CH3:49])=[O:44])[CH2:39][CH2:38]3)=[N:32][CH:33]=2)[N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCOc2ncc(B3OC(C)(C)C(C)(C)O3)cc2C(F)(F)F)CC1
Reactant: Cn1cnc2c(Cl)nc(Cl)nc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1cnc2c(-c3cnc(OCCC4CCN(C(=O)OC(C)(C)C)CC4)c(C(F)(F)F)c3)nc(Cl)nc21
Temperature: 85 °C
Reaction time: 5 h
Yield: 63.7 %

Procedure:
2,6-Dichloro-9-methyl-9H-purine (5.6 g), Na2CO3 (11.7 g), water (16.8 mL), and tetrakis(triphenylphosphine)palladium (0) (1.6 g) were added to a solution of tert-butyl 4-(2-{[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-yl]oxy}ethyl)piperidine-1-carboxylate (13.8 g) in dioxane (112 mL) at room temperature in an argon atmosphere, and the mixture was stirred at an internal temperature of 85° C. for 5 hours. After the reaction mixture was cooled to room temperature, water (700 mL) was added thereto, and the mixture was stirred for 3 hours. The precipitate was collected by filtration, then, washed with water and diisopropyl ether, and dried. The obtained solid was purified by silica gel column chromatography (Hex:EtOAc:CHCl3=1:1:1), whereby tert-butyl 4-(2-{[5-(2-chloro-9-methyl-9H-purin-6-yl)-3-(trifluoromethyl)pyridin-2-yl]oxy}ethyl)piperidine-1-carboxylate (9.5 g) was obtained as a solid.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[CH3:2].[Cl:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([Cl:17])[C:15]=1Cl.C(N(CC)CC)C>CN1C(=O)CCC1>[Cl:17][C:14]1[CH:13]=[N:12][CH:11]=[C:10]([Cl:9])[C:15]=1[N:6]1[CH2:7][CH2:8][N:3]([CH2:1][CH3:2])[CH2:4][CH2:5]1
Reactant: Clc1cncc(Cl)c1Cl
Reactant: CCN1CCNCC1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CCN1CCN(c2c(Cl)cncc2Cl)CC1
Yield: 66.9 %

Procedure:
General procedure C was followed using N-ethylpiperazine (31 mg, 0.27 mmol), 3,4,5-trichloropyridine (50 mg, 0.27 mmol), triethylamine (0.76 μL, 0.54 mmol) and NMP (1.5 mL). The crude product was purified by flash column chromatography on silica gel (hexane/EtOAc, 1:1) to furnish the title compound as a colourless oil (47 mg, 66%), umax (CHCl3)/cm−1 2975, 2820, 1559, 1448, 1245, 1151, 957; m/z (ESI) C11H16Cl2N3 requires 260.0716, found [M+H]+ 260.0719.
Reaction SMILES: FC(F)(F)C(O)=O.[S:8]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH3:22])[CH2:20][NH2:21])=[CH:15][CH:14]=2)=[CH:9]1.Cl[C:24]([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:25]>>[S:8]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH2:22][C:24]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:25])[CH2:20][NH2:21])=[CH:15][CH:14]=2)=[CH:9]1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(CN)c1ccc(-c2ccsc2)cc1
Solvent: O=C(O)C(F)(F)F
Product: NCC(CC(=O)Oc1ccccc1)c1ccc(-c2ccsc2)cc1

Procedure:
The title compound was prepared from 2-(4-(3-thienyl)phenyl)propyl amine trifluoroacetate (prepared in example 1) and phenyl chloroformate in a manner analogous to the procedure described in Example 1.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][NH:6][C:7](=[O:10])[CH2:8][CH3:9].Cl[C:12]1[N:17]=[CH:16][C:15]([C:18]([N:20]2[C@H:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][O:22][C:21]2([CH3:30])[CH3:29])=[O:19])=[CH:14][C:13]=1[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1.O>C1COCC1>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([C:13]2[C:12]([O:3][CH2:4][CH2:5][NH:6][C:7](=[O:10])[CH2:8][CH3:9])=[N:17][CH:16]=[C:15]([C:18]([N:20]3[C@H:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][O:22][C:21]3([CH3:30])[CH3:29])=[O:19])[CH:14]=2)=[CH:32][CH:33]=1
Reactant: CC(C)C[C@@H]1COC(C)(C)N1C(=O)c1cnc(Cl)c(-c2ccc(Cl)cc2)c1
Reactant: CCC(=O)NCCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCC(=O)NCCOc1ncc(C(=O)N2[C@H](CC(C)C)COC2(C)C)cc1-c1ccc(Cl)cc1
Reaction time: 6 h
Yield: 33.2 %

Procedure:
Sodium hydride dispersion in oil (˜55%, 72 mg) was added in portions to a well stirred solution of N-(2-hydroxyethyl)propionamide (71 mg, 0.6 mmol) in THF (13 mL). After stirring the mixture for 15 min at RT [6-Chloro-5-(4-chloro-phenyl)-pyridin-3-yl]-((R)-4-isobutyl-2,2-dimethyl-oxazolidin-3-yl)-methanone (225 mg, 0.55 mmol) was added and stirring continued for 6 h at RT. The mixture was poured into water and extracted with diethyl ether. Organic phases were pooled, dried with Na2SO4 and the solvent was evaporated. The residue was purified by column chromatography on silica (cyclohexane/ethyl acetate 8:1) to yield 89 mg of the title compound as a white solid, MS (ISP) 488.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:10])[C:5]([CH2:8][OH:9])=[N:6][CH:7]=1.C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>ClCCl>[CH3:18][S:19]([O:9][CH2:8][C:5]1[C:4]([F:10])=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1)(=[O:21])=[O:20]
Reactant: OCc1ncc(Br)cc1F
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1ncc(Br)cc1F
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
(5-Bromo-3-fluoropyridin-2-yl)methanol (0.20 g, 0.99 mmol) was dissolved in dichloromethane (5 mL), cooled to 0° C. and treated with triethylamine (0.15 mL, 1.1 mmol, 1.1 equiv) and methanesulfonyl chloride (0.085 mL, 1.1 mmol, 1.1 equiv). After 15 minutes, the mixture was diluted with dichloromethane (100 mL) and washed once with sodium bicarbonate (20 mL, aqueous saturated) and brine (50 mL), dried with sodium sulfate, filtered and concentrated in vacuo, providing the titled compound.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1.[C:17]([C:22]1[CH:27]=[CH:26][C:25](I)=[CH:24][CH:23]=1)([O:19][CH2:20][CH3:21])=[O:18]>CC([O-])=O.CC([O-])=O.[Pd+2].C(O)C>[C:17]([C:22]1[CH:27]=[CH:26][C:25]([C:9]2[CH2:10][C:11]3[C:16]([CH:8]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:24][CH:23]=1)([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: C1=Cc2ccccc2C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1ccc(C2=Cc3ccccc3C2)cc1
Temperature: 25 °C
Yield: 58.6 %

Procedure:
20 ml of triethylamine, 2.2 g (20 mmole) of indene, 5.52 g (20 mmole) of para-carbethoxy iodo-benzene and 0.134 g (0.6 mmole) of Pd(OAc)2 were stirred under reflux for 10 h. After that the mixture was cooled to room temperature and treated with 100 mnl of ethanol. The crystalline precipitate was isolated, washed with cold ethanol and dried under vacuum to obtain 3.1 g (59%) of 2-(4-carbethoxy-phenyl)-indene.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1C(C1C=C(C)C=CC=1C1C=NN(C)C=1)=O.[F:25][C:26]1[C:34](F)=[CH:33][C:29]([C:30]([OH:32])=O)=[C:28]([N:36]2[N:40]=[CH:39][CH:38]=[N:37]2)[CH:27]=1>>[NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:30]([C:29]1[CH:33]=[CH:34][C:26]([F:25])=[CH:27][C:28]=1[N:36]1[N:40]=[CH:39][CH:38]=[N:37]1)=[O:32]
Reactant: O=C(O)c1cc(F)c(F)cc1-n1nccn1
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: C[C@@H]1CCCN(C(=O)c2ccc(F)cc2-n2nccn2)[C@@H]1CN

Procedure:
The title compound was prepared following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone in Example A1 using 4,5-difluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid. MS (ESI) 318.4 (M+H).
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[CH3:22][C:23]1[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][C:24]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:33]2[CH2:34][CH2:35][N:30]([C:24]3[CH:25]=[CH:26][CH:27]=[C:28]([CH3:29])[C:23]=3[CH3:22])[CH2:31][CH2:32]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: Cc1cccc(N2CCNCC2)c1C
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Product: CCc1cc(NC(=O)N2CCN(c3cccc(C)c3C)CC2)c(OC)nc1C
Yield: 82 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(2,3-dimethylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([C:12]([OH:14])=O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][O:16][C:17](=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][NH2:25])[CH:19]=1>>[CH3:15][O:16][C:17](=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][NH:25][C:12]([C:10]2[O:11][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][CH:9]=2)=[O:14])[CH:19]=1
Reactant: COC(=O)c1cccc(CN)c1
Reactant: O=C(O)c1ccc(-c2ccccc2)o1
Product: COC(=O)c1cccc(CNC(=O)c2ccc(-c3ccccc3)o2)c1

Procedure:
5-Phenyl-furan-2-carboxylic acid (6) (17 mg, 0.10 mmol) was coupled to 3-aminomethyl-benzoic acid methyl ester (19.4 mg, 0.10 mmol) using Method D to give the title compound
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH2:10](O)[CH2:11][OH:12].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]2[O:12][CH2:11][CH2:10][O:7]2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: Brc1ccc(C2OCCO2)cc1
Temperature: 25 °C

Procedure:
A mixture of 4-bromobenzaldehyde (1 Scheme 18, 9.5 g, 51.4 mmol) and ethylene glycol (6.4 g, 113 mmol) and p-toluenesulfonic acid (120 mg) in benzene (200 mL) was refluxed in a Dean Stark apparatus for 4 h. The reaction mixture was cooled to room temperature, and the solution was extracted with cold water/ethyl acetate. The organic layer was washed with brine, dried (Na2SO4), and concentrated to give a colorless oil (11.4, 95%); 1H NMR (300 MHz, CDCl3) δ 4.01-4.14 (4 H), 5.78 (s, 1 H), 7.37 (d, J=8.34 Hz, 2 H), 7.53 (d, J=8.34 Hz, 2 H); HRMS (EI) calcd for C9H9BrO2 227.9786, 229.9766, found 227.9771, 229.9754.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:19])[CH3:18])[CH2:13][CH2:12]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O>C(O)C>[NH2:8][C:7]1[CH:6]=[CH:5][C:4]([N:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:19])[CH3:18])[CH2:13][CH2:12]2)=[CH:3][C:2]=1[Cl:1]
Reactant: CC(=O)N1CCN(c2ccc([N+](=O)[O-])c(Cl)c2)CC1
Solvent: CCO
Product: CC(=O)N1CCN(c2ccc(N)c(Cl)c2)CC1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
The compound prepared in Step 1 was dissolved in ethanol (10 ml) and distilled water (1.0 ml), added with iron (powder, 2.0 g) and ammonium chloride (1.0 g), and stirred at 90° C. for 2 hours. Then, the resultant was filtered using celite and the filtrate was distilled under reduced pressure to remove the solvent. The resulting white solid was used in the subsequent reaction without further purification.
Reaction SMILES: CS[C:3]1[N:13]2[C:14]3[N:9]([C:10]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=4)=[CH:11][CH2:12]2)[N:8]=[CH:7][C:6]=3[C:5](=[O:25])[N:4]=1.[Cl:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH2:32])=[CH:29][CH:28]=1>>[Cl:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH:32][C:3]2[N:13]3[C:14]4[N:9]([C:10]([C:15]5[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:22])([F:23])[F:24])[CH:16]=5)=[CH:11][CH2:12]3)[N:8]=[CH:7][C:6]=4[C:5](=[O:25])[N:4]=2)=[CH:29][CH:28]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CSc1nc(=O)c2cnn3c2n1CC=C3c1cccc(C(F)(F)F)c1
Product: O=c1nc(NCc2ccc(Cl)cc2)n2c3c1cnn3C(c1cccc(C(F)(F)F)c1)=CC2

Procedure:
A 400 mg amount of 5-(methylthio)-8-[3-(trifluoromethyl)phenyl]-3H,6H-1,4,5a,8a-tetraazaacena-phthylen-3-one (prepared as described in Example 9) in 25.0 mg of 4-chlorobenzylamine was heated at 70° C. for 36 hours. The precipitate which formed was collected by filtration to give the product of the example as a white solid, m.p. 281°-282° C.