Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]#[N:2].C([O:6][C@@H:7]1[C@@H:12]([O:13]C(=O)C)[C@@H:11]([O:17]C(=O)C)[C@@H:10]([CH2:21][O:22]C(=O)C)[O:9][C@H:8]1[S:26][CH2:27][CH2:28][C:29]([NH:31][C@H:32]([C:66]([NH:68][C@H:69]([C:102]([OH:104])=[O:103])[CH2:70][CH2:71][CH2:72][CH2:73][NH:74][C:75](=[O:101])[CH2:76][CH2:77][C@@H]1O[C@H](COC(=O)C)[C@H](OC(=O)C)[C@H](OC(=O)C)[C@H]1OC(=O)C)=[O:67])[CH2:33][CH2:34][CH2:35][CH2:36][NH:37][C:38](=[O:65])[CH2:39][CH2:40][S:41][C@@H:42]1[O:59][C@H:58]([CH2:60][O:61]C(=O)C)[C@H:53]([O:54]C(=O)C)[C@H:48]([O:49]C(=O)C)[C@H:43]1[O:44]C(=O)C)=[O:30])(=O)C>CO.O.C(N(CC)CC)C>[N:1]#[N:2].[C@@H:8]1([S:26][CH2:27][CH2:28][C:29]([NH:31][C@H:32]([C:66]([NH:68][C@H:69]([C:102]([OH:104])=[O:103])[CH2:70][CH2:71][CH2:72][CH2:73][NH:74][C:75](=[O:101])[CH2:76][CH2:77][S:26][C@@H:8]2[O:9][C@H:10]([CH2:21][OH:22])[C@H:11]([OH:17])[C@H:12]([OH:13])[C@H:7]2[OH:6])=[O:67])[CH2:33][CH2:34][CH2:35][CH2:36][NH:37][C:38](=[O:65])[CH2:39][CH2:40][S:41][C@@H:42]2[O:59][C@H:58]([CH2:60][OH:61])[C@H:53]([OH:54])[C@H:48]([OH:49])[C@H:43]2[OH:44])=[O:30])[O:9][C@H:10]([CH2:21][OH:22])[C@H:11]([OH:17])[C@H:12]([OH:13])[C@H:7]1[OH:6]
Reactant: CC(=O)OC[C@H]1O[C@@H](CCC(=O)NCCCC[C@H](NC(=O)[C@H](CCCCNC(=O)CCS[C@@H]2O[C@H](COC(C)=O)[C@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)NC(=O)CCS[C@@H]2O[C@H](COC(C)=O)[C@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)C(=O)O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: N#N
Solvent: O
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(CCS[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O)NCCCC[C@H](NC(=O)[C@H](CCCCNC(=O)CCS[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O)NC(=O)CCS[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O)C(=O)O
Yield: 61 %

Procedure:
A solution of 19 (50 mg) in methanol-water-triethylamine 5:4:1 (v/v/v, 2 ml) was kept for 18 hours at room temperature, and evaporated in vacuo to dryness. The residue was put on a column of silica gel and eluted with chloroform-methanol-water 60:40:10 (v/v/v). The title compound was isolated in 61% yield (20 mg): RF 0.15 (CHCl3 -MeOH-H2O, 60:40:10); NMR (D2O)δ: 4.51 (d, J1,2 =9.5 Hz, 2H, H-1), 4.52 (d, J1,2 =9.5 Hz, 1H, H-1), 4.34, 4.18 (q, q, α-CH), 3.99 (d, J4,3 =3.0 Hz, 3H, H-4), 3.22 (m, εCH2), 3.02 (m, SCH2), 2.70 (t, J=6.5 Hz, 2H, SCH2CH2), 2.62 (t, J=6.5 Hz, 4H, SCH2CH2); [α]D27 -17.3° (c 1.5, H2O).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][C:6]1[S:10][C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:8][C:7]=1[CH3:16].[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C([O-])([O-])=O.[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:16][C:7]1[N:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[S:10][C:6]=1[CH2:5][C:4]1[CH:17]=[CH:18][CH:19]=[C:2]([N:24]2[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]2)[CH:3]=1
Reactant: CN1CCNCC1
Reactant: CCOC(=O)c1nc(C)c(Cc2cccc(Br)c2)s1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nc(C)c(Cc2cccc(N3CCN(C)CC3)c2)s1
Temperature: 25 °C
Yield: 75.1 %

Procedure:
A mixture of ethyl 5-(3-bromobenzyl)-4-methylthiazole-2-carboxylate (340 mg, 1.0 mmol), 1-methylpiperazine (0.2 mL, 2 mmol) and Cs2CO3 (652 mg, 2 mmol) in toluene (5 mL) was degassed (argon bubbling for 5 min), tris(dibenzylideneacetone)dipalladium(0) (46 mg, 0.05 mmol) and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (48 mg, 0.1 mmol) were quickly added. The reaction mixture was refluxed overnight, cooled to RT, then quenched with H2O and extracted with EtOAc (3×30 mL). The organic layers were washed with H2O (30 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated to afford the crude product, which was purified by silica gel column chromatography (DCM:MeOH=20:1) to give ethyl 4-methyl-5-(3-(4-methylpiperazin-1-yl)benzyl)thiazole-2-carboxylate as a yellow solid (270 mg, 75%). MS (ES+) C19H25N3O2S requires: 359, found: 360[M+H]+.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=3[Cl:21])[NH:10][C:9]=2[C:8]([OH:22])=[CH:7][CH:6]=1)=[O:4].O[Li].O>C1COCC1.CO.O>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[C:11]1[NH:10][C:9]2[C:8]([OH:22])=[CH:7][CH:6]=[C:5]([C:3]([OH:4])=[O:2])[C:13]=2[N:12]=1
Reactant: COC(=O)c1ccc(O)c2[nH]c(-c3ccc(Cl)cc3Cl)nc12
Agent: [Li]O
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(O)c2[nH]c(-c3ccc(Cl)cc3Cl)nc12
Temperature: 25 °C
Yield: 89.4 %

Procedure:
Wang resin-supported 2-(2,4-dichloro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid methyl ester (570 mg, 0.47 mmol) obtained in step 5 was dissolved in THF, LiOH.H2O (99 mg, 2.35 mmol) in MeOH—H2O (2:1) was added thereto and the resulting mixture was refluxed for 5 hours. The resulting solution was cooled to room temperature and filtered. The filtrate was washed with MeOH and CH2Cl2, and dried to obtain the title compound (551 mg, 0.42 mmol) in a yield of 90%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12](=O)[C:13]([O:15]CCCCCC)=O)[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[OH:8].[NH2:23][C:24]1[C:33]([NH2:34])=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=1>C(O)CCCCC.CO>[OH:1][C:2]1[CH:3]=[C:4]([C:12]2[C:13](=[O:15])[NH:34][C:33]3[CH:32]=[C:31]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]4=[CH:25][C:24]=3[N:23]=2)[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[OH:8]
Reactant: CCCCCCOC(=O)C(=O)c1cc(O)c(O)c([N+](=O)[O-])c1
Reactant: Nc1cc2ccccc2cc1N
Solvent: CCCCCCO
Solvent: CO
Product: O=c1[nH]c2cc3ccccc3cc2nc1-c1cc(O)c(O)c([N+](=O)[O-])c1

Procedure:
A solution of 1.07 g of n-hexyl 3,4-dihydroxy-5-nitrophenylglyoxylate and 696.3 mg of 2,3-diaminonaphthalene in 3 ml of 1-hexanol is heated to boiling under reflux for 3 hours. The reaction mixture is then cooled and diluted with methanol. The crude product is filtered under suction and recrystallized from N,N-dimethylformamide/water, There is obtained 3-(3,4-dihydroxy-5-nitrophenyl)benzo[g]quinoxalin-2(1H)-one of m.p.>300°.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6]3=[C:7]([S:22][CH2:23][CH2:24][N:5]3[C:4](=[O:25])[CH:3]=1)[CH:8]=[C:9]([C:12]([OH:21])([C:17]([F:20])([F:19])[F:18])[C:13]([F:16])([F:15])[F:14])[CH:10]=2.C(Cl)(=[O:28])C.Cl>N1C=CC=CC=1>[C:12]([OH:21])(=[O:28])[CH3:17].[CH3:1][C:2]1[C:11]2[C:6]3=[C:7]([S:22][CH2:23][CH2:24][N:5]3[C:4](=[O:25])[CH:3]=1)[CH:8]=[C:9]([C:12]([OH:21])([C:13]([F:16])([F:14])[F:15])[C:17]([F:18])([F:19])[F:20])[CH:10]=2
Reactant: CC(=O)Cl
Agent: Cc1cc(=O)n2c3c(cc(C(O)(C(F)(F)F)C(F)(F)F)cc13)SCC2
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)O

Procedure:
To a solution of 2,3-dihydro-7-methyl-9-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-5H-1,4-thiazino[2,3,4-ij]-quinolin-5-one in dry pyridine can be added acetyl chloride. The solution is heated at reflux, and when the reaction is complete, the solution can be poured into cold 1 N hydrochloric acid solution, extracted, isolated and purified to give 2,3-dihydro-7-methyl-9-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-5H-1,4-thiazino-[2,3,4-ij]-quinolin-5-one acetate.
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH2:8](O)[CH2:9][CH2:10]C.[C-]#N.[K+].COC1C=CC(O)=CC=1.C(OC)(=O)C(C)=C.CO>>[C:1]([O:6][CH2:7][CH2:8][CH2:9][CH3:10])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: CCCCO
Reactant: C=C(C)C(=O)OC
Agent: COc1ccc(O)cc1
Agent: [C-]#N
Agent: [K+]
Solvent: CO
Product: C=C(C)C(=O)OCCCC
Temperature: 75 °C
Reaction time: 4 h

Procedure:
400 g of methyl methacrylate (4 mole), 148 g of n-butanol (2 mole), 2.74 g of potassium cyanide (0.5%) and 0.137 g of hydroquinone monomethyl ether (250 ppm) are added to a 1 liter round-bottomed flask. The batch is heated to approximately 75° C. by conducting air through, and at a temperature of 65° C. at the head of the column, the methyl methacrylate/methanol-azeotrope is distilled-off by way of a 1 m vigreux column. After 4 hours, the trans-esterification is finished. After cooling of the flask, the sump is filtered to remove the potassium cyanide, and the filter residue is washed with a little methyl methacrylate. The filtrate is concentrated at 40° C. under a water jet vacuum. There results a residue of n-butyl methacrylate of 280 g = 98.5%. The n-butyl methacrylate thus obtained can be used without any further processing.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([Cl:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:12][S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH2:22])(=[O:15])=[O:14].Cl.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>>[Cl:11][C:9]1[N:10]=[C:3]2[C:2]([NH:22][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[S:13]([CH3:12])(=[O:15])=[O:14])=[CH:7][CH:6]=[CH:5][N:4]2[N:8]=1
Reactant: Clc1nc2c(Br)cccn2n1
Reactant: CS(=O)(=O)c1ccccc1N
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: Cl
Product: CS(=O)(=O)c1ccccc1Nc1cccn2nc(Cl)nc12

Procedure:
To a cooled, stirred suspension of 8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (0.961 g, 4.51 mmol) and copper(II)chloride dihydrate (0.20 g, 1.2 mmol) in 12 M of hydrochloric acid (10.0 mL) at 5° C. was added dropwise a solution of sodium nitrite (0.37 g, 5.4 mmol) in water (2 mL). Gentle gas evolution was noted. The mixture was stirred for 30 minutes at 5° C. then at room temperature for 18 hours. The yellow mixture was diluted with water (80 mL) and the resulting precipitate was filtered, rinsed with water and dried in-the-air. 8-Bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine was isolated as a pale yellow solid (0.947 g, 90%) and was used without further purification. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.98 (d, J=6.9 Hz, 1H), 8.10 (d, J=7.8 Hz, 1H), 7.22 (t, J=7.0 Hz, 1H). MS=232, 234, 236 (MH)+. 68b) (2-Chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(2-methanesulfonyl-phenyl)-amine was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (234.0 mg, 1.007 mmol) and 2-methanesulfonyl-phenylamine; hydrochloride (220.0 mg, 1.059 mmol) with 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (105.0 mg, 0.1815 mmol) as the ligand in a manner analogous to Step 2d. The reaction product was isolated as a pale yellow solid (0.115 g, 35%). MP=180-182° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.52 (s, 1H), 8.18 (d, J=6.7 Hz, 1H), 8.00 (d, J=8.0 Hz, 1H), 7.60-7.54 (m, 1H), 7.51 (d, J=8.2, 1H), 7.34 (d, J=7.7 Hz, 1H), 7.18 (t, J=7.2 Hz, 1H), 6.98 (t, J=7.2 Hz, 1H), 3.12 (s, 3H). MS=323, 325 (MH)+. 68c) N(8)-(2-Methanesulfonyl-phenyl)-N(2)-[3-(4-methyl-piperazin-1-yl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridine-2,8-diamine was prepared from (2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(2-methanesulfonyl-phenyl)-amine (95.0 mg, 0.294 mmol) and 3-(4-methylpiperazin-1-yl)aniline (70.0 mg, 0.366 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (32.0 mg, 0.0585 mmol) as the ligand in a manner analogous to Step 2d. The title compound was isolated as a light brown foam (0.077 g, 55%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.51 (s, 1H), 8.11 (d, J=6.5, 1H), 7.98 (d, J=7.8 Hz, 1H), 7.58-7.51 (m, 2H), 7.43 (s, 1H), 7.30-7.25 (m, 1H), 7.20 (t, J=8.1 Hz, 1H), 6.92 (d, J=8.0 Hz, 1H), 6.84-6.78 (m, 2H), 6.57 (d, J=8.1 Hz, 1H), 3.33-3.25 (m, 4H), 3.13 (s, 3H), 2.70-2.57 (m, 4H), 2.39 (s, 3H). MS=478 (MH)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:5]=[C:6]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:20][C:21](=[O:23])[CH3:22])[CH:15]=2)[S:7][C:8]=1[C:9]1[NH:13][CH:12]=[N:11][N:10]=1)[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:36]1[CH:41]=[CH:40][CH2:39][CH2:38][CH2:37]1>O1CCCC1>[CH2:1]([O:3][C:4]1[N:5]=[C:6]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:20][C:21](=[O:23])[CH3:22])[CH:15]=2)[S:7][C:8]=1[C:9]1[N:13]=[CH:12][N:11]([CH:37]2[CH2:38][CH2:39][CH2:40][CH2:41][O:36]2)[N:10]=1)[CH3:2]
Reactant: C1=COCCC1
Reactant: CCOc1nc(-c2ccnc(NC(C)=O)c2)sc1-c1nnc[nH]1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCOc1nc(-c2ccnc(NC(C)=O)c2)sc1-c1ncn(C2CCCCO2)n1
Yield: 59.7 %

Procedure:
Using N-{4-[4-ethoxy-5-(4H-1,2,4-triazol-3-yl)-1,3-thiazol-2-yl]pyridin-2-yl}acetamide (6.2 g, 19 mmol) produced in Example 8-B (v), p-toluenesulfonic acid monohydrate (4.3 g, 23 mmol), 3,4-dihydro-2H-pyran (7.9 g, 94 mmol) and tetrahydrofuran (188 mL) as starting materials and in the same manner as in Example 4-B(i), the title compound (4.7 g, 60%) was obtained as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].Cl>C(O)(C)(C)C>[C:3]([NH:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5])([CH3:12])([CH3:4])[CH3:2]
Reactant: Nc1ccccc1C(=O)c1ccccc1
Agent: Cl
Solvent: CC(C)(C)O
Product: CC(C)(C)Nc1ccccc1C(=O)c1ccccc1
Temperature: 25 °C
Yield: 43.8 %

Procedure:
A mixture of 2-aminobenzophenone (20 g), tert-butyl alcohol (100 ml) and 10M ethanolic hydrogen chloride (10 ml) was heated in a steel bomb at 120° C. for 20 minutes. After being cooled to room temperature, solvents were removed under vacuum and the residue was purified by flash chromatography (silica gel, hexane-toluene, 30:70) to give the title compound (5.62 g) as an oil, δH (360 MHz, CDCl3) 8.95 (1H, s), 7.61-7.28 (7H, m), 7.01 (1H, d, J=8.6 Hz), 6.48 (1H, t, J=7.4 Hz), 1.49 (9H, s); m/z (CI) 253 (M-).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[NH:12][C:13](=[O:18])[CH2:14][CH2:15][CH:16]=[CH2:17])[C:5]([O:7][CH3:8])=[O:6].[K].[CH3:20][C:21](C)([O-])[CH3:22].C(Br)C=C.O>CN(C=O)C>[CH2:22]([N:12]([C:13](=[O:18])[CH2:14][CH2:15][CH:16]=[CH2:17])[C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[CH3:1])[CH:21]=[CH2:20]
Reactant: C=CCCC(=O)Nc1ccc(C(=O)OC)cc1C
Reactant: CC(C)(C)[O-]
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Solvent: C=CCBr
Product: C=CCCC(=O)N(CC=C)c1ccc(C(=O)OC)cc1C
Temperature: 70 °C

Procedure:
1.00 g (4.04 mmol) methyl 3-methyl-4-(pent-4-en-1-oyl-amino)-benzoate dissolved in 5 ml DMF are combined with 500 mg (4.37 mmol) potassium-tert.-butoxide and at 40° C. 350 μl (489 mg, 4.04 mmol) allylbromide are slowly added with stirring. Then the mixture is heated to 70° C. for 3 hours. Then the reaction mixture is poured into water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate, evaporated down i. vac., the residue is applied to silica gel and purified by chromatography on silica gel (eluant: petroleum ether/ethyl acetate 9:1).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]2[CH:8]=[C:9]([C:11]([OH:13])=O)[N:10]=[C:4]2[NH:3]1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:44][C@@H:45]([CH3:62])[CH2:46][N:47]1[CH:51]=[CH:50][C:49]([C:52]2[CH:59]=[C:58]([F:60])[C:55]([C:56]#[N:57])=[C:54]([Cl:61])[CH:53]=2)=[N:48]1>CN(C=O)C.O.CCOC(C)=O>[Cl:61][C:54]1[CH:53]=[C:52]([C:49]2[CH:50]=[CH:51][N:47]([CH2:46][C@@H:45]([NH:44][C:11]([C:9]3[N:10]=[C:4]4[NH:3][C:2](=[O:1])[CH2:7][CH2:6][N:5]4[CH:8]=3)=[O:13])[CH3:62])[N:48]=2)[CH:59]=[C:58]([F:60])[C:55]=1[C:56]#[N:57]
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Reactant: O=C1CCn2cc(C(=O)O)nc2N1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1cn2c(n1)NC(=O)CC2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 1.6 %

Procedure:
7-Oxo-5,6,7,8-tetrahydroimidazo[1,2-a]pyrimidine-2-carboxylic acid (1.513 mmol, 0.274 g) was dissolved in DMF (5 ml) under nitrogen atmosphere. EDCI (1.891 mmol, 0.362 g), DIPEA (3.78 mmol, 0.489 g) and HOBt (1.891 mmol, 0.255 g) were added and the resulting mixture was stirred for 20 min at RT. (S)-4-(1-(2-Aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (1.260 mmol, 0.351 g) dissolved in DMF (5 ml) was added and the resulting mixture was stirred at RT for 2 days. The mixture was diluted with water and EtOAc, washed with 2M Na2CO3, water and brine. The combined organics were dried, filtered and evaporated. The crude product was purified by preparative HPLC. 0.0089 g of the title compound was obtained. 1H-NMR (400 MHz, CDCl3): δ 1.28 (d, 3H), 2.89 (t, 2H), 4.16 (t, 2H), 4.33-4.39 (m, 2H), 4.54-4.65 (m, 1H), 6.59 (d, 1H), 7.36 (s, 1H), 7.53 (d, 1H), 7.57 (dd, 1H), 7.72-7.75 (m, 1H), 7.83 (d, 1H).
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:14]=[CH:13][C:12]3[NH:11][CH2:10][C@@H:9]4[CH2:15][C@H:16]([N:18]([CH2:22][CH2:23][CH3:24])[CH2:19][CH2:20][CH3:21])[CH2:17][C:7]=2[C:8]=34)=[CH:4][N:3]=[CH:2]1>C(Cl)Cl.O=[Mn]=O>[O:1]1[C:5]([C:6]2[CH:14]=[CH:13][C:12]3[NH:11][CH:10]=[C:9]4[CH2:15][C@H:16]([N:18]([CH2:22][CH2:23][CH3:24])[CH2:19][CH2:20][CH3:21])[CH2:17][C:7]=2[C:8]=34)=[CH:4][N:3]=[CH:2]1
Reactant: CCCN(CCC)[C@@H]1Cc2c(-c3cnco3)ccc3c2[C@H](CN3)C1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CCCN(CCC)[C@H]1Cc2c[nH]c3ccc(-c4cnco4)c(c23)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 34.4 %

Procedure:
A mixture of (-)(2aR,4S)-6-(5-oxazolyl)-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole (300 mg, 0.9 mmol) and 0.5 g of MnO2 in 50 ml of methylene chloride was stirred at room temperature for 16 hours. The oxidant was removed by filtration through celite. The crude product obtained after filtering and removing the solvent was purified by flash chromatography, using ethyl acetate as eluent, to provide 100 mg of title compound. Recrystallization from hexane gave 60 mg of pure title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.F[C:15]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:16]=1[CH:17]=[O:18]>>[CH:17]([C:16]1[CH:19]=[C:20]([C:23]([F:24])([F:25])[F:26])[CH:21]=[CH:22][C:15]=1[O:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1)=[O:18]
Reactant: O=Cc1cc(C(F)(F)F)ccc1F
Reactant: CC(C)(C(=O)O)c1cccc(O)c1
Product: CC(C)(C(=O)O)c1cccc(Oc2ccc(C(F)(F)F)cc2C=O)c1

Procedure:
Prepared according to the procedure described in Example 10, Step 4, using the following starting materials: 2-(3-hydroxy-phenyl)-2-methyl-propionic acid and 2-fluoro-5-(trifluoromethyl)benzaldehyde.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([CH:10]=O)=[CH:8][S:9][C:4]2=[CH:3][CH:2]=1.[S:12]([NH2:16])([NH2:15])(=[O:14])=[O:13].S(=O)(=O)(O)N.[BH4-].[Li+].Cl>C1COCC1>[S:9]1[CH:8]=[C:7]([CH2:10][NH:15][S:12]([NH2:16])(=[O:14])=[O:13])[C:5]2[CH:6]=[CH:1][CH:2]=[CH:3][C:4]1=2
Reactant: O=Cc1csc2ccccc12
Reactant: NS(N)(=O)=O
Agent: Cl
Agent: NS(=O)(=O)O
Agent: [BH4-]
Solvent: C1CCOC1
Product: NS(=O)(=O)NCc1csc2ccccc12
Temperature: 45 °C
Reaction time: 1 h

Procedure:
Thianaphthene-3-carboxaldehyde (5 g, 30.8 mmol) was dissolved in THF (50 mL). Sulfamide (12.22 g, 123.30 mmoles) and sulfamic acid (0.29 g, 3.08 mmoles) were added and the reaction mixture heated to 45° C. for 18 h. The reaction mixture was then cooled to room temperature and filtered through a sintered glass funnel. The resulting solution was treated with lithium borohydride (2.0 M in THF, 5 mL, 10 mmol) via addition funnel. After addition (5 minutes) the reaction mixture was stirred for 1 hour. 1N HCl (20 mL, 20 mmol) was added and the reaction mixture concentrated to remove THF. The resulting suspension was treated with water (100 mL) and vigorously stirred. The resulting solid was filtered and dried to yield the title compound as a light pink solid.
Reaction SMILES: [Br:1][C:2]1[C:3]2[CH2:10][CH2:9][C:8](=[O:11])[C:4]=2[CH:5]=[N:6][CH:7]=1.[CH3:12][Mg]Br.[NH4+].[Cl-]>C1COCC1>[Br:1][C:2]1[C:3]2[CH2:10][CH2:9][C:8]([CH3:12])([OH:11])[C:4]=2[CH:5]=[N:6][CH:7]=1
Reactant: O=C1CCc2c(Br)cncc21
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1(O)CCc2c(Br)cncc21
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 39.5 %

Procedure:
A brown suspension of 4-bromo-5H-cyclopenta[c]pyridin-7(6H)-one (intermediate A-4[B]) (424 mg, 2.0 mmol) in THF (5 mL) was cooled (−78° C.) and treated during 10 min with methylmagnesium bromide (2.1 mL, 3.0 mmol, 1.4 M in THF:toluene 1:3). The reaction was allowed to warm up to RT over 3 h then stirred for 1.5 h at RT. The mixture was poured on aq. sat. NH4Cl-solution and extracted with EtOAc (3×). The organic layer was dried over Na2SO4 and concentrated in vacuo. Purification by flash chromatography (50 g SiO2, Telos-cartridge, CH2Cl2/MeOH (4%)) gave the title compound (180 mg, 40%) as dark green viscous oil. MS: 228.0 (M+H+, 1Br).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.[C:30]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)([OH:32])=[O:31].C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:22]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[O:1][C:37]1[CH:38]=[C:33]([CH:34]=[CH:35][CH:36]=1)[C:30]([OH:32])=[O:31])=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1
Reactant: O=C(O)c1cccc(B(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)c1cccc(Oc2cccc(-c3c(C(=O)c4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21 %

Procedure:
To [4-(3-hydroxy-phenyl)-8-trifluoromethylquinolin-3-yl]-phenyl methanone (0.1 g, 0.00025 mole) and 3-carboxyphenyl boronic acid (0.12 g, 0.00072 mole) in 2 ml dichloromethane was added copper acetate (0.091 g, 0.0005 mole) and triethylamine (0.1 ml, 0.00072 mole). This mixture was stirred at room temperature overnight. The reaction was then filtered and the filtrate evaporated to dryness. The crude product was purified by flash chromatography to give 0.027 g of 3-[3-(3-benzoyl-8-trifluoromethyl-quinolin-4-yl)-phenoxy]-benzoic acid: MS: MS (ESI) m/z 514; MS (ESI) m/z 512.
Reaction SMILES: [F:1][C:2]1[C:3]([C:18]([F:21])([F:20])[F:19])=[C:4]([C:8]2(O)[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH3:16])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1>Cl>[F:1][C:2]1[C:3]([C:18]([F:21])([F:19])[F:20])=[C:4]([C:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH3:16])[CH2:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCCN1CCC(O)(c2cccc(F)c2C(F)(F)F)CC1
Agent: Cl
Product: CCCN1CC=C(c2cccc(F)c2C(F)(F)F)CC1

Procedure:
Preparation according to preparation 2: 4-[3-fluoro-2-(trifluoromethyl)phenyl]-1-propylpiperidin-4-ol (2.98 g, 9.8 mmol), hydrochloric acid (40 ml, cone). Yield: 2.37 g. MS m/z (rel. intensity, 70 eV) 305 (M+, 7), 277 (14), 276 (bp), 258 (57), 163 (7).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8](Cl)=[N:7][CH:6]=1)[CH3:2].[C:13]1(OB(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+].O>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>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(Cl)nc1
Reactant: OB(O)Oc1ccccc1
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: O
Solvent: C1COCCO1
Product: CCOC(=O)c1ccc(-c2ccccc2)nc1
Yield: 86.8 %

Procedure:
Under nitrogen atmosphere, 6-chloronicotinic acid ethyl ester (24.0 g) and phenylboric acid (23.6 g) were dissolved in dioxane (200 mL) and aqueous sodium carbonate solution (2M, 100 mL), tetrakis(triphenylphosphine)palladium (7.0 g) was added, and the mixture was refluxed for 8 hr. The reaction mixture was cooled, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=7:1 to 5:1) to give the title compound (25.5 g) as a white solid.