Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][C:9](=[O:25])[C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C:14]2=[O:24])[CH2:6]1)([O:3][CH3:4])=[O:2].[BH4-].[Na+]>ClCCl.CO>[C:1]([C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH:9]([OH:25])[C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[OH:24])[CH2:6]1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)[C@H]1CC[C@@]2(C)C(=CC(=O)[C@@H]3[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]32)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)[C@H]1CC[C@@]2(C)C(=CC(O)[C@H]3[C@@H]4CC[C@H](O)[C@@]4(C)CC[C@@H]32)C1
Temperature: 25 °C
Yield: 71.7 %

Procedure:
3β-Carbomethoxyandrost-5-ene-7,17-dione (42) (0.5 g, 0.0014 mol) was dissolved in a mixture of dichloromethane (5 mL) and methanol (10 mL). The mixture was stirred at room temperature and finely powdered sodium borohydride (0.16 g, 0.004 mol) was added slowly. After 15 min the reaction mixture was quenched with water and the product was extracted with methylene dichloride. The organic layer was washed, dried and solvent removed. The product was crystallized from acetone-petroleum ether to afford 0.35 g (70%) of 3β-carbomethoxyandrost-5-ene-7,17β-diol (49) as a white crystalline solid, m.p. 150-52° C. LC-MS and 1H NMR analysis of the product showed a 8:2 ratio of isomeric 7β-hydroxy and 7α-hydroxy compound.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([NH2:23])=[CH:10][C:11]=3[C:12]2([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:16][CH2:17][CH3:18])=[CH:4][CH:3]=1.[CH2:24]([C:28]1([CH2:42][CH2:43][CH2:44][CH3:45])[C:40]2[CH:39]=[C:38](I)[CH:37]=[CH:36][C:35]=2[C:34]2[C:29]1=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:25][CH2:26][CH3:27]>>[Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([N:23]([C:9]4[CH:8]=[CH:7][C:6]5[C:5]6[C:13](=[CH:14][CH:2]=[CH:3][CH:4]=6)[C:12]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:15][CH2:16][CH2:17][CH3:18])[C:11]=5[CH:10]=4)[C:31]4[CH:32]=[CH:33][C:34]5[C:35]6[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=6)[C:28]([CH2:42][CH2:43][CH2:44][CH3:45])([CH2:24][CH2:25][CH2:26][CH3:27])[C:29]=5[CH:30]=4)=[CH:10][C:11]=3[C:12]2([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:16][CH2:17][CH3:18])=[CH:4][CH:3]=1
Reactant: CCCCC1(CCCC)c2ccccc2-c2ccc(I)cc21
Reactant: CCCCC1(CCCC)c2cc(N)ccc2-c2ccc(Br)cc21
Product: CCCCC1(CCCC)c2ccccc2-c2ccc(N(c3ccc4c(c3)C(CCCC)(CCCC)c3ccccc3-4)c3ccc4c(c3)C(CCCC)(CCCC)c3cc(Br)ccc3-4)cc21

Procedure:
As shown in Scheme 3, 7-bromo-9H-fluoren-2-ylamine is reacted with 1-iodobutane to form 7-bromo-9,9-dibutyl-9H-fluoren-2-ylamine (31); and 2-Iodo-9H-fluorene is reacted with 1-iodobutane to form 9,9-dibutyl-2-iodo-9H-fluorene (32). Then, 7-bromo-9,9-dibutyl-9H-fluoren-2-ylamine (31) is reacted with 9,9-dibutyl-2-iodo-9H-fluorene (32) by Ullman coupling reaction to obtain (7-bromo-9,9-dibutyl-9H-fluoren-2-yl)-bis-(9,9-dibutyl-9H-fluoren-2-yl)amine (33). Next, (7-bromo-9,9-dibutyl-9H-fluoren-2-yl)-bis-(9,9-dibutyl-9H-fluoren-2-yl)amine (33) is reacted with 5-formyl-2-thiopheneboronic acid by Suzuki coupling reaction to obtain 5-{7-[bis-(9,9-dibutyl-9H-fluoren-2-yl)amino]-9,9-dibutyl-9H-fluoren-2-yl}-thiophene-2-carbaldehyde (34a). Finally, in acetonitrile, 5-{7-[bis-(9,9-dibutyl-9H-fluoren-2-yl)amino]-9,9-dibutyl-9H-fluoren-2-yl}-thiophene-2-carbaldehyde (34a) is reacted with cyanoacetic acid by using piperidine as a catalyst, to obtain 3-(5-{7-[bis-(9,9-dibutyl-9H-fluoren-2-yl)amino]-9,9-dibutyl-9H-fluoren-2-yl}-thiophen-2-yl)-2-cyano-acrylic acid (35a).
Reaction SMILES: C(#N)C.[CH3:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH3:17])[N:12]=[CH:11][CH:10]=[C:9]2[O:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[O:27])=[CH:21][CH:20]=1.[CH3:35][C:36]1[CH:43]=[CH:42][CH:41]=[CH:40][C:37]=1[CH2:38]Br.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH3:17])[N:12]=[CH:11][CH:10]=[C:9]2[O:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][CH:29]2[CH2:34][CH2:33][N:32]([CH2:35][C:36]3[CH:43]=[CH:42][CH:41]=[CH:40][C:37]=3[CH3:38])[CH2:31][CH2:30]2)=[O:27])=[CH:21][CH:20]=1
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)NC4CCNCC4)cc3)c2cc1OC
Reactant: Cc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1cc2nccc(Oc3ccc(NC(=O)NC4CCN(Cc5ccccc5C)CC4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 45 %

Procedure:
Acetonitrile (10 ml) was added to the compound (1) (139 mg), 2-methylbenzyl bromide (0.03 ml), and potassium carbonate (81 mg), and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with chloroform. The extract was washed with saturated brine and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin-layer chromatography using chloroform/methanol for development. Diethyl ether was added to the purification product, and the precipitated crystal was collected by filtration and was washed to give the title compound (46 mg, yield 45%).
Reaction SMILES: [CH2:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH2:4][CH2:3][CH:2]1[NH2:14].[C:15]12([C:25](Cl)=[O:26])[CH2:24][CH:19]3[CH2:20][CH:21]([CH2:23][CH:17]([CH2:18]3)[CH2:16]1)[CH2:22]2.C(N(CC)CC)C>O1CCCC1>[CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH:14][C:25]([C:15]12[CH2:24][CH:19]3[CH2:18][CH:17]([CH2:23][CH:21]([CH2:20]3)[CH2:22]1)[CH2:16]2)=[O:26]
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: NC1CCc2oc3ccccc3c2C1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc2oc3c(c2c1)CCCC3)C12CC3CC(CC(C3)C1)C2
Yield: 56.1 %

Procedure:
Following the procedure of Example 1, tetrahydro-dibenzofuran-2-ylamine (0.94 g, 5.0 mmol), adamantanecarbonyl chloride (1.1 g, 5.3 mmol), and triethylamine (2.1 mL, 15 mmol) in tetrahydrofuran (20 mL) provided adamantane-1-carboxylic acid (6,7,8,9-tetrahydro-dibenzofuran-2-yl)-amide (0.98 g). Mp 247-248° C.; Anal. Calcd. for C23H27NO2: C, 79.05; H, 7.79; N, 4.01; Found: C, 78.75; H, 7.73; N, 3.75.
Reaction SMILES: [C:1]([N:4]1[CH2:8][C@H:7]([O:9][CH2:10][CH3:11])[C@H:6]([NH:12][C:13]2[C:18]([CH2:19][CH3:20])=[N:17][C:16]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[Cl:28])=[C:15]([CH2:29][CH3:30])[N:14]=2)[CH2:5]1)(=[O:3])C.[CH3:31][N:32](C)[C:33](Cl)=O>>[Cl:28][C:22]1[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:21]=1[C:16]1[N:17]=[C:18]([CH2:19][CH3:20])[C:13]([NH:12][C@H:6]2[C@@H:7]([O:9][CH2:10][CH3:11])[CH2:8][N:4]([C:1]([N:32]([CH3:33])[CH3:31])=[O:3])[CH2:5]2)=[N:14][C:15]=1[CH2:29][CH3:30]
Reactant: CCO[C@H]1CN(C(C)=O)C[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Reactant: CN(C)C(=O)Cl
Product: CCO[C@H]1CN(C(=O)N(C)C)C[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC

Procedure:
Following the procedure for the preparation of N-[(cis)-1-acetyl-4-ethoxypyrrolidin-3-yl]-5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-amine but substituting dimethylcarbamyl chloride and making non-critical variations provided the title compound as an oil:
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.O=S(Cl)[Cl:13]>>[Br:1][C:2]1[N:7]=[C:6]([C:8]([Cl:13])=[O:10])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(Br)n1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cccc(Br)n1
Temperature: 70 °C

Procedure:
A mixture of 6-bromo-2-pyridinecarboxylic acid (1 g, 5 mmol) in SOCl2 (10 ml, 140 mmol) was heated to 70° C. for 6 hours and concentrated to dryness to provide the title compound.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([CH3:24])=[CH:21][CH:22]=3)[N:17]=[C:16]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[OH:31])[N:15]=2)[CH2:10]1.Cl[C:33]([O:35][CH2:36][CH:37]([CH3:39])[CH3:38])=[O:34]>CN(C=O)C>[OH:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:16]1[N:15]=[C:14]([N:11]2[CH2:12][CH2:13][C@@H:9]([NH:8][C:33](=[O:34])[O:35][CH2:36][CH:37]([CH3:39])[CH3:38])[CH2:10]2)[C:23]2[C:18](=[CH:19][C:20]([CH3:24])=[CH:21][CH:22]=2)[N:17]=1
Reactant: Cc1ccc2c(N3CC[C@@H](N)C3)nc(-c3ccccc3O)nc2c1
Reactant: CC(C)COC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc2c(N3CC[C@@H](NC(=O)OCC(C)C)C3)nc(-c3ccccc3O)nc2c1
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 58.2 %

Procedure:
Under an N2 atmosphere, triethylamine (0.35 mL, 2.5 mmol) was added to a solution of (R)-2-(4-(3-aminopyrrolidin-1-yl)-7-methylquinazolin-2-yl)phenol (0.40 g, 1.25 mmol) in DMF (6.0 mL). The reaction mixture was cooled to −20° C. external temperature, and isobutyl chloroformate (180 μL, 1.38 mmol) was added dropwise. The reaction was stirred for 10 minutes at −20° C. and 15 minutes at RT. The mixture was quenched with H2O, and partitioned between CH2Cl2 and H2O, and the aqueous layer was extracted once more with CH2Cl2. The organic phase was dried over Na2SO4, filtered and purified via silica gel chromatography using 6% EtOAc in a 1:1 mixture of hexanes and CH2Cl2 to yield (R)-isobutyl 1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate (compound 5) (306 mg, 58%). 1H NMR (400 MHz, DMSO-d6) δ 8.43 (m, 1H), 8.18 (d, J=8.6 Hz, 1H), 7.59 (s, 2H), 7.35 (m, 2H), 6.92 (m, 2H), 4.06 (m, 5H), 3.75 (d, J=4.4 Hz, 2H), 2.49 (s, 3H), 2.23 (m, 1H), 2.03 (m, 1H), 1.83 (m, 1H), 0.87 (d, J=6.5 Hz, 6H) ppm. LC/MS: m/z 421.3 (M+H)+ at 2.54 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:27])([CH2:24][CH2:25][CH3:26])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[CH2:28]([O:35][C:36]1[CH:37]=[CH:38][C:39]([CH3:45])=[C:40]([CH:44]=1)[C:41](O)=[O:42])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([O:35][C:36]1[CH:37]=[CH:38][C:39]([CH3:45])=[C:40]([C:41]([N:20]2[CH2:21][CH2:22][CH:17]([N:15]3[C:14](=[O:23])[C:13]([CH3:27])([CH2:24][CH2:25][CH3:26])[C:12]([C:6]4[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH3:2])[CH:5]=4)=[N:16]3)[CH2:18][CH2:19]2)=[O:42])[CH:44]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: Cc1ccc(OCc2ccccc2)cc1C(=O)O
Reactant: CCCC1(C)C(=O)N(C2CCNCC2)N=C1c1ccc(OC)c(OC)c1
Agent: Cl
Product: CCCC1(C)C(=O)N(C2CCN(C(=O)c3cc(OCc4ccccc4)ccc3C)CC2)N=C1c1ccc(OC)c(OC)c1

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-(3,4-dimethoxyphenyl)-4-methyl-2-piperidin-4-yl-4-propyl-2,4-dihydro-3H-pyrazol-3-one (compound B8) and 5-(benzyloxy)-2-methylbenzoic acid (compound F1) as starting compounds. The crude product is purified by chromatography (amino phase silica gel and DCM) and by a second chromatography (silica gel and cyclohexane/EA=6:4) to yield the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[CH:6][C:7]=1[NH2:8].Cl.O.O.[C:13](O)(=[O:17])[C:14](O)=[O:15].[OH-].[Na+]>>[CH3:9][C:4]1[CH:3]=[C:2]2[C:7](=[CH:6][CH:5]=1)[NH:8][C:14](=[O:15])[C:13](=[O:17])[NH:1]2
Reactant: Cc1ccc(N)c(N)c1
Reactant: O=C(O)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc2[nH]c(=O)c(=O)[nH]c2c1
Temperature: 25 °C
Yield: 518.2 %

Procedure:
To a stirred solution of 3,4-diaminotoluene (0.302 g, 0.247 mmol, Aldrich) in 2 N HCl (4 mL, 8 mmol), oxalic acid dihydrate (0.330 g, 0.261 mmol, Fisher) was added in one portion. The resulting deep purple solution was refluxed for 13 h, to give a purple suspension. This was cooled to 25° C., filtered, washed with water (5 mL), and dried in vacuo (0.1 mm Hg) to give a blue-grey powder. This was taken up in 2 N NaOH (34 mL, 68 mmol), giving a brown solution, which was filtered. The brown filtrate was acidified to pH 1.0 by addition of 2 N HCl (42 mL, 84 mmol), resulting in a tan suspension. Filtration of the suspension and washing of the filter cake with water (5 mL) gave the title compound as a grey powder (225.5 mg, 43%); mp 318° C. (the block was preheated to 300° C.); 1H NMR (DMSO-d6) δ 2.32 (s, 3H), 6.90-6.99 (m, 3H), 11.22 (s, 1H), 11.90 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[C:6]3[CH2:7][CH2:8][CH2:9][NH:10][C:11]=3[CH2:12][CH2:13][C:4]=2[CH:3]=1.[C:16]1(=[O:32])[N:20]([CH2:21][CH2:22][CH2:23][C:24](Cl)=[O:25])[C:19](=[O:27])[C:18]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:17]12>C(Cl)Cl>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[C:6]3[CH2:7][CH2:8][CH2:9][N:10]([C:24](=[O:25])[CH2:23][CH2:22][CH2:21][N:20]4[C:16](=[O:32])[C:17]5=[CH:31][CH:30]=[CH:29][CH:28]=[C:18]5[C:19]4=[O:27])[C:11]=3[CH2:12][CH2:13][C:4]=2[CH:3]=1
Reactant: Clc1ccc2c(c1)CCC1=C2CCCN1
Reactant: O=C(Cl)CCCN1C(=O)c2ccccc2C1=O
Solvent: ClCCl
Product: O=C(CCCN1C(=O)c2ccccc2C1=O)N1CCCC2=C1CCc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
31.4 g (0.143 mol) of 8-chloro-1,2,3,4,5,6-hexahydrobenzo[f]quinoline dissolved in 300 ml of methylene chloride are added at 0° to a solution of 36.0 g (0.143 mol) of 4-phthalimidobutyryl chloride in 360 ml of methylene chloride and the mixture is stirred at room temperature for 1 hour. The solution is concentrated, extracted with methylene chloride and aqueous sodium hydrogen carbonate solution dried with magnesium sulfate and the solvent is distilled in a vacuum. Extractive crystallization with acetone gives 8-chloro-1,2,3,4,5,6-hexahydro-4-(4-phthalimidobutyryl)benzo[f]quinoline as white crystals with melting point 182-183°.
Reaction SMILES: Cl[CH:2]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)[C:3]1[CH:4]=[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)[C:6]([O:9][CH3:10])=[N:7][CH:8]=1.ClC1C=C(C2C=C(C(C3C=CC(F)=CC=3)O)[CH:35]=[N:36]C=2OC)C=CC=1.S(Cl)(Cl)=O>C(Cl)Cl>[Cl:17][C:13]1[CH:12]=[C:11]([C:5]2[CH:4]=[C:3]([CH:2]([NH:36][CH3:35])[C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH:8]=[N:7][C:6]=2[O:9][CH3:10])[CH:16]=[CH:15][CH:14]=1
Reactant: COc1ncc(C(Cl)c2ccc(F)cc2)cc1-c1cccc(Cl)c1
Reactant: COc1ncc(C(O)c2ccc(F)cc2)cc1-c1cccc(Cl)c1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CNC(c1ccc(F)cc1)c1cnc(OC)c(-c2cccc(Cl)c2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-(Chloro(4-fluorophenyl)methyl)-3-(3-chlorophenyl)-2-methoxypyridine. To a cooled solution, 0° C., of [5-(3-chlorophenyl)-6-methoxypyridin-3-yl](4-fluorophenyl)methanol (Example 14, 1.43 g, 4.17 mmol), in DCM (10 mL), was added thionyl chloride (744 mg, 6.25 mmol) dropwise. The solution was allowed to warm up to room temperature, and stirred for 1 h. The reaction mixture was concentrated under reduced pressure. Purification (FCC, SiO2, 0-10% EtOAc/hexanes) afforded the title compound, which was used directly for the next step.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12](CC2C=CC(C3SC=CN=3)=CC=2)([NH2:24])[C:13]2[N:18]=[C:17]([NH:19][CH2:20][C:21]([OH:23])=[O:22])[CH:16]=[CH:15][CH:14]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.Cl.N1C=CC=C(S(C(N[CH2:60][C:61]2[CH:66]=[CH:65][C:64]([C:67]3[S:68][CH:69]=[CH:70][N:71]=3)=[CH:63][CH:62]=2)C2N=C(NCC(O)=O)C=CC=2)(=O)=O)C=1>>[F:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH:12]([NH:24][CH2:60][C:61]2[CH:62]=[CH:63][C:64]([C:67]3[S:68][CH:69]=[CH:70][N:71]=3)=[CH:65][CH:66]=2)[C:13]2[N:18]=[C:17]([NH:19][CH2:20][C:21]([OH:23])=[O:22])[CH:16]=[CH:15][CH:14]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: NC(Cc1ccc(-c2nccs2)cc1)(c1cccc(NCC(=O)O)n1)S(=O)(=O)c1ccc(F)cc1
Reactant: O=C(O)CNc1cccc(C(NCc2ccc(-c3nccs3)cc2)S(=O)(=O)c2cccnc2)n1
Agent: Cl
Product: O=C(O)CNc1cccc(C(NCc2ccc(-c3nccs3)cc2)S(=O)(=O)c2ccc(F)cc2)n1
Yield: 95 %

Procedure:
Reaction and post-treatment were carried out in the same manner as in Example 2-(c) except for using (6-{(4-fluorobenzenesulfonyl)[4-(thiazol-2-yl)benzyl]-aminomethyl}pyridin-2-ylamino)acetic acid hydrochloride (148 mg, 0.248 mmol) obtained in Example 4-(b) in place of (6-{(pyridin-3-ylsulfonyl)[4-(thiazol-2-yl)-benzyl]aminomethyl}pyridin-2-ylamino)acetic acid hydrochloride to afford the title compound (122 mg) as a pale brown solid. (Yield: 95%)
Reaction SMILES: [CH:1]1([N:6]2[C:11]([CH3:12])=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]([F:21])[F:20])[CH:14]=3)[C:9](=[O:22])[C:8]([C:23](O)=[O:24])=[CH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:59][C:60]1[O:64][C:63]([CH2:65][NH2:66])=[N:62][N:61]=1>CN(C=O)C>[CH3:59][C:60]1[O:64][C:63]([CH2:65][NH:66][C:23]([C:8]2[C:9](=[O:22])[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]([F:20])[F:21])[CH:14]=3)=[C:11]([CH3:12])[N:6]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[CH:7]=2)=[O:24])=[N:62][N:61]=1
Reactant: Cc1c(-c2cccc(C(F)F)c2)c(=O)c(C(=O)O)cn1C1CCCC1
Reactant: Cc1nnc(CN)o1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nnc(CNC(=O)c2cn(C3CCCC3)c(C)c(-c3cccc(C(F)F)c3)c2=O)o1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 1-cyclopentyl-5-(3-difluoromethyl-phenyl)-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid (preparation 9, 116 mg, 0.334 mmol), HBTU (140 mg, 0.369 mmol), DIPEA (116 μL, 0.668 mmol) in DMF (1 mL) is stirred for 15 min at room temperature. C-(5-methyl-1,3,4-oxadiazol-2-yl)-methylamine (46 mg, 0.407 mmol) is added and the reaction mixture is stirred for 72 h at room temperature. The reaction mixture is purified by preparative reversed-phase HPLC (XBridge, gradient of methanol in water, 0.3% NH4OH, 60° C.). Yield: 67 mg (45% of theory); ESI mass spectrum: [M+H]+=443; Retention time HPLC: 0.98 min (Z003_001).
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[CH:4][C:3]1=2.[CH:16]1([CH:21]=O)[CH2:20][CH2:19][CH2:18][CH2:17]1.N1CCCC1>CO>[CH:16]1([CH:21]=[C:11]2[CH2:10][CH2:9][C:8]3[CH:7]=[C:6]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[CH:4][C:3]=3[C:2]2=[O:1])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COC(=O)c1ccc2c(c1)CCCC2=O
Reactant: O=CC1CCCC1
Solvent: C1CCNC1
Solvent: CO
Product: COC(=O)c1ccc2c(c1)CCC(=CC1CCCC1)C2=O
Temperature: 25 °C
Yield: 59 %

Procedure:
To a solution of methyl 5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate (3.4 g, 16.7 mmol) in methanol (30 mL) was added cyclopentanecarboxaldehyde (3.3 g, 33.3 mmol) and pyrrolidine (2.78 mL, 33.3 mmol). The solution was stirred for twenty hours at ambient temperature. The reaction was recharged with 0.5 mL of cyclopentanecarboxaldehyde. The resulting precipitate was collected by vacuum filtration to provide methyl 6-(cyclopentylmethylene)-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate as a solid (2.8 g, 60% yield). LC/MS on 4.6×50 mm C-18 column, tR=6.71 minutes (10 to 90% acetonitrile/water over 8 minutes at 2 mL/minute with detection 254 nm, at 50° C.); ES-MS m/z 285 (M+H); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.24-1.39 (m, 2H), 1.52-1.74 (m, 4H), 1.76-1.89 (m, 2H), 2.77 (t, J=5.77 Hz, 2H), 2.79-2.90 (m, 1H), 2.97 (t, J=6.44 Hz, 2H), 3.85 (s, 3H), 6.71 (d, J=9.94 Hz, 1H), 7.88 (d, J=6.44 Hz, 1H), 7.91 (s, 1H), 7.98 (d, J=8.06 Hz, 1H).
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([N:25]3[CH2:30][CH2:29][CH:28]([CH2:31][CH2:32][O:33][Si:34]([CH:41]([CH3:43])[CH3:42])([CH:38]([CH3:40])[CH3:39])[CH:35]([CH3:37])[CH3:36])[CH2:27][CH2:26]3)=[N:23][N:24]=2)[CH:21]=1>CN(C=O)C.O>[CH:38]([Si:34]([CH:35]([CH3:37])[CH3:36])([CH:41]([CH3:43])[CH3:42])[O:33][CH2:32][CH2:31][CH:28]1[CH2:29][CH2:30][N:25]([C:22]2[N:20]3[CH:21]=[C:16]([O:12][C@H:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C@@H:2]([NH2:1])[CH2:3][CH2:4]4)[CH:17]=[CH:18][C:19]3=[N:24][N:23]=2)[CH2:26][CH2:27]1)([CH3:39])[CH3:40]
Reactant: CC(C)[Si](OCCC1CCN(c2nnc3ccc(F)cn23)CC1)(C(C)C)C(C)C
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)[Si](OCCC1CCN(c2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)CC1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 42.6 %

Procedure:
To a solution of Intermediate A (122 mg, 0.75 mmol) in DMF (3 mL) was added NaH (60% dispersion in oil, 60 mg, 1.5 mmol) and the mixture stirred at RT for 25 min. A solution of Intermediate 66b (315 mg, 0.75 mmol) in DMF (2.5 mL) was added and the mixture stirred at 60° C. for 1.5 h. The cooled mixture was diluted with water and extracted with DCM (5×25 mL). The combined organics were dried and concentrated in vacuo. The residue was purified by FCC, using 0-14% [2M NH3 in MeOH] in DCM, to give the title compound as a dark brown gum (180 mg, 42%). LCMS (Method 3): Rt 3.35 min, m/z 564 [MH+].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[NH:4][C:5]1[O:6][C:7]2[C:13](I)=[CH:12][CH:11]=[C:10]([O:15][CH3:16])[C:8]=2[N:9]=1.C([Sn](CCCC)(CCCC)[C:23]1[CH2:24][CH2:25][O:26][CH2:27][CH:28]=1)CCC.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>O1CCOCC1.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]>[CH3:1][O:2][C:3](=[O:17])[NH:4][C:5]1[O:6][C:7]2[C:13]([C:23]3[CH2:28][CH2:27][O:26][CH2:25][CH:24]=3)=[CH:12][CH:11]=[C:10]([O:15][CH3:16])[C:8]=2[N:9]=1
Reactant: CCCC[Sn](CCCC)(CCCC)C1=CCOCC1
Reactant: COC(=O)Nc1nc2c(OC)ccc(I)c2o1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: C1COCCO1
Product: COC(=O)Nc1nc2c(OC)ccc(C3=CCOCC3)c2o1
Temperature: 100 °C
Yield: 42.3 %

Procedure:
To a stirred solution of 350 g (10.1 mmol) (7-iodo-4-methoxy-benzooxazol-2-yl)-carbamic acid methyl ester in 50 ml dioxane were added 5.63 g (15.1 mmol) tributyl-(3,6-dihydro-2H-pyran-4-yl)-stannane, 173 mg (0.30 mmol) bis(dibenzylideneacetone)palladium(0), 374 mg (1.61 mmol) tri(2-furyl)phospine. The mixture was heated at 100° C. for 22 h and then poured onto water and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. Flash chromatography (2/98 methanol/dichloromethane then 5/95 methanol/dichloromethane) followed by trituration in dichloromethane afforded 1.30 g (42%) [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-benzooxazol-2-yl]-carbamic acid methyl ester as a white solid. ES-MS m/e (%): 305 (M+H+, 100).
Reaction SMILES: [ClH:1].[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][N:11]3[CH:14]=[N:15][CH:16]=[C:10]3[CH:9]=2)[CH2:4][CH2:3]1.Br[C:18]1C=CN=C(C(N)C)C=1.BrC1C=CN=C(CN)C=1>>[ClH:1].[CH3:18][C:16]1[N:15]=[CH:14][N:11]2[CH:12]=[CH:13][C:8]([CH:5]3[CH2:4][CH2:3][NH:2][CH2:7][CH2:6]3)=[CH:9][C:10]=12
Reactant: c1cn2cncc2cc1C1CCNCC1
Reactant: CC(N)c1cc(Br)ccn1
Agent: Cl
Agent: NCc1cc(Br)ccn1
Product: Cc1ncn2ccc(C3CCNCC3)cc12

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 39.5, except 1-(4-bromopyridin-2-yl)ethanamine (compound 66.1) was used in place of (4-bromopyridin-2-yl)methanamine (compound 39.1).
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][N:17]=3)=[O:15])[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1.[CH2:50]([CH2:52][NH2:53])[OH:51]>C(Cl)Cl.O1CCCC1>[NH2:1][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[CH:24]=[CH:23][C:19]([C:20](=[O:21])[NH:53][CH2:52][CH2:50][OH:51])=[CH:18][N:17]=3)=[O:15])[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCO
Reactant: Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)O)cn2)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: C1CCOC1
Product: Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)NCCO)cn2)CC1
Reaction time: 2 h
Yield: 78 %

Procedure:
6-[1-(3-Amino-2-pyridyl)piperazine-4-yl-carbonyl]nicotinic acid (0.5 g) was added to a co-solvent of tetrahydrofuran (10 ml) and methylene chloride (10 ml) and with the successive addition of 1,3-dicyclohexylcarbodimide (0.65 g) and 1-hydroxybenzotriazole (0.23 g) at 15˜20° C., the mixture was stirred for 2 hours. With the addition of ethanolamine (0.18 ml), the mixture was stirred again at 20˜25° C. for 2 hours. Methylene chloride (30 ml) was added again to the mixture, washed with water 3 times, dried over magnesium sulfate and concentrated under reduced pressure. The concentrated residue was treated with ether for crystallization. The solid was recrystallized with ethanol and hexane to give a desired compound of 0.44 g (yield: 78%).