Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[C:20]2[N:21]=[C:22]([CH2:29][CH2:30][CH2:31][CH3:32])[N:23]([CH2:24][CH2:25][CH2:26][CH2:27][NH2:28])[C:19]=2[C:18]2[N:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1>>[NH2:10][C:11]1[C:20]2[N:21]=[C:22]([CH2:29][CH2:30][CH2:31][CH3:32])[N:23]([CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:19]=2[C:18]2[N:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCCc1nc2c(N)nc3cccnc3c2n1CCCCN
Product: CCCCc1nc2c(N)nc3cccnc3c2n1CCCCNC(=O)c1ccccc1
Yield: 55 %

Procedure:
Using the general method of Example 47, benzoyl chloride (56 μL, 0.48 mmol) was reacted with 4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine (0.15 g, 0.48 mmole) to provide 0.11 g of N-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]benzamide as a white solid. Analysis: Calculated for C24H28N6O+¼H2O: %C, 68.47; %H, 6.82; %N, 19.96: Found: %C, 68.24; %H, 6.76; %N, 19.90.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH2:13][O:14][CH3:15])[CH:6]=O.CC([O-])=O.[K+].[NH2:21]O.Cl.O>CC(O)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH2:13][O:14][CH3:15])[C:6]#[N:21]
Reactant: NO
Reactant: COCCOc1ccc(C=O)cc1OC
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: COCCOc1ccc(C#N)cc1OC
Temperature: 130 °C
Yield: 91.3 %

Procedure:
To a solution of 3-methoxy-4-(2-methoxyethoxy)benzaldehyde (10 g) in AcOH (80 mL) was added KOAc (9.5 g) and NH2OH.HCl (6.7 g). The resulting mixture was heated at 130° C. for 18 h under N2 atmospheres. After reaction finished, the mixture was poured into water (400 mL). The solid was collected, washed with water (100 mL) and air-dried to give 3-methoxy-4-(2-methoxyethoxy)benzonitrile (9 g) as a light yellow solid. 1H-NMR (400 MHz, CDCl3): δ: 7.26 (dd, J=8.4, 1.6, 1H), 7.08 (d, J=1.6, 1H), 6.93 (d, J=8.4, 1H), 4.23-4.20 (m, 2H), 3.88 (s, 3H), 3.82-3.80 (m, 2H), 3.45 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[C:20]([N:39]1[CH:43]=[C:42]([C:44](=[O:46])[CH3:45])[N:41]=[CH:40]1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[Cl-].[NH4+]>C1COCC1.CCCCCC>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([C:44]([C:42]3[N:41]=[CH:40][N:39]([C:20]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH:43]=3)([OH:46])[CH3:45])[CH:3]=2)=[CH:9][CH:10]=1
Reactant: CC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: Fc1ccc(-c2cccc(Br)c2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(O)(c1cccc(-c2ccc(F)cc2)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reaction time: 0.33 h
Yield: 55.2 %

Procedure:
To a solution of 3-bromo-4′-fluoro-1,1′-biphenyl (1.50 g) in THF (20 ml) was added dropwise a solution (1.6 M; 3.73 ml) of n-butyllithium in hexane at −78° C., and the mixture was stirred for 20 min. A solution of 1-(1-trityl-1H-imidazol-4-yl)-1-ethanone (1.91 g) in THF (25 ml) was added dropwise at −78° C., and the mixture was stirred at −78° C. for 1 h, at −35 to −10° C. for 1 h and at 0° C. for 1 h. Saturated aqueous ammonium chloride solution was added to the reaction mixture and the mixture was extracted with ethyl acetate, washed with saturated brine and dried. The solvent was evaporated under reduced pressure and the residue was purified by column chomatography (eluent, hexane:ethyl acetate=3:1→1:1) and recrystallized from ethyl acetate-hexane to give the title compound (1.57 g) as colorless prism crystals.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([CH2:18][C:19]3[N:23]4[CH:24]=[CH:25][C:26]([C:28](=O)[CH3:29])=[CH:27][C:22]4=[N:21][CH:20]=3)[CH:15]=[CH:14][C:12]=2[N:13]=1.Cl.[NH2:32][OH:33].N1C=CC=CC=1>CCO>[OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([CH2:18][C:19]3[N:23]4[CH:24]=[CH:25][C:26]([C:28](=[N:32][OH:33])[CH3:29])=[CH:27][C:22]4=[N:21][CH:20]=3)[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: CC(=O)c1ccn2c(Cc3ccc4nc(N[C@@H]5CCCC[C@H]5O)sc4c3)cnc2c1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CC(=NO)c1ccn2c(Cc3ccc4nc(N[C@@H]5CCCC[C@H]5O)sc4c3)cnc2c1
Temperature: 90 °C
Yield: 55.6 %

Procedure:
To a stirred solution of 1-(3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)imidazo[1,2-a]pyridin-7-yl)ethanone (40 mg, 0.095 mmol) from Example 200 in EtOH (2 mL) at rt were added hydroxylamine hydrochloride (120 mg, excess) and pyridine (200 μL, excess). The mixture was heated at 90° C. for 1 h, and then cooled to rt. Purification by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH), CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C18 column as the stationary phase afforded 1-(3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)imidazo[1,2-a]pyridin-7-yl)ethanone oxime (23 mg, 61%) as yellow powder. 1H NMR (500 MHz, DMSO-d6) δ 11.46 (br s, 1H), 8.13 (d, J=7.4 Hz, 1H), 7.90 (d, J=7.4 Hz, 1H), 7.72 (s, 1H), 7.51 (s, 1H), 7.45 (s, 1H), 7.08 (d, J=8.4 Hz, 1H), 6.44-6.58 (m, 1H), 5.89 (s, 1H), 4.78 (d, J=2.5 Hz, 1H), 4.29 (s, 2H), 3.50 (br s, 1H), 2.18 (s, 3H), 2.04 (d, J=12.3 Hz, 1H), 1.87 (d, J=10.8 Hz, 1H), 1.56-1.67 (m, 2H), 1.15-1.32 (m, 4H). LCMS (ESI) m/z 436 (M+H)+.
Reaction SMILES: C(O[C@H]1CN(C2N=CC=CN=2)C[C@H]1NC1C(CC)=NC(C2C(C)=NC(OC)=CC=2)=C(CC)N=1)C.Br[C:36]1[S:37][CH:38]=[CH:39][N:40]=1.[CH3:41][O:42][C:43]1[C:48]([C:49]2[N:50]=[C:51]([CH2:66][CH3:67])[C:52]([NH:57][C@H:58]3[C@@H:62]([O:63][CH2:64][CH3:65])[CH2:61][NH:60][CH2:59]3)=[N:53][C:54]=2[CH2:55][CH3:56])=[CH:47][CH:46]=[C:45]([O:68][CH3:69])[N:44]=1>>[CH3:41][O:42][C:43]1[C:48]([C:49]2[N:50]=[C:51]([CH2:66][CH3:67])[C:52]([NH:57][C@H:58]3[C@@H:62]([O:63][CH2:64][CH3:65])[CH2:61][N:60]([C:36]4[S:37][CH:38]=[CH:39][N:40]=4)[CH2:59]3)=[N:53][C:54]=2[CH2:55][CH3:56])=[CH:47][CH:46]=[C:45]([O:68][CH3:69])[N:44]=1
Reactant: CCO[C@H]1CNC[C@H]1Nc1nc(CC)c(-c2ccc(OC)nc2OC)nc1CC
Reactant: Brc1nccs1
Agent: CCO[C@H]1CN(c2ncccn2)C[C@H]1Nc1nc(CC)c(-c2ccc(OC)nc2C)nc1CC
Product: CCO[C@H]1CN(c2nccs2)C[C@H]1Nc1nc(CC)c(-c2ccc(OC)nc2OC)nc1CC

Procedure:
Following the procedure for the preparation of N-[(3R,4S)-4-ethoxy-1-pyrimidin-2-ylpyrrolidin-3-yl]-3,6-diethyl-5-(6-methoxy-2-methylpyridin-3-yl)pyrazin-2-amine but substituting 2-bromothiazole and starting with 5-(2,6-dimethoxypyridin-3-yl)-N-[(3R,4S)-4-ethoxypyrrolidin-3-yl]-3,6-diethylpyrazin-2-amine provided the title compound as an amorphous solid. 1H NMR (400 MHz, CDCl3) δ) 7.54, 7.23, 6.52, 6.43, 5.21, 4.92, 4.25, 4.00, 3.97, 3.93, 3.80–3.73, 3.54, 3.44, 2.72, 2.52, 1.33–1.26, 1.18; IR (diffuse reflectance) 2963, 2327 (w), 2187 (w), 2056 (w), 1997 (w), 1604, 1580, 1567, 1538 (s), 1474 (s), 1397, 1377, 1311, 1235, 1031 cm−1 HRMS (ESI) calcd for C24H32N6O3S+H1 485.2335. found 485.2333.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:15]=[C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:17]=1[OH:18])[C:8]([C:10]1[CH:14]=[CH:13][NH:12][CH:11]=1)=[O:9])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C)C=O>[CH2:25]([N:12]1[CH:13]=[CH:14][C:10]([C:8](=[O:9])[C:7]2[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:17]([OH:18])=[C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:15]=2)=[CH:11]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)c1cc(C(=O)c2cc[nH]c2)cc(C(C)(C)C)c1O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(C(=O)c2ccn(Cc3ccccc3)c2)cc(C(C)(C)C)c1O
Reaction time: 0.5 h

Procedure:
2 G (6.6 mmol) of 3-(3,5-di-t-butyl-4-hydroxybenzoyl)pyrrole were added to a cooled, stirred suspension of 0.70 g of sodium hydride (50% in mineral oil) in 50 ml of anhydrous dimethylformamide under nitrogen. After 30 minutes at room temperature, 1.0 ml of benzyl bromide was added. Stirring at room temperature was continued for an additional 16 hours. The reaction mixture was poured over a 10% HCl-ice mixture, then extracted three times with 250 ml ethyl acetate. The organic layer was washed five times with 200 ml water, dried and evaporated to dryness. The residue was purified by chromatography on alumina (3% water, 100 g) eluting with hexane:ethyl acetate (9:1). Crystallization from methylene chloride-hexane gave 1.5 g of N-benzyl-3-(3,5-di-t-butyl-4-hydroxybenzoyl)pyrrole (mp 123°-124° C.).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C(=O)([O-])[O-].[K+].[K+].[C:19]([O:23][C:24](=[O:27])[CH2:25]Br)([CH3:22])([CH3:21])[CH3:20]>O1CCCC1>[C:19]([O:23][C:24](=[O:27])[CH2:25][N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:9][CH2:10][OH:11])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: OCCNCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)CN(CCO)Cc1ccccc1

Procedure:
15.1 g (100 mmol) of N-benzylethanolamine is dissolved in 50 ml of tetrahydrofuran and mixed with 15 ml of water and 13.8 g (100 mmol) of potassium carbonate. After instillation of 20.5 g (105 mmol) of bromoacetic acid-tert-butyl ester, it is stirred for 6 hours at 65° C. After cooling, it is filtered, concentrated by evaporation in a vacuum and the residue is chromatographed on silica gel with diethyl ether/hexane/triethylamine. The product fractions are concentrated by evaporation in a vacuum and dried.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Cl:24])(Cl)(Cl)Cl.[CH2:25]([S:27]([C:30]1[CH:50]=[CH:49][C:33]([CH2:34][C:35]2[C:44]3[C:39](=[CH:40][CH:41]=[C:42]([F:45])[CH:43]=3)[CH:38]=[C:37](CO)[C:36]=2[CH3:48])=[CH:32][CH:31]=1)(=[O:29])=[O:28])[CH3:26]>O1CCCC1.C(OCC)(=O)C>[CH2:25]([S:27]([C:30]1[CH:50]=[CH:49][C:33]([CH2:34][C:35]2[C:44]3[C:39](=[CH:40][CH:41]=[C:42]([F:45])[CH:43]=3)[CH:38]=[C:37]([CH2:20][Cl:24])[C:36]=2[CH3:48])=[CH:32][CH:31]=1)(=[O:28])=[O:29])[CH3:26]
Reactant: ClC(Cl)(Cl)Cl
Reactant: CCS(=O)(=O)c1ccc(Cc2c(C)c(CO)cc3ccc(F)cc23)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCS(=O)(=O)c1ccc(Cc2c(C)c(CCl)cc3ccc(F)cc23)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 55.1 %

Procedure:
A mixture of triphenylphosphine (1.10 g, 4.19 mmol), carbon tetrachloride (1.62 mL, 16.8 mmol) and tetrahydrofuran (5 mL) was stirred at room temperature for 10 minutes. A mixture of [4-(4-ethanesulfonyl-benzyl)-6-fluoro-3-methyl-naphthalen-2-yl]-methanol (780 mg, 2.09 mmol) in tetrahydrofuran (2.5 mL) was added, and the reaction mixture was stirred at 75° C. for 4 hours. The reaction mixture was cooled to room temperature, and then diluted with ethyl acetate. The resulting mixture was washed with water. The organic phase was dried over MgSO4, filtered, and concentrated. A solution of the crude product in dichloromethane was evaporated over silica gel, and the silica gel supported crude product was loaded onto an Analogix SuperFlash™ column. Flash chromatography (10%-30% ethyl acetate in hexanes) afforded 450 mg (55%) of 1-(4-ethanesulfonyl-benzyl)-3-chloromethyl-7-fluoro-2-methyl-naphthalene as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.04 (s, 1 H), 7.96-8.04 (m, 1 H), 7.76 (d, J=8.2 Hz, 2 H), 7.68-7.75 (m, 1 H), 7.41 (td, J=8.6, 2.1 Hz, 1 H), 7.30 (d, J=8.2 Hz, 2 H), 5.01 (s, 2 H), 4.63 (s, 2 H), 3.22 (q, J=7.2 Hz, 2 H), 2.47 (s, 3 H), 1.06 (t, J=7.2 Hz, 3 H). MS (ES+) cald. for C21H20CIFO2S [(M−Cl)+] 355, obsd. 355.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=3)[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[C:23]([NH:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1)(=[O:25])[CH3:24].C(OCC)(=O)C>N1C=CC=CC=1>[C:23]([NH:26][C:27]1[CH:28]=[CH:29][C:30]([S:33]([NH:1][C:2]2[CH:3]=[C:4]([CH:8]3[C:17]([CH3:18])([CH3:19])[CH2:16][C:15]4[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=4)[NH:9]3)[CH:5]=[CH:6][CH:7]=2)(=[O:35])=[O:34])=[CH:31][CH:32]=1)(=[O:25])[CH3:24]
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(N)c1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2cccc(C3Nc4ccc(C(=O)O)cc4CC3(C)C)c2)cc1
Reaction time: 20 h
Yield: 50.7 %

Procedure:
2-(3-aminophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid (100 mg, 0.34 mmol) was dissolved in 2 mL of dry pyridine under nitrogen. Then 4-acetamid obenzene-1-sulfonyl chloride (209 mg, 0.85 mmol) was added drop wise to the reaction mixture. The reaction mixture was allowed to stir for 20 h. Thin layer chromatography (petroleum ether:ethyl acetate=1:1, Rf=0.5) showed the reaction was complete. Pyridine was removed in vacuo and the residue was purified by column chromatography (petroleum ether:ethyl acetate=1:1) to afford 85 mg of 2-(3-(4-acetamidophenylsulfonamido)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid. Yield: 51%. MS (ES+APCI) M+1=494.2.
Reaction SMILES: C([BH3-])#N.[Na+].[NH2:5][CH2:6][CH2:7][CH2:8][P:9]([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)(=[O:11])[OH:10].[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([Cl:28])[CH:27]=1)[CH:23]=O.C(O)(=O)C>CO>[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([Cl:28])[CH:27]=1)[CH2:23][NH:5][CH2:6][CH2:7][CH2:8][P:9]([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)(=[O:10])[OH:11]
Reactant: O=Cc1cc(Cl)cc(Cl)c1
Reactant: NCCCP(=O)(O)CC1CCCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=P(O)(CCCNCc1cc(Cl)cc(Cl)c1)CC1CCCCC1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
2.0 g of sodium cyanoborohydride are added in portions to a solution of 6.27 g of 3-aminopropyl-(cyclohexylmethyl)-phosphinic acid and 5.0 g of 3,5-dichlorobenzaldehyde and 1.91 g of glacial acetic acid in 50 ml of anhydrous methanol and the mixture is stirred at room temperature for 4 days. The solvent is removed, the white residue is taken up in 2.0M hydrochloric acid and filtered. The filtrate is concentrated to dryness by evaporation and the white solid that remains behind is suspended in ethyl acetate, filtered off and crystallised from propanol, yielding 3-[(3,5-dichlorobenzyl)amino]-propyl-(cyclohexylmethyl)-phosphinic acid, m.p. 231°-233°.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15]Cl)=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[C-:18]#[N:19].[Na+]>C(O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:18]#[N:19])=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ccc(OCc2ccccc2)cn1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N#CCc1ccc(OCc2ccccc2)cn1
Reaction time: 0.42 h
Yield: 86.6 %

Procedure:
To a solution of 5-benzyloxy-2-chloromethyl-pyridine (2.13 g, 9.11 mmol) described in Manufacturing Example 127-1-3 in ethanol (30 mL) and water (10 mL) was added sodium cyanide (580 mg, 11.8 mmol), which was stirred for 4 hours and 25 minutes under reflux. Water was added to the reaction mixture at room temperature, which was extracted with ethyl acetate. The organic layer was separated, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane: ethyl acetate=1:1) to obtain the title compound (1.77 g, 87%).
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:10]=[C:11]([C:15]([OH:17])=O)[CH:12]=[N:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH:51]1[CH2:56][CH:55]=[C:54]([C:57]2[CH:58]=[C:59]([CH:62]=[CH:63][CH:64]=2)[C:60]#[N:61])[CH2:53][CH2:52]1>CN(C)C=O>[C:1]1([C:7]#[C:8][C:9]2[CH:10]=[C:11]([C:15]([N:51]3[CH2:52][CH:53]=[C:54]([C:57]4[CH:58]=[C:59]([CH:62]=[CH:63][CH:64]=4)[C:60]#[N:61])[CH2:55][CH2:56]3)=[O:17])[CH:12]=[N:13][CH:14]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1cncc(C#Cc2ccccc2)c1
Reactant: N#Cc1cccc(C2=CCNCC2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[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: N#Cc1cccc(C2=CCN(C(=O)c3cncc(C#Cc4ccccc4)c3)CC2)c1
Reaction time: 0.25 h
Yield: 31.1 %

Procedure:
A solution of 5-phenylethynyl-pyridine-3-carboxylic acid (0.46 g, 2.1 mmol) in anhydrous dimethylformamide (7 ml) is treated with HATU (0.78 g, 2.1 mmol) and diisopropylethylamine (0.98 ml, 5.6 mmol). The reaction mixture is stirred 15 mins. at ambient temperature before being treated with a solution of 3-(1,2,3,6-tetrahydropyridin-4-yl)-benzonitrile (1.9 mmol) in dimethylformamide (6 ml). The reaction mixture is stirred at ambient temperature 3 hours, concentrated under vacuum and the residue partitioned between ethyl acetate (200 ml) and saturated aqueous sodium bicarbonate ((45 ml). The organic layer is dried (magnesium sulfate), concentrated under vacuum and the residue chromatographed on silica gel (dichloromethane/methanol 39:1) to give 3-[1-(5-phenylethynyl-pyridine-3-carbonyl)-1,2,3,6-tetrahydropyridin-4-yl]-benzonitrile as a yellow oil (0.23 g). This material is dissolved in methanol (15 ml), cooled to 0° C. and saturated with hydrogen chloride gas. The reaction vessel is sealed and allowed to stand at 0° C. for 18 hours. The reaction mixture is concentrated to dryness under vacuum, redissolved in methanol (15 ml) and cooled to 0° C. The solution is saturated with ammonia gas and the vessel sealed before being allowed to stand at 0° C. for 48 hours. The reaction mixture is concentrated to dryness under vacuum and the residue chromatographed on silica gel (dichloromethane/methanol 9:1) to give the title compound as a yellow amorphous solid (0.2 g). 1H NMR (DMSO, 500 MHz) δ8.85 (s, 1H), 8.67 (s, 1H), 8.10 (s, 1H), 7.85 (s, 1H), 7.80 (m, 1H), 7.75 (m, 1H), 7.60 (m, 3H), 7.48 (m, 3H), 6.38 (m, 1H), 4.38 (br m, 1H), 4.19 (br m, 1H), 3.90 (br m, 1H), 3.60 (br m, 1H), 2.63 (br m, 2H). EI MS M++H: 407.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1.[H-].[Na+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C)C=O.ClCCl>[CH2:20]([O:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])[C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1C[C@@H](OCc2ccccc2)CN1C(=O)OC(C)(C)C
Reaction time: 0.17 h
Yield: 108.5 %

Procedure:
(2S,4R)-1-tert-Butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate (2.65 g, 10.80 mmol) was dissolved in dimethylformamide (75 ml) and cooled in an ice bath. Sodium hydride (60% in hexanes, 0.57 g, 23.75 mmol) was added and stirred for 10 min. To this solution, benzyl bromide (1.39 ml, 11.69 mmol) dissolved in dichloromethane (9 ml) was dropwise added and the reaction mixture was overnight stirred at room temperature. The solvent was evaporated under reduced pressure and the residue redissolved in ethyl acetate. This organic phase was washed with water, dried over magnesium sulphate, filtered and the solvent evaporated under reduced pressure. 3.93 g (77% yield) of the final product were obtained, pure enough to perform the next synthetic step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[S:47]1[C:56]2[CH2:55][CH2:54][NH:53][CH2:52][CH2:51][C:50]=2[NH:49][C:48]1=[O:57]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:53]3[CH2:54][CH2:55][C:56]4[S:47][C:48](=[O:57])[NH:49][C:50]=4[CH2:51][CH2:52]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=c1[nH]c2c(s1)CCNCC2
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Agent: CN(C)C(On1nnc2cccnc21)=[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: O=C(c1cc2ncc(Cl)cn2n1)N1CCc2[nH]c(=O)sc2CC1

Procedure:
The title compound was prepared in accordance with the general method of example 1 from 0.25 mmol 6-chloro-pyrazolo[1,5-A]pyrimidine-2-carboxylic acid, 0.30 mmol HATU, 1.52 mmol DIPEA and 0.51 mmol 3,4,5,6,7,8-hexahydro-thiazolo[4,5-d]azepin-2-one in 1 mL DMF. The reaction mixture was purified by HPLC chromatography and lyophilized. Yield: 20 mg (23% of theory). ESI-MS: m/z=350 (M+H)+.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[C:8]([O:21][CH2:22][CH2:23][OH:24])=[C:7]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)[CH:6]=1)C.[CH3:36][NH:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>>[CH3:36][N:37]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)[C:4](=[O:3])[C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:18])[F:19])[CH:12]=2)[C:8]([O:21][CH2:22][CH2:23][OH:24])=[C:7]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:33])([F:34])[F:32])[CH:26]=2)[CH:6]=1
Reactant: CNCCCCCCCCc1ccccc1
Reactant: CCOC(=O)c1cc(-c2cccc(C(F)(F)F)c2)c(OCCO)c(-c2cccc(C(F)(F)F)c2)c1
Product: CN(CCCCCCCCc1ccccc1)C(=O)c1cc(-c2cccc(C(F)(F)F)c2)c(OCCO)c(-c2cccc(C(F)(F)F)c2)c1

Procedure:
N-methyl-N-(8-phenyloctyl)-3,5-bis(m-trifluoromethylphenyl)-4-(2-hydroxyethoxy)-benzamide was prepared as a white solid (0.238 g, 67%) from 3,5-bis-(m-trifluoromethylphenyl)-4-(2-hydroxyethoxy)-benzoic acid ethyl ester and N-methyl-N-(8-phenyloctyl)amine using a procedure similar to step 2 of Example 175. 1H NMR (CDCl3) δ7.94 (s, 2H); 7.84 (d, 2H); 7.68-7.56 (m, 4H); 7.44 (s, 2H); 7.30-7.12 (m, 5H); 3.24 (t, 2H); 3.52 and 3.33 (2bt, 2H); 3.40 (t, 2H); 3.08 (2s, 3H); 2.58 (bt, 2H); 1.60 (m, 4H); 1.42-1.12 (m, 8H).
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:10]([CH2:22][CH3:23])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH:13]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([N:33]([CH3:41])[CH2:34][CH2:35][C:36]([O:38]CC)=[O:37])=[O:32])=[CH:27][CH:26]=1>>[CH:1]1([CH:7]([NH:24][C:25]2[CH:26]=[CH:27][C:28]([C:31]([N:33]([CH3:41])[CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[O:32])=[CH:29][CH:30]=2)[C:9]2[C:10]([CH2:22][CH3:23])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Reactant: CCc1nn(-c2ccc(OC)cc2)cc1C(O)C1CCCCC1
Product: CCc1nn(-c2ccc(OC)cc2)cc1C(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Yield: 0 %

Procedure:
Using cyclohexyl[3-ethyl-1-(4-methoxyphenyl)-1H-pyrazol-4-yl]methanol (0.5 g) synthesized in Example 50(1) and ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (0.40 g) synthesized in Example 2(2) and in the same manner as in Example 1(7), the title object compound (0.15 mg, 18%) was obtained as a white solid.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH:6]([CH2:12][C:13]([OH:15])=[O:14])[CH2:5]2.C([O-])([O-])=O.[K+].[K+].[NH:22]1[CH:26]=[CH:25][N:24]=[CH:23]1>N1C=CC=CC=1>[N:22]1([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[C:7](=[O:11])[CH:6]([CH2:12][C:13]([OH:15])=[O:14])[CH2:5]3)[CH:26]=[CH:25][N:24]=[CH:23]1
Reactant: c1c[nH]cn1
Reactant: O=C(O)CC1Cc2cc(F)ccc2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: O=C(O)CC1Cc2cc(-n3ccnc3)ccc2C1=O
Yield: 39.4 %

Procedure:
A mixture of 3.3 g of 5-fluoro-2,3-dihydro-1-oxo-1H-indene-2-acetic acid [prepared by following the procedure of G. Cignarella, M. Loriga, G. A. Pinna, M. A. Pirisi, P. Schaitti, and D. Selva, Il Farmaco, Ed. Sci. 37(2), 133-40 (1981)], 2.2 g of anhydrous K2CO3, 1.65 g of imidazole, and 0.15 g of CuO in 15 ml of pyridine is heated to reflux for 24 hours. The reaction mixture is filtered, the filtrate is diluted with water, and the pH of the solution is adjusted to 5. The solid is filtered, washed with water, and crystallized from ethanol to yield 1.6 g of the product, 2,3-dihydro-5-(1H-imidazol -1-yl)-1-oxo-1H-indene-2 acetic acid, mp 224°-226° dec.