Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[N:26](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:25]=[N:24][N:23]=3)=[CH:12][CH:11]=2)[C:7]2[C:46]([C:50]([O:52][C:53]([O:56][C:57]([O:59][CH2:60][CH2:61][CH:62]([CH3:74])[C@@H:63]([O:70][N+:71]([O-:73])=[O:72])[C@H:64]([O:66][N+:67]([O-:69])=[O:68])[CH3:65])=[O:58])([CH3:55])[CH3:54])=[O:51])=[CH:47][CH:48]=[CH:49][C:6]=2[N:5]=1)[CH3:2].CO>C(Cl)Cl>[CH2:1]([O:3][C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:23][N:24]=[N:25][N:26]=3)=[CH:14][CH:15]=2)[C:7]2[C:46]([C:50]([O:52][C:53]([O:56][C:57]([O:59][CH2:60][CH2:61][CH:62]([CH3:74])[C@@H:63]([O:70][N+:71]([O-:73])=[O:72])[C@H:64]([O:66][N+:67]([O-:69])=[O:68])[CH3:65])=[O:58])([CH3:54])[CH3:55])=[O:51])=[CH:47][CH:48]=[CH:49][C:6]=2[N:5]=1)[CH3:2]
Reactant: CCOc1nc2cccc(C(=O)OC(C)(C)OC(=O)OCCC(C)[C@@H](O[N+](=O)[O-])[C@@H](C)O[N+](=O)[O-])c2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: ClCCl
Product: CCOc1nc2cccc(C(=O)OC(C)(C)OC(=O)OCCC(C)[C@@H](O[N+](=O)[O-])[C@@H](C)O[N+](=O)[O-])c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
1-[({[(4R,5R)-3-Methyl-4,5-bis(nitrooxy)hexyl]oxy}carbonyl)oxy]-1-methylethyl 2-ethoxy-1-{[2′-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylate (1.77 g, 1.76 mmol) was dissolved in CH2Cl2 (5 mL) and MeOH was added (30 mL). After stirring at room temperature for 72 hrs, the solution was concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage SP1, SNAP 100 g column, CH2Cl2/MeOH 98:2) affording the tile compound as a white solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:11]=[C:10]2[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]4[NH:34][N:33]=[N:32][N:31]=4)=[CH:20][CH:19]=3)[C:13]([CH2:15][CH3:16])=[N:14][C:9]2=[C:8]([CH3:35])[CH:7]=1)=O)C.[H-].C([Al+]CC(C)C)C(C)C.CC(O)=O>C1COCC1>[CH2:15]([C:13]1[N:12]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[NH:34][N:33]=[N:32][N:31]=3)=[CH:22][CH:23]=2)[C:10]2=[N:11][C:6]([CH2:4][OH:3])=[CH:7][C:8]([CH3:35])=[C:9]2[N:14]=1)[CH3:16]
Reactant: CCOC(=O)c1cc(C)c2nc(CC)n(Cc3ccc(-c4ccccc4-c4nnn[nH]4)cc3)c2n1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCc1nc2c(C)cc(CO)nc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.5 %

Procedure:
To 5-(ethoxycarbonyl)-2-ethyl-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine (50 mg) in THF (1 mL) at -78° C. was added Diisobutylaluminum hydride (0.534 mL, 1M/THF). After 1 hour at -78° C., the mixture was warmed to RT and 1% aqueous HOAc (2 mL) was added. Extractive workup (EtOAc), and purification (SiO2, 80/20/1 CH2Cl2 /MeOH/NH4OH) gave 28 mg of a solid.
Reaction SMILES: [CH2:1]([O:3][CH:4]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[F:16])[C:5]([OH:7])=O)[CH3:2].[NH2:17][CH2:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][C:20]=1[Cl:27]>>[Cl:27][C:20]1[CH:21]=[C:22]([C:23]#[N:24])[CH:25]=[CH:26][C:19]=1[CH2:18][NH:17][C:5](=[O:7])[CH:4]([O:3][CH2:1][CH3:2])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[F:16]
Reactant: CCOC(C(=O)O)c1ccc(OC)cc1F
Reactant: N#Cc1ccc(CN)c(Cl)c1
Product: CCOC(C(=O)NCc1ccc(C#N)cc1Cl)c1ccc(OC)cc1F

Procedure:
(RS)-Ethoxy-(2-fluoro-4-methoxy-phenyl)-acetic acid, described in example 63.1 was coupled with 4-aminomethyl-3-chlorobenzonitrile (CAS 202521-97-9) according to general procedure C to give (RS)-N-(2-chloro-4-cyano-benzyl)-2-ethoxy-2-(2-fluoro-4-methoxy-phenyl)-acetamide. Yellow oil. MS 377.2 ([M+H]+)
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:23]#[N:24])=[C:4]([CH:20]=[CH:21][CH:22]=1)[O:5][CH2:6][C:7]([CH3:19])([CH3:18])[C:8]([O:10]CC1C=CC=CC=1)=[O:9].O=[C:26]([CH3:33])[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>>[NH2:24][C:23]1[C:3]2[C:2](=[CH:22][CH:21]=[CH:20][C:4]=2[O:5][CH2:6][C:7]([CH3:18])([CH3:19])[C:8]([OH:10])=[O:9])[N:1]=[C:26]([CH3:33])[C:27]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29]
Reactant: CC(C)(COc1cccc(N)c1C#N)C(=O)OCc1ccccc1
Reactant: CCOC(=O)CC(C)=O
Product: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)C(=O)O)c2c1N

Procedure:
Prepared as in Example 2a from benzyl 3-(3-amino-2-cyanophenoxy)-2,2-dimethylpropanoate (Example 47c) and ethyl 3-oxobutanoate as a brown solid (80%). MS 192 (MH+).
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]=[C:17]([CH2:22][N:23]2[CH2:26][CH:25]([C:27]([OH:29])=[O:28])[CH2:24]2)[CH:16]=[C:15]3[CH:30]2[CH2:32][CH2:31]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[C:33]([C@H]1CC[C@H](OC2C=C3C(=CC=2)N=C(CN2CCC(C(O)=O)C2)C=C3C)CC1)(C)(C)C>>[C:1]([C@H:5]1[CH2:6][CH2:7][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]=[C:17]([CH2:22][N:23]2[CH2:33][CH2:26][CH:25]([C:27]([OH:29])=[O:28])[CH2:24]2)[CH:16]=[C:15]3[CH:30]2[CH2:32][CH2:31]2)[CH2:9][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3nc(CN4CC(C(=O)O)C4)cc(C4CC4)c3c2)CC1
Reactant: Cc1cc(CN2CCC(C(=O)O)C2)nc2ccc(O[C@H]3CC[C@H](C(C)(C)C)CC3)cc12
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3nc(CN4CCC(C(=O)O)C4)cc(C4CC4)c3c2)CC1

Procedure:
Synthesized as per 1-[6-(trans-4-tert-Butyl-cyclohexyloxy)-4-cyclopropyl-quinolin-2-ylmethyl]-azetidine-3-carboxylic acid using the appropriate intermediate available from the synthesis of 1-[6-(trans-4-tert-Butyl-cyclohexyloxy)-4-methyl-quinolin-2-ylmethyl]-pyrrolidine-3-carboxylic acid). ESI-MS(M+H+): 451.3; 1H NMR (400 MHz, METHANOL-d4) Shift 7.99 (d, J=9.29 Hz, 1H), 7.70 (d, J=2.51 Hz, 1H), 7.42 (dd, J=2.64, 9.16 Hz, 1H), 7.13 (s, 1H), 4.60-4.72 (m, 2H), 4.35-4.49 (m, 1H), 3.81 (dd, J=6.53, 12.05 Hz, 1H), 3.72 (dd, J=8.66, 11.92 Hz, 1H), 3.50-3.66 (m, 2H), 3.37-3.49 (m, 1H), 2.42-2.55 (m, 2H), 2.38 (td, J=6.96, 13.68 Hz, 1H), 2.29 (d, J=10.29 Hz, 2H), 1.85-1.98 (m, 2H), 1.36-1.52 (m, 2H), 1.18-1.34 (m, 4H), 1.03-1.18 (m, 1H), 0.91 (s, 9H), 0.79-0.89 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][C:18]([C:23]#[C:24][CH2:25][S:26][CH3:27])=[CH:17][C:16]=3[F:28])=[O:11])=[CH:4][CH:3]=1>[Pd].C(Cl)Cl.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][C:18](/[CH:23]=[CH:24]\[CH2:25][S:26][CH3:27])=[CH:17][C:16]=3[F:28])=[O:11])=[CH:6][CH:7]=1
Reactant: CSCC#Cc1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: CSC/C=C\c1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Reaction time: 2 h

Procedure:
A mixture of N-[(4-Chlorophenyl)methyl]-8-fluoro-4-hydroxy-6-[3-(methylthio)-1-propynyl]-3-quinolinecarboxamide from Example 126 (0.226 g) and Pd/C (10%, 0.032 g) in 3:1 CH2Cl2 /MeOH (20 mL) are placed on a Parr hydrogenator under 38 psi of H2 and shaken for 2 h. Another 0.060 g of Pd/C is added, and the resulting
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11](Cl)=[O:12].[C:14]12([NH2:24])[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2.O>N1C=CC=CC=1>[C:14]12([NH:24][C:11]([C:2]3[CH:3]=[N:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]=3)=[O:12])[CH2:21][CH:20]3[CH2:19][CH:18]([CH2:17][CH:16]([CH2:22]3)[CH2:15]1)[CH2:23]2
Reactant: O=C(Cl)c1cnc2ccccc2n1
Reactant: NC12CC3CC(CC(C3)C1)C2
Solvent: O
Solvent: c1ccncc1
Product: O=C(NC12CC3CC(CC(C3)C1)C2)c1cnc2ccccc2n1
Reaction time: 0.5 h

Procedure:
2-Quinoxaloyl chloride (0.84 g, 4.4 mmol) was added to a solution of 1-adamantanamine (0.60 g, 4.0 mmol) in pyridine (10 mL). The reaction was then stirred for 30 min. To the stirring reaction mixture was added water (100 mL) which caused the product to precipitate. This precipitate was filtered, washed with water (3×25 mL), and dried under high vacuum for 16 h. This provided 1.00 g (82%) of (91):
Reaction SMILES: [C:1]([OH:11])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:12](=O)[CH2:13][CH:14]=[CH2:15].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[C:4]1([CH:3]=[CH:2][C:1]([OH:11])=[O:10])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:15][CH2:14][CH:13]=[CH2:12]
Reactant: C=CCC=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C(O)C=Cc1ccccc1
Solvent: ClCCl
Product: C=CCC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
22.2 g of cinnamic acid, 12.5 g of but-3-en-1-al and 0.2 g of 4-N,N-dimethylaminopyridine were placed in 80 ml of dichloromethane. A solution of 33.05 g of dicyclohexylcarbodiimide in 80 ml of dichloromethane was added dropwise at 5°-10° C. within 120 minutes. The mixture was stirred at room temperature for a further 18 hours. Subsequently, the precipitated N,N'-dicyclohexylurea was filtered off and washed with 150 ml of dichloromethane. The dichloromethane solution was washed with 200 ml of 5% acetic acid and subsequently three times with 250 ml of water each time, filtered and dried over sodium sulphate. After concentrating the solution the residue was chromatographed on silica gel with dichloromethane. Drying in a high vacuum gave 22.1 g of but-3-ene 3-phenylacrylate as a colourless liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][NH:12][C:13]([NH:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[CH:21]=2)=[O:14])=O)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[O:14][C:13]([NH:15][CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][N:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)[CH:21]=3)=[N:12][N:11]=2)=[CH:4][CH:3]=1
Reactant: O=C(NCCCOc1cccc(CN2CCCCC2)c1)NNC(=O)Nc1ccc(Cl)cc1
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1ccc(Nc2nnc(NCCCOc3cccc(CN4CCCCC4)c3)o2)cc1

Procedure:
The compound is prepared by a method analogous to that of Example 40 from N-4-chlorophenyl-N'-[3-[3-(1piperidinylmethyl)phenoxy]propyl]-1,2-hydrazine dicarboxamide and phosphorus oxychloride. The analytical values are summarized in Table III.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:15](=[O:18])(=[O:17])[NH2:16])[C:10]=1[NH:11][CH:12]([CH3:14])[CH3:13])[C:5]([OH:7])=[O:6].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)C>[CH2:19]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:15](=[O:18])(=[O:17])[NH2:16])[C:10]=1[NH:11][CH:12]([CH3:13])[CH3:14])[C:5]([OH:7])=[O:6])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)Nc1c(N)cc(C(=O)O)cc1S(N)(=O)=O
Reactant: BrCc1ccccc1
Solvent: CCO
Product: CC(C)Nc1c(NCc2ccccc2)cc(C(=O)O)cc1S(N)(=O)=O

Procedure:
A mixture of 3-amino-4-isopropylamino-5-sulphamyl-benzoic acid (2.62 g), benzyl bromide (4.28 g), and anhydrous ethanol (25 ml) was refluxed for 24 hours. The reaction mixture was evaporated in vacuo. 1N sodium hydroxide (30 ml) was added, and the mixture was heated on a steam bath for 1 hour. After cooling and extracting with diethyl ether, the aqueous layer was adjusted to a pH of 3 by addition of a 4N hydrochloric acid. The precipitated 3-benzylamino-4-isopropylamino-5-sulphamyl-benzoic acid was collected by suction and recrystalized from aqueous ethanol. The melting point was 233°-234° C.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:36])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][C@@H:30]3[CH3:35])[C:15]3[CH2:21][CH2:20][N:19]([C:22](OC(C)(C)C)=O)[CH2:18][C:16]=3[N:17]=2)=[CH:8][CH:7]=1)[CH3:2].ClC1N=C(N2CCOC[C@@H]2C)C2CCN(C)CC=2N=1.[F:56]C1C=C(C=CC=1B1OC(C)(C)C(C)(C)O1)N>>[CH2:1]([NH:3][C:4]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][C@@H:30]3[CH3:35])[C:15]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][C:16]=3[N:17]=2)=[C:8]([F:56])[CH:7]=1)=[O:36])[CH3:2]
Reactant: CC1(C)OB(c2ccc(N)cc2F)OC1(C)C
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C(=O)OC(C)(C)C)C3)cc1
Agent: C[C@H]1COCCN1c1nc(Cl)nc2c1CCN(C)C2
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C)C3)c(F)c1

Procedure:
Method as described for intermediate 5 using (S)-4-(2-chloro-7-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3-methylmorpholine (intermediate 13) and as 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline as starting materials. The reaction mixture was filtered through a celite 545 pre-packed cartridge (2.5 g), washed with methanol and solvent removed in vacuo. The residue was purified by trituration with a (9:1) mixture of petrol ether (40-60)/ethyl acetate, yielding the title compound after filtration and drying of the solid obtained (85 mg, 0.24 mmol, 67%).
Reaction SMILES: [NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:13])=[O:5].[Cl:19][CH2:20][C:21](Cl)=O>C(O)(=O)C>[Cl:18][C:17]1[CH:16]=[CH:15][CH:14]=[C:3]2[C:2]=1[N:1]=[C:21]([CH2:20][Cl:19])[N:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:13])[C:4]2=[O:5]
Reactant: O=C(Cl)CCl
Reactant: Nc1c(Cl)cccc1C(=O)Nc1ccccc1Cl
Solvent: CC(=O)O
Product: O=c1c2cccc(Cl)c2nc(CCl)n1-c1ccccc1Cl
Yield: 74.1 %

Procedure:
Prepared according to Procedure B with 1h (500 mg, 1.78 mmol) and chloroacetyl chloride (0.49 mL, 6.13 mmol) in acetic acid (10 mL). Purified by extraction from aqueous K2CO3, followed by recrystallization from isopropanol to afford 448 mg of a yellow solid (74%). 1H NMR (CDCl3) δ: 8.23 (dd, J=1.4, 8.0 Hz, 1H); 7.90 (dd, J=1.4, 7.8 Hz, 1H); 7.61-7.66 (m, 1H); 7.51-7.55 (m, 3H); 7.47 (t, J=8.0 Hz, 1H); 4.48 (d, J=12 Hz, 1H), 4.12 (d, J=12 Hz, 1H). MS (ES): m/z 339.0 (M+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:9][N:8](C3CCCCO3)[C:5]2=[CH:6][N:7]=1.[NH:23]1[CH:27]=[N:26][CH:25]=[N:24]1>>[C:11]1([C:10]2[C:4]3[C:5](=[CH:6][N:7]=[C:2]([N:23]4[CH:27]=[N:26][CH:25]=[N:24]4)[CH:3]=3)[NH:8][N:9]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Brc1cc2c(-c3ccccc3)nn(C3CCCCO3)c2cn1
Reactant: c1nc[nH]n1
Product: c1ccc(-c2n[nH]c3cnc(-n4cncn4)cc23)cc1
Yield: 27 %

Procedure:
Following the procedures of Examples 146 and 131, 5-bromo-3-phenyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine and 1,2,4-triazole were reacted to give 142 as a white solid (20 mg, 27%) over two steps. ESI MS m/z 263.0 (M+1). 1H NMR (400 MHz, DMSO): 14.32 (s, 1H), 9.36 (s, 1H), 9.09 (d, J=1.0 Hz, 1H), 8.38 (d, J=1.0 Hz, 1H), 8.30 (s, 1H), 8.07-8.00 (m, 2H), 7.60 (t, J=7.6 Hz, 2H), 7.48 (t, J=7.4 Hz, 1H)
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]2[C:3]=1[C:4](=[O:13])[CH2:5][CH:6]=[N:7]2.[N+:14]([O-])([OH:16])=[O:15]>S(=O)(=O)(O)O>[CH3:1][C:2]1[C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]([CH3:12])=[C:8]2[C:3]=1[C:4](=[O:13])[CH2:5][CH:6]=[N:7]2
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(C)c2c1N=CCC2=O
Agent: O=S(=O)(O)O
Product: Cc1cc([N+](=O)[O-])c(C)c2c1N=CCC2=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
In a flask is placed 5,8-dimethyl-4-quinolone (5.18 g, 29.9 mmol) (prepared according to Burckhalter, et al., J. Am. Chem. Soc., Vol. 70 (1948), p. 1363) with sulfuric acid (30 mL). After stirring for 10 minutes, the flask is cooled in ice and concentrated nitric acid (1.90 mL, 30.2 mmol) is added dropwise. After the addition is completed, the mixture is stirred for 15 minutes in ice. The mixture is then poured onto crushed ice and allowed to warm to room temperature. The gray solid is filtered and washed with water. The solid is recrystallized from hot methanol to give 5,8-dimethyl-6-nitro-4-quinolone.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([CH3:7])[NH:4][N:3]=1.[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])#[C:9][C:10]([O-])=[O:11]>C(O)C>[CH2:16]([O:15][C:13]([C:8]1[CH:9]=[C:10]([OH:11])[N:6]2[C:5]([CH3:7])=[N:4][N:3]=[C:2]2[N:1]=1)=[O:14])[CH3:17]
Reactant: CCOC(=O)C#CC(=O)[O-]
Reactant: Cc1nc(N)n[nH]1
Solvent: CCO
Product: CCOC(=O)c1cc(O)n2c(C)nnc2n1
Reaction time: 1 h
Yield: 32.4 %

Procedure:
A suspension of 14.7 g of 3-amino-5-methyl-s-triazole and 26.8 g of ethyl acetylenedicarboxylate in 120 ml of ethanol was refluxed for three hours, the reaction mixture was allowed to stand at room temperature for one hour, and the formed crystals were collected by filtration. The filtrate was concentrated and the residue was recrystallized from dichloromethane, and the crystals were joined with those obtained above. Purification by silica gel chromatography gave 10.8 g of the objective compound as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][CH:7]([C:25](=O)[CH3:26])[C:8]([C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])=[O:9])=[CH:4][CH:3]=1.Cl.[NH2:31]O>C(O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][C:7]2[C:25]([CH3:26])=[N:31][O:9][C:8]=2[C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])=[CH:4][CH:3]=1
Reactant: NO
Reactant: CC(=O)C(Cc1ccc(Cl)cc1)C(=O)[C@H]1CCCN1C(=O)OCc1ccccc1
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1noc([C@H]2CCCN2C(=O)OCc2ccccc2)c1Cc1ccc(Cl)cc1
Temperature: 70 °C
Yield: 75.4 %

Procedure:
To a solution of (2R)-benzyl 2-(2-(4-chlorobenzyl)-3-oxobutanoyl)pyrrolidine-1-carboxylate (300 mg, 0.71 mmol) in ethanol (10 mL) was added hydroxylamine hydrochloride (490 mg, 7.1 mmol). The resulting solution was heated at 70° C. for 3 h and then diluted with EtOAc (30 mL). The organic layer was washed with saturated NaHCO3 solution (1×40 mL) and then brine (1×40 mL). The separated organic layer was then dried over Na2SO4 and concentrated in vacuo. Purification of the resulting residue by silica gel column chromatography (hexanes/ethyl acetate gradient, 10-100% EtOAc) afforded (R)-benzyl 2-(4-(4-chlorobenzyl)-3-methylisoxazol-5-yl)pyrrolidine-1-carboxylate (220 mg, 76%). LCMS: calculated: 410, found (MH+): 411.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][CH2:29][OH:30].[Cl-].[NH4+]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][CH2:29][O:30][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8]
Reactant: OCCc1ccccc1F
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)OCCc2ccccc2F)cc1
Temperature: 0 °C
Reaction time: 6 h
Yield: 70.4 %

Procedure:
1.02 g of p-toluenesulfonyl chloride (5.35 mM), 1.24 ml of diisopropyl ethylamine (7.13 mmol) and 86 mg of 4-(dimethylamino)pyridine (0.71 mmol) were added to the reaction solution (3.57 mmol) containing 500 mg of 2-(2-fluoro-phenyl)-ethanol (3.57 mmol) dissolved in methylene chloride solution with stirring for 6 hrs at 0° C. under Ar atmosphere, and then the reaction mixture was stirred for 12 hrs at room temperature. The resulting mixture was neutralized with ammonium chloride, extracted with ethyl acetate and washed with saturated NaCl solution to separate into an organic layer and water layer. The organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo. The resultant was purified by Silica gel column chromatography with a solvent mixture mixed with methanol and chloroform (1:7) as an eluant to give 740 mg of toluen-4-sulfonate-2-(2-fluoro-phenyl)-ethyl ester (u) (yield: 70%).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21](N2CCN(S(C)(=O)=O)CC2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH3:33][N:34]([CH3:43])[C:35]([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)=[O:36]>>[CH3:33][N:34]([CH3:43])[C:35]([N:37]1[CH2:38][CH2:39][N:40]([C:21]([C:16]2[NH:17][C:18]3[C:14]([CH:15]=2)=[CH:13][C:12]([C:10]([N:7]2[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]2)=[O:11])=[CH:20][CH:19]=3)=[O:22])[CH2:41][CH2:42]1)=[O:36]
Reactant: CN(C)C(=O)N1CCNCC1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCN(S(C)(=O)=O)CC4)cc3c2)CC1
Product: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCN(C(=O)N(C)C)CC4)cc3c2)CC1
Yield: 59 %

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid hydrochloride (example 1, intermediate b) and piperazine-1-carboxylic acid dimethylamide to afford the desired product as light-brown foam (59%). MS (ISP): 455.4 (M+H)+.
Reaction SMILES: CCN=C=NCCCN(C)C.[F:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=1[C:20]1[CH:25]=[C:24]([C:26]2[N:27]([CH:31]([CH3:33])[CH3:32])[N:28]=[CH:29][CH:30]=2)[CH:23]=[C:22]([C:34](O)=[O:35])[CH:21]=1.C1C=CC2N(O)N=NC=2C=1.CN1C(=O)CCC1.[NH2:54][CH:55]([CH3:58])[CH2:56][OH:57]>C(Cl)Cl>[OH:57][CH2:56][CH:55]([NH:54][C:34]([C:22]1[CH:21]=[C:20]([C:14]2[CH:15]=[CH:16][C:17]([CH3:19])=[CH:18][C:13]=2[F:12])[CH:25]=[C:24]([C:26]2[N:27]([CH:31]([CH3:33])[CH3:32])[N:28]=[CH:29][CH:30]=2)[CH:23]=1)=[O:35])[CH3:58]
Reactant: CC(N)CO
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(-c3ccnn3C(C)C)c2)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: Cc1ccc(-c2cc(C(=O)NC(C)CO)cc(-c3ccnn3C(C)C)c2)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.6 %

Procedure:
EDCI (54.0 mg, 0.282 mmol) was added in one portion to a solution of 2′-fluoro-5-(2-isopropyl-2H-pyrazol-3-yl)-4′-methyl-biphenyl-3-carboxylic acid (77.4 mg, 0.229 mmol), HOBt (40.0 mg, 0.296 mmol) and NMP (101.5 mg, 1.000 mmol) in CH2Cl2 (5 mL) at 0° C. After the reaction stirred at the same temperature for 1 hour, 2-amino-propan-1-ol (54 mg, 0.72 mmol) was added. The mixture was allowed to warm to room temperature and was stirred overnight. Solvent was removed under reduced pressure and the residue was purified by column chromatography to afford 2′-Fluoro-5-(2-isopropyl-2H-pyrazol-3-yl)-4′-methyl-biphenyl-3-carboxylic acid (2-hydroxy-1-methyl-ethyl)-amide as white solid (54 mg, 46%). MS (N+H)=396.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]2[N:11]([N:13]=[CH:14][N:15]=2)[N:12]=1)=[O:5].[C:16]1([CH:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:29]1([CH:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:23]2[CH2:24][CH2:25][N:26]([CH2:2][CH2:3][C:4]([NH:6][C:7]3[CH:8]=[CH:9][C:10]4[N:11]([N:13]=[CH:14][N:15]=4)[N:12]=3)=[O:5])[CH2:27][CH2:28]2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: O=C(CCCl)Nc1ccc2ncnn2n1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: O=C(CCN1CCN(C(c2ccccc2)c2ccccc2)CC1)Nc1ccc2ncnn2n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 61.5 %

Procedure:
6-(3-Chloropropionamido)[1,2,4]triazolo[1,5-b]pyridazine (339 mg) and 1-(diphenylmethyl)piperazine (379 mg) were dissolved in acetonitrile (15 ml), followed by addition of sodium iodide (447 mg) and potassium carbonate (249 mg). The mixture was stirred at room temperature for 15 hours and refluxed under heating for 8 hours. After the mixture was cooled, ice-water was added thereto, followed by extraction with ethyl acetate. The extract was washed with an aqueous sodium chloride saturated solution, dried over magnesium sulfate and concentrated under reduced pressure. The resulting crystals were recrystalized from ethanol to yield the title compound (408 mg).