Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH:5]=O.Cl.[CH2:14]([O:16][C:17](=[O:20])[CH2:18][NH2:19])[CH3:15].C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.[OH-].[Na+]>ClC(Cl)C>[CH2:14]([O:16][C:17](=[O:20])[CH2:18][NH:19][CH2:5][C:4]1[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:3]=1[O:2][CH3:1])[CH3:15]
Reactant: CCOC(=O)CN
Reactant: COc1ccc(C=O)c(OC)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)CNCc1ccc(OC)cc1OC
Reaction time: 72 h
Yield: 56.3 %

Procedure:
A mixture of 2,4-dimethoxy-benzaldehyde (50 g, 0.30 mole), glycine ethyl ester hydrochloride (44 g, 0.32 mole) and triethylamine (43.9 mL, 0.32 mole) in dichloroethane was stirred for one hour before sodium triacetoxyborohydride (100 g, 0.47 mole) was added in four portions. The mixture was stirred for three days before it was quenched with saturated sodium bicarbonate. The organic layer was extracted with 3N HCl (2×400 mL, 2.4 mole). The aqueous layers were combined, adjusted with solid sodium hydroxide (97.68 g, 2.4 mole) to pH=8 and extracted with ethyl acetate (500 mL). The ethyl acetate extract was washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by flash column chromatography with a gradient of methanol and dichloromethane on silica gel (120 g) to give the title compound as a yellow oil (42.77 g) 1H NMR (CDCl3, 200 MHz): δ=7.11 (m, 1H), 6.41 (m, 2H), 4.15 (q, J=7.2 Hz, 2H), 3.81 (s, 3H), 3.80 (s, 3H), 3.74 (s, 2H), 3.37 (s, 2H), 1.27 (t, J=7.2 Hz, 3H).
Reaction SMILES: [Br:1][CH2:2][C:3](=O)[C:4]([OH:6])=[O:5].[CH:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>S(=O)(=O)(O)O.O>[Br:1][CH2:2][C:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:4]([OH:6])=[O:5]
Reactant: c1ccccc1
Reactant: O=C(O)C(=O)CBr
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)C(CBr)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
3-Bromopyruvic acid (170 g) is suspended in cold sulfuric acid (0.85 L) and maintained at 0° C. while benzene (0.255 L) is added over 1.5 hours. The temperature is allowed to warm to 35°-36° C. and then kept at 25° C. for three hours. Pouring over crushed ice (4 L) followed by trituration in cold water and recrystallization from 95% ethanol affords 76 g of 3-bromo-2,2-diphenylpropionic acid (mp 201°-202° C.). This acid (75 g) is suspended in benzene and thionyl chloride (55 ml) is added. After refluxing, the mixture is filtered, and the filtrate affords 40 g of the acid chloride (mp 98°14 100° C.). The acid chloride is added portionwise to aqueous ammonium hydroxide with stirring and left overnight, with filtration yielding 3-bromo-2,2-diphenylpropionamide. The amide (10 g) is added portionwise with stirring to a solution of sodium (1.5 g) in absolute ethanol (0.2 L), and the resulting solution is heated for one hour on a steam bath. Dilution with water affords a solid (mp >310° C.), 2,2-diphenyl azetidin-2-one. The azetidinone (2 g) is heated at reflux in methanol saturated with HCl (50 ml) affording the title compound after crystallization from methanol/ether (mp 207°-208° C.).
Reaction SMILES: Br.Br[CH:3]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)[C:4]1[CH:17]=[CH:16][C:7]2[NH:8][C:9]([NH:11][C:12](=[O:15])[O:13][CH3:14])=[N:10][C:6]=2[CH:5]=1.[CH3:25][C:26]1[NH:27][CH:28]=[CH:29][N:30]=1.CN(C)C=O>O>[F:24][C:21]1[CH:22]=[CH:23][C:18]([CH:3]([N:27]2[CH:28]=[CH:29][N:30]=[C:26]2[CH3:25])[C:4]2[CH:17]=[CH:16][C:7]3[NH:8][C:9]([NH:11][C:12](=[O:15])[O:13][CH3:14])=[N:10][C:6]=3[CH:5]=2)=[CH:19][CH:20]=1
Reactant: COC(=O)Nc1nc2cc(C(Br)c3ccc(F)cc3)ccc2[nH]1
Reactant: Cc1ncc[nH]1
Agent: Br
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Nc1nc2cc(C(c3ccc(F)cc3)n3ccnc3C)ccc2[nH]1
Temperature: 25 °C
Reaction time: 17 h
Yield: 34.2 %

Procedure:
A mixture of 9.18 parts of methyl [5-[bromo(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]carbamate monohydrobromide, 12.3 parts of 2-methyl-1H-imidazole and 56.4 parts of N,N-dimethylformamide was stirred for 17 hours at room temperature. The reaction mixture was diluted with 300 parts of water. The precipitated product was filtered off and dissolved in dichloromethane. The organic layer was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane, methanol and methanol, saturated with ammonia, (90:5:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 27 parts of ethyl acetate. The product was filtered off, washed with 1,1'-oxybisethane and dried, yielding 2.6 parts (34.2%) of methyl [5-[(4-fluorophenyl)(2-methyl-1H-imidazol-1-yl)methyl]-1H-benzimidazol-2-yl]carbamate; mp. >300° C. (compound 6).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[C:11]1([N:17]=C=O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>[O-]CC.[Na+].O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:17][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])=[CH:9][CH:10]=1
Reactant: O=C=Nc1ccccc1
Reactant: O=C(O)c1ccc(O)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Product: O=C(Nc1ccccc1)c1ccc(O)cc1
Temperature: 23 °C
Reaction time: 1.57 h

Procedure:
p-Hydroxybenzoic acid (96.68 grams, 0.70 mole), sodium ethoxide catalyst (0.218 gram, 0.225% wt. of the p-hydroxybenzoic acid used) and N,N'-dimethylacetamide solvent (550 grams) are added to a reactor equipped with a reflux condenser and stirred under a nitrogen atmosphere at 23° C. to provide a solution. Phenyl isocyanate (87.55 grams, 0.735 mole) is added inducing a maximum exotherm of 46° C. four minutes later. Three minutes after the maximum exotherm temperature is achieved, heating of the reactor commences and a 160° C. reaction temperature is achieved 94 minutes later. After three hours at the 160° C. reaction temperature, the reactor is cooled to 50° C. then the contents poured into 4 liters of deionized water. A precipitated product is recovered via filtration of the aqueous slurry, washed with deionized water (500 milliliters) then dissolved into boiling methanol (850 milliliters) and refluxed therein (67° C.). After cooling the methanol solution to room temperature (23° C.) and maintaining therein for sixteen hours, a white crystalline product is filtered off, washed with methanol (100 milliliters) and dried in a vacuum oven at 80° C. and 1 mm Hg to a constant weight of 99.49 grams. Fourier transform infrared spectrophotometric analysis of a potassium bromide pellet of a portion of the product revealed the presence of the expected hydroxyl group O-H and secondary amide (solid state) N--H stretching at 3336 cm-1 (sharp) with a shoulder at 3409 cm-1 and the secondary amide carbonyl stretching (solid state) at 1656 cm-1 (sharp).
Reaction SMILES: [C:1]([Si:5]([CH3:35])([CH3:34])[O:6][CH:7]1[CH2:23][N:11]2[C:12](=[O:22])[CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:15]=[C:10]2[N:9]([C:24]2[CH:29]=[CH:28][N:27]=[C:26](S(C)(=O)=O)[N:25]=2)[CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[C:36]1([C@@H:42]([NH2:44])[CH3:43])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>O1CCOCC1.CCOC(C)=O>[C:1]([Si:5]([CH3:35])([CH3:34])[O:6][CH:7]1[CH2:23][N:11]2[C:12](=[O:22])[CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:15]=[C:10]2[N:9]([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([NH:44][CH:42]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH3:43])[N:25]=2)[CH2:8]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC1CN(c2ccnc(S(C)(=O)=O)n2)c2nc(-c3ccccc3)cc(=O)n2C1
Reactant: C[C@H](N)c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(Nc1nccc(N2CC(O[Si](C)(C)C(C)(C)C)Cn3c2nc(-c2ccccc2)cc3=O)n1)c1ccccc1
Temperature: 110 °C

Procedure:
A mixture of 7-(tert-butyl-dimethyl-silanyloxy)-9-(2-methanesulfonyl-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one, prepared from last step (0.6 mmol) and (S)-1-phenylethylamine (1.0 mL, 7.8 mmol) in dioxane (6 mL) was heated at 110° C. for 17 h. The brown solution was cooled to room temperature and was diluted with EtOAc (10 ML). The mixture was washed with H2O (2×), dried (Na2SO4), and concentrated to oil. Purification on silica (0-1% 2N NH3-MeOH in DCM) provided the product as a white solid. M+1: 555.
Reaction SMILES: [CH3:1][C:2]([CH:17]1[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]1)([S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[N:8]=1)(=[O:6])=[O:5])[CH3:3].FC(F)(F)C(O)=O.ClCCl>C(OCC)(=O)C>[CH3:3][C:2]([S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:15])([F:16])[F:14])[N:8]=1)(=[O:6])=[O:5])([CH:17]1[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]1)[CH3:1]
Reactant: CC(C)(C)OC(=O)N1CCC(C(C)(C)S(=O)(=O)c2cccc(C(F)(F)F)n2)CC1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C1CCNCC1)S(=O)(=O)c1cccc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
To a 25 ml round bottom flask was added tert-butyl 4-(1-methyl-1-{[6-(trifluoromethyl)pyridin-2-yl]sulfonyl}ethyl)piperidine-1-carboxylate (0.806 g, 1.85 mmol), trifluoroacetic acid (1.5 ml) and dichloromethane (5 ml). The resulting solution was stirred at room temperature for 1 hour. It was diluted with 50 ml ethyl acetate, washed with 50 ml 10% KOH and then 30 ml brine. The organics were dried over sodium sulfate, filtered and concentrated to give 0.33 g desired product as cyrstalline solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C@:8]2([CH3:18])[CH2:14][C:13]([CH3:16])([CH3:15])[O:12][CH2:11][C:10](=[S:17])[NH:9]2)[CH:7]=1.[F:20][C:21]1([F:27])[CH2:23][CH:22]1[C:24](O)=[O:25]>>[F:19][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:24]([CH:22]2[CH2:23][C:21]2([F:27])[F:20])=[O:25])=[CH:7][C:6]=1[C@:8]1([CH3:18])[CH2:14][C:13]([CH3:16])([CH3:15])[O:12][CH2:11][C:10](=[S:17])[NH:9]1
Reactant: CC1(C)C[C@@](C)(c2cc(N)ccc2F)NC(=S)CO1
Reactant: O=C(O)C1CC1(F)F
Product: CC1(C)C[C@@](C)(c2cc(NC(=O)C3CC3(F)F)ccc2F)NC(=S)CO1
Yield: 61 %

Procedure:
The compound was prepared in an analogous manner as described for intermediate B14A from (S)-5-(5-amino-2-fluoro-phenyl)-5,7,7-trimethyl-[1,4]oxazepane-3-thione (intermediate A17A) (151 mg, 0.54 mmol) and commercially available 2,2-difluoro-cyclopropanecarboxylic acid [CAS No. 107873-03-0] (82 mg, 0.67 mmol). The compound was obtained as light yellow foam (158 mg, 61%). MS (ISP): m/z=387.1 [(M+H)+].
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[C:24](O)(=[O:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>>[CH3:1][O:2][C:3]([N:5]1[C@H:13]2[C@H:8]([C@:9]([O:23][C:24](=[O:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Reactant: CCCCCC(=O)O
Product: CCCCCC(=O)O[C@@]1(C#Cc2cccc(C)c2)CCC[C@@H]2[C@H]1CCN2C(=O)OC

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and hexanoic acid to yield (3aR,4S,7aR)-4-hexanoyloxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester. MS [M+H] 296 (ester elimination ion); RT=1.53 min; UPLC Method I
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH:8]2[CH3:15])=O.[C:16]([O:20]C)(=[S:19])[NH:17][NH2:18]>C(#N)C>[O:20]=[C:16]1[NH:17][N:18]=[C:3]([C:5]2[CH:6]=[C:7]3[C:11](=[CH:12][CH:13]=2)[NH:10][C:9](=[O:14])[CH:8]3[CH3:15])[CH2:2][S:19]1
Reactant: CC1C(=O)Nc2ccc(C(=O)CCl)cc21
Reactant: COC(=S)NN
Solvent: CC#N
Product: CC1C(=O)Nc2ccc(C3=NNC(=O)SC3)cc21

Procedure:
1.0 g 5-(2-chloroacetyl)-1,3-dihydro-3-methyl-2H-indol-2-one, 0.37 g O-methyl thiocarbazate, and 20 ml acetonitrile were refluxed for 2 hrs. The precipitate was isolated by filtration and washed with hot acetonitrile to yield a yellowish powder, 450 mg.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].CO[CH:12](OC)[N:13]([CH3:15])[CH3:14]>>[CH3:12][N:13]([CH3:15])[CH:14]=[CH:2][C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: CC(=O)c1cccnc1
Reactant: COC(OC)N(C)C
Product: CN(C)C=CC(=O)c1cccnc1

Procedure:
In accordance with Example 1, Part A, 0.1 mole of 3-acetylpyridine was reacted under reflux with a slight excess of N,N-dimethylformamide dimethylacetal; 3-dimethylamino-1-(3-pyridyl)-2-propen-1-one was isolated as a solid, m.p. 66°-67° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([CH2:7][CH2:8][OH:9])=[CH:5][CH:4]=1.[Cl:12][C:13]1[CH:18]=[N:17][CH:16]=[C:15](Cl)[N:14]=1>>[Cl:12][C:13]1[CH:18]=[N:17][CH:16]=[C:15]([O:9][CH2:8][CH2:7][C:6]2[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:14]=1
Reactant: COc1ccc(CCO)cc1
Reactant: Clc1cncc(Cl)n1
Product: COc1ccc(CCOc2cncc(Cl)n2)cc1

Procedure:
The title compound was prepared according to the procedure of example 50, step 1, starting from 4-methoxyphenethyl alcohol (1.99 g, 13.1 mmol), K-t-BuO (1.34 g, 12.0 mmol) and 2,6-dichloropyrazine (1.56 g, 10.5 mmol). The yield of the title compound was 2.14 g (77%) and was obtained as a white solid. Anal. (C13H13ClN2O2) C, H, N.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][N:12]=[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=23)=[CH:6][CH:5]=1.[C-]#[N:20].[K+].O.O1CCOCC1>C(Cl)Cl>[N:12]1[O:11][C:10]([C:7]2[CH:8]=[CH:9][C:4]([CH2:3][C:2]#[N:20])=[CH:5][CH:6]=2)=[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=12
Reactant: [C-]#N
Reactant: BrCCc1ccc(-c2onc3ccccc23)cc1
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: N#CCc1ccc(-c2onc3ccccc23)cc1

Procedure:
A mixture of 11.1 g (0.039 mole) of 3-[4-(bromoethyl)phenyl]-2,1-benzisoxazole, 13.0 g (0.2 mole) of potassium cyanide, 55 ml of water and 80 ml of dioxane was heated at reflux under a nitrogen atmosphere for 2 hrs. The mixture was cooled, 200 ml of methylene chloride was added and the layers were separated. The organic layer was washed twice with water, dried over sodium sulfate and concentrated to give a gummy solid as residue. The residue was chromatographed on 150 g of silica gel and the product was eluted with 10% methanol in benzene to yield 4.4 g (48%) of solid, m.p. 118°-121° C. (after recrystallization from 2-propanol, charcoal).
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:38][C:39]1[CH:40]=[C:41]([C:45]2[C:50]3[N:51]([CH2:63][C@H:64]4[CH2:69][CH2:68][C@H:67]([CH3:70])[CH2:66][CH2:65]4)[C:52]([N:54]4[CH2:59][CH2:58][NH:57][C@@H:56]5[CH2:60][CH2:61][CH2:62][C@@H:55]45)=[N:53][C:49]=3[CH:48]=[C:47]([C:71]#[N:72])[N:46]=2)[CH:42]=[N:43][CH:44]=1>CS(C)=O.CCOC(C)=O>[C:1]([N:57]1[CH2:58][CH2:59][N:54]([C:52]2[N:51]([CH2:63][C@H:64]3[CH2:69][CH2:68][C@H:67]([CH3:70])[CH2:66][CH2:65]3)[C:50]3[C:45]([C:41]4[CH:42]=[N:43][CH:44]=[C:39]([Cl:38])[CH:40]=4)=[N:46][C:47]([C:71]#[N:72])=[CH:48][C:49]=3[N:53]=2)[C@@H:55]2[CH2:62][CH2:61][CH2:60][C@@H:56]12)(=[O:4])[CH3:2]
Reactant: C[C@H]1CC[C@H](Cn2c(N3CCN[C@@H]4CCC[C@H]43)nc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Reactant: CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCN(c2nc3cc(C#N)nc(-c4cncc(Cl)c4)c3n2C[C@H]2CC[C@H](C)CC2)[C@@H]2CCC[C@H]21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Acetic acid (60.7 mg, 1.01 mmol), N,N-diisopropylethylamine (174 mg, 1.348 mmol) and HATU (513 mg, 1.348 mmol) were added to 4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(4aR,7aR)-octahydro-1H-cyclopenta[b]pyrazin-1-yl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile (177 mg, 0.33 mmol) in DMSO (1.5 ml), and the mixture was stirred at room temperature overnight. The reaction was then diluted with EtOAc, washed with water and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with EtOAc/isohexane to give 2-[(4aR,7aR)-4-acetyloctahydro-1H-cyclopenta[b]pyrazin-1-yl]-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile. MS ESI calc'd. for C29H34ClN7O [M+H]+ 532. found 532.
Reaction SMILES: [OH-].[K+].[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30]CC)=[O:29])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)#[N:4]>C(O)C>[C:3]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:13][CH:12]=2)=[CH:9][CH:10]=1)#[N:4]
Reactant: CCOC(=O)CCCCCCCCCCOc1ccc(-c2ccc(C#N)cc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: N#Cc1ccc(-c2ccc(OCCCCCCCCCCC(=O)O)cc2)cc1
Yield: 74 %

Procedure:
Ethanol solution with 1.4 g of potassium hydroxide dissolved therein was added to 7.7 g of ethyl 11-(4-cyanobiphenyl-4'-oxy)undecylate obtained in step 2. The mixture was reacted under reflux conditions for 24 hours to obtain 11-(4-cyanobiphenyl-4'-oxy)undecanoic acid which is the target compound. The yield was about 74%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:30])=[C:14]([C:25](OCC)=[O:26])[C:15](=[O:24])[N:16]3[CH2:19][C:20]([F:23])([F:22])[F:21])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:31][CH2:32][CH2:33][OH:34]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:30])=[C:14]([C:25]([NH:31][CH2:32][CH2:33][OH:34])=[O:26])[C:15](=[O:24])[N:16]3[CH2:19][C:20]([F:22])([F:23])[F:21])=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: NCCO
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(F)(F)F)c1=O
Product: O=C(NCCO)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(F)(F)F)c1=O
Yield: 29 %

Procedure:
In a similar manner to that described in example 196, from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydro-1,5-naphthyridine-3-carboxylate (10 mg, 0.024mmol) and 2-aminoethanol (0.05 mL) was prepared 7-[(4-fluorophenyl)methyl]-4-hydroxy-N-(2-hydroxyethyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydro-1,5-naphthyridine-3-carboxamide (3 mg, 29% yield) as a white solid after purification by reverse phase HPLC. 1H NMR (methanol-d4/CDCl3) δ 8.53 (s, 1 H), 7.42 (s, 1 H), 7.13-7.09 (m, 2 H), 7.00-6.96 (m, 2 H), 4.85 (br s, 2 H), 4.10 (s, 2 H), 3.74 (m, 2 H), 3.55 (m, 2 H); MS m/z 440 M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].[C:11](O)(=[O:18])[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1>>[N+:1]([C:4]1[CH:5]=[C:6]([NH:7][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[CH:8]=[CH:9][CH:10]=1)([O-:3])=[O:2]
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: O=C(O)c1ccncc1
Product: O=C(Nc1cccc([N+](=O)[O-])c1)c1ccncc1

Procedure:
The general procedure for 8 was followed using 3-nitro aniline 31 and isonicotinic acid to afforded (68%) as a yellow solid. 1H NMR (DMSO-d6, 400 MHz) δ 7.67-7.71 (m, 1H), 7.89-7.91 (m, 2H), 8.01 (dd, J, =8.4 Hz, J2=1.6 Hz, 1H), 8.19 (dd, J, =8 Hz, J2=1.6 Hz, 1H), 8.79-8.83 (m, 3H), 10.9 (NH, s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH:13](=[O:17])[CH:14]([CH3:16])[CH3:15]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH:13]([OH:17])[CH:14]([CH3:16])[CH3:15])=[CH:11][CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(-n2cccn2)cc1
Reactant: CC(C)C=O
Product: CC(C)C(O)c1ccnn1-c1ccc(F)cc1
Yield: 45 %

Procedure:
This compound was prepared from 1-(4-fluorophenyl)-1H-pyrazole and isobutyraldehyde using the method described in example 10B and isolated as an oil in 45% yield. 1H NMR (400 MHz, DMSO-d6) δ 7.61 (m, 1H), 7.57 (m, 2H), 7.37 (t, 2H, J=8.9 Hz), 6.41 (m, 1H), 5.41 (m, 1H), 4.13 (m, 1H), 1.85 (m, 1H), 0.87 (d, 3H, J=6.6 Hz), 0.61 (d, 3H, J=6.8 Hz).
Reaction SMILES: CO[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10]Br.[F:13][C:14]([F:31])([F:30])[C:15]1[CH:29]=[CH:28][C:18]([O:19][C:20]2[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=2)=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[F:13][C:14]([F:30])([F:31])[C:15]1[CH:29]=[CH:28][C:18]([O:19][C:20]2[CH:27]=[CH:26][C:23]([CH2:24][N:25]3[CH2:10][C:5]4[C:4](=[CH:9][CH:8]=[CH:7][CH:6]=4)[C:3]3=[O:12])=[CH:22][CH:21]=2)=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccccc1CBr
Reactant: NCc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2CN1Cc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 60.5 %

Procedure:
A mixture of 2-bromomethyl-benzoic acid methyl ester (0.115 g, 0.5 mmol), 4-(4-trifluoromethyl-phenoxy)-benzylamine (0.133 g, 0.5 mmol), and K2CO3 (0.235 g, 1.7 mmol) in toluene (5 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 2-[4-(4-trifluoromethyl-phenoxy)-benzyl]-2,3-dihydro-isoindol-1-one (0.116 g, 60%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.32 (s, 2H), 4.81 (s, 2H) 7.01-7.56 (m, 1H), 7.91 (d, 1H). GC-MS: m/z 383 (M)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5](Cl)=[N:6][OH:7].[CH3:12][O:13][C:14](=[O:18])[CH2:15][C:16]#[N:17].C[O-].[Na+]>CO>[NH2:17][C:16]1[O:7][N:6]=[C:5]([C:4]2[CH:9]=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)[C:15]=1[C:14]([O:13][CH3:12])=[O:18]
Reactant: ON=C(Cl)c1cccc(F)c1
Reactant: COC(=O)CC#N
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1c(-c2cccc(F)c2)noc1N
Yield: 77.3 %

Procedure:
In a similar manner as described in Preparation Example 17, by using methanol (160 mL), 3-fluoro-N-hydroxybenzimidoyl chloride (8.00 g, 46.09 mmol), methylcyanoacetate (5.94 g, 59.92 mmol) and sodium methoxide (4.98 g, 92.18 mmol), a white solid required compound (8.42 g, 35.64 mmol, 77%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:10][C:11](=[O:23])[C:12]2[N:13]([N:15]=[C:16]([C:18](OCC)=[O:19])[CH:17]=2)[CH:14]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].CO.Cl>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:10][C:11](=[O:23])[C:12]2[N:13]([N:15]=[C:16]([CH2:18][OH:19])[CH:17]=2)[CH:14]=1
Reactant: CCOC(=O)c1cc2c(=O)[nH]c(-c3ccc(Cl)cc3Cl)cn2n1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CO
Product: O=c1[nH]c(-c2ccc(Cl)cc2Cl)cn2nc(CO)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5 g (12.55 mmol) of ethyl 6-(2,4-dichlorophenyl)-4-oxo-4,5-dihydropyrazolo[1,5-a]pyrazine-2-carboxylate (Example 11A) were dissolved in 700 ml of THF, and 952 mg (25.1 mmol) of lithium aluminum hydride were added at RT. The mixture was stirred at RT for 2 h, after complete conversion methanol was added first, and the pH was then adjusted to 6 using dilute hydrochloric acid. The mixture was extracted repeatedly with ethyl acetate. Removal of the solvent gave 3.12 g (80% of theory) of the product as a solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]2([CH2:12][CH2:11]2)[C:3]1=[O:13].[N+:14]([O-])([OH:16])=[O:15].O>C(O)(=O)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:14]([O-:16])=[O:15])=[CH:8][CH:9]=2)[C:4]2([CH2:12][CH2:11]2)[C:3]1=[O:13]
Reactant: CN1C(=O)C2(CC2)c2ccccc21
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)O
Product: CN1C(=O)C2(CC2)c2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1′-methyl-spiro[cyclopropane-1,3′-indoline]-2′-one (8 g) in acetic acid (150 ml) is added nitric acid (fuming, 5.5 ml) over a period of 15 min at 15° C. The mixture is stirred at RT for 3 h and then poured into water. The precipitate is collected by filtration and washed with water, 2-propanol and tertbutyl-methyl-ether to give the title compound (8.80 g).