Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@@:8]2([CH3:24])[N:13]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:12](=[O:23])[CH2:11][O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH:25](N)(C)C.[Li].[N+](=C)=[N-]>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([C@@:8]2([CH3:24])[N:13]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:12](=[O:23])[C@H:11]([CH3:25])[O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CN2C(=O)COC[C@@]2(C)c2cccc(Br)c2)cc1
Reactant: CC(C)N
Agent: C=[N+]=[N-]
Agent: [Li]
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)[C@H](C)OC[C@@]2(C)c2cccc(Br)c2)cc1
Temperature: -75 °C

Procedure:
A dried flask was charged under an argon atmosphere with a solution of (R)-5-(3-bromo-phenyl)-4-(4-methoxy-benzyl)-5-methyl-morpholin-3-one (600 mg, 1.5 mmol) in tetrahydrofuran (16 ml) which was cooled to −75° C. Lithium isopropylamine (1.54 ml, 3 mmol) was added, and after the addition of diazomethane (502 mg, 3.5 mmol) the reaction was complete. For the workup, the cold reaction mixture was quenched with a saturated ammonium chloride solution (15 ml) and extracted with a mixture of dichloromethane (40 ml) and water (15 ml). The organic layer was dried over sodium sulfate and evaporated to yield the crude (2S,5R)-5-(3-bromo-phenyl)-4-(4-methoxy-benzyl)-2,5-dimethyl-morpholin-3-one as a brownish oil which was engaged in the next step without further purification. Mass (calculated) C20H22BrNO3 [404.307]; (found) [M+H]+=404, [M+2-H]+=406.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)=[CH:19][CH:18]=2)[C:11](=[O:15])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Reactant: Ic1ccc(OC2CCCCO2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1cc(OCc2ccccc2)ccn1-c1ccc(OC2CCCCO2)cc1
Temperature: 150 °C
Reaction time: 8 h
Yield: 57.5 %

Procedure:
A mixture of 4-benzyloxy-1H-pyridin-2-one (7.04 g, 35.0 mmols), 2-[(4-iodophenyl)oxy]tetrahydropyran (13.6 g, 44.8 mmols), cuprous iodide (2.1 g, 11.2 mmols), potassium carbonate (10.3 g, 73.5 mmols) and N,N-dimethylformamide (200 mL) was stirred overnight at 150° C. The reaction liquid was cooled to room temperature, into which water (1.2 L) was poured, and the formed insoluble matter was recovered by filtration. Chloroform (300 mL) was added to the insoluble matter, followed by another filtration. The filtered organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. Concentrating the solvent under reduced pressure, ethyl acetate was added to the resulting residue. The precipitate was recovered by filtration and dried to provide the title compound (7.6 g, 58%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:20]=4[O:27][CH3:28])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:30][C:31]([N:33]1[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]1)=[O:32]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:14][CH2:15][CH:16]([C:19]4[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:20]=4[O:27][CH3:28])[CH2:17][CH2:18]3)=[O:12])=[CH:7][N:8]2[CH2:30][C:31]([N:33]2[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]2)=[O:32])=[CH:4][CH:3]=1
Reactant: COc1cccc(OC)c1C1CCN(C(=O)c2c[nH]c3cc(Cl)ccc23)CC1
Reactant: CN1CCN(C(=O)CCl)CC1
Product: COc1cccc(OC)c1C1CCN(C(=O)c2cn(CC(=O)N3CCN(C)CC3)c3cc(Cl)ccc23)CC1

Procedure:
Following general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2,6-dimethoxy-phenyl)-piperidin-1-yl]-methanone (preparation described herein), with (commercially available) 2-chloro-1-(4-methyl-piperazin-1-yl)-ethanone gave the title compound.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[CH2:10][C:9]3[CH:11]=[CH:12][C:13]([O:15][CH3:16])=[CH:14][C:8]=3[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:6][N:5]2[C:23]=1[C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1.[CH2:30]([O:32]C([Sn](CCCC)(CCCC)CCCC)=C)[CH3:31].Cl.N>C1(C)C=CC=CC=1.C(OCC)(=O)C.CN(C)C=O>[C:30]([C:2]1[N:3]=[C:4]2[CH2:10][C:9]3[CH:11]=[CH:12][C:13]([O:15][CH3:16])=[CH:14][C:8]=3[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:6][N:5]2[C:23]=1[C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)(=[O:32])[CH3:31]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: COc1ccc2c(c1)C(c1ccccc1)=Nn1c(nc(Br)c1-c1cccnc1)C2
Agent: Cl
Agent: N
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)C(c1ccccc1)=Nn1c(nc(C(C)=O)c1-c1cccnc1)C2
Temperature: 120 °C
Reaction time: 0.17 h
Yield: 26.6 %

Procedure:
82 mg of 2-bromo-3-(3-pyridyl)-8-methoxy-6-phenyl-11H-imidazo[1,2-c][2,3]benzodiazepine is mixed in 3 ml of toluene and 0.5 ml of dimethylformamide with 650 mg of (1-ethoxyvinyl)tributylstannane and 10 mg of palladium(O)tetrakistriphenylphosphine, and it is heated for 4 hours to a bath temperature of 120° C. Then, (1-ethoxyvinyl)tributylstannane and 10 mg of palladium(O)tetrakistriphenylphosphine are added again, and it is heated for 10 hours to a bath temperature of 120° C. After cooling, it is mixed with 2 ml of 1N hydrochloric acid, stirred for 10 minutes, made alkaline with ammonia and shaken out with ethyl acetate. The ethyl acetate phase is washed with water and saturated common salt solution, dried, filtered and concentrated by evaporation. After chromatography of the residue on silica gel with ethyl acetate as an eluant, 20 mg of 2-acetyl-3-(3-pyridyl)-8-methoxy-6-phenyl-11H-imidazo[1,2-c][2,3]benzodiazepine is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.C([BH3-])#N.[Na+].Cl.[CH:18](=O)[CH3:19]>CO>[CH2:18]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=1)[CH3:19]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: CC=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCNc1ccc(C(=O)OCC)cc1

Procedure:
To a solution of 5 g of ethyl 4-aminobenzoate in 100 ml of methanol, 0.74 ml of acetaldehyde, 1.89 g of sodium cyanoborohydride and 2.1 ml of hydrochloric acid 23% were added.
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6]/[C:7](=[CH:9]/[CH2:10][OH:11])/[CH3:8])[CH3:3].OC/C=C(/C)\CCC=C(C)C.CC(C)=CCCC(CCO)=C.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>>[CH3:1][C:2](=[CH:4][CH2:5][CH2:6][CH:7]([CH2:9][CH2:10][OH:11])[CH3:8])[CH3:3]
Reactant: CC(C)=CCC/C(C)=C/CO
Agent: C=C(CCO)CCC=C(C)C
Agent: CC(C)=CCC/C(C)=C\CO
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Product: CC(C)=CCCC(C)CCO

Procedure:
The asymmetric hydrogenation of geraniol, nerol and γ-geraniol using a ruthenium complex has already been reported (J. Am. Chem. Soc. 109, 1596, 4129 (1987); J. Organomet. Chem. 548, 65 (1997); Chem. Ind. (Dekker), 68, (1996)). When geraniol, nerol and γ-geraniol are subjected to asymmetric hydrogenation using the rhutenium complex of (S)-BINAP to produce citronellol, one of the enantiomers of citronellol is obtained when geraniol is hydrogenated and the other is obtained when nerol or γ-geraniol is hydrogenated.
Reaction SMILES: [N:1]([C@@H:4]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[C@H:8]([OH:15])[CH2:7][CH2:6][C@H:5]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=1[F:23])=[N+:2]=[N-:3].[O:24]=[C:25]1[NH:33][C:28]2=[N:29][CH:30]=[CH:31][CH:32]=[C:27]2[N:26]1[CH:34]1[CH2:39][CH2:38][N:37]([C:40](OC2C=CC([N+]([O-])=O)=CC=2)=[O:41])[CH2:36][CH2:35]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>CN(C)C=O>[O:24]=[C:25]1[NH:33][C:28]2=[N:29][CH:30]=[CH:31][CH:32]=[C:27]2[N:26]1[CH:34]1[CH2:35][CH2:36][N:37]([C:40]([O:15][C@H:8]2[C:9]3=[N:10][CH:11]=[CH:12][CH:13]=[C:14]3[C@@H:4]([N:1]=[N+:2]=[N-:3])[C@H:5]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=3[F:23])[CH2:6][CH2:7]2)=[O:41])[CH2:38][CH2:39]1
Reactant: [N-]=[N+]=N[C@@H]1c2cccnc2[C@H](O)CC[C@H]1c1cccc(F)c1F
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=N[C@@H]1c2cccnc2[C@H](OC(=O)N2CCC(n3c(=O)[nH]c4ncccc43)CC2)CC[C@H]1c1cccc(F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.8 %

Procedure:
In a 100 mL round-bottom flask was dissolved (5S,6S,9R)-5-azido-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-ol (0.490 g, 1.549 mmol) (azeotroped with dry benzene) and 4-nitrophenyl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate (0.713 g, 1.859 mmol) in dimethylformamide (8 mL) to give a light yellow suspension under nitrogen. After cooling to −15° C. (ice-methanol bath), NaHMDS (4.18 mL, 4.18 mmol) was added dropwise. The resulting tan solution was stirred under nitrogen at −10° C.˜0° C. for 2 h and at room temperature for 2 h. LCMS showed complete conversion. The reaction was quenched with sodium bicarbonate solution. The mixture was diluted with ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried with sodium sulfate, and concentrated to give a tan oil. Purification by FCC up to 8% methanol/methylene chloride afforded the desired product (major peak, 632 mg, 73% for 3 steps) as a light yellow foam.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1O.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.P(O)(O)O>O>[C:13]1([NH:12][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Oc1ccc2ccccc2c1
Reactant: Nc1ccccc1
Agent: OP(O)O
Solvent: O
Product: c1ccc(Nc2ccc3ccccc3c2)cc1
Temperature: 173 °C
Yield: 94 %

Procedure:
288 parts of β-naphthol, 220 parts of aniline and 5 parts of phosphorous acid are mixed and heated to 173° C. At this temperature, the elimination of water commences. The reaction temperature rises to 230° C in the course of 4 hours. At that stage, the reaction has ended and 36 parts of water have been removed. The further working up is carried out as described in Example 8. 412 parts of N-phenyl-β-naphthylamine of melting point 100° - 102° C are obtained, corresponding to a yield of 94% of theory.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:11]3[C:10](=[CH:12][CH:13]=1)[S:9](=[O:15])(=[O:14])[NH:8][C:7]=3[CH:6]=[CH:5][CH:4]=2.Cl[CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH2:22][CH2:21]1.[H-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[C:3]2[C:11]3[C:10](=[CH:12][CH:13]=1)[S:9](=[O:15])(=[O:14])[N:8]([CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][N:23]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)[CH2:22][CH2:21]1)[C:7]=3[CH:6]=[CH:5][CH:4]=2
Reactant: Fc1ccc(N2CCN(CCCCl)CC2)cc1
Reactant: O=S1(=O)Nc2cccc3c(Cl)ccc1c23
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S1(=O)c2ccc(Cl)c3cccc(c23)N1CCCN1CCN(c2ccc(F)cc2)CC1
Temperature: 90 °C
Yield: 44.7 %

Procedure:
The experiment is carried out as in Example 18, starting with 6-chloronaphtho[1,8-cd]isothiazole 1,1-dioxide (1.4 g), 1-(3-chloropropyl)-4-(4-fluorophenyl) piperazine (1.5 g), sodium hydride (0.18 g) in an 80dispersion in vaseline oil and dimethylformamide (15 cc). The reaction mixture is heated for 1 hour 30 minutes at 90° C., cooled to a temperature of about 20° C. and then concentrated to dryness at 60° C. under reduced pressure (0.5 mm Hg; 0.07 kPa). The residue is redissolved in dichloromethane (50 cc) and the solution is washed with distilled water (20 cc), dried over magnesium sulphate and concentrated to dryness at 20° C. under reduced pressure (20 mm Hg; 2.7 kPa). The residue is purified by chromatography on a silica column with a mixture of dichloromethane and ethyl acetate (95-5 vol) as eluant, then recrystallized from boiling acetonitrile (10 cc). 6-Chloro-2-{3-[4-(4-fluorophenyl)-1-piperazinyl]propyl}-naphtho[1,8-cd]isothiazole 1,1-dioxide (1.2 g) is obtained, m.p. 125° C.
Reaction SMILES: Cl.[O:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH:7]([NH2:10])[C:8]#[N:9].[OH-].[Na+].N1C=CC=CC=1.[CH3:19][C:20]1[CH:24]=[C:23]([C:25](Cl)=[O:26])[S:22][N:21]=1>C(OCC)(=O)C>[C:8]([CH:7]([NH:10][C:25]([C:23]1[S:22][N:21]=[C:20]([CH3:19])[CH:24]=1)=[O:26])[C:3]1[O:2][CH:6]=[CH:5][CH:4]=1)#[N:9]
Reactant: N#CC(N)c1ccco1
Reactant: Cc1cc(C(=O)Cl)sn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)NC(C#N)c2ccco2)sn1
Reaction time: 1 h
Yield: 73.5 %

Procedure:
5.0 g of alpha-(2-furyl)-alpha-aminoacetonitrile hydrochloride was dehydrochlorinated with sodium hydroxide in ethyl acetate by the same method as in the above Synthesis Example 6. Pyridine (2.5 g) was added, and furthermore, an ethyl acetate solution of 4.0 g of 3-methylisothiazole-5-carboxylic acid chloride was added dropwise After the addition, the mixture was stirred for 1 hour. The reaction mixture was washed with water, dilute hydrochloric acid and a dilute aqueous solution of sodium bicarbonate. Sodium sulfate, and active carbon were added to dehydrate and decolorize the reaction mixture. The solvent was removed under reduced pressure, and the residue was washed with ethyl ether to give 4.5 g (yield 74%) of the desired N-(alpha-cyanofurfuryl)-3-methylisothiazole-5-carboxylic acid amide.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH2:9][CH2:10][CH2:11][CH3:12])[NH:5][C:6](=[O:8])[CH:7]=1.[OH-].[Na+].[Cl-].[C:16]1([N+:22]#[N:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.NC1C=CC=CC=1>O>[NH2:1][C:2]1[N:3]=[C:4]([CH2:9][CH2:10][CH2:11][CH3:12])[NH:5][C:6](=[O:8])[C:7]=1[N:23]=[N:22][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: N#[N+]c1ccccc1
Reactant: CCCCc1nc(N)cc(=O)[nH]1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Nc1ccccc1
Product: CCCCc1nc(N)c(N=Nc2ccccc2)c(=O)[nH]1

Procedure:
To a solution of 4-amino-2-butylpyrimid-6-one (7.65 g.) and sodium hydroxide (3.7 g.) in water (115 ml.) was added, at below 5° C, benzene diazonium chloride solution prepared (by the method well known in the art) from aniline (4.64 ml.), and the mixture was then heated to reflux for 1 hour. The pH was adjusted to 6 by the addition of aqueous sodium hydroxide solution, the product was filtered off, washed with water, dried and recrystallised from ethanol to give 4-amino-2-n-butyl-5-phenylazopyrimid-6-one (2.52 g.), m.p. 266°-270° C, pure enough for use in the next stage of the preparation.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[Br:14][C:15]1[C:16]([F:22])=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=1>CC(C)=O>[Br:14][C:15]1[C:16]([F:22])=[C:17]([O:21][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH:18]=[CH:19][CH:20]=1
Reactant: Oc1cccc(Br)c1F
Reactant: CCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCCOc1cccc(Br)c1F
Yield: 86.8 %

Procedure:
117 g of potassium carbonate and 55.6 g of bromohexane are added to a solution of 53.6 g of 3-bromo-2-fluorophenol in 650 ml of acetone, and the mixture is refluxed for 8 hours. The mixture is filtered, evaporated to ⅓ of the original volume and poured into 600 ml of water. The pH is adjusted to 1 using hydrochloric acid, and the mixture is extracted three times with 150 ml of tert-butyl methyl ether each time. The combined organic phases are concentrated under reduced pressure, and the residue is subjected to vacuum distillation (103° C.; 1 mbar), giving 67 g of 6-bromo-2-hexyloxyfluorobenzene as a colorless oil. 1H-NMR (CDCl3): 6.9-7.1 (m; 3H); 4.0 (t; 2H), 0.9-1.8 (m, 11H), 19F-NMR (CDCl3): −128 ppm. A solution of 67.3 g of 6-bromo-2-hexyloxyfluorobenzene, 24.7 g of 2-methyl-3-butyn-2-ol [115-19-5], 0.7 g of bis(triphenylphosphine)palladium(II) chloride and 0.7 g of copper iodide in 340 ml of triethylamine is refluxed for 5 hours. The mixture is then poured into 1.5 of ice-water, the pH is adjusted to 1 using hydrochloric acid, and the mixture is extracted three-times with 200 ml of tert-butyl methyl ether each time. The combined organic phases are dried under reduced pressure. The crude 4-(2-fluoro-3-hexyloxyphenyl)2methyl-3-butyn-1-ol is refluxed for 3 hours in 1000 ml of toluene together with three mole-equivalents of sodium hydroxide. The mixture is filtered and washed with dilute hydrochloric acid, the solvent is removed by distillation, and the residue is distilled (90° C.; 0.5 mbar), giving 34 g of 1-(2-fluoro-3-hexyloxyphenyl)ethyne.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([OH:17])=[C:8]2[CH:14]=[N:13][N:12]([CH2:15][CH3:16])[C:9]2=[N:10][CH:11]=1)=O)C.[NH3:18]>CN(C)C=O>[CH2:15]([N:12]1[C:9]2=[N:10][CH:11]=[C:6]([C:4]([NH2:18])=[O:3])[C:7]([OH:17])=[C:8]2[CH:14]=[N:13]1)[CH3:16]
Reactant: N
Reactant: CCOC(=O)c1cnc2c(cnn2CC)c1O
Solvent: CN(C)C=O
Product: CCn1ncc2c(O)c(C(N)=O)cnc21

Procedure:
6.8 g. of ethyl-1-ethyl-4-hydroxy-1H-pyrazolo-[3,4-b]pyridine-5-carboxylate (J. Het. Chem., supra) (0.029 mol.) and 100 ml. of ammonia in dimethylformamide (48 g. NH3 /1; cooled at 4°) are filled into a steel autoclave. The mixture is heated to 150° for 6 hours. After cooling, the solution is evaporated to dryness and the residue is treated with ether. The 1-ethyl-4-hydroxy-1H-pyrazolo[3,4-b]pyridine-5-carboxamide is used in the next step without further purification. A sample, recrystallized from ethanol, melts at 267°-268° (dec.), yield 3.6 g. (60%).
Reaction SMILES: C(O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C[Si](C)(C)N[Si](C)(C)C.[Li].O1CCCC1>CN(C)C=O.C(#N)C>[C:11]1([NH:10][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)c1ccccc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CC#N
Product: c1ccc(Nc2ccccc2)cc1
Temperature: -78 °C

Procedure:
In Scheme 1, Step A, a 2-(arylamino)-benzoic acid or diphenylamine (3) is prepared from the coupling of a suitable benzoic acid (1) and a suitable aniline (2) in the presence of a strong base, for example, lithium 1,1,1,3,3,3-hexamethyldisilazane (LiHMDS), in a polar aprotic solvent such as tetrahydrofuran, acetonitrile or dimethylformamide. For example, the aniline (2) and the benzoic acid (1) are dissolved in a suitable organic solvent and cooled to about −78° C. under nitrogen. The suspension is treated with an excess of a suitable base, such as LiHMDS, and allowed to warm to room temperature. The reaction is typically complete within about 2 hours to about 5 days. The resulting benzoic acid (3) can be isolated by removing the solvent, for example by evaporation under reduced pressure or by filtering the precipitated solid through Celite® and washing with a suitable solvent. The benzoic acid (3) can be further purified, if desired, by standard methods such as chromatography, crystallization, or distillation.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:9])=[C:6]([F:16])[C:5]([F:17])=[C:4]([F:18])[C:3]=1[F:19].[C:20]([O:23][C:24](=O)C)(=O)[CH3:21].C([O-])([O-])OCC>>[CH3:1][C:2]1[C:7]([C:8]([C:10](=[CH:24][O:23][CH2:20][CH3:21])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:9])=[C:6]([F:16])[C:5]([F:17])=[C:4]([F:18])[C:3]=1[F:19]
Reactant: CCOC(=O)CC(=O)c1c(C)c(F)c(F)c(F)c1F
Reactant: CC(=O)OC(C)=O
Agent: CCOC([O-])[O-]
Product: CCOC=C(C(=O)OCC)C(=O)c1c(C)c(F)c(F)c(F)c1F
Yield: 99.1 %

Procedure:
To ethyl 6-methyl-2,3,4,5-tetrafluorobenzoylacetate (4.20 g) are added acetic anhydride (3.7 g) and ethyl orthoformate (4 ml) and the mixture is refluxed for 1 hour. After concentrating, ethyl 2-(6-methyl-2,3,4,5-tetrafluorobenzoyl)-3-ethoxyacrylate (5 g) is obtained.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[N:21]=[C:20]([C:22]5[CH:23]=[N:24][C:25]([O:28]C)=[CH:26][CH:27]=5)[CH:19]=[C:18]([CH3:30])[CH:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[CH2:3][CH2:2]1.[Si](I)(C)(C)C.CO>CC#N>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]([CH3:30])[CH:19]=[C:20]([C:22]5[CH:27]=[CH:26][C:25](=[O:28])[NH:24][CH:23]=5)[N:21]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: COc1ccc(-c2cc(C)cc(NC(=O)C3(c4ccc5c(c4)CCO5)CC3)n2)cn1
Agent: C[Si](C)(C)I
Solvent: CO
Solvent: CC#N
Product: Cc1cc(NC(=O)C2(c3ccc4c(c3)CCO4)CC2)nc(-c2ccc(=O)[nH]c2)c1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 1-(2,3-dihydrobenzofuran-5-yl)-N-(6′-methoxy-4-methyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide (180 mg, 0.45 mmol) in CH3CN (7 mL) was added TMSI (130 uL, 0.90 mmol) dropwise at 20° C. The reaction was stirred at 50° C. for 30 min. MeOH (1.0 mL) was added and the solution was evaporated to dryness. The residue was re-dissolved in DCM-EtOAc (1:3) before it was washed with NaHSO3 (2×) and brine. The organics were dried over MgSO4 and evaporated to dryness. The crude material was purified by HPLC to yield 1-(2,3-dihydrobenzofuran-5-yl)-N-(4-methyl-6-(6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide. ESI-MS m/z calc. 387.2. found 388.1 (M+1)+. Retention time 1.35 minutes.
Reaction SMILES: NC(C1C=CC2C(=CC=C(O[C@H]3CC[C@H](C(C)(C)C)CC3)C=2)C=1)(C)CCC(O)=O.[C:30]([C@H:34]1[CH2:39][CH2:38][C@H:37]([O:40][C:41]2[C:42]([C:61]([F:64])([F:63])[F:62])=[C:43]3[C:48](=[CH:49][CH:50]=2)[CH:47]=[C:46]([C:51]([N+:58]([O-])=O)([CH3:57])[CH2:52][CH2:53][C:54]([OH:56])=[O:55])[CH:45]=[CH:44]3)[CH2:36][CH2:35]1)([CH3:33])([CH3:32])[CH3:31]>>[NH2:58][C:51]([C:46]1[CH:45]=[CH:44][C:43]2[C:48](=[CH:49][CH:50]=[C:41]([O:40][C@H:37]3[CH2:36][CH2:35][C@H:34]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:39][CH2:38]3)[C:42]=2[C:61]([F:63])([F:64])[F:62])[CH:47]=1)([CH3:57])[CH2:52][CH2:53][C:54]([OH:56])=[O:55]
Reactant: CC(CCC(=O)O)(c1ccc2c(C(F)(F)F)c(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2c1)[N+](=O)[O-]
Agent: CC(N)(CCC(=O)O)c1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2c1
Product: CC(N)(CCC(=O)O)c1ccc2c(C(F)(F)F)c(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2c1

Procedure:
4-amino-4-(6-(trans-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)pentanoic acid was synthesized as per 4-amino-4-(6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)pentanoic acid (Example 207) in 26% yield using 4-(6-(trans-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)-4-nitropentanoic acid as starting material. MS: m/z=449.71 [M−NH2]+. 1H NMR (MeOD) δ: 8.25-8.31 (m, 1H), 8.14 (d, J=9.3 Hz, 1H), 7.96 (d, J=2.3 Hz, 1H), 7.69 (dd, J=9.3, 2.5 Hz, 7.60 (d, J=9.3 Hz, 1H), 4.46-4.56 (m, 1H), 2.65-2.70 (m, 3H), 2.37-2.54 (m, 2H), 2.18-2.35 (m, 2H), 2.07-2.18 (m, 2H), 1.95 (br. s., 2H), 1.87 (s, 2H), 1.50 (br. s., 2H), 1.19-1.34 (m, 2H), 1.07-1.18 (m, 1H), 0.88-0.95 (m, 9H)
Reaction SMILES: C(N)C=C.[CH2:5]([N:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:21])C1=S)[CH:6]=[CH2:7]>ClCCl>[CH2:5]([NH:8][CH2:13][CH2:12][CH2:11][NH:10][C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:21])[CH:6]=[CH2:7]
Reactant: C=CCN1CCCN(c2c(C)cccc2Cl)C1=S
Solvent: ClCCl
Solvent: C=CCN
Product: C=CCNCCCNc1c(C)cccc1Cl
Yield: 68.4 %

Procedure:
A mixture of allylamine (20 mL) and the hydrobromide salt of Step B (8.6 g) was heated at 100° C. under nitrogen for 30 minutes. The reaction mixture was cooled and partitioned between dichoromethane and 1N sodium hydroxide. The aqueous layer was extracted with dichloromethane, and the combined organic layers were dried over sodium sulfate and concentrated in vacuo to give a yellow oil. The crude material was dissolved in dichloromethane and absorbed onto a column of Merck-60 flash silica gel. Elution with 1:1 ethyl acetate-hexane followed by 80:20 dichloromethane-methanol containing 0.2% ammonium hydroxide gave the title compound (5.0 g, 83.8%) as a yellow oil which was used as such in the next step.