Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[N+:10]([O-])=O.[C:13]([OH:18])(=[O:17])[C:14]([CH3:16])=O>CC(O)C.[Pd]>[F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[NH:10][CH:14]([CH3:16])[C:13]([OH:18])=[O:17]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1F
Reactant: CC(=O)C(=O)O
Agent: [Pd]
Solvent: CC(C)O
Product: CC(Nc1ccc(F)c(F)c1F)C(=O)O
Temperature: 40 °C
Reaction time: 3 h
Yield: 97.8 %

Procedure:
2,3,4-Trifluoronitrobenzene (5.03 g) and pyruvic acid (2.75 g) were dissolved in IPA (40 ml). After adding 10% Pd—C (0.21 g), the mixture was stirred at 40° C. under a hydrogen gas pressure of 2.94 MPa for 3 hours. After filtering off Pd—C, the obtained filtrate was concentrated under reduced pressure. Thus the title compound (6.09 g) was obtained as colorless crystals. Various spectral data of this product was identical with those of a specimen synthesized separately.
Reaction SMILES: [CH3:1][CH:2]([CH2:13][CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])[CH2:3][CH2:4][O:5][C:6](=[O:12])[CH2:7][CH2:8][C:9](O)=[O:10].N1C=CC=CC=1.S(Cl)([Cl:27])=O>CCOCC>[CH3:1][CH:2]([CH2:13][CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])[CH2:3][CH2:4][O:5][C:6](=[O:12])[CH2:7][CH2:8][C:9]([Cl:27])=[O:10]
Reactant: CC(C)=CCCC(C)CCOC(=O)CCC(=O)O
Reactant: O=S(Cl)Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(C)=CCCC(C)CCOC(=O)CCC(=O)Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.8 %

Procedure:
A solution of 35.5 g succinic acid mono-(3,7-dimethyl-oct-6-enyl) ester and 12.3 g pyridine in 200 ml of ether was cooled in an ice bath. Then a solution of 18.0 g thionyl chloride in 100 ml of ether was added dropwise at 5-10° C. during 90 min. The resulting solution was stirred overnight at room temperature, then it was filtered and evaporated to dryness. The residue was not further purified to yield 31.5 g of a yellow liquid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([CH3:10])[C:7](=O)[C:6]=2[CH:12]=1.[CH2:13]([O:15][C:16](=[O:37])[CH:17]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:14]>C1(C)C=CC=CC=1.Cl.C(O)C>[CH2:13]([O:15][C:16](=[O:37])[CH2:17][C:7]1[C:6]2[CH:12]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=2[O:9][C:8]=1[CH3:10])[CH3:14]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC1Oc2ccc(Br)cc2C1=O
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)Cc1c(C)oc2ccc(Br)cc12
Temperature: 120 °C
Yield: 77.6 %

Procedure:
A mixture of 5-bromo-2-methyl-benzofuran-3-one (6.8 g, 29.9 mmol) and (triphenyl-phosphanylidene)-acetic acid ethyl ester (17.4 g, 44.9 mmol) in anhydrous toluene is heated for 40 h at 120° C. under an argon atmosphere. After cooling to room temperature the volatiles are removed by rotary evaporation. The residue is purified by flash column chromatography (silica gel, gradient of cyclohexane/EtOAc 100:0 to 90:10) to afford a mixture of two regioisomeric products. The product mixture (7.1 g, 31.3 mmol) is dissolved in a 1.25 M solution of HCl in ethanol and heated at reflux for 1 h. After cooling to room temperature the solvent is removed by rotary evaporation to yield the title compound as a pale yellow oil (6.9 g, 23.2 mmol, 78%). 1H NMR (400 MHz, CDCl3, 298 K): δ=7.59 (d, J=2.0 Hz, 1H), 7.31-7.22 (m, 2H), 4.15 (q, J=7.1 Hz, 2H), 3.54 (s, 2H), 2.42 (s, 3H), 1.25 (t, J=7.1 Hz, 3H). MS (ES+): 297 (M(C13H1379BrO3)+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][NH:5][C:4](=[O:11])[CH:3]=1.[CH3:12][O:13][C:14]1[CH:22]=[C:21]([S:23][CH3:24])[CH:20]=[CH:19][C:15]=1[C:16](Cl)=[O:17]>ClC1C=CC=CC=1>[CH3:12][O:13][C:14]1[CH:22]=[C:21]([S:23][CH3:24])[CH:20]=[CH:19][C:15]=1[C:16]([NH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][NH:5][C:4](=[O:11])[CH:3]=1)=[O:17]
Reactant: Nc1cc(=O)[nH]cc1[N+](=O)[O-]
Reactant: COc1cc(SC)ccc1C(=O)Cl
Solvent: Clc1ccccc1
Product: COc1cc(SC)ccc1C(=O)Nc1cc(=O)[nH]cc1[N+](=O)[O-]

Procedure:
A mixture of 0.45 g of 4-amino-5-nitro-1H-pyridin-2-one and 0.87 g of 2-methoxy-4-methylmercapto-benzoyl chloride was refluxed for 8 hours in 10 ml of chlorobenzene. The precipitated product was suction-filtered off, washed with methylene chloride and used in the next step as the crude product without further purification.
Reaction SMILES: [Cl-:1].[NH2:2][N+:3]1[CH:7]=[CH:6][N:5]([CH2:8][C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)[C:4]=1[CH2:21][CH3:22].[CH3:23][N:24]([CH3:33])[C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=1>C(O)(=O)C>[Cl-:1].[CH2:21]([C:4]1[N:5]([CH2:8][C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)[CH:6]=[CH:7][N+:3]=1[N:2]=[CH:29][C:28]1[CH:31]=[CH:32][C:25]([N:24]([CH3:33])[CH3:23])=[CH:26][CH:27]=1)[CH3:22]
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: CCc1n(Cc2cc(OC)c(OC)c(OC)c2)cc[n+]1N
Agent: [Cl-]
Solvent: CC(=O)O
Product: CCc1n(Cc2cc(OC)c(OC)c(OC)c2)cc[n+]1N=Cc1ccc(N(C)C)cc1
Temperature: 25 °C
Reaction time: 52 h

Procedure:
1.9 g (5.8 mmol) of 1-amino-2-ethyl-3-(3,4,5-trimethoxybenzyl)imidazolium chloride are dissolved in 38 ml of glacial acetic acid, whereupon the solution is treated with 0.86 g (5.8 mmol) of p-dimethylaminobenzaldehyde, stirred at room temperature for 52 hours and then evaporated. The product is recrystallized from ethanol/ether. There is obtained 2-ethyl-1-[[p-(dimethylamino)benzylidene]amino]-3-(3,4,5-trimethyoxybenzyl)imidazolium chloride of melting point 211°.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:11]=[CH:10][C:9]([C:12](=O)[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][CH:7]=1.Cl[C:22]1[C:27]([CH:28]=O)=[C:26]([NH:30]C(=O)OC(C)(C)C)[CH:25]=[CH:24][N:23]=1.[CH3:38][O-:39].[Na+].CO>CO>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:28][C:27]3[C:26](=[CH:25][CH:24]=[N:23][C:22]=3[O:39][CH3:38])[N:30]=2)=[CH:8][CH:7]=1
Reactant: O=C(Cc1ccccc1)c1ccc(C2OCCO2)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccnc(Cl)c1C=O
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nccc2nc(-c3ccc(C4OCCO4)cc3)c(-c3ccccc3)cc12
Temperature: 65 °C

Procedure:
To a partial solution of 1-[4-(1,3-dioxolan-2-yl)phenyl]-2-phenylethanone (997 mg, 3.72 mmol) and tert-butyl (2-chloro-3-formylpyridine-4-yl)carbamate (924 mg, 3.6 mmol) in dry methanol (14 mL) was added 25 wt % sodium methoxide/methanol (2.5 mL, 11.4 mmol). The reaction mixture was warmed at 65° C. for four hours. The cooled reaction was concentrated to remove the methanol and the residue was partitioned between water and ethyl acetate. The organic layer was dried (Na2SO4), filtered and evaporated. The residue was triturated with cold ether to give pure 2-[4-(1,3-dioxolan-2-yl)phenyl]-5-methoxy-3-phenyl-1,6-naphthyridine. The mother liquors were purified by chromatography on silica gel and elution with 20-40% ethyl acetate/hexane gave additional product. 1H-NMR (500 MHz, CDCl3): δ 8.54 (1H, s), 8.23 (1H, d, J=5.9 Hz), 7.55 (1H, d, J=5.9 Hz), 7.48 (2H, d, J=8 Hz), 7.40 (2H, d, J=8 Hz), 7.29-7.30 (3H, m), 7.22-7.25 (2H, m), 4.16 (3H, s), 4.02-411 (4H, 2 m). m/e (m+1): 385.1.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH3:24])[N:9]=2)[CH:5]=[CH:4][N:3]=1.[C:25]([NH:29][S:30]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)(=[O:32])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([NH:29][S:30]([C:33]1[CH:34]=[CH:35][CH:36]=[C:37]([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=4)[CH:11]=[C:10]([CH3:24])[N:9]=3)[CH:5]=[CH:4][N:3]=2)[CH:38]=1)(=[O:32])=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(Cl)n2)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)n2)n1

Procedure:
The title compound was prepared from 2-chloro-4-[6-methyl-4-(4-trifluoromethylphenyl)-pyridin-2-yl]-pyrimidine (example E.83) (0.5 g, 1.432 mmol) and commercially available 3-(tert-butylsulfamoyl)-benzeneboronic acid (0.404 g, 1.575 mmol) according to the general procedure VI. Obtained as a white solid (0.10 g, 13%) and additional off-white solid (0.48 g, 64%). MS (ISP) 527.2 [(M+H)+]; mp 218° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH2:3][CH2:2]1.[CH3:21][O:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[NH2:25]>>[CH3:21][O:22][C:23](=[O:28])[C:24]([NH:25][C:12]([C:10]1[CH:9]=[CH:8][C:7]([CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])([CH3:27])[CH3:26]
Reactant: O=C(O)c1ccc(C2CCOCC2)c(OCC2CC2)n1
Reactant: COC(=O)C(C)(C)N
Product: COC(=O)C(C)(C)NC(=O)c1ccc(C2CCOCC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(tetrahydro-pyran-4-yl)-pyridine-2-carboxylic acid and 2-methyl-alanine methyl ester as starting materials, MS (EI): m/e 377.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]=[C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([O:24]C)=[O:23])=[C:18]([CH3:26])[CH:17]=4)=[CH:12][CH:11]=3)[S:8][C:4]=2[CH:3]=1.CO.O.[OH-].[Na+]>C1COCC1>[F:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]=[C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([OH:24])=[O:23])=[C:18]([CH3:26])[CH:17]=4)=[CH:12][CH:11]=3)[S:8][C:4]=2[CH:3]=1
Reactant: COC(=O)c1ccc(-c2ccc(Nc3nc4ccc(F)cc4s3)cc2)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(-c2ccc(Nc3nc4ccc(F)cc4s3)cc2)ccc1C(=O)O
Temperature: 50 °C

Procedure:
As shown in Reaction Scheme 7, methyl 4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]-3-methylbiphenyl-4-carboxylate (0.25 g, 0.65 mmol) was suspended in THF (5 mL), MeOH (5 mL) and water (2.5 mL), and NaOH (0.26 g, 6.5 mmol) was added. The reaction mixture was heated at 50° C. for 3 h. Upon cooling to rt, the reaction mixture was concentrated in vacuo, acidified with 2N HCl, and the resulting solid was collected by filtration. This yielded 0.25 g (quantitative) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 2.62 (s, 3H), 7.05 (t, 1H), 7.57-7.90 (m, 9H), 10.62 (br, 1H)
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]3[CH2:15][C@H:14]([C:16](OCCCC)=[O:17])[O:13][C:12]3=[O:23])=[CH:10][C:5]=2[S:4][C:3]1=[O:24].[NH3:25]>CO.O1CCCC1>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]3[CH2:15][C@H:14]([C:16]([NH2:25])=[O:17])[O:13][C:12]3=[O:23])=[CH:10][C:5]=2[S:4][C:3]1=[O:24]
Reactant: CCCCOC(=O)[C@H]1CN(c2ccc3c(c2)sc(=O)n3C)C(=O)O1
Reactant: N
Solvent: CO
Solvent: C1CCOC1
Product: Cn1c(=O)sc2cc(N3C[C@H](C(N)=O)OC3=O)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The butyl (5R)-3-(2,3-dihydro-3-methyl-2-oxo-6-benzothiazolyl)-2-oxo-5-oxazolidinecarboxylate (Step 2, 685 mg, 1.95 mmol) is treated with 7N ammonia in MeOH (19 mL) with vigorous stirring, and the mixture is diluted with additional MeOH (20 mL) and tetrahydrofuran (20 mL) and stirred at ambient temperature for 1 h. The resulting slurry is concentrated under reduced pressure and then triturated and filtered from acetone to give the title compound, mp 274-276° C. (dec.); MS (ESI−) for C12H11N3O4S m/z 292 (M−H)−; [α]25D−27 (c 0.98, DMSO).
Reaction SMILES: CN[C:3]([O:5][CH:6]1[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:13][C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)=O.[CH2:20](O)[CH:21]=C>>[CH:18]1[C:19]2[CH:6]([O:5][CH2:3][CH:20]=[CH2:21])[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[O:13][C:14]=2[CH:15]=[CH:16][CH:17]=1
Reactant: C=CCO
Reactant: CNC(=O)OC1c2ccccc2Oc2ccccc21
Product: C=CCOC1c2ccccc2Oc2ccccc21

Procedure:
9-(N-Methylcarbamoyloxy)xanthene (27.0 g., 0.016 moles) was stirred with 150 ml. of allyl alcohol for 1.5 hours at room temperature, and the mixture was then filtered. The filtrate was evaporated in vacuo, and the residue was dissolved in 200 ml. of ice-cold ether and washed twice each with 100 ml. portions of ice-cold 10% aqueous acetic acid, water and 5% aqueous sodium bicarbonate solution. After drying over potassium carbonate, the solvent was removed in vacuo, and the resulting oil was distilled to give allyl 9-xanthenyl ether, b.p. 100°-105°C. at 0.005 mm.
Reaction SMILES: [N:1](OCCCC)=O.[N+:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:12]=1[CH3:18])([O-:10])=[O:9].CC(C)([O-])C.[K+].Cl>CN(C)C=O>[CH3:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([N+:8]([O-:10])=[O:9])[C:12]=1[C:18]#[N:1]
Reactant: CCCCON=O
Reactant: Cc1cccc([N+](=O)[O-])c1C
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc([N+](=O)[O-])c1C#N
Temperature: 25 °C
Reaction time: 144 h

Procedure:
35 A solution of 16 g (150 mmol) of n-butyl nitrite (97%) and 7.7 g (50 mmol) of 3-nitro-o-xylene (97%) in 50 ml of dimethylformamide is cooled to from −5 to −10° C., and a solution of 11 g (100 mmol) of potassium tert-butoxide in 50 ml of dimethylformamide is added at this temperature, over a period of 1.5 hours. The reaction mixture is stirred at room temperature for another 6 days. For work-up, the mixture is poured onto ice-water and adjusted to pH 1 using hydrochloric acid, and the aqueous phase is extracted with ethyl acetate. The organic phase is washed with water, dried over magnesium sulfate and concentrated. This gives 8.2 g of product. The 2-methyl-6-nitrobenzonitrile can be purified by silica gel chromatography using the mobile phase toluene. M.p.: 101-103° C.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH3:17])[C:14](O)=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.S(Cl)([Cl:20])=O>C1C=CC=CC=1>[C:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH3:17])[C:14]([Cl:20])=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: CC(C(=O)O)c1ccc(C2=CCCCC2)cc1
Solvent: c1ccccc1
Product: CC(C(=O)Cl)c1ccc(C2=CCCCC2)cc1

Procedure:
A solution of 17 g of α-[para-(1-cyclohexenyl)-phenyl]-propionic acid in 100 ml of absolute benzene is treated with 8 ml of thionyl chloride and then heated at 80°-90°C for one hour. The solution is evaporated under reduced pressure, the residue dissolved in 3 × 50 ml of absolute benzene, followed each time by evaporation under reduced pressure. There is thus obtained as residue α-[para-(1-cyclohexenyl)-phenyl]-propionic acid chloride which can be used as it is for the manufacture of the afore-described ester.
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:11]1([CH:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)CCO)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1(C)C=CC=CC=1>[C:11]1([CH:17]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:9][CH2:8][O:7][C:5](=[O:6])[CH2:4][C:3]([CH2:2][Cl:1])=[O:10])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=O)CC(=O)CCl
Reactant: OCCC(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: O=C(CCl)CC(=O)OCCC(c1ccccc1)c1ccccc1

Procedure:
3.2 ml (23.7 mmol) of ethyl 4-chloroacetoacetate and 5.00 g (23.6 mmol) of 3,3-diphenyl-1-propanol were heated at 130° C. in 100 ml of toluene overnight. Toluene was distilled out under reduced pressure to obtain the title compound.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([N:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21][N:20]3[C:28]([C:31]([NH:33][CH2:34][C:35]4[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=4)=[O:32])=[CH:29][CH:30]=[C:19]3[CH2:18]2)=[O:16])=[CH:11][CH:10]=1)=O.[NH:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1>>[N:41]1([CH2:1][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[C:9]2[CH:10]=[CH:11][C:12]([C:15]([N:17]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[CH2:21][N:20]4[C:28]([C:31]([NH:33][CH2:34][C:35]5[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=5)=[O:32])=[CH:29][CH:30]=[C:19]4[CH2:18]3)=[O:16])=[CH:13][CH:14]=2)[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1
Reactant: O=Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)cc1
Reactant: C1CCNCC1
Product: O=C(NCc1cccnc1)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(-c3ccccc3CN3CCCCC3)cc1)C2

Procedure:
The title compound was prepared from 10-[(2′-formyl-1,1′-biphenyl-4-yl)carbonyl]-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide of Example 56, Step B, and piperidine, in the manner of Example 42, m.p. 199-202° C.
Reaction SMILES: [F:1][C:2]1[C:3]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16]O)=[CH:12][C:11]=2[C:18]2([CH:23]=[CH2:24])[CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.S(Cl)([Cl:27])=O>CN(C=O)C.C(Cl)Cl>[Cl:27][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([C:3]2[C:2]([F:1])=[CH:7][N:6]=[C:5]([O:8][CH3:9])[CH:4]=2)=[C:11]([C:18]2([CH:23]=[CH2:24])[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:12]=1
Reactant: O=S(Cl)Cl
Reactant: C=CC1(c2cc(CO)ccc2-c2cc(OC)ncc2F)CCCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C=CC1(c2cc(CCl)ccc2-c2cc(OC)ncc2F)CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (4-(5-fluoro-2-methoxypyridin-4-yl)-3-(1-vinylcyclopentyl)phenyl)methanol (47.0 mg, 144 μmol) in DMF (0.01 mL) and DCM (4.0 mL) was slowly added thionyl chloride (14.7 μL, 201 μmol) at 0° C. After addition, the resulting mixture was stirred at room temperature for 1 hour. The solvent was removed, and the product thus obtained was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ ppm 8.01-8.11 (1H, m), 7.98 (1H, m), 7.47 (1H, s), 6.94 (1H, d, J=7.8 Hz), 6.69-6.82 (1H, m), 5.80 (1H, dd, J=17.2, 10.6 Hz), 4.89 (1H, d, J=10.2 Hz), 4.52-4.69 (3H, m), 3.89 (3H, s), 1.68-1.84 (4H, m), 1.49-1.67 (4H, m).
Reaction SMILES: [C:1]([O:9][C@@H:10]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C@@H:12]([CH2:13][CH2:14][C@@H:15]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:31])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[C:20](=[O:22])[CH3:21])[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[CH3:32][I:33]>CC(C)=O>[I-:33].[CH3:32][N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:1]([O:9][C@@H:10]2[CH2:29][CH2:28][C@@:27]3([CH3:30])[C@@H:12]([CH2:13][CH2:14][C@@H:15]4[C@@H:26]3[CH2:25][CH2:24][C@@:23]3([CH3:31])[C@H:16]4[CH2:17][CH2:18][C@@H:19]3[C:20](=[O:22])[CH3:21])[CH2:11]2)=[O:8])[CH2:3]1
Reactant: CI
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](OC(=O)c5cccnc5)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: CC(C)=O
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](OC(=O)C5=CC=CN(C)C5)CC[C@]4(C)[C@H]3CC[C@]12C
Product: [I-]

Procedure:
A mixture of 3α-nicotinoyloxy-5α-pregnan-20-one (770 mg, 421 g/m, 1.8 mmol) and methyliodide (3.0 mL, 141 g/m, -20 mmol) in 30 mL of acetone was refluxed gently for 17 hours. The reaction mixture was concentrated in vacuo to give the crude product.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([NH:5][CH2:6][C:7]#[CH:8])=[O:4].[H][H]>[Pd]>[F:1][C:2]([F:10])([F:9])[C:3]([NH:5][CH2:6][CH2:7][CH3:8])=[O:4]
Reactant: [H][H]
Reactant: C#CCNC(=O)C(F)(F)F
Agent: [Pd]
Product: CCCNC(=O)C(F)(F)F

Procedure:
In Reaction Scheme 4,6-amino-4-methoxypyrazolo[3,4-d]pyrimidine was converted to the iodo derivative (14) which was treated with 1-chloro-1,2-dideoxy-3,5-di-O-toluoylribofuranose to yield the nucleoside (15). Compound (15) was treated with NaOMe/MeOH to hydrolyze the toluoyl groups and yield the unblocked nucleoside (16). Treatment of (16) with aqueous sodium hydroxide gave (17) which could be converted to the trifluoro-N-prop-2-ynyl acetamide derivative (18). Compound (18) was reduced with hydrogen and a Pd catalyst to yield the trifluoro-N-propylacetamide derivative (19). The 4 amino group of compound (19) was protected by treatment with N,N-dimethylformamide dimethylacetal to give compound (20) which was converted to DMTr derivative (21) and then to the phosphoramidite derivative (22).
Reaction SMILES: Br.[CH3:2][CH:3]1[CH2:9][NH:8][CH2:7][CH2:6][CH:5]([CH3:10])[NH:4]1.C1CCN2C(=NCCC2)CC1.[Cl:22][S:23]([C:26]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:27]=1[C:28]([CH3:36])=[CH:29][N:30]=[CH:31]2)(=[O:25])=[O:24]>N1C=CC=CC=1>[ClH:22].[CH3:2][CH:3]1[NH:4][CH:5]([CH3:10])[CH2:6][CH2:7][N:8]([S:23]([C:26]2[CH:35]=[CH:34][CH:33]=[C:32]3[C:27]=2[C:28]([CH3:36])=[CH:29][N:30]=[CH:31]3)(=[O:24])=[O:25])[CH2:9]1
Reactant: CC1CCNCC(C)N1
Reactant: Cc1cncc2cccc(S(=O)(=O)Cl)c12
Agent: Br
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccncc1
Product: Cc1cncc2cccc(S(=O)(=O)N3CCC(C)NC(C)C3)c12
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.4 %

Procedure:
To a suspension of 1.5 g of 2,7-dimethyl-hexahydro-1H-1,4-diazepine hydrobromide obtained in Reference Example 3 in 30 ml of pyridine was added 1.58 g of 1,8-diazabicyclo[5.4.0]-7-undecene, and after addition of 0.84 g of 5-chlorosulfonyl-4-methyl-isoquinoline, the mixture was stirred at room temperature for 1 hour. This reaction mixture was concentrated and the residue was diluted with water, extracted with chloroform, dried, and concentrated. The residue was purified by silica gel column chromatography (chloroform/methanol=30/1) and converted to the hydrochloride in the routine manner to provide 0.70 g of the objective compound (white crystals).
Reaction SMILES: [Na].Cl.Cl[CH2:4][C:5]1[N:6]=[CH:7][NH:8][CH:9]=1.[CH2:10]([OH:14])[CH2:11][CH2:12][OH:13]>>[OH:13][CH2:12][CH2:11][CH2:10][O:14][CH2:4][C:5]1[N:6]=[CH:7][NH:8][CH:9]=1
Reactant: OCCCO
Reactant: ClCc1c[nH]cn1
Agent: Cl
Agent: [Na]
Product: OCCCOCc1c[nH]cn1
Reaction time: 8 h

Procedure:
Sodium (13.5 g.) was added over 3 hours to propane-1,3-diol (450 ml.) under nitrogen at 70° with stirring. This solution was added over 20 minutes to a stirred solution of 4-chloromethylimidazole hydrochloride (50.0 g.) under nitrogen at 40°-60°. Subsequent heating at 60°-65° for 3 hours followed by overnight cooling, filtration and concentration gave 4-(3-hydroxypropoxy)methylimidazole. Subsequent reaction with thionyl chloride gave 4-(3-chloropropoxy)methylimidazole hydrochloride (38.3 g.).
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:12]=1[C:13]([OH:15])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[O:42]=[C:43]([N:60]1[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]1)[CH2:44][NH:45][C:46]([C:48]1[CH:53]=[CH:52][C:51]([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)=[CH:50][CH:49]=1)=[O:47]>CN(C=O)C.O>[F:20][C:16]1[CH:17]=[CH:18][CH:19]=[C:11]([F:10])[C:12]=1[C:13]([N:63]1[CH2:62][CH2:61][N:60]([C:43](=[O:42])[CH2:44][NH:45][C:46]([C:48]2[CH:53]=[CH:52][C:51]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)=[CH:50][CH:49]=2)=[O:47])[CH2:65][CH2:64]1)=[O:15]
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(-c2ccccc2)cc1
Reactant: O=C(O)c1c(F)cccc1F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCN(C(=O)c2c(F)cccc2F)CC1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 39.6 %

Procedure:
DIPEA (179.7 mg, 0.24 mL, 1.39 mmol) was added to a stirred solution of 2,6-difluoro-benzoic acid (48.8 mg, 0.30 mmol) in DMF (3 mL). HOBT (45.9 mg, 0.34 mmol) and EDCI (148.1 mg, 0.77 mmol) were then added at room temperature. After 2 minutes, Biphenyl-4-carboxylic acid (2-oxo-2-piperazin-1-yl-ethyl)-amide (120 mg, 0.37 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to get the residue. The obtained residue was purified by column chromatography (using silica gel of 60-120 mesh and 60% EtOAc in Hexane as eluent) to afford 55 mg (38.4% yield) of biphenyl-4-carboxylic acid {2-[4-(2,6-difluoro-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide. LCMS Purity: 99.12%. 1H NMR (DMSO-d6): δ 8.7-8.6 (t, 1H), 8.0-7.94 (d, 2H), 7.82-7.7 (q, 4H), 7.62-7.54 (m, 1H), 7.54-7.38 (m, 3H), 7.3-7.2 (t, 2H), 4.2 (dd, 2H), 3.8-3.4 (m, 8H).