Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]=[C:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[N:15][C:10]=2[CH2:9][O:8][C:7]2[CH:16]=[CH:17][C:18]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:19][C:6]1=2.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH:32]2[CH3:37])=[CH:27][CH:26]=1.[I-].[K+]>C(O)(C)C>[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([N:31]2[CH2:36][CH2:35][N:34]([CH2:2][CH2:3][CH:4]=[C:5]3[C:11]4[CH:12]=[CH:13][CH:14]=[N:15][C:10]=4[CH2:9][O:8][C:7]4[CH:16]=[CH:17][C:18]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:19][C:6]3=4)[CH2:33][CH:32]2[CH3:37])=[CH:29][CH:30]=1
Reactant: CC1CNCCN1c1ccc(Cl)cc1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Agent: [I-]
Agent: [K+]
Solvent: CC(C)O
Product: CC1CN(CCC=C2c3cc(C(C)(C)O)ccc3OCc3ncccc32)CCN1c1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 68.2 %

Procedure:
A solution of 2-[5-(3-Bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.24 g, 0.64 mmol) in isopropanol (5 mL) was treated with 1-(4-Chloro-phenyl)-2-methyl-piperazine (0.25 g, 1.2 mmol) and catalytic potassium iodide. The solution was stirred at 80° C. for 5 hr, and evaporated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate→87:10:3 ethyl acetate/methanol/triethylamine) to yield 0.22 g (69%) of the title compound, 1H-NMR (CDCl3) δ: 1.00 (3H, m), 1.60 (6H, s), 2.20-2.70 (8H, m), 3.10 (2H, m), 3.75 (1H, m), 5.30 (2H, brs), 6.12 (1H, t), 6.87 (4H, d), 7.18-7.32 (3H, m), 7.45 (1H, s), 7.70 (1H, d), 8.55 (1H, d).
Reaction SMILES: CS[C:3]1[N:4]=[C:5]([CH2:12][C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[NH:6][C:7](=[O:11])[C:8]=1[C:9]#[N:10].[NH:18]1[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20][CH2:19]1>>[OH:24][CH:21]1[CH2:22][CH2:23][N:18]([C:3]2[N:4]=[C:5]([CH2:12][C:13]3[CH:17]=[CH:16][S:15][CH:14]=3)[NH:6][C:7](=[O:11])[C:8]=2[C:9]#[N:10])[CH2:19][CH2:20]1
Reactant: OC1CCNCC1
Reactant: CSc1nc(Cc2ccsc2)[nH]c(=O)c1C#N
Product: N#Cc1c(N2CCC(O)CC2)nc(Cc2ccsc2)[nH]c1=O

Procedure:
In analogy to the preparation of Example 1, 100 mg (0.38 mmol) of 4-(methylsulphanyl)-6-oxo-2-(3-thienylmethyl)-1,6-dihydropyrimidine-5-carbonitrile are reacted with 384 mg (3.80 mmol) of piperidin-4-ol to give 47 mg (39% of theory) of the title compound.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:34])[CH2:7][S:8][C:9]1[N:18]=[C:17]([CH3:19])[CH:16]=[C:15]2[C:10]=1[C:11](=[O:33])[CH:12]=[C:13]([NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[N:14]2[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)C>CCO>[NH:26]([C:13]1[N:14]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]2[C:10]([C:11](=[O:33])[CH:12]=1)=[C:9]([S:8][CH2:7][C:6]([OH:34])=[O:5])[N:18]=[C:17]([CH3:19])[CH:16]=2)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCOC(=O)CSc1nc(C)cc2c1c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc2c(c(SCC(=O)O)n1)c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Reaction time: 4 h
Yield: 58.3 %

Procedure:
Aqueous NaOH (2N, 1 mL) was added to a stirred solution of ethyl[(2-anilino-7-methyl-4-oxo-1-phenyl-1,4-dihydro-1,6-naphthyridin-5-yl)sulfanyl]acetate (100 mg, 0.23 mmol) in EtOH (8 mL) at room temperature. The mixture was allowed to stir for 4 h and was concentrated in vacuo. The reaction mixture was acidified with 1N HCl and extracted with CH2Cl2. The organic layer was dried over MgSO4 and concentrated in vacuo. Purification by reverse-phase preparative HPLC (10% CH3CN in water with 0.1% TFA to 95% CH3CN in water, 10 mL/min, 10 min) provided [(2-anilino-7-methyl-4-oxo-1-phenyl-1,4-dihydro-1,6-naphthyridin-5-yl)sulfanyl]acetic acid (56 mg, 60%): LCMS RT: 2.61 min, MH30: 418.2.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C@H:5]([C@@H:7]([NH2:11])[CH2:8][S:9][CH3:10])[CH2:4][O:3]1.C([BH3-])#N.[Na+].[CH2:17]([O:24][CH2:25][N:26]1[C:34]2[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[N:32][CH:31]=[N:30][C:29]=2[C:28]([CH:40]=O)=[CH:27]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([O:24][CH2:25][N:26]1[C:34]2[C:33]([O:35][C:36]([CH3:38])([CH3:37])[CH3:39])=[N:32][CH:31]=[N:30][C:29]=2[C:28]([CH2:40][NH:11][C@H:7]([C@@H:5]2[CH2:4][O:3][C:2]([CH3:12])([CH3:1])[O:6]2)[CH2:8][S:9][CH3:10])=[CH:27]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)Oc1ncnc2c(C=O)cn(COCc3ccccc3)c12
Reactant: CSC[C@H](N)[C@@H]1COC(C)(C)O1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CSC[C@H](NCc1cn(COCc2ccccc2)c2c(OC(C)(C)C)ncnc12)[C@@H]1COC(C)(C)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.7 %

Procedure:
A mixture of the product from Example 27.4 (0.130 g, 0.68 mmol), sodium cyanoborohydride (0.071 g, 1.13 mmol) and 5-(benzyloxymethyl)-4-tert-butyloxy-5H-pyrrolo[3,2-d]pyrimidin-7-carbaldehyde (0.192 g, 0.57 mmol) were evaporated from methanol (3×). The residue was dissolved in methanol (10 ml) and acetic acid added (5 drops). The reaction mixture was stirred at ambient temperature for 2 h. The reaction mixture was evaporated on to silica gel and chromatographed (methanol-triethylamine-DCM, 3:1:96) giving an orange oil (0.272 g, 93%). 1H NMR indicated that the product contained some (co-polar) starting amine. 1H NMR (CDCl3) δ 8.47 (s, 1H), 7.38 (s, 1H), 7.34-7.22 (m, 5H), 5.73 (s, 2H), 4.47 (s, 2H), 4.34 (q, J=6.8 Hz, 1H), 4.10 (Abq, 2H), 4.03 (m, 1H), 3.82 (m, 1H), 2.87 (q, J=5.7 Hz; 1H), 2.72 (dd, J=13.2, 5.7 Hz, 1H), 2.60 (dd, J=13.2, 6.0 Hz, 1H), 2.05 (s, 3H), 1.69 (s, 9H), 1.39 (s, 3H), 1.34 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]1[CH:7]=[C:8]([CH:12]([NH2:14])[CH3:13])[CH:9]=[CH:10][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:15][O:16][CH2:17][C:18](OC(C)C)=[O:19].S(=O)(=O)(O)O>O>[C:1]([O:5][C:6]1[CH:7]=[C:8]([C@H:12]([NH:14][C:18](=[O:19])[CH2:17][O:16][CH3:15])[CH3:13])[CH:9]=[CH:10][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(N)c1cccc(OC(C)(C)C)c1
Reactant: COCC(=O)OC(C)C
Agent: O=S(=O)(O)O
Solvent: O
Product: COCC(=O)N[C@H](C)c1cccc(OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.6 %

Procedure:
1-(3-tert-Butoxyphenyl)ethylamine (86 g, 0.45 mol) was admixed with isopropyl methoxyacetate (129 g, 0.98 mol) and Novozyme® 435 (0.9 g), and stirred at room temperature for 16 h. The subsequent analysis of the optical purity showed that the S enantiomer of 1-(3-tert-butoxyphenyl)ethylamine was enantiomerically pure. The acylated R enantiomer had an optical purity of 99.1%. The mixture was filtered through kieselguhr and washed with toluene (200 ml), and the filtrate was concentrated at 40° C. on a rotary evaporator. The residue was taken up in toluene (200 ml) and admixed dropwise with 37% sulfuric acid (29.5 g, 0.12 mol). A greasy, unfilterable precipitate formed, which was dissolved in water (250 ml). The aqueous solution was washed 3 times with 50 ml each time of toluene. The combined organic phases were washed once with 50 ml of water and then dried over sodium sulfate. After the solvent had been removed, the residue was freed of further volatile constituents in an oil-pump vacuum at 0.5 bar and 85° C. 70 g of crude (R)—N-1-(3-tert-butoxyphenyl)ethylmethoxyacetamide were obtained, whose chemical purity, according to GC analysis, was 93%. The optical purity was 99% ee.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].N12CCN(CC1)CC2.CN(C)C=O.[CH3:27][N:28]([CH3:32])[C:29](Cl)=[S:30]>O>[CH3:27][N:28]([C:29](=[S:30])[O:1][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])[CH3:32]
Reactant: COC(=O)c1ccc(OC)cc1O
Reactant: CN(C)C(=S)Cl
Agent: C1CN2CCN1CC2
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(OC)cc1OC(=S)N(C)C
Temperature: 50 °C
Reaction time: 7 h
Yield: 76.5 %

Procedure:
To a mixture of 350 g of methyl 2-hydroxy-4-methoxybenzoate, 648 g of 1,4-diazabicyclo[2.2.2]-octane (DABCO) and 3 L of dimethylformamide was added 712 g of dimethylthiocarbamoyl chloride. The mixture was warmed to 50° C. and held for 7 hours, then allowed to cool overnight. The mixture was poured into 10 L water; the aqueous mixture was extracted with 8 L of benzene-hexane (4:1). The organic solution was washed with 1N HCl, 10% NaOH, and dried over magnesium sulfate. Evaporation of the solvent in vacuo gave 396 g of the title compound, m.p. 95°-105° C. Further extraction of the aqueous mixture gave additional product, 171 g, m.p. 117°-120° C. Recrystallization of a portion of the crude product from methanol gave pure material, m.p. 122°-124° C.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([OH:23])([C:14]2[CH:19]=[CH:18][C:17]3[O:20][CH2:21][O:22][C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.Cl>[Pd].CO>[OH:23][C:11]1([C:14]2[CH:19]=[CH:18][C:17]3[O:20][CH2:21][O:22][C:16]=3[CH:15]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: OC1(c2ccc3c(c2)OCO3)CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: OC1(c2ccc3c(c2)OCO3)CCNCC1

Procedure:
39.4 g. 1-benzyl-4-hydroxy-4-(3.4-methylene dioxy phenyl)-piperidine are dissolved in 400 ml. methanol and the solution is mixed with 30 ml. 4-N hydrochloric acid. To this mixture is then added 3 g. of a palladium/carbon catalyst which has been suspended in 60 ml. alcohol. The mixture is hydrogenized at 35° - 40°C under normal pressure. After 3300 ml. hydrogen has been absorbed, hydrogenation is stopped and the cataylst is removed from the mixture by filtering. The mother liquor is heavily concentrated and the 4-hydroxy-4-(3.4-methylene dioxy phenyl)-piperidine hydrochloride with a melting point of 198° - 200°C crystallizes out.
Reaction SMILES: [O:1]=[S:2]1(=[O:29])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]2[CH:11]=[C:12]([NH:15][C:16](OCC3C=CC([N+]([O-])=O)=CC=3)=[O:17])[CH:13]=[CH:14][C:3]1=2.[CH2:30]([NH:32][CH2:33][C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1)[CH3:31].C(N(CC)CC)C>CCOC(C)=O.CN(C)C1C=CN=CC=1>[O:29]=[S:2]1(=[O:1])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]2[CH:11]=[C:12]([NH:15][C:16]([N:32]([CH2:33][C:34]3[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=3)[CH2:30][CH3:31])=[O:17])[CH:13]=[CH:14][C:3]1=2
Reactant: O=C(Nc1ccc2c(c1)-c1ccccc1S2(=O)=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CCNCc1ccncc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCN(Cc1ccncc1)C(=O)Nc1ccc2c(c1)-c1ccccc1S2(=O)=O
Reaction time: 18 h

Procedure:
5,5-Dioxo-2-(4-nitrobenzoxycarbonylamino)dibenzothiophene (Example 24; 0.396 g, 1 mmol) was dissolved in EtOAc (10 ml) and treated with 4-(ethylaminomethyl)pyridine (0.150 g, 1.1 mmol), triethylamine (0.202 g, 2 mmol) and 4-(dimethylamino)pyridine (0.006 mg, 0.05 mmol). The reaction was stirred for 18 hours and the suspended solids collected, washed with 1 M aq. NaOH solution, water and then ether to leave the product as a colourless solid. NMR: 9.00 (s, 1H), 8.54 (m, 2H), 8.27 (s, 1H), 7.93 (m, 2H), 7.81 (m, 1H), 7.75 (m, 2H), 7.65 (m, 1H), 7.28 (m, 2H), 4.63 (s, 2H), 3.43 (q, 2H), 1.12 (t, 3H); m/z 394.42.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[CH:7]=[C:8]([P:12]1(=[O:18])[O:17][CH2:16][CH2:15][CH2:14][O:13]1)[C:9]([CH3:11])=O)([O-:3])=[O:2].[CH2:22]([N:29]([CH2:31][CH2:32][O:33][C:34](=[O:39])/[CH:35]=[C:36](\[NH2:38])/[CH3:37])[CH3:30])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(O)(C)C>[CH3:37][C:36]1[NH:38][C:9]([CH3:11])=[C:8]([P:12]2(=[O:18])[O:17][CH2:16][CH2:15][CH2:14][O:13]2)[CH:7]([C:6]2[CH:19]=[CH:20][CH:21]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:35]=1[C:34]([O:33][CH2:32][CH2:31][N:29]([CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH3:30])=[O:39]
Reactant: C/C(N)=C/C(=O)OCCN(C)Cc1ccccc1
Reactant: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)P1(=O)OCCCO1
Solvent: CC(C)O
Product: CC1=C(C(=O)OCCN(C)Cc2ccccc2)C(c2cccc([N+](=O)[O-])c2)C(P2(=O)OCCCO2)=C(C)N1
Yield: 59.2 %

Procedure:
A mixture of 3.11 grams of 2-(1-(3-nitrobenzylidene)-acetonyl)-2-oxo-1,3,2-dioxaphosphorinane and 2.48 grams of 2 -(N-benzyl-N-methylamino)ethyl3-aminocrotonate was dissolved in 30 ml of isopropanol and the mixture was heated to reflux for eight hours. The reaction solution was concentrated in vacuo and the residue was purified by subjecting to a column chromatography (silica gel, n-hexane-ethyl acetate). The resulting pale yellow oil (3.8 grams) was crystallized with ether and recrystallized from a mixture of ethyl acetate and ether to give 3.2 grams of 2-(N-benzyl-N-methylamino)ethyl 2,6-dimethyl-4-(3-nitrophenyl)-5-(2-oxo-1,3,2-dioxaphosphorinan- 2-yl)-1,4-dihydropyridine-3-carboxylate, pale yellow crystals, m.p. 139°-40° C.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].[CH:9](OC)=[O:10]>C(N(CC)CC)C>[CH:9]([NH:7][CH2:6][C:5]([O:4][CH2:2][CH3:3])=[O:8])=[O:10]
Reactant: COC=O
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)CNC=O
Temperature: 25 °C
Yield: 93 %

Procedure:
To a 5 L three neck round bottom flask equipped with a mechanic stirrer, a pressure-equalizing funnel and a condenser bearing a calcium chloride drying tube was added glycine ethyl ester hydrochloride (500 g, 3.583 mol) and methyl formate (1.8 L). The suspension was brought to reflux and triethylamine (556 mL) was added to the reaction. The reaction was stirred and refluxed overnight. The reaction was cooled to room temperature and filtered through a Buchner funnel to remove triethylamine hydrochloride salt. The filtrate was concentrated and dried over high vacuum to yield 320 g (93%) of the title compound.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([S:12][C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:20].[F:21][C:22]1[CH:23]=[C:24]([CH2:29][C:30](O)=[O:31])[CH:25]=[C:26]([F:28])[CH:27]=1>>[Br:19][C:16]1[CH:17]=[CH:18][C:13]([S:12][C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:20])[N:2]([NH:1][C:30](=[O:31])[CH2:29][C:24]3[CH:23]=[C:22]([F:21])[CH:27]=[C:26]([F:28])[CH:25]=3)[N:11]=2)=[CH:14][CH:15]=1
Reactant: Nn1nc(Sc2ccc(Br)cc2)c2ccccc2c1=O
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Product: O=C(Cc1cc(F)cc(F)c1)Nn1nc(Sc2ccc(Br)cc2)c2ccccc2c1=O

Procedure:
The product from Example 195B and 2-(3,5-difluorophenyl)acetic acid were processed using a method similar to that described in Example 10C to afford the title compound. 1H NMR (500 MHz, DMSO-d6) δ 11.76 (s, 1H), 8.39-8.32 (m, 1H), 8.08-8.04 (m, 1H), 8.02 (ddd, J=8.1, 7.6, 1.3, 1H), 7.95 (td, J=8.2, 1.3, 1H), 7.59-7.52 (m, 2H), 7.38 (ddd, J=6.6, 2.4, 1.4, 2H), 7.19-7.13 (m, 1H), 7.12-7.05 (m, 2H), 3.73 (s, 2H); MS (DCI+) M/Z 502 (M+H)+.
Reaction SMILES: [C:1]([C:3]([S:13][CH2:14][CH3:15])=[CH:4][C@@H:5]1[C@@H:7]([C:8](O)=[O:9])[C:6]1([CH3:12])[CH3:11])#[N:2].S(Cl)([Cl:18])=O>CN(C)C=O.C1(C)C=CC=CC=1>[C:1]([C:3]([S:13][CH2:14][CH3:15])=[CH:4][C@@H:5]1[C@@H:7]([C:8]([Cl:18])=[O:9])[C:6]1([CH3:12])[CH3:11])#[N:2]
Reactant: CCSC(C#N)=C[C@@H]1[C@@H](C(=O)O)C1(C)C
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCSC(C#N)=C[C@@H]1[C@@H](C(=O)Cl)C1(C)C
Temperature: 65 °C
Reaction time: 4 h
Yield: 98.9 %

Procedure:
To methyl=(1R)-trans-3-[(1EZ)-2-cyano-2-(ethylthio)ethenyl]-2,2-dimethylcyclopropanecarboxylic acid (8.98 g, 39.9 mmol), toluene (25 mL) was added and then thionyl chloride (5.0 g, 42.0 mmol) was added. Furthermore, N,N-dimethylformamide (50 mg) was added, followed by stirring at an inner temperature of 60 to 70° C. for 4 hours. The reaction mixture was concentrated under reduced pressure to obtain 9.62 g of (1R)-trans-3-[(1EZ)-2-cyano-2-(ethylthio)ethenyl]-2,2-dimethylcyclopropanecarboxylic acid chloride represented by the following formula:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([C:19]([OH:21])=[O:20])[CH:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].Cl.[CH2:23](N=C=NCCCN(C)C)C>CO.ClCCl>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([C:19]([O:21][CH3:23])=[O:20])[CH:14]=2)[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(-c2ccnc(C(=O)O)c2)cc(OC)c1OC
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cc(-c2cc(OC)c(OC)c(OC)c2)ccn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-(3,4,5-Trimethoxyphenyl)pyridine-2-carboxylic acid (587 mg) was dissolved in methanol (2 mL) and dichloromethane (8 mL), and to the solution 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (583 mg) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate. After the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure, the residue was purified by column chromatography on silica gel (chloroform:methanol=40:1) to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:30])=[C:6]([C:8]([CH3:29])([CH3:28])[CH2:9][C:10]([OH:27])([C:23]([F:26])([F:25])[F:24])[CH2:11][N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[CH:14]=[CH:13]2)[CH:7]=1.Cl[C:32]([F:38])([F:37])C(OC)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[F:37][CH:32]([F:38])[O:30][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][C:6]=1[C:8]([CH3:28])([CH3:29])[CH2:9][C:10]([OH:27])([C:23]([F:25])([F:26])[F:24])[CH2:11][N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:22])[CH:14]=[CH:13]1
Reactant: COC(=O)C(F)(F)Cl
Reactant: CC(C)(CC(O)(Cn1ccc(=O)c2ccccc21)C(F)(F)F)c1cc(F)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(CC(O)(Cn1ccc(=O)c2ccccc21)C(F)(F)F)c1cc(F)ccc1OC(F)F
Temperature: 60 °C

Procedure:
A mixture of 1-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one (0.05 g), methyl 2-chloro-2,2-difluoroacetate (0.014 mL) and cesium carbonate (0.195 g) in 1.5 mL of DMF was heated at 60° C. for 20 hours, cooled to room temperature, diluted with ethyl acetate, and washed with aqueous acetic acid, water, and brine. The residue was purified by reverse-phase HPLC using acetonitrile/water as the eluent. The product rich fractions were concentrated in vacuo and provided 1-[4-(2-difluoromethoxy-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one, m.p. 150° C.-155° C.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12])=[O:5].[CH:18](O)=[O:19]>>[Cl:17][C:14]1[CH:15]=[CH:16][C:2]([NH:1][CH:18]=[O:19])=[C:3]([CH:13]=1)[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12])=[O:5]
Reactant: O=CO
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1Cl
Product: O=CNc1ccc(Cl)cc1C(=O)c1ccccc1Cl

Procedure:
2-Amino-5,2'-dichlorobenzophenone is reacted with formic acid, whereby 5, 2'-dichloro-2-formylaminobenzophenone (pale yellow granules melting at 106° to 107° C) is obtained. The product is then reacted with hydrazine hydrate, whereby 3-amino-6-chloro-4-(2-chlorophenyl)-3,4-dihydro-4-hydroxyquinazoline (colorless granules melting at 198° C (effervescence)) is obtained. The product is reacted with chloroacetyl chloride, whereby a bis-(monochloroacetyl) derivative of 3-amino-6-chloro-4-(2-chlorophenyl)-3,4-dihydro-4-hydroxyquinazoline (colorless powdery crystals melting at 157° to 158° C) is obtained. Further, the product is treated with monochloroacetic acid in dry benzene under refluxing, whereby crystals of 2-(3-chloromethyl-s-triazol-4-yl)-5, 2'-dichlorobenzophenone are obtained. Recrystallization from chloroform-n-hexane gives colorless granules melting at 139° to 140° C. Overall yield: 34%.
Reaction SMILES: [CH3:1][C:2](=[CH2:54])[C:3]([NH:5][C:6]1[N:7]=[C:8]([CH2:51][CH2:52][CH3:53])[N:9]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[N:31](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[C:10]=1[C:11]([O-:13])=[O:12])=[O:4].Cl.[CH2:56](O)[CH3:57]>>[CH3:1][C:2](=[CH2:54])[C:3]([NH:5][C:6]1[N:7]=[C:8]([CH2:51][CH2:52][CH3:53])[N:9]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[NH:28][N:29]=[N:30][N:31]=3)=[CH:19][CH:20]=2)[C:10]=1[C:11]([O:13][CH2:56][CH3:57])=[O:12])=[O:4]
Reactant: CCO
Reactant: C=C(C)C(=O)Nc1nc(CCC)n(Cc2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)c1C(=O)[O-]
Agent: Cl
Product: C=C(C)C(=O)Nc1nc(CCC)n(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c1C(=O)OCC
Yield: 42 %

Procedure:
To 250 mg of ethyl ,4-[N-(2-methylacryloyl)amino]-2-n-propyl-1-[[2'-(N-triphenylmethyltetrazol-5-yl)biphenyl-4-yl]methyl]imidazole-5-carboxylate was added 10 mL of 2N--HCl-ethanol (1:1) and the mixture was stirred at an external temperature of 90° C. for 4 hours. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel chromatography (chloroform-methanol=20:1) and recrystallized from acetonitrile to provide 71 mg of ethyl 4-[N-(2-methylacryloyl)amino]-2-n-propyl-1-[[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-imidazole-5-carboxylate (yield 42%).
Reaction SMILES: [Na].Cl.[C:3]1([CH3:11])[CH:8]=[CH:7][CH:6]=[C:5]([NH:9][NH2:10])[CH:4]=1.C(O[CH2:15][CH2:16][C:17]#[N:18])C>C(O)C>[NH2:18][C:17]1[CH2:16][CH2:15][N:9]([C:5]2[CH:4]=[C:3]([CH3:11])[CH:8]=[CH:7][CH:6]=2)[N:10]=1
Reactant: CCOCCC#N
Reactant: Cc1cccc(NN)c1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: Cc1cccc(N2CCC(N)=N2)c1
Reaction time: 0.08 h

Procedure:
A 2.8 g. amount of sodium metal is dissolved in 100 ml. of absolute ethanol, then 15.8 g. of m-tolylhydrazine hydrochloride is added followed in 5 minutes by 9.9 g. of β-ethoxypropionitrile. The reaction mixture is refluxed for 16 hours, then is evaporated to dryness in vacuo. Water is added and the precipitate is collected by filtration. The solid is dissolved in dichloromethane and is passed through a short column of a hydrous magnesium silicate. The column effluent is refluxed on a steam bath with the gradual addition of hexane to crystallize a product. The mixture is cooled and filtered to give 10.1 g. of the product of the Example as colorless crystals, m.p. 119°-120° C.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]2[CH2:15][CH2:14][CH2:13][CH2:12][C:8]=2[S:9][C:10]=1[NH2:11])=[O:5])C.[CH3:16][O:17][CH2:18][C:19]#[N:20]>O1CCOCC1.Cl>[CH3:16][O:17][CH2:18][C:19]1[N:20]=[C:4]([OH:5])[C:6]2[C:7]3[CH2:15][CH2:14][CH2:13][CH2:12][C:8]=3[S:9][C:10]=2[N:11]=1
Reactant: CCOC(=O)c1c(N)sc2c1CCCC2
Reactant: COCC#N
Agent: Cl
Solvent: C1COCCO1
Product: COCc1nc(O)c2c3c(sc2n1)CCCC3
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a stirred mixture of 2-Amino-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic acid ethyl ester (2.0 g, 0.0088 mol) and methoxyacetonitrile (1.3 ml, 0.0177 mol) in 1,4-dioxane (200 nml), dry HCl gas was purged for 30-45 minutes at 0-5° C. The reaction mixture was then warmed to room temperature and stirred for about 20 h under inert atmosphere. After completion of the reaction, the mixture was quenched with the addition of crushed ice (˜200 g). The aqueous layer was then extracted well with ethyl acetate (2×250 ml). Combined organic layers was washed with brine solution (100 ml) dried over anhydrous Na2SO4 and concentrated under vacuum to get crude 2-Methoxymethyl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-ol as brown colored solid which was forwarded as such for the next step. Yield: (2 g, 90%); 1H NMR (400 MHz, DMSO) δ ppm=12.27 (s, 1H), 4.28 (s, 2H), 3.31 (s, 3H), 2.87-2.84 (m, 2H), 2.74-2.71 (m, 2H), 1.81-1.73 (m, 4H); LCMS: [M+H]=251.1.