Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=3)[O:11][C:10](=[O:20])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].CN(C)C=O.[CH2:32](Br)[CH2:33][CH3:34]>C(#N)C>[CH2:32]([O:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=3)[O:11][C:10](=[O:20])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1)[CH2:33][CH3:34]
Reactant: CCCBr
Reactant: COc1ccc2c(-c3cccc(O)c3)cc(=O)oc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCCOc1cccc(-c2cc(=O)oc3cc(OC)ccc23)c1
Temperature: 98.5 °C
Reaction time: 21 h

Procedure:
4-[3′-(hydroxy)phenyl]-7-methoxycoumarin (1.78 kg) and K2CO3 (1.65 kg) were suspended in acetonitrile (7.20 L) and N,N-dimethylformamide (1.80 L) and the mechanically stirred mixture was heated to 65° C. When the reaction had reached 65° C., neat n-propylbromide (1.48 kg) was added and the mixture was stirred another 21 hours. The slurry was heated to 88-109° C. and concentrated by distillation. When 6.8-7.0 L of distillate had been removed, the slurry was cooled to 40° C. and diluted with water (14.4 L) and stirred while cooling slowly to 20° C. The slurry was filtered to collect the title compound as a pink, amorphous solid, which was washed with water (2.0 L). The air-dried product was recrystallized from a mixture of hexanes (11.9 L) and isopropanol (6.2 L) at 50° C. Filtration at 22° C. gave a very pale pink, crystalline solid which was washed with hexanes (250 mL) and air-dried. Weight=1.70 kg (5.58 mol, 83%). A second crop of product was isolated from the partially concentrated mother liquors; the light pink, crystalline solid weighed 307 g (0.989 mol, 15%).
Reaction SMILES: [NH2:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])[CH:9]=[C:10](Br)[C:5]=2[NH:4][N:3]=1.[CH3:20][N:21]1[CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=[N:22]1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[NH2:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])[CH:9]=[C:10]([C:24]3[CH:23]=[N:22][N:21]([CH3:20])[CH:25]=3)[C:5]=2[NH:4][N:3]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1ccccc1-n1cc(Br)c2[nH]nc(N)c2c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccccc1-n1cc(-c2cnn(C)c2)c2[nH]nc(N)c2c1=O
Temperature: 140 °C
Yield: 11.5 %

Procedure:
A mixture of 3-amino-7-bromo-5-(2-methylphenyl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one obtained in Step F of Example 1 (200 mg), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (196 mg), tetrakis(triphenylphosphine)palladium(0) (72.4 mg), aqueous sodium carbonate solution (2 M, 0.630 mL) and N,N-dimethylformamide (3.0 mL) was heated with microwave irradiation at 140° C. for 3 hr. The reaction mixture was cooled to room temperature, and poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (methanol/dichloromethane) to give the title compound (23.0 mg).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH:15][CH2:16][CH2:17][CH2:18][OH:19])=[N:12][O:13][N:14]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:26][C:27]1[CH:36]=[CH:35][C:30]([C:31](=[O:34])[CH2:32]Br)=[CH:29][CH:28]=1>CN(C=O)C.C(OCC)(=O)C>[Cl:26][C:27]1[CH:36]=[CH:35][C:30]([C:31](=[O:34])[CH2:32][N:3]2[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:1]=[C:2]2[C:10]2[C:11]([NH:15][CH2:16][CH2:17][CH2:18][OH:19])=[N:12][O:13][N:14]=2)=[CH:29][CH:28]=1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: OCCCNc1nonc1-c1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Cn1c(-c2nonc2NCCCO)nc2ccccc21)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of 4-(1H-benzimidazol-2-yl)-furazan-3-yl-N-(3-hydroxypropyl)-amine (0.70 g, 0.27 mmol), potassium carbonate (0.472 g, 3.42 mmol) and 4-chlorophenacyl bromide (0.069 g, 0.29 mmol) in DMF (5 ml) is stirred at room temperature for 16 hours. The reaction mixture is diluted with ethyl acetate, washed with water and dried over sodium sulphate. Filtration of the sodium sulphate, concentration of the filtrate under reduced pressure and chromatography of the residue on silicagel using hexane-ethyl acetate as eluent gives the title compound as a yellowish solid, m.p. 166-169° C.
Reaction SMILES: N1C=CN=[C:2]1[NH:6][C:7]([C:9]1[C:17]2[N:16]=[C:15]([NH:18][C:19]([C:21]3[N:22]=[CH:23][C:24]4[C:29]([CH:30]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)=[O:20])[NH:14][C:13]=2[CH:12]=[CH:11][CH:10]=1)=[O:8].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[F:64][C:65]1[CH:73]=[CH:72][C:68]([CH2:69]NC)=[CH:67][CH:66]=1>CN(C=O)C>[F:64][C:65]1[CH:73]=[CH:72][C:68]([CH2:69][N:6]([CH3:2])[C:7]([C:9]2[C:17]3[NH:16][C:15]([NH:18][C:19]([C:21]4[N:22]=[CH:23][C:24]5[C:29]([CH:30]=4)=[CH:28][CH:27]=[CH:26][CH:25]=5)=[O:20])=[N:14][C:13]=3[CH:12]=[CH:11][CH:10]=2)=[O:8])=[CH:67][CH:66]=1
Reactant: CNCc1ccc(F)cc1
Reactant: O=C(Nc1nc2c(C(=O)Nc3ncc[nH]3)cccc2[nH]1)c1cc2ccccc2cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(Cc1ccc(F)cc1)C(=O)c1cccc2nc(NC(=O)c3cc4ccccc4cn3)[nH]c12
Temperature: 70 °C
Reaction time: 0.08 h
Yield: 66.2 %

Procedure:
To a solution of 100 mg (0.3 mmol) of 2-[(isoquinoline-3-carbonyl)-amino]-3H-benzoimidazole-4-carboxylic acid (from Example 58) in DMF (2 mL) was added 200 mg (0.53 mmol) of HBTU and DIEA (0.5 mL). The mixture was stirred for 5 min then 140 mg (1.0 mmol) of N-(4-fluoro-benzyl)-N-methyl-amine was added. The resulted reaction mixture was heated at 70° C. for 1 h. After usual workup as described in general procedure A, the residue was purified by column chromatography eluting with DCM/EtOAc (v/v=1:1) to afford the 90 mg (66%) of isoquinoline-3-carboxylic acid {7-[(4-fluoro-benzyl)-methyl-carbamoyl]-1H-benzoimidazol-2-yl}-amide. LCMS: 454 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][N:5]1[CH2:11][C:10]([C:12](C)(C)[O:13][SiH2]C(C)(C)C)=[CH:9][CH2:8][CH:7]([NH:21]C(OC(C)(C)C)=O)[C:6]1=[O:29].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:30])[CH2:4][N:5]1[CH2:11][C:10]([CH2:12][OH:13])=[CH:9][CH2:8][CH:7]([NH2:21])[C:6]1=[O:29]
Reactant: COC(=O)CN1CC(C(C)(C)O[SiH2]C(C)(C)C)=CCC(NC(=O)OC(C)(C)C)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CN1CC(CO)=CCC(N)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of [3-tert-Butoxycarbonylamino-6-(tert-butyl-dimethyl-silanyloxymethyl)-oxo-2,3,4,7-tetrahydro-azepin-1-yl]-acetic acid methyl ester, 17, (4.32 g, 9.7 mmol) in CH2Cl2 (20 mL) is treated with wet TFA (5 mL) and stirred at rt for 30 min. The solution is concentrated in vacuo using toluene to azeotrope off the solvent. The crude product is used without further purification.
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([NH2:9])[N:6]=[C:5]([NH2:10])[C:4]=1[N:11]1[CH2:16][CH2:15][N:14](CC2C=CC=CC=2)[CH2:13][CH2:12]1)[CH3:2].[H][H]>C(O)(=O)C.[Pd]>[CH2:1]([C:3]1[N:8]=[C:7]([NH2:9])[N:6]=[C:5]([NH2:10])[C:4]=1[N:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]1)[CH3:2]
Reactant: CCc1nc(N)nc(N)c1N1CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: CCc1nc(N)nc(N)c1N1CCNCC1
Yield: 79.9 %

Procedure:
A solution of 33.5 g (0.107 mole) of 6-ethyl-5-[4-(phenylmethyl)-1-piperazinyl]-2,4-pyrimidinediamine in 400 ml of acetic acid was hydrogenated over 2 g of 20% palladium on charcoal under 3.5 atmospheres of hydrogen for 23 hours and filtered. The filtrate was concentrated in vacuo to dryness. The solid residue was poured into one liter of 2N sodium hydroxide solution. The solid was collected and washed with 500 ml of water. Recrystallization from acetonitrile and drying in vacuo at 59° C. for 16 hours gave 19.0 g of the product as a white solid; mp 204°-207° C.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([O:6][C:7]1[CH:12]=[C:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[Cl:24])[CH:10]=[CH:9][C:8]=1[C:25]#[N:26])[CH3:5].O.[NH3:29]>C1C=CC=CC=1>[C:25]([C:8]1[CH:9]=[CH:10][C:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:16][C:15]=2[Cl:24])=[CH:12][C:7]=1[O:6][CH:4]([CH3:5])[C:3]([NH2:29])=[O:2])#[N:26]
Reactant: N
Reactant: COC(=O)C(C)Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1C#N
Solvent: c1ccccc1
Solvent: O
Product: CC(Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1C#N)C(N)=O
Temperature: 0 °C
Yield: 57.1 %

Procedure:
A 10 g of methyl-α-[2-cyano-5-(2-chloro-4-trifluoromethyl phenoxy)phenoxy]propionate was dissolved in 20 ml of benzene. The solution was cooled at 0° C. and 10 g of 28% ammonia water was added dropwise to react them at room temperature for 2 hours. After the reaction, the benzene phase was separated and was washed with water. The benzene was distilled off and the product was recrystallized from methanol to obtain 5.5 g of the object compound having a melting point of 134° to 137° C.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH2:16]([O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[C:32](O)(=[O:37])[CH:33]([CH2:35][OH:36])[OH:34].ON1C2C=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C>[CH2:16]([O:23][C:24]1[CH:25]=[CH:26][C:27]([CH2:28][NH:29][C:35](=[O:36])[CH:33]([CH2:32][OH:37])[OH:34])=[CH:30][CH:31]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: O=C(O)C(O)CO
Reactant: CCCCCCCOc1ccc(CN)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCCCOc1ccc(CNC(=O)C(O)CO)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 28.6 %

Procedure:
Dicyclohexylcarbodiimide (160 mg) was added to a solution of 200 mg of p-heptyloxybenzylamine, 150 mg of glyceric acid (65% aqueous solution) and 110 mg of 1-hydroxybenzotriazole in 2 ml of N,N-dimethylformamide. The reaction mixture was stirred at room temperature for 16 hours, then diluted with ethyl acetate, washed in sequence with saturated aqueous solution of sodium hydrogen carbonate, water and saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by preparative silica gel thin layer chromatography to give 80 mg of N-(p-heptyloxybenzyl)glyceramide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][CH2:13][CH:14]([C:18]2([CH2:32][CH:33]([CH3:35])[CH3:34])[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]2=[O:31])[C:15]([OH:17])=O)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.CN1CCOCC1.Cl.[CH2:56]([O:63][NH2:64])[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1>C(Cl)Cl>[CH2:56]([O:63][NH:64][C:15](=[O:17])[CH:14]([CH2:13][NH:12][S:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)(=[O:11])=[O:10])[C:18]1([CH2:32][CH:33]([CH3:34])[CH3:35])[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]1=[O:31])[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1
Reactant: NOCc1ccccc1
Reactant: COc1ccc(S(=O)(=O)NCC(C(=O)O)C2(CC(C)C)CCN(CCc3ccccc3)C2=O)cc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COc1ccc(S(=O)(=O)NCC(C(=O)NOCc2ccccc2)C2(CC(C)C)CCN(CCc3ccccc3)C2=O)cc1
Temperature: 25 °C
Reaction time: 65 h
Yield: 108.4 %

Procedure:
A solution of α-[[[(4-methoxyphenyl)sulfonyl]amino]methyl]-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetic acid (290 mg, 0.577 mmol) in dry CH2Cl2 (5 mL) is treated with CDI (112 mg, 0.692 mmol). Afar 1 h, 4-methylmorpholine (0.095 mL, 0.866 mmol) and O-benzylhydroxyamine HCl (138 mg, 0.866 mmol) are added. The solution is stirred at room temperature under N2 for 65 h. The solvent had evaporated, and the residual gel is diluted with EtOAc (25 mL). The solution is washed with 1N HCl (10 mL), 1N NaOH (10 mL), and brine (10 mL). The organic layer is dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to give 380 mg of an oil. The oil is purified by silica gel chromatography (30 g SG; 50% EtOAc/hexane) to provide 249 mg (71%) of the title compound as an oil:
Reaction SMILES: Cl.Cl.[CH3:3][CH:4]1[CH2:9][N:8]([C:10]2[N:15]=[N:14][C:13]([NH:16][NH2:17])=[CH:12][CH:11]=2)[CH2:7][CH:6]([CH3:18])[O:5]1.C([O-])(=O)C.[Na+].[CH3:24][C:25](=O)[CH2:26][CH2:27][C:28](=O)[CH3:29]>C(O)(=O)C>[CH3:3][CH:4]1[CH2:9][N:8]([C:10]2[N:15]=[N:14][C:13]([NH:16][N:17]3[C:28]([CH3:29])=[CH:27][CH:26]=[C:25]3[CH3:24])=[CH:12][CH:11]=2)[CH2:7][CH:6]([CH3:18])[O:5]1
Reactant: CC(=O)CCC(C)=O
Reactant: CC1CN(c2ccc(NN)nn2)CC(C)O1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1ccc(C)n1Nc1ccc(N2CC(C)OC(C)C2)nn1

Procedure:
The compound is prepared according to the procedure of example 2 by contacting 3.8 g (12.8 m moles) of 6-(2,6-dimethyl-morpholino)-3-hydrazino-pyridazine dihydrochloride (prepared according to the procedure described in U.K. Pat. No. 1.157.642; m.p. 217°-220° C.), 2.2 g (25.6 m moles) of sodium acetate and 1.61 g (14.1 m moles) of 2,5-hexanedione in 20 ml of acetic acid. The yield is 1.8 g (47%) of the product of the title which melts at 147°-148° C. when crystallized from ethyl ether.
Reaction SMILES: C([O:4][C:5](=[O:7])[CH3:6])(=O)C.O[N:9]=[C:10]1[C:24]2[C:25]3[C:20]([CH:21]=[CH:22][N:23]=2)=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]2[C:11]1=[CH:12][CH:13]=[CH:14]2>N1C=CC=CC=1>[C:5]([O:4][N:9]=[C:10]1[C:24]2[C:25]3[C:20]([CH:21]=[CH:22][N:23]=2)=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]2[C:11]1=[CH:12][CH:13]=[CH:14]2)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: ON=c1c2nccc3cccc(c32)n2cccc12
Solvent: c1ccncc1
Product: CC(=O)ON=c1c2nccc3cccc(c32)n2cccc12
Temperature: 10 °C
Reaction time: 0.08 h

Procedure:
Acetic anhydride (20 cc.) is added, over the course of 5 minutes, to a stirred suspension of 7-hydroxyimino-7H-indolizino[5,6,7-ij]isoquinoline (10 g.) in pyridine (100 cc.) kept at between 8° and 10° C. A brown solution is thus obtained. After stirring for 5 minutes at 10° C., the acetic acid ester crystallises. The mixture is kept at ambient temperature for a further 2 hours and then water (600 cc.) is added. The ochre-yellow crystals thus obtained are filtered off and washed copiously with water. After drying, 7-acetyloxyimino-7H-indolizino[5,6,7-ij]isoquinoline (11.0 g.), melting at 177°-179° C. with decomposition, is obtained.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4].[C:21]([CH2:29][NH:30][CH2:31][CH2:32][CH2:33][CH:34]1[CH2:39][CH2:38][CH2:37][NH:36][CH2:35]1)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:21]([CH2:29][NH:30][CH2:31][CH2:32][CH2:33][CH:34]1[CH2:39][CH2:38][CH2:37][N:36]([CH2:2][C:3]([N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9](=[O:16])[NH:8][C:7]3[CH:17]=[CH:18][CH:19]=[N:20][C:6]2=3)=[O:4])[CH2:35]1)(=[O:28])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(CNCCCC1CCCNC1)c1ccccc1
Reactant: O=C1Nc2cccnc2N(C(=O)CCl)c2ccccc21
Product: O=C(CNCCCC1CCCN(CC(=O)N2c3ccccc3C(=O)Nc3cccnc32)C1)c1ccccc1

Procedure:
Prepared analogously to Example 8 from 11-(chloroacetyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]-benzodiazepin-6-one and 3-[3-[(benzoyl)methylamino]-propyl]piperidine. Purification is carried out by chromatography on silica gel using a mixture of methylene chloride/methanol=99:1 as eluant.
Reaction SMILES: CO[CH:3]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)[C:4]([O:6][CH3:7])=[O:5].[CH2:18]([SH:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>C(Cl)Cl.S(=O)(=O)(O)O>[CH2:18]([S:24][CH:3]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)[C:4]([O:6][CH3:7])=[O:5])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: COC(=O)C(OC)c1ccc(OC)c(OC)c1
Reactant: CCCCCCS
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CCCCCCSC(C(=O)OC)c1ccc(OC)c(OC)c1
Reaction time: 0.5 h

Procedure:
To a stirred solution of methyl α-methoxy-3,4-dimethoxyphenylacetate (0.39 g) in methylene chloride (5 ml) were added hexanethiol (0.35 ml) and 3 drops of concentrated sulfuric acid and the mixture was stirred for 30 minutes. Then it was washed with water and brine, dried (magnesium sulfate) and evaporated to give an oily residue. Purification by column chromatography on silica gel with elution by 1:9 ethyl acetate-hexane provided methyl α-hexylthio-3,4-dimethoxyphenylacetate (0.37 g), a compound of Formula 4 wherein X is S, R5 is 3,4-dimethoxyphenyl and R7 is hexyl.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[NH2:18][N:19]1[CH2:24][CH2:23][CH2:22][O:21][C:20]1=[O:25]>>[O:25]=[C:20]1[N:19]([NH:18][C:15]([C:7]2[CH:6]=[CH:5][C:4]([CH:1]3[CH2:2][CH2:3]3)=[C:9]([O:10][CH2:11][CH:12]3[CH2:13][CH2:14]3)[N:8]=2)=[O:17])[CH2:24][CH2:23][CH2:22][O:21]1
Reactant: NN1CCCOC1=O
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Product: O=C(NN1CCCOC1=O)c1ccc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and 3-aminotetrahydro-2H-1,3-oxazin-2-one (CAN 54924-47-9) as starting materials; LC-MS (UV peak area/ESI) 98.7%, 332.1612 (M+H)+.
Reaction SMILES: N[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].N([O-])=[O:13].[Na+].C(=O)(O)[O-].[Na+]>S(=O)(=O)(O)O.O>[F:9][C:8]([F:11])([F:10])[C:7]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[OH:13]
Reactant: O=N[O-]
Reactant: Nc1cnccc1C(F)(F)F
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Oc1cnccc1C(F)(F)F
Reaction time: 0.5 h
Yield: 95.4 %

Procedure:
A solution of 2 g (12.34 mmol) of 3-amino-4-(trifluoromethyl)pyridine in 28 ml of 50% sulfuric acid is cooled to −5° C. and a solution of 1.03 g (14.8 mmol) of sodium nitrite in 10 ml of water is added slowly. The mixture is left to return to room temperature and stirring is continued for 30 min. 25 ml of concentrated sulfuric acid are then added and the reaction mixture is stirred at 100-110° C. for 2 hours. After cooling, the reaction medium is neutralized by adding saturated sodium bicarbonate solution to pH 6-7, and the mixture is extracted with ethyl acetate. The organic phase obtained is washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give 1.92 g of the expected compound in the form of a brown powder (yield=95%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[NH:8][C:9](=O)[C:10]3[CH:15]=[CH:14][S:13][C:11]=3[N:12]=2)[CH:2]=1.N.O.O=P(Cl)(Cl)[Cl:21]>>[Cl:21][C:9]1[C:10]2[CH:15]=[CH:14][S:13][C:11]=2[N:12]=[C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c(-c2cccnc2)nc2sccc12
Agent: N
Solvent: O
Product: Clc1nc(-c2cccnc2)nc2sccc12
Temperature: 120 °C
Reaction time: 10 h

Procedure:
The suspension of 2-(pyridin-3-yl)thieno[2,3-d]pyrimidin-4(3H)-one (6.0 g, containing salts) in POCl3 (30 ml.) was stirred at 120° C. for 10 h. After the reaction was completed, the mixture was added to ice-water slowly. The pH was adjusted to ˜7 by slowly adding NH3.H2O at 0° C., then a precipitate formed. The solid was collected and 540 mg of 4-chloro-2-(pyridin-3-yl)thieno[2,3-d]pyrimidine was obtained as a brown solid, LCMS m/z=247.9, 250.0 (M+1) (Method B) (retention time=1.85 min).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:23][CH3:24])[C:4]1[C:13]([CH2:14][N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][C:16]2=[O:22])=[CH:12][C:11]2[CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[N:5]=1.[Si](OCC1C=C2C(=NC=1C(OC)OC)N([C:49]([O:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:50])CCC2)(C(C)(C)C)(C)C>>[CH3:1][O:2][CH:3]([O:23][CH3:24])[C:4]1[N:5]=[C:6]2[C:11]([CH2:10][CH2:9][CH2:8][N:7]2[C:49]([O:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)=[O:50])=[CH:12][C:13]=1[CH2:14][N:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][C:16]1=[O:22]
Reactant: COC(OC)c1nc2c(cc1CO[Si](C)(C)C(C)(C)C)CCCN2C(=O)Oc1ccccc1
Reactant: COC(OC)c1nc2c(cc1CN1CCN(C)CC1=O)CCCN2
Product: COC(OC)c1nc2c(cc1CN1CCN(C)CC1=O)CCCN2C(=O)Oc1ccccc1

Procedure:
From intermediate 81, synthesized in an analogous manner to intermediate 38, the title compound was obtained as a light yellow oil. (UPLC-MS 6) tR 0.73; ESI-MS 455.3 [M+H]+.
Reaction SMILES: C([NH:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([C:12](=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16]Cl)=[C:7]([O:19][CH2:20][C:21]2[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:29][CH3:30])[CH:22]=2)[CH:6]=1)(=O)C.N1CCCCC1.[CH2:37]([CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)[CH2:38][CH3:39]>>[NH2:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([C:12](=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16][N:43]2[CH2:44][CH2:45][CH:40]([CH2:37][CH2:38][CH3:39])[CH2:41][CH2:42]2)=[C:7]([O:19][CH2:20][C:21]2[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:29][CH3:30])[CH:22]=2)[CH:6]=1
Reactant: CCCC1CCNCC1
Reactant: COc1cc(COc2cc(NC(C)=O)c(Cl)cc2C(=O)CCCCCl)cc(OC)c1
Solvent: C1CCNCC1
Product: CCCC1CCN(CCCCC(=O)c2cc(Cl)c(N)cc2OCc2cc(OC)cc(OC)c2)CC1

Procedure:
Proceeding as in Example 4, Step (c), but replacing 1-(4-acetylamino-5-chloro-2-methoxyphenyl)-5-chloropentan-1-one with 1-[4-acetylamino-5-chloro-2-(3,5-dimethoxybenzyloxy)phenyl]-5-chloropentan-1-one and piperidine with 4-(prop-1-yl)piperidine, gave 1-[4-amino-5-chloro-2-(3,5-dimethoxybenzyloxy)-phenyl]-5-[4-(prop-1-yl)piperidin-1-yl]pentan-1-one, m.p. 119-120° C.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15].[CH3:16][O:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][C:19]=1[C:27]([F:30])([F:29])[F:28]>>[CH3:16][O:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([N:2]([CH3:1])[C:3]2[CH:4]=[N:5][CH:6]=[CH:7][C:8]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])=[O:24])=[CH:20][C:19]=1[C:27]([F:30])([F:29])[F:28]
Reactant: COc1ccc(C(=O)O)cc1C(F)(F)F
Reactant: CNc1cnccc1-c1ccccc1C
Product: COc1ccc(C(=O)N(C)c2cnccc2-c2ccccc2C)cc1C(F)(F)F

Procedure:
The title compound was prepared in analogy to example 90, from N-methyl-4-o-tolylpyridin-3-amine (example 1, intermediate a) and 4-methoxy-3-(trifluoromethyl)benzoic acid (CAS RN 213598-09-5) after a reaction time of 88 hours. Brown solid (4%). MS (ESI): m/z=401.15 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([Li])CCC.CN(C)[CH:20]=[O:21]>O1CCCC1>[CH:1]1([CH2:7][N:8]2[C:12]([CH:20]=[O:21])=[CH:11][CH:10]=[N:9]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN(C)C=O
Reactant: c1cnn(CC2CCCCC2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1ccnn1CC1CCCCC1
Temperature: -78 °C
Yield: 67.6 %

Procedure:
To a solution of pyrazole (1.00 g, 14.7 mmol) in of dimethylformamide (10=L) was added sodium hydride (60% oil dispersion, 450 mg, 11 mmol). After 5 min bromomethylcyclohexane (2.4 mL, 17 mmol) was added by syringe and the mixture was maintained overnight. The reaction mixture was quenched with methanol, diluted with water, and extracted with ether (2×). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residue was purified by chromatography (95/5 hexanes/ethyl acetate) to provide 500 mg (27%) of 1-cyclohexylmethyl-1H-pyrazole. To a solution of 1-cyclohexylmethyl-1H-pyrazole (490 mg, 3.00 mmol) in tetrahydrofuran (10 mL) at −78° C. was added a 2.5 M solution of n-butyllithium in hexanes (1.5 mL, 3.8 mmol). The reaction mixture was maintained at −78° C. for 1 h and was treated with dimethylformamide (1.0 mL, 13 mmol). The reaction mixture was allowed to warm to rt, maintained overnight, and was quenched with methanol. The reaction mixture was diluted with water and was extracted with ether (2 x). The combined organic layers were died over magnesium sulfate and concentrated in vacuo. The residue was purified by chromatography (95/5 hexanes/ethyl acetate) to provide 390 mg (68%) of 2-cyclohexylmethyl-2H-pyrazole-3-carbaldehyde.