Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]([CH2:29][CH3:30])[CH:16]2[CH2:25][CH2:24][C:23]3[C:18](=[CH:19][C:20]([N+:26]([O-])=O)=[CH:21][CH:22]=3)[CH2:17]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]([CH:16]2[CH2:25][CH2:24][C:23]3[C:18](=[CH:19][C:20]([NH2:26])=[CH:21][CH:22]=3)[CH2:17]2)[CH2:29][CH3:30])[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: [H][H]
Reactant: CCN(CC1CCN(C(=O)OC(C)(C)C)CC1)C1CCc2ccc([N+](=O)[O-])cc2C1
Agent: [Pd]
Solvent: CCO
Product: CCN(CC1CCN(C(=O)OC(C)(C)C)CC1)C1CCc2ccc(N)cc2C1
Yield: 87.1 %

Procedure:
To a solution of 4-{[ethyl-(7-nitro-1,2,3,4-tetrahydro-naphthalen-2-yl)-amino]-methyl}-piperidine-1-carboxylic acid tert-butyl ester (490 mg, 1.2 mmol) in ethanol (30 mL) was added 10% palladium on charcoal (50 mg). The solution was shaken on a Parr shaker for 24 h at 55 psi of hydrogen. The solution was filtered through Celite® and concentrated to afford 4-{[(7-amino-1,2,3,4-tetrahydro-naphthalen-2-yl)-ethyl-amino]-methyl}-piperidine-1-carboxylic acid tert-butyl ester as an oil (405 mg) which was used directly.
Reaction SMILES: [C:1]([O:5][SiH:6]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].[CH2:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1C2NC3C(=CC=CC=3)SC=2C=CC=1>C1(C)C(C)=CC=CC=1>[C:8]([O:7][Si:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: C=Cc1ccccc1
Reactant: CC(C)(C)O[SiH](OC(C)(C)C)OC(C)(C)C
Agent: c1ccc2c(c1)Nc1ccccc1S2
Solvent: Cc1ccccc1C
Product: CC(C)(C)O[Si](C=Cc1ccccc1)(OC(C)(C)C)OC(C)(C)C
Temperature: 175 °C
Yield: 90 %

Procedure:
Into a 45 cc Parr bomb was added 2.5 g (0.02 mol) tritertbutoxysilane, 4.2 g (0.04 mol) styrene, 1.0 g xylene, 30 mg phenothiazine and 2000 ppm Ru3CO12 (20 mg). The reaction was heated in a fluidized sand bath at 175° C. for 5 hours. A single product 1-tritertbutoxysilyl-2-phenylethylene was formed in greater than 90% yield.
Reaction SMILES: C(N1CCC(=O)CC1)C1C=CC=CC=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=1.FC1C=CC(N2[C:35]3([CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)[C:34](=[O:41])[NH:33][CH2:32]2)=CC=1>>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:35]3([CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)[C:34](=[O:41])[NH:33][CH2:32]2)=[CH:19][CH:18]=1
Reactant: O=C1NCN(c2ccc(F)cc2)C12CCNCC2
Reactant: COc1ccc(N)cc1
Agent: O=C1CCN(Cc2ccccc2)CC1
Product: COc1ccc(N2CNC(=O)C23CCNCC3)cc1

Procedure:
This compound was prepared from 1-benzyl-4-piperidone and 4-methoxy-phenyl amine in analogy of the procedure described for the synthesis of 1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one. 1-(4-Methoxy-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one was obtained as colorless solid: MS (ISP): 262.1 MH+.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=[N:4]1)[CH3:2].O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:22][C:23]1[CH:24]=[C:25]([CH:42]=[CH:43][C:44]=1[CH3:45])[O:26][C:27]1[CH:28]=[CH:29][C:30]2[N:31]([CH:33]=[C:34]([NH:36][C:37]([CH:39]3[CH2:41][CH2:40]3)=[O:38])[N:35]=2)[N:32]=1>CN(C)C=O.CN(C)C(=O)C>[CH:39]1([C:37]([NH:36][C:34]2[N:35]=[C:30]3[CH:29]=[CH:28][C:27]([O:26][C:25]4[CH:42]=[CH:43][C:44]([CH3:45])=[C:23]([NH:22][C:8]([C:7]5[N:3]([CH2:1][CH3:2])[N:4]=[CH:5][CH:6]=5)=[O:10])[CH:24]=4)=[N:32][N:31]3[CH:33]=2)=[O:38])[CH2:40][CH2:41]1
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Reactant: CCn1nccc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Product: CCn1nccc1C(=O)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1C
Yield: 76 %

Procedure:
In the same manner as in Example 259 and using 1-ethyl-1H-pyrazole-5-carboxylic acid (110 mg, 0.80 mmol), tetrahydrofuran (5 mL), N,N-dimethylformamide (1 drop), oxalyl chloride (83 μL, 0.97 mmol), N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (200 mg, 0.62 mmol) and N,N-dimethylacetamide (7 mL) as starting materials, the title compound (210 mg, 75%) was obtained as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=O.S(Cl)(Cl)=O.[CH3:16][C:17]1[NH:31][C:20]2=[C:21]([NH:25][C:26]([CH:28]3[CH2:30][CH2:29]3)=[O:27])[N:22]=[CH:23][CH:24]=[C:19]2[CH:18]=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl.CO>[F:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:2]([F:1])[C:3]=1[C:4]([C:18]1[C:19]2[C:20](=[C:21]([NH:25][C:26]([CH:28]3[CH2:29][CH2:30]3)=[O:27])[N:22]=[CH:23][CH:24]=2)[NH:31][C:17]=1[CH3:16])=[O:6]
Reactant: Cc1cc2ccnc(NC(=O)C3CC3)c2[nH]1
Reactant: O=C(O)c1c(F)cccc1F
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CO
Product: Cc1[nH]c2c(NC(=O)C3CC3)nccc2c1C(=O)c1c(F)cccc1F
Temperature: 100 °C
Reaction time: 8 h
Yield: 40.9 %

Procedure:
To a solution of 2,6-difluorobenzoic acid (176 mg, 1.15 mmol) in dry dichloromethane, was added thionyl chloride (5 mL) and heated at 100° C. for about 3 hours. The reaction mass was concentrated under vacuum. The residual mass was dissolved in dry dichloromethane (3 mL) and added to a well stirred solution of N-(2-methyl-1H-pyrrolo[2,3-c]pyridin-7-yl)cyclopropanecarboxamide (120 mg, 0.55 mmol) in aluminium chloride (743 mg, 5.57 mmol) drop wise. The resulting reaction mixture was stirred overnight at room temperature. After completion, methanol (10 mL) was added cautiously to quench the reaction mass followed by concentration under vacuum. The reaction mass was diluted with water and extracted with ethyl acetate. The combined organic layer was neutralized using aq. sodium bicarbonate solution, washed with brine, dried over anhydrous sodium sulfate, and concentrated. Purification by silica gel (100-200) column chromatography using dichloromethane and methanol gradient as eluent afforded N-[3-(2,6-difluorobenzoyl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-7-yl]cyclopropanecarboxamide (80 mg, 42%).
Reaction SMILES: C(O[C:4]([C:6]1[NH:7][N:8]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[S:19]([OH:22])(=[O:21])=[O:20])[C:9](=[O:11])[CH:10]=1)=[O:5])C.[CH2:23]([CH2:25][NH2:26])[OH:24].CO>C(O)(C)C>[OH:24][CH2:23][CH2:25][NH:26][C:4]([C:6]1[NH:7][N:8]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[S:19]([OH:22])(=[O:20])=[O:21])[C:9](=[O:11])[CH:10]=1)=[O:5]
Reactant: CCOC(=O)c1cc(=O)n(Cc2ccccc2S(=O)(=O)O)[nH]1
Reactant: NCCO
Solvent: CC(C)O
Solvent: CO
Product: O=C(NCCO)c1cc(=O)n(Cc2ccccc2S(=O)(=O)O)[nH]1
Temperature: 25 °C
Yield: 86.5 %

Procedure:
A mixture of 14.5 g of (Intermediate A) and 5.3 g of ethanolamine was reacted under reduced pressure of 30 mmHg at 120° C. for 2 hours. The reaction mixture was cooled to room temperature and dissolved with an additional 30 ml of methanol. 300 ml of isopropanol was further added to the mixture to precipitate crystals. The crystals were filtered off, washed with isopropanol and dried to obtain 13 g (Yield: 86.5%) of 3-(2-hydroxyethylcarbamoyl)-1-(2-sulfobenzyl)pyrazolin-5-one.
Reaction SMILES: [NH2:1][NH2:2].O.[CH2:4]([O:6][C:7](=[O:19])[C:8](=O)[CH2:9][C:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)C>CO>[CH3:4][O:6][C:7]([C:8]1[CH:9]=[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:2][N:1]=1)=[O:19]
Reactant: CCOC(=O)C(=O)CC(=O)c1ccccc1
Reactant: NN
Solvent: CO
Solvent: O
Product: COC(=O)c1cc(-c2ccccc2)[nH]n1
Yield: 77.3 %

Procedure:
NH2—NH2—H2O (1.0 g, 20 mmol) was added to a solution of 2,4-dioxo-4-phenyl-butyric acid ethyl ester (1.94 g, 8.81 mmol) in methanol (17 mL). The resulting reaction mixture was heated to reflux for two and half hours. The methanol was evaporated and the resulting solid was heated with 2.5% ethyl acetate in hexane to afford 5-phenyl-1H-pyrazole-3-carboxylic acid methyl ester as a solid in 77.3% yield. LC-MS purity: 93.345%.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[OH:10][CH2:11][CH:12]([CH2:14]O)[OH:13].S(=O)(=O)(O)O.O>C1C=CC=CC=1>[OH:13][CH:12]1[CH2:11][O:10][CH:5]([C:4]2[CH:7]=[CH:8][CH:9]=[C:2]([CH3:1])[CH:3]=2)[O:6][CH2:14]1
Reactant: Cc1cccc(C=O)c1
Reactant: OCC(O)CO
Agent: O=S(=O)(O)O
Solvent: O
Solvent: c1ccccc1
Product: Cc1cccc(C2OCC(O)CO2)c1
Yield: 64.6 %

Procedure:
A mixture of 3-methylbenzaldehyde (24.0 g, 0.2 mole), glycerol (18.4 g, 0.2 mole) and 40% sulfuric acid (2.0 ml) in 150 ml of benzene was heated under a Dean-Stark apparatus until no more water was collected (approximately 2.5 hours). The mixture was cooled, neutralized with potassium carbonate, diluted by the addition of 200 ml of ether and the ether solution washed with water (3 × 100 ml). The organic layer was dried over magnesium sulfate and concentrated to give a residue of 25.1 g of the desired 5-hydroxy-2-(3-methylphenyl)-1,3-dioxane nD25 1.5346.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([NH:9]Cl)=O)=[CH:5][CH:4]=1.[CH:13]#[C:14][CH:15]([OH:18])[CH2:16][CH3:17].C(N(CC)CC)C.[OH2:26]>C1C=CC=CC=1>[OH:18][CH:15]([C:16]1[O:26][N:9]=[C:7]([C:6]2[CH:11]=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:17]=1)[CH2:14][CH3:13]
Reactant: COc1ccc(C(=O)NCl)cc1
Reactant: O
Reactant: C#CC(O)CC
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCC(O)c1cc(-c2ccc(OC)cc2)no1
Reaction time: 2 h

Procedure:
To a solution of 79.8 g (43 mmol) of 4-methoxybenzhydroxamic acid chloride and 7.23 g (86 mmol) of 1-pentyn-3-ol in 160 ml of benzene, a solution of 6.53 g (64.5 mmol) of triethylamine in 80 ml of benzene was added dropwise while maintaining the internal temperature at 3°-5° C. After the mixture was stirred for 2 hours, water was added so that the reaction product was extracted in the organic layer. The organic layer was separated and collected and the solvent was distilled off, whereby an oily residue was obtained. The oily residue was purified by silica gel chromatography (eluent: 30:1 chloroform/methyl alcohol), so that the title compound was obtained as yellow oil [yield: 8.07 g (81%)].
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[C:7](N1C=CN=C1)(N1C=CN=C1)=[O:8].[CH:19]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([CH3:21])[CH3:20]>ClC(Cl)C>[CH:19]([N:22]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:7]([NH:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1)=[O:8])([CH3:21])[CH3:20]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1nccs1
Reactant: CC(C)Nc1ccccc1Oc1ccccc1
Solvent: CC(Cl)Cl
Product: CC(C)N(C(=O)Nc1nccs1)c1ccccc1Oc1ccccc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 79.2 %

Procedure:
To a solution of 2-aminothiazole (0.20 g, 2.00 mmol) in dichloroethane (20 ml) was added 1,1′-carbonyldiimidazole (0.40 g, 2.5 mmol) and N,N-dimethylaminopyridine (0.05 g, 0.4 mmol) then the solution was refluxed at 80° C. for 1 h. N-Isopropyl-2-phenoxyaniline (0.46 g, 2.0 mmol) was added and the reaction mixture was then stirred overnight at 80° C. The reaction mixture was concentrated under reduced pressure to afford crude product, which was purified by silica gel chromatography (hexanes:ethyl acetate from 80:20 to 50:50 as eluent system) to afford title product (0.56 g, 79%).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11]Br)=[CH:9][CH:8]=1>C(Cl)Cl.CCOC(C)=O>[Br:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:9][CH:8]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: C1CCNC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Brc1ccc(CN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.9 %

Procedure:
Pyrrolidine (20.0 mL, 0.240 mole) was added to a stirred solution of 4-bromobenzyl bromide (10.0 g, 40.0 mmol) in anhydrous CH2Cl2 (20 mL) at 0° C. under nitrogen. The resultant solution was allowed to stir at room temperature for 1 h. The reaction mixture was diluted with EtOAc (150 mL) before it was washed with half-saturated aqueous NaHCO3 (50 mL). After drying over MgSO4, filtration, and concentration, the oily residue was chromatographed on silica [20% EtOAc in hexanes, then 10% EtOH/Et3N (2/1) in THF/hexanes (1/1)] to provide 9.02 g of the benzyl pyrrolidine (94%) as an oil.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14])[O:5][CH3:6].[NH2:16][C:17]([NH2:19])=[NH:18]>C(O)C>[ClH:13].[Cl:14][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]([Cl:13])[C:7]=1[CH:4]([O:5][CH3:6])[C:3]([NH:18][C:17]([NH2:19])=[NH:16])=[O:2]
Reactant: COC(=O)C(OC)c1c(Cl)cccc1Cl
Reactant: N=C(N)N
Solvent: CCO
Product: COC(C(=O)NC(=N)N)c1c(Cl)cccc1Cl
Product: Cl

Procedure:
The compound of Example 1b was prepared by stirring 4.0 g (0.016 mols) 2-(2,6-dichlorophenyl)-2-methoxy-acetic acid methyl ester with 0.025 mols guanidine (from 2.4 g guanidine hydrochloride and 0.6 g sodium) in 50 ml ethanol for 2 days at room temperature. After evaporation, the residue is taken up in a water/chloroform mixture, and the chloroform phase is further mixed with ethanolic hydrochloric acid. In this way, the desired hydrochloride salt is obtained. It decomposes at 242 to 243 degrees C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:13][CH2:14][CH2:15][OH:16])=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[C:5]([O:7][CH3:8])=[O:6].[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[N:25]=[C:26]=[S:27]>O1CCCC1>[Cl:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[C:3]([NH:13][CH2:14][CH2:15][OH:16])[C:2]=1[NH:1][C:26](=[S:27])[NH:25][C:19]1[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:18]=1[Cl:17]
Reactant: S=C=Nc1ccc(Cl)cc1Cl
Reactant: COC(=O)c1ccc(Cl)c(N)c1NCCO
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cl)c(NC(=S)Nc2ccc(Cl)cc2Cl)c1NCCO
Yield: 48.4 %

Procedure:
A solution of methyl 3-amino-4-chloro-2-[(2-hydroxyethyl)amino]benzoate (1.068 g, 3.16 mmol) and 2,4-dichlorophenylisothiocyanate (0.86 g, 4.21 mmol) in tetrahydrofuran (40 mL) was stirred at 50° C. for 14 hr. The reaction mixture was concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 25-70% ethyl acetate/n-hexane gradient mixture and flash chromatography on NH-silica gel eluting with a 50-100% ethyl acetate/n-hexane gradient mixture to give the title compound (686.9 mg, 1.53 mmol, 48%) as a pale orange amorphous.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[C:31]([F:34])([F:33])[F:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[CH3:78][N:79]([CH3:83])[CH2:80][CH2:81][NH2:82]>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:82][CH2:81][CH2:80][N:79]([CH3:83])[CH3:78])=[O:28])=[CH:24][C:23]=4[C:31]([F:34])([F:32])[F:33])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3C(F)(F)F)ncc21
Reactant: CN(C)CCN
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCNC(=O)c1ccc(Nc2ncc3c(n2)N(C2CCCC2)CC(F)(F)C(=O)N3C)c(C(F)(F)F)c1
Reaction time: 0.17 h
Yield: 83.2 %

Procedure:
To a mixture of 0.125 g (0.257 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-trifluoromethyl-benzoic acid (I-204) and 9 mL of dimethylformamide was added 0.0521 g (0.386 mmole) of 1-hydroxybenzotriazole, 0.146 g (0.385 mmole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 0.140 g (1.081 mmole) of diisopropylethylamine. The mixture was stirred for 10 minutes, then 0.034 g (0.385 mmole) of N,N-dimethylethylenediamine was added. The reaction mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 80 mL of ethyl acetate and washed three times with 10 mL of 1M sodium hydroxide, twice with 15 mL of brine, dried, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-80:20) gave 0.1188 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(2-dimethylamino-ethyl)-3-trifluoromethyl-benzamide (I-208) as a white solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])=[CH:10][C:9]=1[NH2:21])(C)(C)C.CC1(C)O[C:28]([C:30]2[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=2)[C:33]#[N:34])=[CH:27][C:26](=[O:38])O1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:28]([C:30]3[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=3)[C:33]#[N:34])[CH2:27][C:26](=[O:38])[NH:21][C:9]=2[CH:10]=1
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2Cl)cc1N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cccc(C2=Nc3ccc(-c4ccccc4Cl)cc3NC(=O)C2)c1

Procedure:
Prepared from (3-amino-2′-chloro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G22) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4) according to the general procedure K. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a white powder (43 mg).
Reaction SMILES: [C:1]1(=O)[CH:6]=[CH:5][C:4](=[O:7])[CH:3]=[CH:2]1.[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[SH:16]>CO>[CH:2]1[C:1]2[C:6]([S:16][C:11]3[C:10]([N:9]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:5][C:4](=[O:7])[CH:3]=1
Reactant: Nc1ccccc1S
Reactant: O=C1C=CC(=O)C=C1
Solvent: CO
Product: O=c1ccc2nc3ccccc3sc-2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.7 %

Procedure:
To a stirring suspension of 1.72 kg (16 mol) of p-benzoquinone in 13 liters MeOH at room temperature was added slowly a solution of 1.0 kg (8 mol) of 2-aminothiophenol in 600 ml MeOH over a period of 1 hour. The resulting red mixture was stirred at room temperature for another 2 hours and then the product 3H-phenothiazin-3-one was filtered off. This 3H-phenothiazin-3-one was washed thoroughly with methanol and dried to give 1.07 kg of 3H-phenothiazin-3-one (61.49% yield), m.p. 157°-159° C.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].C(O)C.C(N(CC)CC)C.Cl.[CH3:29][O:30][NH2:31]>C(OCC)(=O)C>[N+:15]([C:3]1[CH:4]=[C:5]([C:11]([F:14])([F:13])[F:12])[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[NH:31][O:30][CH3:29])([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cc([N+](=O)[O-])c1Cl
Reactant: CON
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: CCOC(C)=O
Product: CONc1c([N+](=O)[O-])cc(C(F)(F)F)cc1[N+](=O)[O-]
Reaction time: 1.5 h

Procedure:
To a solution prepared from 27.0 g. (0.1 mole) of 4-chloro-3,5-dinitrobenzotrifluoride in 200 ml. of ethanol there was added 25.25 g. (0.25 mole) of triethylamine, and 12.5 g. (0.15 mole) of methoxyamine hydrochloride. Upon the addition of the methoxyamine hydrochloride, the temperature of the reaction mixture rose to about 50° C. The reaction mixture was allowed to stir for about 1.5 hours and the reaction product mixture was worked up by diluting it with ethyl acetate, washing several times with dilute hydrochloric acid and water, and drying the organic layer over anhydrous magnesium sulfate. The drying agent was filtered off and the filtrate concentrated on the steam bath to leave a residue. The residue was allowed to chill over the weekend in the refrigerator and crystals separated. The crystalline product was filtered off. It had a melting point of about 135°-137° C., weighed 21.0 g., and was identified by NMR spectrum and elemental analyses as 2,6-dinitro-N-methoxy-α,α,α-trifluoro-p-toluidine.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([C:13](=[O:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[C:11]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)[C:10]2[C:5](=[CH:6][C:7]([O:32][CH3:33])=[C:8]([O:30][CH3:31])[CH:9]=2)[N:4]=1.[SH:34][C:35]1[N:36]([CH3:40])[CH:37]=[CH:38][N:39]=1>>[CH3:29][O:28][C:22]1[CH:21]=[C:20]([C:11]2[C:10]3[C:5](=[CH:6][C:7]([O:32][CH3:33])=[C:8]([O:30][CH3:31])[CH:9]=3)[N:4]=[C:3]([CH2:2][S:34][C:35]3[N:36]([CH3:40])[CH:37]=[CH:38][N:39]=3)[C:12]=2[C:13](=[O:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:25]=[CH:24][C:23]=1[O:26][CH3:27]
Reactant: Cn1ccnc1S
Reactant: CCCCCC(=O)c1c(CBr)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Product: CCCCCC(=O)c1c(CSc2nccn2C)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1

Procedure:
According to the same manner as that described in Example 4, 2-bromomethyl-4-(3,4-dimethoxyphenyl)-3-hexanoyl-6,7-dimethoxyquinoline was reacted with 2-mercapto-1-methylimidazole to give 4-(3,4-dimethoxyphenyl)-3-hexanoyl-6,7-dimethoxy-2-[(1-methylimidazol-2-yl)thiomethyl]quinoline. This compound was recrystallized from ethanol to give colorless prisms. mp. 128°-129° C.
Reaction SMILES: CO[C:3]1[CH:4]([CH3:11])[CH2:5][CH2:6][CH2:7][CH:8]([CH3:10])[N:9]=1.[Cl-:12].[NH4+:13]>CO.C(Cl)Cl>[ClH:12].[CH3:11][CH:4]1[CH2:5][CH2:6][CH2:7][CH:8]([CH3:10])[NH:9][C:3]1=[NH:13]
Reactant: [Cl-]
Reactant: COC1=NC(C)CCCC1C
Reactant: [NH4+]
Solvent: ClCCl
Solvent: CO
Product: CC1CCCC(C)C(=N)N1
Product: Cl
Yield: 104.1 %

Procedure:
The product of EXAMPLE 40 (380 mg, 2.4 mmol) in 15 mL of MeOH and 5 mL of CH2Cl2 was reacted with ammonium chloride (104 mg, 2.0 mmol) by the method of EXAMPLE 27 to yield 368 mg (100%) of the title material.
Reaction SMILES: [CH:1]1([CH2:4][O:5][CH2:6][C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][N:15]=2)[C:10]([OH:12])=O)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:49]1[CH2:54][CH2:53][O:52][CH2:51][CH:50]1[C:55]1[C:63]2[S:62][C:61]([NH2:64])=[N:60][C:59]=2[C:58]([O:65][CH3:66])=[CH:57][CH:56]=1>C1COCC1.C(Cl)(Cl)Cl>[CH:1]1([CH2:4][O:5][CH2:6][C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][N:15]=2)[C:10]([NH:64][C:61]2[S:62][C:63]3[C:55]([CH:50]4[CH2:51][O:52][CH2:53][CH2:54][O:49]4)=[CH:56][CH:57]=[C:58]([O:65][CH3:66])[C:59]=3[N:60]=2)=[O:12])[CH2:2][CH2:3]1
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Reactant: O=C(O)c1ccnc(COCC2CC2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccnc(COCC4CC4)c3)nc12

Procedure:
From 2-cyclopropylmethoxymethyl-isonicotinic acid, HATU and N-ethyldiisopropylamine in THF, then treatment with (+)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine. [α]D20=+6.7° (c=1.04, CHCl3), ES-MS m/e (%): 456 (M+H+, 100).
Reaction SMILES: [F:1][C:2]([F:39])([C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][OH:38])=[CH:29][CH:28]=1)[O:3][C:4]1[CH:25]=[CH:24][C:7]([O:8][C:9]([F:23])([F:22])[C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21])=[CH:12][CH:11]=2)=[C:6]([CH3:26])[CH:5]=1.[C:40](Cl)(=[O:44])[C:41]([CH3:43])=[CH2:42]>>[C:40]([O:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][C:30]1[CH:31]=[CH:32][C:27]([C:2]([O:3][C:4]2[CH:25]=[CH:24][C:7]([O:8][C:9]([C:10]3[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:2](=[O:3])[C:27]([CH3:32])=[CH2:28])=[CH:14][CH:15]=3)([F:22])[F:23])=[C:6]([CH3:26])[CH:5]=2)([F:39])[F:1])=[CH:28][CH:29]=1)(=[O:44])[C:41]([CH3:43])=[CH2:42]
Reactant: C=C(C)C(=O)Cl
Reactant: Cc1cc(OC(F)(F)c2ccc(CCCCCO)cc2)ccc1OC(F)(F)c1ccc(CCCCCO)cc1
Product: C=C(C)C(=O)OCCCCCc1ccc(C(F)(F)Oc2ccc(OC(F)(F)c3ccc(CCCCCOC(=O)C(=C)C)cc3)c(C)c2)cc1

Procedure:
An analogous synthesis to that described under 1.3. starting from 5-{4-[(4-{difluoro-[4-(5-hydroxypentyl)phenyl]methoxy}-2-methylphenoxy)difluoromethyl]phenyl}pentan-1-ol and methacryloyl chloride gives 5-{4-[(4-{[4-(5-methacryloyloxypentyl)phenyl]difluoromethoxy}-3-methylphenoxy)difluoromethyl]phenyl}pentyl methacrylate as a colourless solid of m.p. 26° C.