Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([Si:7]([CH3:28])([CH3:27])[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][O:18][CH3:19])[C:11]=1[C:20](=[CH2:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])([CH3:6])[CH3:5].[CH3:29]S(C)=O>>[CH3:3][C:4]([Si:7]([CH3:27])([CH3:28])[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][O:18][CH3:19])[C:11]=1[C:20]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:29][CH2:26]1)([CH3:5])[CH3:6]
Reactant: C=C(C(=O)OCC)c1c(CO[Si](C)(C)C(C)(C)C)cccc1OCOC
Reactant: CS(C)=O
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C1(c2c(CO[Si](C)(C)C(C)(C)C)cccc2OCOC)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
NaH 60% disp in mineral oil (140 mg, 3.49 mmol) was added and the reaction mixture was stirred for 30 minutes at room temperature. A solution of ethyl 2-(2-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)-6-{[(methyloxy)methyl]oxy}phenyl)-2-propenoate (Intermediate 132, 830 mg) in dry dimethyl sulfoxide (5 mL) was added and the reaction mixture was stirred for 30 minutes at room temperature The reaction was quenched with ice, diluted with brine (10 ml) and water (10 ml) and extracted with ethyl acetate (2×30 ml). The organic layer was washed with water (3×15 ml) and brine (1×20 ml), dried over sodium sulphate, filtered and evaporated and the residue was purified by flash chromatography (Biotage system) on silica gel using a 50 g SNAP column and cyclohexane to cyclohexane/ethyl acetate 7:3 as eluent. This afforded the title compound as a colourless oil (780 mg).
Reaction SMILES: [OH-].[Na+].C([O:6][CH:7]([CH2:9][CH2:10][C:11]1[CH:23]=[CH:22][C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14](=[O:24])[C:13]=2[CH:12]=1)[CH3:8])(=O)C>CO.O>[O:24]=[C:14]1[C:13]2[CH:12]=[C:11]([CH2:10][CH2:9][CH:7]([OH:6])[CH3:8])[CH:23]=[CH:22][C:21]=2[C:20]2[C:15]1=[CH:16][CH:17]=[CH:18][CH:19]=2
Reactant: CC(=O)OC(C)CCc1ccc2c(c1)C(=O)c1ccccc1-2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(O)CCc1ccc2c(c1)C(=O)c1ccccc1-2
Yield: 95.2 %

Procedure:
Sodium hydroxide (0.2 gram) was dissolved in a mixture of 20 ml of methanol and 5 ml of water, then 1.47 grams of 4-(9-oxo-2-fluorenyl)-butan-2-ol acetate was added thereto, and the mixture was heated to reflux for two hours. After removal of methanol by evaporation therefrom, chloroform was added to the residue, the mixture was washed with water, and dried with magnesium sulfate. Chlorform was evaporated therefrom and the residue was allowed to stand to give crystals. They were recrystallized from isopropyl ether to give 1.2 grams of 4-(9-oxo-2-fluorenyl)-butan-2-ol, yellow crystals, m.p. 77°-78° C.
Reaction SMILES: C([C:4]1[S:8][C:7]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[C:6]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[CH:5]=1)(=O)C.[OH2:26].O.O.[N+]([O-])([O-])=O.[Tl+3].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.Cl(O)(=O)(=O)=O.[O:47]1[CH2:52]CO[CH2:49][CH2:48]1>CO>[F:15][C:12]1[CH:11]=[CH:10][C:9]([C:7]2[S:8][C:4]([CH2:49][C:48]([O:47][CH3:52])=[O:26])=[CH:5][C:6]=2[C:16]2[CH:17]=[CH:18][C:19]([S:22]([CH3:25])(=[O:23])=[O:24])=[CH:20][CH:21]=2)=[CH:14][CH:13]=1
Reactant: CC(=O)c1cc(-c2ccc(S(C)(=O)=O)cc2)c(-c2ccc(F)cc2)s1
Reactant: O
Reactant: C1COCCO1
Agent: O=[N+]([O-])[O-]
Agent: [O-][Cl+3]([O-])([O-])O
Agent: [Tl+3]
Solvent: CO
Product: COC(=O)Cc1cc(-c2ccc(S(C)(=O)=O)cc2)c(-c2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
A mixture of 5-acetyl-2-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]thiophene (1 g), thallium(III) nitrate trihydrate (1.4 g) and perchloric acid (70%; 3 ml) in methanol (15 ml) and dioxane (7 ml) was stirred at ambient temperature for 7 hours. The insoluble material was filtered. The filtrate was diluted with water and extracted with chloroform. The extract was dried over magnesium sulfate and concentrated to give an oil of methyl 5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]thiophene-2-acetate (1.2 g).
Reaction SMILES: [O:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH:4](C(OCC)=O)[CH2:3][CH2:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].C1C[O:26][CH2:25]C1>>[O:1]1[C:7]2=[CH:8][CH:9]=[CH:10][C:11]([CH2:25][OH:26])=[C:6]2[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCOC1
Reactant: CCOC(=O)C1CCOc2ccccc2C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCc1cccc2c1CCCCO2
Reaction time: 18 h

Procedure:
A solution of ethyl 2,3,4,5-tetrahydrobenzoxepin-4-carboxylate (2.85 g, 13 mmol) in THF (30 ml) was stirred as LAH (1 g, 26 mmol) was slowly added. The mixture was stirred for 18 hr, and then quenched by the sequential addition of water (1 ml), 15% sodium hydroxide (1 ml), and water (3 ml). The mixture was filtered and the filter cake washed with ethanol. The filtrate was concentrated in vacuo to an oil (2.3 g, 100%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[F:20][C:21]([F:32])([F:31])[C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>ClCCl>[F:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH:8][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][C:22]([C:21]([F:20])([F:31])[F:32])=[CH:23][CH:24]=2)=[CH:4][CH:3]=1
Reactant: NCCc1ccc(F)cc1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCCc1ccc(F)cc1)c1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A 250-mL, round-bottomed flask containing a solution of 4-fluorophenethylamine (4.8 mL, 37 mmol) and diisopropylethylamine (6.4 mL, 37 mmol) in dichloromethane (40 mL) was cooled to 0° C. and treated dropwise with 4-(trifluoromethyl)benzoyl chloride (5.5 mL, 37 mmol) over 5 min. The ice-bath was removed after 2 h and the reaction mixture was stirred overnight. The precipitate formed was collected by filtration. The filtrate was diluted with dichloromethane (100 mL) and transferred to a separatory funnel, extracted with water (35 mL), brine (25 mL), and 1N HCl (25 mL). The dichloromethane layer was separated and formation of more precipitate was observed which was collected by filtration. The solids collected were combined and dried under vacuum to yield N-(4-fluorophenethyl)-4-(trifluoromethyl)benzamide as an off-white solid. MS (ESI pos. ion) m/z: 312 (M+H).
Reaction SMILES: NCC1C=C(NC(OCCC2C=CC(C(N[C:26]3[CH:27]=[C:28]4[C:33](=[CH:34][CH:35]=3)[C:32]([N:36](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=N[CH:30]=[CH:29]4)C(O)=O)=CC=2C)=O)C=CC=1.[CH2:52]1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)C[CH2:53]1.F[P-](F)(F)(F)(F)F.C(O)(C(F)(F)F)=[O:86]>>[CH2:52]([C:27]1[C:28]([CH2:29][CH3:30])=[C:33]([CH:34]=[CH:35][CH:26]=1)[C:32]([NH2:36])=[O:86])[CH3:53]
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1cc(C(Nc2ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc3c2)C(=O)O)ccc1CCOC(=O)Nc1cccc(CN)c1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Product: CCc1cccc(C(N)=O)c1CC
Yield: 42 %

Procedure:
Using a procedure analogous to that used to prepare Example 28, 30F (140 mg, 0.2 mmol) was cyclized with PyBOP instead of BOP, deprotected with TFA, and purified by reverse phase HPLC to give Example 30 (40 mg, 42%) as a white solid. 1H NMR (400 MHz, CD3OD) δ ppm 2.32 (s, 1.5 H) 2.48 (s, 1.5 H) 2.70-2.88 (m, 1 H) 3.04-3.22 (m, 1 H) 3.88-4.23 (m, 2 H) 4.41-4.61 (m, 1 H) 4.64-4.80 (m, 1 H) 5.09-5.17 (m, J=3.54 Hz, 1 H) 6.09-6.26 (m, J=12.13 Hz, 1 H) 6.61-6.72 (m, 2 H) 6.72-6.83 (m, J=12.88, 7.07 Hz, 1 H) 6.83-6.94 (m, J=7.58 Hz, 1 H) 7.03-7.20 (m, 3 H) 7.21-7.33 (m, 2 H) 7.36-7.54 (m, 1 H) 7.98-8.10 (m, J=9.09, 5.05 Hz, 1 H) 8.50-8.70 (m, 1 H), mixture of two atropisomers. MS (ESI) m/z 482.20 (M+H)+.
Reaction SMILES: I[CH2:2][I:3].N(OCCC(C)C)=O.NC1[N:21]=[C:20]([C:22]2[C:30]3[C:25](=[N:26][CH:27]=[CH:28][CH:29]=3)[N:24]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[F:38])[N:23]=2)[N:19]=[C:18]2[C:14]=1[N:15]([CH:40]([CH3:42])[CH3:41])[C:16](=[O:39])[NH:17]2>>[F:38][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[CH2:31][N:24]1[C:25]2=[N:26][CH:27]=[CH:28][CH:29]=[C:30]2[C:22]([C:20]2[N:19]=[C:18]3[C:14]([N:15]([CH:40]([CH3:42])[CH3:41])[C:16](=[O:39])[NH:17]3)=[C:2]([I:3])[N:21]=2)=[N:23]1
Reactant: CC(C)n1c(=O)[nH]c2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(N)c21
Reactant: ICI
Agent: CC(C)CCON=O
Product: CC(C)n1c(=O)[nH]c2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(I)c21
Temperature: 85 °C
Reaction time: 8 h
Yield: 57.7 %

Procedure:
To a mixture of 2.59 ml (32.20 mmol) of diiodomethane and 2.78 ml (20.61 mmol) of isoamyl nitrite were added 539 mg (approx. 1.08 mmol) of the compound from example 115, and the reaction mixture was stirred at 85° C. overnight. The mixture was concentrated, and the residue was stirred with dichloromethane and filtered. The solids were washed with dichloromethane and dried under high vacuum. 330 mg of the title compound were obtained (92% purity; 53% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[N:15]([C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[CH:20]=[CH:21][N:22]=[CH:23]2)=[C:16]=[O:17]>C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([C:16]([NH:15][C:18]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:19]=3[CH:20]=[CH:21][N:22]=[CH:23]4)=[O:17])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C=Nc1cccc2cnccc12
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Solvent: CCOCC
Product: O=C(Nc1cccc2cnccc12)N1CCN(c2ccc(Cl)c(Cl)c2)CC1
Yield: 80 %

Procedure:
1-(3,4-Dichlorophenyl)piperazine (1280 mg, 5.55 mmol) in diethyl ether (30 mL) was treated with the product from Example 61A (˜40 mL). The mixture was filtered, the filter cake washed with diethyl ether, and dried under reduced pressure to provide the title compound as a white solid (1.78 g, 80%). 1H NMR (300 MHz, DMSO-d6) δ 9.29 (d, J=1.0 Hz, 1H), 8.84 (s, 1H), 8.49 (d, J=5.8 Hz, 1H), 7.92 (d, J=7.8 Hz, 1H), 7.78 (m, 1H), 7.61-7.71 (m, 2H), 7.44 (d, J=8.8 Hz, 1H), 7.22 (d, J=3.1 Hz, 1H), 7.01 (dd, J=9.1, 2.7 Hz, 1H), 3.68 (m, 4H), 3.30 (m, 4H); MS (ESI+) m/z 401/403 (M+H+, 35Cl/37Cl).
Reaction SMILES: O.C([O-])=O.[NH4+].C([N:13]1[C:17]([CH:18]([OH:34])[CH2:19][CH2:20][CH:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:16][N:15]=[CH:14]1)C1C=CC=CC=1>C(O)C.[Pd]>[OH:34][CH:18]([C:17]1[N:13]=[CH:14][NH:15][CH:16]=1)[CH2:19][CH2:20][CH:21]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: OC(CCC(c1ccccc1)c1ccccc1)c1cncn1Cc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: OC(CCC(c1ccccc1)c1ccccc1)c1c[nH]cn1

Procedure:
A concentrated water solution of ammonium formate (4,0 g) is added dropwise to the boiling mixture of 1-benzyl-5-(1-hydroxy-4,4-diphenylbutyl)-1H-imidazole (4,5 g) and 10% Pd/C (0,5 g) in 50 ml of 50% ethanol. The mixture is refluxed for 2 hours. The catalyst is filtrated and the solvent is evaporated. 2M NaOH is added and the product is extracted into ethyl acetate. The ethyl acetate phase is dried and evaporated to dryness to give the product which is used in the following step b).
Reaction SMILES: [CH3:1][NH:2][NH2:3].CO[C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:9]([CH3:18])[C:8](=[O:19])[N:7]=1>CO>[CH3:1][NH:2][NH:3][C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:9]([CH3:18])[C:8](=[O:19])[N:7]=1
Reactant: COc1nc(-c2ccccc2)n(C)c(=O)n1
Reactant: CNN
Solvent: CO
Product: CNNc1nc(-c2ccccc2)n(C)c(=O)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.71 ml of methylhydrazine dissolved in 30 ml of methanol are added to a stirred solution of 4-methoxy-1-methyl-6-phenyl-1,2-dihydro-1,3,5-triazin-2-one in 100 ml of methanol. The mixture is stirred for one hour at RT and then refluxed for four hours. The reaction mixture is concentrated and the triazinone precipitated from ethyl acetate and hexane, filtered, washed with ether, and dried to yield 1.95 g of the desired product.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[N:15]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20]C(=O)OC(C)(C)C)[CH:14]=[N:13][C:12]=3[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(O)(C(F)(F)F)=O.C([SiH](C(C)C)C(C)C)(C)C>O>[NH2:20][CH2:19][CH2:18][CH2:17][CH2:16][N:15]1[C:11]([C:9]2[S:8][C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]=3[CH:10]=2)=[C:12]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:13]=[CH:14]1
Reactant: CC(C)(C)OC(=O)NCCCCn1cnc(-c2ccccc2)c1-c1cc2c(N)ncnc2s1
Agent: CC(C)[SiH](C(C)C)C(C)C
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: NCCCCn1cnc(-c2ccccc2)c1-c1cc2c(N)ncnc2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
tert-Butyl {4-[5-(4-aminothieno[2,3-d]pyrimidin-6-yl)-4-phenyl-1H-imidazol-1-yl]butyl}carbamate (Example 173) (23 mg) was added to a mixture of TFA, water and triisopropyl silane (5:5:1) (5 ml) and stirred at ambient temperature for 1 hour. The reaction mixture was concentrated in vacuo and the residue purified by preparative RPHPLC (eluting with a gradient of MeCN and water containing 0.1% TFA) to give the title compound as a colourless solid (18 mg, 90%);
Reaction SMILES: [CH3:1][C:2]1[CH:7]([OH:8])[CH2:6][CH2:5][C:4]([CH3:10])([CH3:9])[C:3]=1[CH:11]=[CH:12][C:13](=[O:15])[CH3:14].O.O.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].S(=O)(=O)(O)O>CCOCC>[CH3:1][C:2]1[C:7](=[O:8])[CH2:6][CH2:5][C:4]([CH3:9])([CH3:10])[C:3]=1[CH:11]=[CH:12][C:13](=[O:15])[CH3:14]
Reactant: CC(=O)C=CC1=C(C)C(O)CCC1(C)C
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CC(=O)C=CC1=C(C)C(=O)CCC1(C)C
Temperature: 5 °C
Yield: 734.3 %

Procedure:
To a solution, pre-cooled to 0° C., of 140 g (0.068 mol) of 4-(2,6,6-trimethyl-3-hydroxy-cyclohex-1-en-1-yl)-but-3-en-2-one in 500 ml of ether are added dropwise over a period of 10 minutes 700 ml of an aqueous solution, cooled to 0° C., of 202.6 g of sodium dichromate dihydrate and 186 g of concentrated sulphuric acid with intensive cooling and good stirring so that a temperature of 5° C. is not exceeded. The mixture is then stirred for a further 5 minutes at 5° C., treated with 500 ml of ether, the ether phase is washed three times with water, three times with soda solution and again three times with water, dried over sodium sulphate and concentrated. Distillation of the resulting 125 g of crude product over a 10 cm Widmer column gave 103 g of more than 94% pure 4-(2,6,6-trimethyl-3-oxo-cyclohex-1-en-1-yl)-but- 3-en-2-one of boiling point 109°-110° C./0.05 mm Hg; melting point 50°-51° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH3:8])[NH:5][C:6]=1[Cl:7].[H-].[Na+].Br[CH2:12][C:13]1[S:28][C:16]2[N:17]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:18](=[O:23])[N:19]([CH3:22])[C:20](=[O:21])[C:15]=2[C:14]=1[C:29]([O:31][CH3:32])=[O:30].O>O1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]([CH3:8])[N:5]([CH2:12][C:13]2[S:28][C:16]3[N:17]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:18](=[O:23])[N:19]([CH3:22])[C:20](=[O:21])[C:15]=3[C:14]=2[C:29]([O:31][CH3:32])=[O:30])[C:6]=1[Cl:7]
Reactant: Cc1nc(Cl)c(Cl)[nH]1
Reactant: COC(=O)c1c(CBr)sc2c1c(=O)n(C)c(=O)n2CC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1c(Cn2c(C)nc(Cl)c2Cl)sc2c1c(=O)n(C)c(=O)n2CC(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4,5-Dichloro-2-methylimidazole (1.3 g) in dry tetrahydrofuran (20 ml) was added dropwise to a suspension of sodium hydride (0.34 g, 60%) in dry tetrahydrofuran (20 ml) at room temperature under nitrogen. After 15 min, a solution of the product of step b) (3.35 g) in dry tetrahydrofuran (20 ml) was added dropwise and the reaction was stirred for 3 h at room temperature. The solution was poured into water and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash silica chromatography eluting with a gradient 50-100% ethyl acetate in isohexane to give the sub-title compound as a white solid (2.28 g).
Reaction SMILES: Cl.[CH2:2]1[C:7]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[S:10][C:6]=2[CH2:5][CH2:4][NH:3]1.Cl[CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24].C([O-])([O-])=O.[Na+].[Na+]>CC(C)CC(=O)C>[CH2:2]1[C:7]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[S:10][C:6]=2[CH2:5][CH2:4][N:3]1[CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)NCCCCCl
Reactant: c1ccc2c3c(sc2c1)CCNC3
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: CC(C)(C)OC(=O)NCCCCN1CCc2sc3ccccc3c2C1
Temperature: 25 °C

Procedure:
A mixture of 1,2,3,4-tetrahydro[1]benzothieno[3,2-c]pyridine HCl (1:1) (0.02 mol), 1,1-dimethylethyl (4chlorobutyl)carbamate (0.044 mol), Na2CO3 (0.05 mol) and KI (catalytic quantity) in 4-methyl-2-pentanone (200 ml) was stirred and refluxed overnight, then cooled to room temperature and the solvent was evaporated. The residue was washed with water and extracted with CH2Cl2. The separated organic layer was dried, filtered and the solvent evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 90/10). The desired fractions were collected and the solvent was evaporated, yielding 1,1-dimethylethyl [4-(3,4-dihydro[1]benzothieno[3,2-c]pyridine-2(1H)-yl)butyl]carbamate (interim.1).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.[O:17]1[CH2:21][CH2:20][CH2:19][CH:18]1[C:22]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)=[O:23]>COC(O)C>[ClH:1].[O:17]1[CH2:21][CH2:20][CH2:19][CH:18]1[C:22]([N:24]1[CH2:25][CH2:26][N:27]([C:2]2[N:11]=[C:10]([NH2:12])[C:9]3[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=3)[N:3]=2)[CH2:28][CH2:29]1)=[O:23]
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Reactant: O=C(C1CCCO1)N1CCNCC1
Agent: COC(C)O
Product: COc1cc2nc(N3CCN(C(=O)C4CCCO4)CC3)nc(N)c2cc1OC
Product: Cl

Procedure:
To 7.00 g 2-chloro-4-amino-6,7-dimethoxyquinazoline (Lancaster Synthesis) in 50 ml methoxyethanol was added 10.8 g, tetrahydrofuroylpiperazine, and the mixture refluxed 3 hours. The clear solution was concentrated and an aqueous solution of potassium bicarbonate was added. The resultant solid that formed was filtered and washed with water. It was then added to methanol and the resulting suspension was acidified with a solution of hydrogen chloride in isopropyl alcohol. The resulting solution was concentrated and the residue crystallized from isopropyl alcohol giving 8.12 g. of product, m.p. 278°-279° C.
Reaction SMILES: [CH:1]1[C:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]=[C:15]=[O:16])=[CH:10][CH:9]=2)=[CH:5][CH:4]=[C:3](N=C=O)[CH:2]=1.C[N:21]([C:23](C(C1C=CC=CC=1)(C1C=CC=CC=1)CCN1CCC(O)(C2C=CC(Cl)=CC=2)CC1)=[O:24])C.Cl>>[N-:14]=[C:15]=[O:16].[N-:21]=[C:23]=[O:24].[C:6]1([CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:1]=[CH:2][CH:3]=[CH:4][CH:5]=1
Reactant: CN(C)C(=O)C(CCN1CCC(O)(c2ccc(Cl)cc2)CC1)(c1ccccc1)c1ccccc1
Reactant: O=C=Nc1ccc(Cc2ccc(N=C=O)cc2)cc1
Agent: Cl
Product: [N-]=C=O
Product: c1ccc(Cc2ccccc2)cc1

Procedure:
An isocyanate composition was produced which contained 0.48 part of a 4,4'- diphenylmethane diisocyanate in which 25-30 weight % of the isocyanate groups have been converted into a uretonimine form (marketed by ICI under the trade name `SUPRASEC` VM 020), 90 parts of a polymethylene polyphenylene polyisocyanate having a functionality of 2.7 and a content of diphenylmethane diisocyanate of 40% weight and between 29.5 and 31.0% by weight of isocyanate groups, and a prepolymer obtained by reacting 8.51 parts of a mixture of 4,440 -diphenylmethane diisocyanate and 2,440 -diphenylmethane diisocyanate (97.4% and 2.6%) with 1.01 parts of a mixture of propylene glycol, 1,3-butane diol and tripropylene glycol (0.8:0.8:1.0 molar ratio).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:9])=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[CH3:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14](Cl)=[O:15]>>[Cl:1][C:2]1[C:3]([O:9][C:14](=[O:15])[C:13]2[CH:17]=[CH:18][CH:19]=[C:11]([CH3:10])[CH:12]=2)=[CH:4][C:5]([O:8][C:14](=[O:15])[C:13]2[CH:17]=[CH:18][CH:19]=[C:11]([CH3:10])[CH:12]=2)=[N:6][CH:7]=1
Reactant: O=c1cc(O)c(Cl)c[nH]1
Reactant: Cc1cccc(C(=O)Cl)c1
Product: Cc1cccc(C(=O)Oc2cc(OC(=O)c3cccc(C)c3)c(Cl)cn2)c1
Yield: 44.3 %

Procedure:
The general procedure of Example 5 was followed using 2.00 g of 5-chloro-4-hydroxy-2-pyridone and 3.00 g of 3-methylbenzoyl chloride, thereby producing 1.64 g of the title compound in a yield of 32%.
Reaction SMILES: [OH-].[Na+].[CH2:3]([C:7]1[N:12]=[CH:11][NH:10][C:9](=[O:13])[C:8]=1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]([O:29]C)=[O:28])=[CH:17][CH:16]=1)[CH2:4][CH2:5][CH3:6].O.CCOCC>O.CO>[CH2:3]([C:7]1[N:12]=[CH:11][NH:10][C:9](=[O:13])[C:8]=1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]([OH:29])=[O:28])=[CH:17][CH:16]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCc1nc[nH]c(=O)c1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CCOCC
Product: CCCCc1nc[nH]c(=O)c1Cc1ccc(-c2ccccc2C(=O)O)cc1
Yield: 86.6 %

Procedure:
0.13 g of NaOH dissolved in 2 ml of H2O were added to a solution containing 0.42 g of 6-butyl-5-[(2'-methoxycarbonylbiphenyl-4-yl) methyl]pyrimidin-4-one in 10 ml of MeOH. After refluxing for 24 hours under stirring the solvent was evaporated. The residue was dissolved in H2O and extracted with Et2O. The aqueous phase was acidified to pH 3. The so obtained waxy solid was treated with a H2O/Et2O mixture. After filtering, 0.35 g of a white solid was obtained (yield 88%; m.p.=197°-200° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.[CH2:20]([C:22]1[CH:23]=[C:24]([N:28]=[C:29]=[O:30])[CH:25]=[CH:26][CH:27]=1)[CH3:21]>>[CH2:20]([C:22]1[CH:23]=[C:24]([NH:28][C:29](=[O:30])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[C:16]4[C:11](=[N:12][CH:13]=[CH:14][CH:15]=4)[NH:10][C:9]=3[C:17]([NH2:19])=[O:18])=[CH:6][CH:7]=2)[CH:25]=[CH:26][CH:27]=1)[CH3:21]
Reactant: NC(=O)c1[nH]c2ncccc2c1-c1ccc(N)cc1
Reactant: CCc1cccc(N=C=O)c1
Product: CCc1cccc(NC(=O)Nc2ccc(-c3c(C(N)=O)[nH]c4ncccc34)cc2)c1

Procedure:
0.8 mg of solid white 3-{4-[3-(3-ethylphenyl)ureido]phenyl}-1H-pyrrolo[2,3-b]pyridine-2-carboxamide is prepared as described in Example 7 starting with 3-(4-aminophenyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide and 3-ethylphenyl isocyanate.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:8]=2[S:9][CH:10]=1)=[O:5])[CH3:2].[NH2:16][C:17]1[N:22]=[C:21](Cl)[CH:20]=[C:19]([Cl:24])[N:18]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CCOC(C)=O>CN1C(=O)CCC1.O>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[CH:14]=[CH:13][C:12]([O:15][C:21]3[CH:20]=[C:19]([Cl:24])[N:18]=[C:17]([NH2:16])[N:22]=3)=[CH:11][C:8]=2[S:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: CCOC(=O)c1csc2cc(O)ccc12
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1csc2cc(Oc3cc(Cl)nc(N)n3)ccc12
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
A mixture of 2.563 g (11.5 mMol) 6-hydroxy-benzo[b]thiophene-3-carboxylic acid ethyl ester, 3.06 g (18.5 mMol) 2-amino-4,6-dichloropyrimidine and 5.15 g (23 mMol) K3PO4 in 87 ml NMP is stirred for 1.5 h at 60° C. Then the mixture is poured into EtOAc and water, the aq. layer separated off and extracted 3 times with EtOAc. The organic phases are washed with water and brine, dried (Na2SO4) and concentrated. Trituration in ether and filtration gives the title compound: m.p.: 178-179° C.; TLC(hexane/EtOAc 2:1): Rf=0.27. More product can be obtained from the filtrate by column chromatography (SiO2; hexane/EtOAc 3:1).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([CH3:12])[C:10]#[N:11])[CH3:2].[CH2:13](N)[CH2:14][NH2:15]>>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([C:10]1[NH:11][CH2:13][CH2:14][N:15]=1)[CH3:12])[CH3:2]
Reactant: CCc1ccccc1C(C)C#N
Reactant: NCCN
Product: CCc1ccccc1C(C)C1=NCCN1

Procedure:
rac-2-[1-(2-Ethyl-phenyl)-ethyl]-4,5-dihydro-1H-imidazole was prepared from rac-2-(2-ethyl-phenyl)-propionitrile and ethylene diamine in analogy to Example 19 b): off-white solid;