Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:8]=[CH:7][C:6]=1[CH2:18][C:19]([OH:21])=O.[C:24]([CH:27]1[CH2:32][N:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[CH3:39])[CH2:30][CH2:29][NH:28]1)(=[O:26])[NH2:25].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>CN(C=O)C>[N:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[O:11][C:9]1[CH:8]=[CH:7][C:6]([CH2:18][C:19]([N:28]2[CH2:29][CH2:30][N:31]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[CH3:39])[CH2:32][CH:27]2[C:24](=[O:26])[NH2:25])=[O:21])=[C:5]([O:4][CH2:3][C:2]([F:1])([F:23])[F:22])[CH:10]=1
Reactant: Cc1ccccc1N1CCNC(C(N)=O)C1
Reactant: O=C(O)Cc1ccc(Oc2ccccn2)cc1OCC(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1ccccc1N1CCN(C(=O)Cc2ccc(Oc3ccccn3)cc2OCC(F)(F)F)C(C(N)=O)C1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a stirred solution of 2-(2,2,2-trifluoroethoxy)-4-(2-pyridyloxy)phenylacetic acid (0.10 g, 0.31 mmol) from Step 4 above and 2-carbamoyl-4-(2-methylphenyl)piperazine (0.08 g, 0.35 mmol) from Step 4 of Example 1 in DMF (2 mL) was added HOBT (0.06 g, 0.35 mmol), EDC (0.10 g, 0.5 mmol), and DIEA (0.09 mL, 0.5 mmol). The solution was stirred at ambient temperature for 14 h and the solvent was removed under reduced pressure. The residue was partitioned between EtOAc (50 mL) and saturated aqueous NaHCO3 (2×25 mL). The organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using 95:5 CH2Cl2 :MeOH as eluant. The product-containing fractions were evaporated under reduced pressure to give the title compound as an amorphous solid.
Reaction SMILES: Cl.[CH2:2](Cl)[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.C(N(CC)CC)C.ClCCl.[NH2:20][C:21]1[C:26]([OH:27])=[C:25]([F:28])[C:24]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:23]([CH3:35])[C:22]=1[C:36]#[N:37]>C(OCC)(=O)C>[F:28][C:25]1[C:24]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:23]([CH3:35])[C:22]([C:36]#[N:37])=[C:21]2[C:26]=1[O:27][C:2]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)=[N:20]2
Reactant: ClCc1cccnc1
Reactant: Cc1c(C#N)c(N)c(O)c(F)c1-c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(-c2ccccc2)c(F)c2oc(-c3cccnc3)nc2c1C#N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Nicotinyl chloride hydrochloride (192 mg, 1.08 mmol) and triethylamine (301 μl, 2.16 mmol) were added to a dichloromethane (9 ml) solution of 4-amino-6-fluoro-5-hydroxy-2-methylbiphenyl-3-carbonitrile (I-41) (218 mg, 0.900 mmol), followed by stirring at room temperature for 2 hours. Ethyl acetate (100 ml) was added to the reaction liquid, followed by washing with water (50 ml) and saturated brine (50 ml).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[NH:11][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([C:19]([O:21][CH3:22])=[O:20])[C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CO.Cl.O>[CH2:1]([O:8][CH2:9][CH:10]1[CH2:18][C:17]2[C:16]([C:19]([O:21][CH3:22])=[O:20])=[CH:15][CH:14]=[CH:13][C:12]=2[NH:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cccc2[nH]c(COCc3ccccc3)cc12
Agent: Cl
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: CO
Solvent: O
Product: COC(=O)c1cccc2c1CC(COCc1ccccc1)N2
Yield: 84 %

Procedure:
To a solution of methyl 2-benzyloxymethylindole-4-carboxylate (650 mg) in methanol (27 ml) and concentrated hydrochloric acid (3.0 ml) was added sodium cyanoborohydride (968 mg) with ice-bath stirring and the mixture was stirred at ambient temperature for 2.5 hours. The resulting mixture was diluted with water (30 ml) and basified with saturated sodium bicarbonate aqueous solution. The mixture was extracted with ethyl acetate (40 ml) and the organic layer was washed successively with water and brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=6:1) to give methyl 2-benzyloxymethylindoline-4-carboxylate (550 mg).
Reaction SMILES: Cl.[C:2](=[NH:7])(OCC)[CH3:3].[NH2:8][CH2:9][CH2:10][O:11][CH:12]1[C:18]2[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:17]=2[N:16]([C:24](=[O:43])[C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:40])[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[Cl:39])=[CH:27][C:26]=2[O:41][CH3:42])[CH2:15][CH2:14][CH2:13]1>C(O)C>[ClH:23].[NH:7]=[C:2]([NH:8][CH2:9][CH2:10][O:11][CH:12]1[C:18]2[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:17]=2[N:16]([C:24](=[O:43])[C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:40])[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[Cl:39])=[CH:27][C:26]=2[O:41][CH3:42])[CH2:15][CH2:14][CH2:13]1)[CH3:3]
Reactant: COc1cc(NC(=O)c2ccccc2Cl)ccc1C(=O)N1CCCC(OCCN)c2cc(Cl)ccc21
Reactant: CCOC(C)=N
Agent: Cl
Solvent: CCO
Product: COc1cc(NC(=O)c2ccccc2Cl)ccc1C(=O)N1CCCC(OCCNC(C)=N)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.8 %

Procedure:
0.129 g of ethyl acetoimidate hydrochloride was added to 15 ml of a suspension of 0.5 g of 5-(2-amino-ethoxy)-7-chloro-1-[2-methoxy-4-(2-chlorobenzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine in ethanol with ice-cooling. The mixture was stirred overnight at room temperature. Then, 0.163 g of ethyl acetoimidate hydrochloride was further added. The mixture was stirred at 50° C. for 7 hours and then refluxed for 3 hours. After cooling, the reaction mixture was subjected to filtration to remove insolubles. The filtrate was concentrated. The residue was purified by silica gel column chromatography (elutant: dichloromethane/methanol=30/1) to obtain 0.2 g of 5-[2-(1-iminoethyl)aminoethoxy]-7-chloro-1-[2-methoxy-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzo-azepine hydrochloride.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH3:9].[I:10]N1C(=O)CCC1=O>FC(F)(F)C(O)=O>[F:8][C:6]1[CH:7]=[C:2]([F:1])[C:3]([CH3:9])=[CH:4][C:5]=1[I:10]
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1ccc(F)cc1F
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(I)c(F)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.6 %

Procedure:
To a solution of 2,4-difluoro-1-methylbenzene (6 g, 47 mmol) in trifluoroacetic acid (15 mL) was added N-iodosuccinimide (12.1 g). The mixture was stirred at rt overnight before it was poured into ice and extracted with hexanes. The organic layer was separated and washed with saturated Na2S2O3, NaHCO3, brine and then dried over MgSO4. The crude product was purified by silica gel chromatography to give 94A (10.7 g, 90% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 2.15-2.30 (m, 3H) 6.73-6.85 (m, 1H) 7.55 (t, J=7.69 Hz, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)([O-])=O.I[CH3:21]>CC(C)=O.C1C=CC=CC=1.CO.[Pt](=O)=O>[CH3:21][N:16]1[CH2:17][CH2:18][CH2:19][CH:14]([C:5]2[CH:6]=[CH:7][C:8]([C:10]([F:13])([F:12])[F:11])=[CH:9][C:4]=2[NH2:1])[CH2:15]1
Reactant: CI
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1-c1cccnc1
Agent: O=[Pt]=O
Solvent: CC(C)=O
Solvent: c1ccccc1
Solvent: CO
Product: CN1CCCC(c2ccc(C(F)(F)F)cc2N)C1
Reaction time: 120 h

Procedure:
To an orange solution of 3-(2-nitro-4-(trifluoromethyl)phenyl)pyridine (1.4 g, 5.2 mmol) in 2 ml acetone and 1 mL benzene was added iodomethane (1.0 ml, 16 mmol). The solution was allowed to stand for 5 days, and was concentrated in vacuo to give an orange solid. A portion of this material was treated with platinum (IV) oxide (0.11 g, 0.49 mmol) in 5 ml MeOH under an atmosphere of hydrogen for approximately 24 h. The reaction was flushed with nitrogen, filtered through celite, and concentrated. Purification by silica gel chromatography (MC/MeOH/conc. NH4OH) provided the title compound. MS (m/z): 259.0 (M+H)+. Calc'd for C13H17F3N2: 258.28.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])=[O:16])=[CH:13][N:12]=[C:11]([NH:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[N:10]=1.C(N(CC)CC)C.Cl[C:40]([O:42][CH3:43])=[O:41]>C(Cl)Cl>[CH3:43][O:42][C:40]([N:29]1[CH2:30][CH2:31][CH:26]([NH:25][C:11]2[N:10]=[C:9]([NH2:8])[C:14]([C:15](=[O:16])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])=[CH:13][N:12]=2)[CH2:27][CH2:28]1)=[O:41]
Reactant: COC(=O)Cl
Reactant: COc1ccccc1C(=O)c1cnc(NC2CCNCC2)nc1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)N1CCC(Nc2ncc(C(=O)c3ccccc3OC)c(N)n2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 80.7 %

Procedure:
To a solution of [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(2-methoxy-phenyl)-methanone trifluoroacetic acid salt (80.9 mg, Example 11) in methylene chloride (4 mL) were added triethylamine (0.095 mL, 0.681 mmol, Aldrich) and methyl chloroformate (9.0 mg, 0.0868 mmol, Aldrich) at 0° C. The mixture was stirred for 1 hour at 0° C., the reaction mixture was concentrated in vacuo and crude product was purified on silica gel with 95:5 of dichloromethane/methanol to give 4-[4-amino-5-(2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidine-1-carboxylic acid methyl ester (27.0 mg). HRMS, observed: 386.1827; Calcd for (M+H)+: 386.1823.
Reaction SMILES: [C:1](#[N:3])C.[F:4][C:5]([F:15])([F:14])[CH:6]([C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)[CH3:7].C[Si](C#N)(C)C>C(N(CC)CC)C>[F:15][C:5]([F:4])([F:14])[CH:6]([C:8]1[CH:13]=[CH:12][N:11]=[C:10]([C:1]#[N:3])[CH:9]=1)[CH3:7]
Reactant: CC(c1ccncc1)C(F)(F)F
Reactant: CC#N
Agent: C[Si](C)(C)C#N
Solvent: CCN(CC)CC
Product: CC(c1ccnc(C#N)c1)C(F)(F)F
Temperature: 90 °C
Reaction time: 16 h

Procedure:
To 8 ml of acetonitrile were added 0.9 g of 4-(2,2,2-trifluoro-1-methyl-ethyl)pyridine=N-oxide, 1.31 ml of triethylamine and 1.4 g of trimethylsilyl cyanide, and the mixture was stirred at 90° C. for 16 hours. Thereafter, the reaction solution was allowed to cool to temperature, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.7 g of 4-(2,2,2-trifluoro-1-methyl-ethyl)pyridine-2-carbonitrile.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]1[C:9]([O:11]CC)=[O:10])[CH3:2].CO.C1COCC1.[OH-].[Na+]>O>[CH2:1]([N:3]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]1[C:9]([OH:11])=[O:10])[CH3:2]
Reactant: CCOC(=O)c1cc(C)cn1CC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCn1cc(C)cc1C(=O)O
Temperature: 25 °C
Reaction time: 204 h
Yield: 78.9 %

Procedure:
To a mixture of ethyl 1-ethyl-4-methyl-1H-pyrrole-2-carboxylate (0.66 g), methanol (5.0 ml), and THF (5.0 ml) was added a 1 M aqueous sodium hydroxide solution (5.0 ml) under ice-cooling, followed by stirring at room temperature for 8.5 days. Water was added to the reaction mixture and the solvent was removed by evaporation under reduced pressure. The residue was washed with diethyl ether, and citric acid was added to the aqueous layer under ice-cooling. The solid precipitated was collected by filtration, washed with water, and dried to obtain 1-ethyl-4-methyl-1H-pyrrole-2-carboxylic acid (0.44 g).
Reaction SMILES: [NH:1]([C:8]([CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([O:17][CH2:18][O:19][CH3:20])[CH2:13][CH2:12]1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].O>O1CCCC1.C(OCC)(=O)C>[NH:1]([CH2:8][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([O:17][CH2:18][O:19][CH3:20])[CH2:13][CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCOC1CCN(CC(=O)Nc2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COCOC1CCN(CCNc2ccccc2)CC1
Yield: 98.6 %

Procedure:
A solution of 3.64 g of 1-(anilinocarbonylmethyl)-4-methoxymethoxypiperidine in 10 ml of tetrahydrofuran was added to a suspension of 630 mg of lithium aluminum hydride in 50 ml of tetrahydrofuran. The mixture was refluxed for 3 hours. To the reaction mixture were added 1.5 ml of an aqueous solution containing 10% of potassim hydroxide and 1.5 ml of water. The mixture was diluted with ethyl acetate, and the dilution was filtered. The solvent in the filtrate was removed by distillation to obtain 3.41 g of 1-(2-anilinoethyl)-4-methoxymethoxypiperidine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Br:13])[C:10]=1[CH2:11][NH2:12])[C:5](N)=[O:6].[OH-:14].[Na+].Cl>CO>[Br:1][C:2]1[CH:3]=[C:4]([C:5]([OH:14])=[O:6])[CH:8]=[C:9]([Br:13])[C:10]=1[CH2:11][NH2:12]
Reactant: NCc1c(Br)cc(C(N)=O)cc1Br
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: NCc1c(Br)cc(C(=O)O)cc1Br
Temperature: 0 °C
Yield: 87 %

Procedure:
A mixture of 3,5-dibromo-4-aminomethyl benzamide (40 g, 0.129 mol), methanol (500 mL) and an aqueous solution of NaOH (10%, 310 mL) was refluxed for 20 h. The reaction mixture was concentrated to 150 mL and cooled to 0° C. The solid precipitate obtained was filtered, washed with diethyl ether (500 mL). The solid obtained was acidified with an aqueous solution of HCl (1.5 N, 100 mL) to pH=6 to give solid precipitate. The solid was filtered, washed with water and dried under vacuum to give 2,6-dibromo-4-carboxy benzylamine (35 g, 87%) as a solid.
Reaction SMILES: [CH2:1]([C:3]1[C:4]2[C:8]([C:9]([CH3:15])=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)=[N:7][O:6][CH:5]=2)[CH3:2].C(=O)(O)[O-].[Na+].[CH2:21]([OH:23])[CH3:22]>>[NH2:7][C:8]1[C:9]([CH3:15])=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=[C:3]([CH2:1][CH3:2])[C:4]=1[C:5]([O:23][CH2:21][CH3:22])=[O:6]
Reactant: CCc1cc([N+](=O)[O-])c(C)c2nocc12
Reactant: CCO
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)c1c(CC)cc([N+](=O)[O-])c(C)c1N
Yield: 76 %

Procedure:
A solution of 4-ethyl-7-methyl-6-nitro-anthranil (300 mg, 0.000146 mol.) in absolute ethanol was mixed with sodium bicarbonate (160 mg, 0.0019 mol.) and was refluxed for 4 hrs. The solution was evaporated to dryness, the residue partitioned between ethyl acetate and 5% hydrochloric acid solution. The organic layer was dried over magnesium sulphate and evaporated to give a solid. This solid was further purified by column chromatography (10% ethyl acetate: pet. ether 30-60) to give ethyl 2-amino-6-ethyl-3-methyl-4-nitro-benzoate as an oil (yield: 276 mg, 76%). IR (neat): 3500, 3400, 2980, 1700, 1620, 1580, 1530 cm-1. H-NMR (CDCl3): 1.20 (t, 3H, CH3), 1.40 (t, 3H, CH3), 2.18 (s, 3H, CH3) 2.78 (q, 3H, CH2), 4.40 (q, 2H, CH2O), 5.05 (br.s, 2H, NH2), 6.91 (s, 1H, ArH).
Reaction SMILES: [C@@H:1]12[N:8]([C:9]3[O:10][C:11]4[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:12]=4[N:13]=3)[CH2:7][C@@H:6]1[CH2:5][CH2:4][NH:3][CH2:2]2.CC1C=C(C)N=C(N2[C@@H]3[C@@H](CCNC3)C2)N=1.[F:35][C:36]1[C:37]([N:45]2[N:49]=[CH:48][CH:47]=[N:46]2)=[C:38]([CH:42]=[CH:43][CH:44]=1)[C:39](O)=[O:40].S1C=CC=C1C1C=CC=CC=1C(O)=O>C(Cl)Cl>[Cl:18][C:15]1[CH:16]=[CH:17][C:11]2[O:10][C:9]([N:8]3[C@@H:1]4[C@@H:6]([CH2:5][CH2:4][N:3]([C:39]([C:38]5[CH:42]=[CH:43][CH:44]=[C:36]([F:35])[C:37]=5[N:45]5[N:49]=[CH:48][CH:47]=[N:46]5)=[O:40])[CH2:2]4)[CH2:7]3)=[N:13][C:12]=2[CH:14]=1
Reactant: O=C(O)c1cccc(F)c1-n1nccn1
Reactant: Clc1ccc2oc(N3C[C@@H]4CCNC[C@@H]43)nc2c1
Agent: Cc1cc(C)nc(N2C[C@@H]3CCNC[C@@H]32)n1
Agent: O=C(O)c1ccccc1-c1cccs1
Solvent: ClCCl
Product: O=C(c1cccc(F)c1-n1nccn1)N1CC[C@H]2CN(c3nc4cc(Cl)ccc4o3)[C@H]2C1

Procedure:
The title compound was prepared in a manner analogous to Example 1, substituting 2-((1R,6S)-3,8-diazabicyclo[4.2.0]octan-8-yl)-5-chlorobenzo[d]oxazole (Intermediate 32) for (1R,6S)8-(4,6-dimethyl-pyrimidin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane and 3-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid (Intermediate 50) for 2-thiophen-2-yl-benzoic acid. DCM was used in place of DMF. MS (ESI) mass calcd. For C22H18ClFN6O2, 452.88; m/z found 453.1 [M+H]+. 1H NMR (CD3OD): 8.01-7.35 (m, 5H), 7.25-6.81 (m, 3H), 4.75-4.24 (m, 2H), 4.12-3.03 (m, 6H), 2.25-1.81 (m, 2H).
Reaction SMILES: C(O[C:4](=[O:20])[CH:5]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19])[C:6]([O:8]CC)=O)C.Cl.[C:22]([C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1)(=[NH:24])[NH2:23]>[Na].CO>[CH3:19][O:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[O:11][C:5]1[C:4]([OH:20])=[N:23][C:22]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)=[N:24][C:6]=1[OH:8]
Reactant: N=C(N)c1ccncc1
Reactant: CCOC(=O)C(Oc1ccccc1OC)C(=O)OCC
Agent: Cl
Agent: [Na]
Solvent: CO
Product: COc1ccccc1Oc1c(O)nc(-c2ccncc2)nc1O

Procedure:
Diethyl-(2-methoxy-phenoxy)malonate is dissolved in a solution of sodium in methanol. Thereafter 4-amidino-pyridine hydrochloride is added to obtain 5-(2-methoxy-phenoxy)-2-(pyridin-4-yl)-pyrimidin-4,6-diol (or a tautomeric derivative). This compound is heated with phosphorus oxychloride to yield 4,6-dichloro-5-(2-methoxy-phenoxy)-2-pyridin-4-yl)-pyrimidine which is boiled with peracetic acid to obtain 4-[4,6-dichloro-5-(2-methoxy-phenoxy)-pyrimidin-2-yl]-pyridine-1-oxide. By reaction of this compound with 5-isopropyl-pyridine-2-sulfonamide potassium there is obtained 5-isopropyl-pyridine-2-sulfonic acid 6-chloro-5-(2-methoxy-phenoxy)-2-(1-oxy-pyridin-4-yl)-pyrimidin-4-yl amide which is added as a solution in dimethoxyethane to a solution of sodium in ethylene glycol. 5-Isopropyl-pyridine-2-sulfonic acid 6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(1-oxy-pyridin-4-yl)-pyrimidin-4-yl amide is obtained which is heated with trimethylsilylcyanide and triethylamine in acetonitrile to obtain 5-isopropyl-pyridine-2-sulphonic acid 2-(2-cyano-pyridin-4-yl)-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl-amide. This is then heated with ammonium chloride and sodium azide in dimethyl formamide to yield 5-isopropyl-pyridine-2-sulfonic acid {6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-[2-(1H-tetrazol-5-yl)-pyridin-4-yl]-pyrimidin-4-yl}-amide (see WO 96/19459).
Reaction SMILES: C(NC(C)C)(C)C.[CH2:8]([O:10][C:11](=[O:23])[CH:12]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:13](C)=O)[CH3:9].C=O>O1CCCC1>[C:17]1([CH2:16][C:12]([C:11]([O:10][CH2:8][CH3:9])=[O:23])=[CH2:13])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)C(Cc1ccccc1)C(C)=O
Agent: C=O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: C=C(Cc1ccccc1)C(=O)OCC
Reaction time: 0.33 h
Yield: 135.7 %

Procedure:
N-butyl lithium (201 ml of 1.6M) was added dropwise to diisopropyl amine (45 ml) in dry tetrahydrofuran (870 ml) at -78° C. After stirring at this temperature for 0.5 hours ethyl-2-benzylacetoacetate (39.6 g, 0.18M) in THF (250 ml) was added dropwise at 0° C. After stirring for 20 minutes, paraformaldehyde (35.42 g) was added at room temperature followed by stirring for one hour and refluxing for 4 hours. The reaction mixture was filtered and the liquid evaporated to dryness. The residue was dissolved in a mixture of KHCO3 /H2O and methylene chloride (1:1) and stirred for 0.5 hours. The layers were separated and the methylene chloride layer was dried over K2CO3 and then evaporated to dryness to yield 46.4 g of named product. This product was purified with a Prep-500 chromatograph eluting with hexane to 5% ethyl acetate/hexane gradient to yield 30 g of a clear liquid. ms (fd)= 190M+
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:15]([CH:16]([CH2:21][CH2:22][CH3:23])[C:17]([O:19]C)=[O:18])=[C:14]([CH3:24])[N:13]=[C:12]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:11]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[OH-].[Na+]>CO>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:15]([CH:16]([CH2:21][CH2:22][CH3:23])[C:17]([OH:19])=[O:18])=[C:14]([CH3:24])[N:13]=[C:12]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:11]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1-c1ccc2[nH]ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc(-c2ccccc2)nc1-c1ccc2[nH]ccc2c1
Yield: 49.8 %

Procedure:
This compound was prepared according to general method D from methyl 2-(4-(1H-indol-5-yl)-6-methyl-2-phenylpyrimidin-5-yl)pentanoate (0.098 g; 0.245 mmol), sodium hydroxide 10N (0.245 mL; 2.45 mmol) in methanol (2.5 mL) to afford 0.047 g (48%) of the title compound as a white solid.
Reaction SMILES: [CH:1]1[C:14]2[C:13]3([C:16](O)=[O:17])[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[OH:23][CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH:11]1[C:12]2[C:13]3([C:16]([N:27]4[CH2:28][CH2:29][CH:24]([OH:23])[CH2:25][CH2:26]4)=[O:17])[CH2:15][CH:6]([C:5]4[C:14]3=[CH:1][CH:2]=[CH:3][CH:4]=4)[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: O=C(O)C12CC(c3ccccc31)c1ccccc12
Reactant: OC1CCNCC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Product: O=C(N1CCC(O)CC1)C12CC(c3ccccc31)c1ccccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 9,10-dihydro-9,10-methano-9-anthracenecarboxylic acid (24.1 mmol) in toluene (70 mL) was added thionyl chloride (2.28 mL, 31.3 mmol, 1.3 eq). The reaction was heated to reflux monitoring gas evolution with a mineral oil bubbler. The system reached a steady state within 40 min at which time it was slightly cooled and 4-hydroxypiperidine (6.08 g, 60.3 mmol, 2.5 eq) was added portionwise. A significant amount of heat is evolved and the reaction became dark. The suspension was heated to reflux for 2 h, cooled to room temperature and stirred for 18 h. The reaction was diluted with ethyl acetate (200 mL) and washed with 3N HCl (2×100 mL), 2.5N NaOH (2×100 mL) and saturated brine (200 mL). The organic phase was dried over anhydrous magnesium sulfate, filtered, and reduced to an oil. The procedure yielded the title compound in quantitative yield as a viscous oil. TLC analysis (Rf 0.54, 10% methanol in CHCl3). MS (Cl, CH4) m/z 320 (M+1, 100), 348 (M+29,22), 302 (16)
Reaction SMILES: [C:1]12([CH2:11][CH2:12][C:13]3[NH:17][C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[CH3:24])=[N:15][C:14]=3[C:25](O)=[O:26])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH2:28][C:29]1[CH:30]=[C:31]([S:35]([NH:38][C:39](=[O:46])[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)(=[O:37])=[O:36])[CH:32]=[CH:33][CH:34]=1>>[C:39]([NH:38][S:35]([C:31]1[CH:30]=[C:29]([NH:28][C:25]([C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH3:24])[NH:17][C:13]=2[CH2:12][CH2:11][C:1]23[CH2:10][CH:5]4[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]4)[CH2:8]2)[CH2:2]3)=[O:26])[CH:34]=[CH:33][CH:32]=1)(=[O:37])=[O:36])(=[O:46])[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: Cc1ccccc1-c1nc(C(=O)O)c(CCC23CC4CC(CC(C4)C2)C3)[nH]1
Reactant: Nc1cccc(S(=O)(=O)NC(=O)c2ccccc2)c1
Product: Cc1ccccc1-c1nc(C(=O)Nc2cccc(S(=O)(=O)NC(=O)c3ccccc3)c2)c(CCC23CC4CC(CC(C4)C2)C3)[nH]1

Procedure:
5-(2-Adamantan-1-yl-ethyl)-2-o-tolyl-1H-imidazole-4-carboxylic acid (Example 93) was reacted with 3-amino-N-benzoyl-benzenesulfonamide using essentially the same procedure as in Example 20, step d. The crude product was purified by flash column chromatography (silica, ethyl acetate/hexane 2:1) to afford the title compound. 1H NMR 300 MHz, d6-DMSO) 12.52 (1H, br s), 9.85 (1H, br s), 8.55 (1H, br s), 7.89 (3H, m), 7.62-7.29 (9H, m), 2.99 (2H, m), 2.54 (3H, s), 1.95 (3H, s), 1.66-1.40 (14H, m). Found: C, 67.51; H, 6.33; N, 8.63%; C36H38N4O4S.1.0 H2O requires: C, 67.48; H, 6.29; N, 8.74%.
Reaction SMILES: NCCCN(C1C=C(C)N=C(N2C=CN=C2)N=1)[CH2:6][C:7]([NH:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)=[O:8].O.[O-]C#N.[K+]>N1C=CC=CC=1>[CH3:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][CH2:10][NH:9][C:7](=[O:8])[CH3:6])=[CH:17][CH:16]=1
Reactant: COc1ccc(CCNC(=O)CN(CCCN)c2cc(C)nc(-n3ccnc3)n2)cc1
Agent: N#C[O-]
Agent: [K+]
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(CCNC(C)=O)cc1
Temperature: 80 °C

Procedure:
To 2-[(3-aminopropyl)[2-(1H-imidazol-1-yl)-6-methyl-4-pyrimidinyl]amino]-N-[2-(4-methoxyphenyl)ethyl]acetamide (135 mg, 0.32 mmol) (a compound of formula (Yc6)) in pyridine (1.5 mL) was added water (1.5 mL) solution of potassium cyanate (64 mg, 0.76 mmol). The mixture was stirred and heated in an oil bath at 80° C. overnight. The mixture was poured into water and extracted with ethyl acetate (3×20 mL). The combined ethyl acetate fractions were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel (9:1 CH3CN/NH4OH) to afford 2-[[3-ureido)propyl][2-(1H-imidazol-1-yl)-6-methyl-4-pyrimidinyl]amino]-N-[2-(4-methoxyphenyl)ethyl]acetamide, a compound of formula (Yc9); as a white solid; NMR (DMSO-d6, 90° C.) 8.4 (s, 1), 7.8 (s, 1), 7.05 (d, 2), 7.0 (s, 1), 6.75 (d, 2), 6.4 (s, 1), 4.1 (s, 2), 3.7 (s, 3), 3.5 (m, 2), 3.25 (m, 2), 3.05 (m, 2), 2.65 (t, 2), 2.3 (s, 3), 1.7 (m, 2) ppm.