Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH2:7][OH:8])[NH2:6].CCN(CC)CC.[C:17]([N:27]1[CH2:34][CH2:33][CH2:32][C@@H:28]1[C:29](O)=[O:30])([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[OH:8][CH2:7][C@H:5]([NH:6][C:29]([C@H:28]1[CH2:32][CH2:33][CH2:34][N:27]1[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])=[O:30])[C:4]([O:3][CH3:2])=[O:9]
Reactant: COC(=O)[C@@H](N)CO
Reactant: O=C(O)[C@H]1CCCN1C(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](CO)NC(=O)[C@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.8 %

Procedure:
To a solution of L-Serine methyl ester hydrochloride (Aldrich, 5.0 g, 32.0 mmoles), in CH2Cl2 (150 mL) at 0° C., were added Et3N (4.88 mL, 35.2 mmoles), Cbz-D-Proline (8.01 g, 32.0 mmoles) and DCC (7.26 g, 35.2 mmoles) sequentially. The reaction was allowed to warm to room temperature and stirred overnight. All the solvent was evaporated and the residue was triturated with ethyl acetate and the precipitate was filtered off. The filtrate was concentrated under low pressure and chromatographed on silica gel (70% ethyl acetate/30% chloroform) to yield 8.5 g of (R)-benzyl 2-((S)-3-hydroxy-1-methoxy-1-oxopropan-2-ylcarbamoyl)pyrrolidine-1-carboxylate.
Reaction SMILES: [N:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH3:10]>CO>[N:1]1([C:7]([NH2:10])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)N1CCOCC1
Reactant: N
Solvent: CO
Product: NC(=O)N1CCOCC1

Procedure:
A solution of morpholine-4-carbonyl chloride (2.0 g) in methanol (10 mL) and 7 N NH3 in methanol (5 mL) was stirred at 45° C. overnight. The mixture was concentrated to give a solid, which was dried under vacuum.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:10]([O:12]C)=[O:11])=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[OH-].[Na+].Cl>CO>[OH:1][C:2]1[C:3]([C:10]([OH:12])=[O:11])=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1
Reactant: COC(=O)c1nc(OC)ccc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(O)c(C(=O)O)n1
Reaction time: 3 h
Yield: 75.8 %

Procedure:
Methyl 3-hydroxy-6-methoxypicolinate (80 mg) was dissolved in 4 ml of methanol. A 1 N aqueous sodium hydroxide solution (2 ml) was added to the solution, and a reaction was allowed to proceed at room temperature for 3 hr. The reaction solution was adjusted to pH 3 by the addition of 1 N hydrochloric acid. The precipitate was collected by filtration to give 56 mg (yield 76%) of the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH2:9]OS(C)(=O)=O)=[C:6]([Cl:15])[N:5]=[CH:4][N:3]=1.[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH2:23])=[CH:20][CH:19]=1>ClCCCl>[Cl:15][C:6]1[C:7]2[CH2:8][CH2:9][N:23]([CH2:22][C:21]3[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=3)[C:2]=2[N:3]=[CH:4][N:5]=1
Reactant: COc1ccc(CN)cc1
Reactant: CS(=O)(=O)OCCc1c(Cl)ncnc1Cl
Solvent: ClCCCl
Product: COc1ccc(CN2CCc3c(Cl)ncnc32)cc1
Yield: 71 %

Procedure:
A solution of methanesulfonic acid 2-(4,6-dichloro-pyrimidin-5-yl)-ethyl ester (0.50 g, 1.84 mmol) and 4-methoxybenzylamine (0.60 g, 4.37 mmol) in DCE (30 mL) and TEA (4 mL) was refluxed overnight. After cooling, the solvent was removed and the residue was subject to column chromatography, eluted by hexane/ethyl acetate (4:1) to give 4-Chloro-7-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine (0.36 g, 71%). 1H NMR (CDCl3, 400 MHz) δ 8.35 (s, 1H), 7.26 (dd, J=2.8 Hz, J=1.6 Hz, 2H), 6.88 (d, J=4.4 Hz, 2H), 5.33 (s, 1H), 4.62 (d, J=5.6 Hz, 2H), 3.81 (s, 3H), 3.73 (t, J=7.2 Hz, 2H), 3.04 (t, J=6.8 Hz, 2H). MS (APCI+) [M+H]+276.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[NH:13][N:12]=1)([O:3][CH3:4])=[O:2].[H-].[Na+].[C:26](Cl)(=[O:28])[CH3:27]>O1CCCC1>[C:26]([N:13]1[C:14]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)=[CH:15][C:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:1]([O:3][CH3:4])=[O:2])=[N:12]1)(=[O:28])[CH3:27]
Reactant: COC(=O)c1ccccc1-c1cc(-c2ccc(OC)cc2)[nH]n1
Reactant: CC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccccc1-c1cc(-c2ccc(OC)cc2)n(C(C)=O)n1

Procedure:
A mixture of 30 g 3-(2-carbomethoxyphenyl)-5-(4-methoxyphenyl)pyrazole, 0.30 g sodium hydride and 0.8 g acetyl chloride in 50 ml anhydrous tetrahydrofuran (THF) is stirred and refluxed overnight. The reaction mixture is filtered and the THF is removed from the filtrate to yield 1-acetyl-3-(2-carbomethoxyphenyl)-5-(4-methoxyphenyl)pyrazole.
Reaction SMILES: CO.C(O)C.C(OC(=O)C)(=O)C.[NH:13]([C:17]1[C:25]2[S:24][N:23]=[CH:22][C:21]=2[C:20]([O:26]C(=O)C)=[CH:19][CH:18]=1)C(C)=O>C(O)(=O)C.C(O)CC>[NH2:13][C:17]1[C:25]2[S:24][N:23]=[CH:22][C:21]=2[C:20]([OH:26])=[CH:19][CH:18]=1
Reactant: CC(=O)Nc1ccc(OC(C)=O)c2cnsc12
Solvent: CCCO
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: Nc1ccc(O)c2cnsc12

Procedure:
This reduction is as a rule carried out under atmospheric pressure or in a closed vessel under superatmospheric pressure, with or without simultaneous heating. The reaction may be carried out in the presence of a diluent or solvent, for example, a lower alcohol, e.g. methanol, ethanol or preferably propanol, or in the acid required for the reduction, preferably in acetic acid, or in the acylating reaction medium of acetic acid and acetic anhydride, described above, in which 7-acetamino-4-acetoxy-1,2-benzisothiazole is obtained. 7-Acetamino-4-acetoxy-1,2-benzisothiazole can subsequently be deacylated in the above manner to give 7-amino-4-hydroxy-1,2-benzisothiazole.
Reaction SMILES: [CH2:1]([N:3]([CH2:15][CH3:16])[C:4]([C:6]1[CH2:11][CH:10]([CH3:12])[CH2:9][CH:8](Br)[C:7]=1O)=[O:5])[CH3:2].[CH2:17]([O:24][CH2:25][CH2:26][NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC(O)C.[Cl-].[Zn+2].[Cl-]>[CH2:1]([N:3]([CH2:15][CH3:16])[C:4]([CH:6]1[C:7]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH2:26][CH2:25][O:24][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:8]=2[CH2:9][CH:10]([CH3:12])[CH2:11]1)=[O:5])[CH3:2]
Reactant: c1ccc(COCCNc2ccccc2)cc1
Reactant: CCN(CC)C(=O)C1=C(O)C(Br)CC(C)C1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(C)O
Product: CCN(CC)C(=O)C1CC(C)Cc2c1c1ccccc1n2CCOCc1ccccc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 8 %

Procedure:
A mixture of 3-bromo-2-hydroxy-5-methyl-cyclohex-1-enecarboxylic acid diethylamide (47) (4.0 g, 14 mmol) and (2-benzyloxy-ethyl)-phenyl-amine (21; prepared according to Example 3(c)) (6.3 g, 28 mmol) was stirred under N2 at 50° C. for 3 h and the reaction turned brown. The resulting mixture was dissolved in propan-2-ol (14 mL) and dry zinc chloride (5.72 g, 42 mmol) was added. The mixture was heated to reflux under N2 for 16 h and then concentrated in vacuo. The residue was dissolved in ethyl acetate (200 mL) and washed with 2 N HCl (50 mL), water (2×50 mL) and aqueous potassium carbonate solution (2×50 mL) then dried and concentrated in vacuo. The crude mixture was purified by SCX cartridge (40 mL) and then silica gel chromatography eluting with petrol (A) and ethyl acetate (B) (10-50% B, 100 g, 12 CV, 85 mL/min) to afford 467 mg (8%) of 9-(2-Benzyloxy-ethyl)-2-methyl-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid diethylamide (48) as a white solid. The structure was confirmed by 1H NMR (300 MHz, CDCl3) δH 1.20-1.40 (9H, m, CH3 and N(CH2CH3)2), 1.90-2.20 (3H, m, 2-CH and 3-CH2), 2.35-2.45 (1H, m, 1-CH2), 2.85-2.95 (1H, m, 1-CH2), 3.40-3.70 (4H, m, N(CH2CH3)2), 3.70-3.80 (1H, m, 4-CH), 4.10-4.30 (4H, m, NCH2CH2OBn), 4.43 (2H, s, OCH2Ph), and 7.00-7.30 (9H, m, CHCHCHCH and Ph).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH3:23])[C:7]=1[NH:8][C:9]1[C:18]2[C:13](=[C:14]([OH:21])[C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[NH:12][C:11](=[O:22])[CH:10]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(C)=O.Br[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][Cl:41]>C(OCC)(=O)C>[Cl:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][O:21][C:14]1[C:15]([O:19][CH3:20])=[CH:16][CH:17]=[C:18]2[C:13]=1[NH:12][C:11](=[O:22])[CH:10]=[C:9]2[NH:8][C:7]1[C:6]([CH3:23])=[CH:5][N:4]=[CH:3][C:2]=1[CH3:1]
Reactant: ClCCCCCCBr
Reactant: COc1ccc2c(Nc3c(C)cncc3C)cc(=O)[nH]c2c1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COc1ccc2c(Nc3c(C)cncc3C)cc(=O)[nH]c2c1OCCCCCCCl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 4-(3,5-dimethylpyridin-4-ylamino)-8-hydroxy-7-methoxyquinolin-2(1H)-one (1.46 g, 4.7 mmol), cesium carbonate (1.83 g, 5.6 mmol), and DMSO (15 mL) was stirred at room temperature for 15min, and then 1-bromo-6-chlorohexane (0.83 mL, 5.6 mmol) was added. After 45 min, the reaction was diluted with ethyl acetate, washed with water (×3), dried, filtered, concentrated, and then triturated with hexane/diethyl ether to remove the excess 1-bromo-6-chlorohexane. The solid residue was purified by silica gel chromatography (49:1→23:2; dichloromethane/methanol) to give 8-(6-chlorohexyloxy)-4-(3,5-dimethylpyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one. 1H NMR (400 MHz, CDCl3): δ 8.59 (s, 1H), 8.38 (s, 2H), 7.42 (d, 1H), 6.90 (d, 1H), 6.05 (s, 1H), 5.13 (d, 1H), 4.12 (t, 2H), 3.97 (s, 3H), 3.56 (t, 2H), 2.21 (s, 6H), 1.82 (m, 4H), 1.52 (m, 4H); MS (ESI): 430.3.
Reaction SMILES: [Li+].[OH-].[Cl:3][C:4]1[CH:8]=[C:7]([C:9]([NH:11][CH:12]2[CH2:14][CH2:13]2)=[O:10])[NH:6][C:5]=1[C:15]([O:17]C)=[O:16]>C1COCC1.CO>[Cl:3][C:4]1[CH:8]=[C:7]([C:9]([NH:11][CH:12]2[CH2:13][CH2:14]2)=[O:10])[NH:6][C:5]=1[C:15]([OH:17])=[O:16]
Reactant: COC(=O)c1[nH]c(C(=O)NC2CC2)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(NC1CC1)c1cc(Cl)c(C(=O)O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
LiOH (1 N in water, 2 mL, 2 mmol) was added to a solution of methyl 3-chloro-5-[(cyclopropylamino)carbonyl]-1H-pyrrole-2-carboxylate (0.0992 g, 0.409 mmol) in THF (2 mL) and methanol (2 mL) and the solution was stirred at RT overnight. The reaction mixture was evaporated to a residue and partitioned between EtOAc and 1 N HCl. The organic layer was separated, dried over MgSO4 and evaporated to a solid to afford the title compound (0.072 g, 77%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.08 (s, 1H), 12.05 (br. s., 1H), 8.32 (d, 1H), 6.73 (d, 1H), 2.71-2.81 (m, 1H), 0.62-0.72 (m, 2H), 0.42-0.53 (m, 2H). LCMS: m/z 229.2 (M+1).
Reaction SMILES: [CH3:1][N:2]1[N:6]2[C:7](=[O:17])[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:10]=[C:5]2[CH:4]=[CH:3]1.C1(OC2C=CC=CC=2)C=CC=CC=1>>[CH3:1][N:2]1[CH:3]=[C:4]2[C:5]([N:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:8]=[C:7]2[OH:17])=[N:6]1
Reactant: Cn1ccc2nc(-c3ccccc3)cc(=O)n21
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cn1cc2c(O)cc(-c3ccccc3)nc2n1
Reaction time: 1.5 h

Procedure:
152 g. of 1-methyl-5-phenylpyrazolo[1,5-a]pyrimidin-7-(1H)-one (0.67 mol.) in 500 ml. of diphenyl ether are heated at 250°, while stirring, for 90 minutes. After standing overnight, the crystallized 2-methyl-6-phenyl-2H-pyrazolo[3,4-b]pyridin-4-ol is filtered off, washed with ether and dried at 70°, yield: 146.6 g. (96%); m.p. 241°-243°. A sample recrystallized from acetonitrile melts at 242°-244°.
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1([CH2:15][N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[O:8][C:7]2=[N:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][N:6]2[CH2:5]1.CN(C=O)C.C(N(CC)CC)C.[C:34]1([CH3:44])[CH:39]=[CH:38][C:37]([CH2:40][C:41](O)=[O:42])=[CH:36][CH:35]=1>C(OCC)(=O)C>[CH3:3][C:4]1([CH2:15][N:16]2[CH2:17][CH2:18][N:19]([C:41](=[O:42])[CH2:40][C:37]3[CH:38]=[CH:39][C:34]([CH3:44])=[CH:35][CH:36]=3)[CH2:20][CH2:21]2)[O:8][C:7]2=[N:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][N:6]2[CH2:5]1
Reactant: Cc1ccc(CC(=O)O)cc1
Reactant: CC1(CN2CCNCC2)Cn2cc([N+](=O)[O-])nc2O1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1ccc(CC(=O)N2CCN(CC3(C)Cn4cc([N+](=O)[O-])nc4O3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.5 %

Procedure:
A mixture of 2-Methyl-6-nitro-2-(piperazin-1-ylmethyl)-2,3-dihydroimidazo[2,1-b]oxazole dihydrochloride prepared in Example 322 (240 mg, 0.79 mmol), DMF (5 ml) and triethylamine (0.22 ml, 1.58 mmol) was added p-tolylacetic acid (140 mg, 0.93 mmol) and WSCD (180 mg, 0.93 mmol) in this order followed by stirring at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, washed with water twice, a saturated sodium hydrogencarbonate solution and a saturated saline solution in this order, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was treated with diethylether to afford 1-[4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazin-1-yl]-2-(4-tolyl)ethanone (172 mg, yield 64%) as a white powder.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4](S([O-])=O)=[CH:3][CH:2]=1.[Na+].Br[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1.[O-2].[Ca+2]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN1CCCC1=O>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:4]2[CH:5]=[CH:6][C:1]([CH3:10])=[CH:2][CH:3]=2)=[CH:14][CH:15]=1
Reactant: Cc1ccc(S(=O)[O-])cc1
Reactant: COc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Ca+2]
Solvent: CN1CCCC1=O
Product: COc1ccc(-c2ccc(C)cc2)cc1
Yield: 75 %

Procedure:
3.56 g (20 mmol) of sodium p-toluenesulfinate, 3.74 g (20 mmol) of p-bromoanisole, 0.0225 g (0.1 mmol) of palladium acetate, 0.0478 g (0.12 mmol) of 1,2-bis(diphenylphosphino)-ethane, 6.73 g (120 mmol) of calcium oxide and 60 ml of N-methyl-2-pyrrolidone were placed in a 100 ml round bottom flask and reacted at 150° C. in a nitrogen gas stream for 6 hours. After the completion of the reaction, the reaction mixture was analyzed by means of high performance liquid chromatography. The analysis showed that 15.0 mmol (yield 75%) of 4'-methoxy-4-methylbiphenyl was formed in the reaction mixture solution.
Reaction SMILES: C([O:5][C:6](=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([O:14][C:15]2[N:16]=[N:17][C:18]([CH2:34][CH2:35][CH2:36][CH3:37])=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:23][CH:22]=3)[CH:20]=2)[CH2:10][CH2:9]1)(C)(C)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:34]([C:18]1[N:17]=[N:16][C:15]([O:14][C@H:11]2[CH2:10][CH2:9][C@H:8]([NH:7][CH:6]=[O:5])[CH2:13][CH2:12]2)=[CH:20][C:19]=1[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:23][CH:22]=1)[CH2:35][CH2:36][CH3:37]
Reactant: CCCCc1nnc(O[C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)cc1-c1ccc(OC2CCCCC2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCc1nnc(O[C@H]2CC[C@H](NC=O)CC2)cc1-c1ccc(OC2CCCCC2)cc1

Procedure:
A solution of trans-{4-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxy]-cyclohexyl}-carbamic acid tert-butyl ester (1 mmol) in anhydrous THF at 0° C. may be treated with LAH in THF (1 M, 2 mL). The reaction may be allowed to come to room temperature. The reaction may be quenched with water and extracted with ethyl acetate. The product may be isolated by flash chromatography using ethyl acetate/hexanes mixtures to give trans-N-{4-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxy]-cyclohexyl}-formamide.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][C:14]([CH3:17])([OH:16])[CH3:15])=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:18](Cl)(=O)[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>ClCCl>[CH3:15][C:14]([OH:16])([CH3:17])[CH2:13][N:12]1[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=[C:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CC(C)(O)CNc1c(N)cnc2ccccc12
Reactant: CCCCCC(=O)Cl
Solvent: ClCCl
Product: CCCCCc1nc2cnc3ccccc3c2n1CC(C)(C)O
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 59.1 %

Procedure:
To a solution of 1-(3-aminoquinolin-4-ylamino)-2-methylpropan-2-ol (CAN 129655-59-0, 0.94 g, 4.06 mmol) in dichloromethane (9.5 mL) in an inert atmosphere was added dropwise with stirring at room temperature over a period of 6 min a solution of hexanoyl chloride (422 μl, 4.47 mmol) in dichloromethane (6.4 mL). After 3 h additional hexanoyl chloride (192 μl, 2.03 mmol) was added and stirring continued for another hour and finally the mixture was concentrated in vacuo. The residue was re-dissolved in ethanol (13.5 mL) and, after addition of sodiumhydroxide solution (1 M, 10.8 mL) the mixture was heated with stirring in argon to 90° C. After 75 min the mixture was allowed to cool to room temperature and concentrated in vacuo. The residue was stirred with ethyl acetate (30 mL) and water (5 mL) dried by filtration over ChemElut® and ethyl acetate was removed in vacuo. The residue was purified by flash chromatography (silica gel-NH2, 0% to 100% ethyl acetate in heptane) to give the title compound (747 mg, 89%) as yellow oil; LC-MS (UV peak area, ESI) 95%, 312.2 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[N:5]2.C1C(=O)N([Br:19])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>>[Br:19][CH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[N:5]2
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2nccnc2c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: BrCc1ccc2nccnc2c1
Yield: 77.5 %

Procedure:
To a solution of 6-methylquinoxaline (10.0 g, 69.4 mmol) in CCL4 (80 mL) was added NBS (13.5 g, 76.3 mmol) and benzoyl peroxide (BP, 1.7 g, 6.9 mmol) at room temperature. The mixture was heated at reflux for 2 hours. After cooling, the mixture was evaporated under vacuum to give a yellow solid, which was extracted with Petroleum Ether (50 mL×5). The extracts were concentrated under vacuum. The organics were combined and concentrated to give crude 6-bromomethylquinoxaline (12.0 g), which was used directly in the next step. 1H NMR (300 MHz, CDCl3) δ 8.85-8.87 (m, 2H), 8.10-8.13 (m, 2H), 7.82 (dd, J=2.1, 8.7 Hz, 1H), 4.70 (s, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:12]([NH2:13])=[CH:11][C:10]([C:14]([CH3:17])([CH3:16])[CH3:15])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[K+].[K+].C([O:45][C:46](=[O:50])[C:47]([CH3:49])=[CH2:48])C>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[NH2:13][C:12]1[N:8]([C:4]2[CH:3]=[C:2](/[CH:48]=[C:47](\[CH3:49])/[C:46]([OH:50])=[O:45])[CH:7]=[CH:6][CH:5]=2)[N:9]=[C:10]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:11]=1
Reactant: CC(C)(C)c1cc(N)n(-c2cccc(Br)c2)n1
Reactant: C=C(C)C(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: C/C(=C\c1cccc(-n2nc(C(C)(C)C)cc2N)c1)C(=O)O
Temperature: 80 °C
Reaction time: 8 h
Yield: 53.4 %

Procedure:
To a suspension of 2-(3-bromo-phenyl)-5-t-butyl-2H-pyrazol-3-ylamine (5.8 g, 20 mmol), Pd(OAc)2 (450 mg, 2 mmol), PPh3 (1.0 g, 4 mmol), and K2CO3 (5.5 g, 40 mmol) in DMF (50 mL) was added 2-methyl-acrylic acid ethyl ester (2.8 g, 25 mmol) at RT under N2. The mixture was stirred at 80° C. overnight, concentrated under reduced pressure, and purified by column chromatography to afford (E)-3-[3-(5-amino-3-t-butyl-1H-pyrazol-1-yl)phenyl]-2-methylacrylic acid (3.2 g). MS (ESI) m/z: 328 (M+H+)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([N:19]([CH:21]([CH3:23])[CH3:22])[CH3:20])[C:16]([OH:18])=[O:17])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1[C:29]2N=CC=C[C:28]=2N=N1.Cl.N=C=N.C(O)C>CN(C)C1C=CN=CC=1.C1COCC1>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([N:19]([CH:21]([CH3:23])[CH3:22])[CH3:20])[C:16]([O:18][CH2:28][CH3:29])=[O:17])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: On1nnc2cccnc21
Reactant: CC(C)N(C)C(C(=O)O)c1ccc(NC(=O)OC(C)(C)C)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: N=C=N
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)C(c1ccc(NC(=O)OC(C)(C)C)cc1)N(C)C(C)C
Reaction time: 0.25 h
Yield: 73 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with 25 (1.50 g, 4.66 mmol), THF (45 mL), 1-hydroxy-7-azabenzotriazole (1.27 g, 9.32 mmol) and 1-ethyl-3-[3-dimethyl amino)propyl]-carbodiimide hydrochloride (1.79 g, 9.32 mmol), and the reaction mixture was stirred for 15 min. Ethanol (429 mg, 9.32 mmol) and 4-dimethylamino pyridine (57 mg, 0.47 mmol) were added, and the reaction mixture was stirred at room temperature for a further 16 h. After this time, the reaction was partitioned between water (40 mL) and methylene chloride (50 mL). The layers were separated, and the aqueous phase was extracted with methylene chloride (2×30 mL). The organic extracts were combined and dried over sodium sulfate. The drying agent was removed by filtration, and the solvent was evaporated under reduced pressure. The resulting residue was dried to a constant weight under vacuum to afford 26 in 73% yield (1.20 g) as a white solid: mp 87-88° C.; 1H NMR (500 MHz, DMSO-d6) δ 9.35 (s, 1H), 7.40 (d, 2H, J=7.5 Hz), 7.28 (d, 2H, J=7.5 Hz), 4.16 (s, 1H), 4.05 (m, 2H), 2.80 (septet, 1H, J=6.5 Hz), 2.02 (s, 3H), 1.47 (s, 9H), 1.11 (t, 3H, J=7.0 Hz), 0.94 (d, 3H, J=6.5 Hz), 0.88 (d, 3H, J=6.5 Hz); MS (ESI+) m/z 351 (M+H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=S)=[N:7]1.[NH3:21]>>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([NH2:21])=[N:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:7]1
Reactant: OCCCCn1ccc(NC(=S)Nc2ccccc2)n1
Reactant: N
Product: NC(=Nc1ccccc1)Nc1ccn(CCCCO)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 100 %

Procedure:
Yellow mercuric oxide (0.295 g.) was added to a solution of 1-(4-hydroxybutyl)-3-(3-phenylthioureido)pyrazole (100 mg.) in ethanolic ammonia (6 M; 10 ml.). The mixture was stirred at room temperature for 48 hours, centrifuged to remove the precipitated mercuric sulphide, and the supernatant evaporated to dryness in vacuo to give 1-(4-hydroxybutyl)-3-(2-phenylguanidino)pyrazole (98 mg; 100%) having the following n.m.r. spectrum in d6DMSO: 7.3 (br m, 9H); 5.7 (d, 1H); 4.2 (br m, 1H); 3.9 (t, 2H); 3.3 (t, 2H); 1.5 (br m, 4H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:13])=[CH:4][N:3]=1.[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[OH:28].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>C(OCC)(=O)C>[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[O:28][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:13])=[CH:4][N:3]=1
Reactant: Oc1ccc(Cl)cc1Cl
Reactant: O=C(c1cnc(Cl)nc1C(F)(F)F)N1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(c1cnc(Oc2ccc(Cl)cc2Cl)nc1C(F)(F)F)N1CCOCC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 14.8 %

Procedure:
A mixture of 4-{[2-chloro-4-(trifluoromethyl)pyrimidin-5-yl]carbonyl}morpholine (170 mg), 2,4-dichlorophenol (112 mg), cesium carbonate (225 mg), and N,N-dimethyl formamide (2 mL) was stirred at room temperature for 15 hours, and then at 100° C. for 10 hours. To the reaction liquid was added ethyl acetate (30 mL), followed by washing with saturated brine (20 mL) and a saturated aqueous ammonium chloride solution (20 mL) in this order, the organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform-ethyl acetate) to obtain 4-{[2-(2,4-dichlorophenoxy)-4-(trifluoromethyl)pyrimidin-5-yl]carbonyl}morpholine (36 mg) as a brown oily substance.