Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11]Br)[N:6]=1)=[O:4].[I:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][O:20][C:17]2[CH:18]=[CH:19][C:14]([I:13])=[CH:15][CH:16]=2)[N:6]=1)=[O:4]
Reactant: Oc1ccc(I)cc1
Reactant: COC(=O)c1cccc(CBr)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)c1cccc(COc2ccc(I)cc2)n1
Yield: 61.3 %

Procedure:
6-Bromomethyl-pyridine-2-carboxylic acid methyl ester (2.27 g, 9.9 mmol; from Step 2 above) was dissolved in acetone (50 mL) and 4-iodophenol (2.37 g, 10.8 mmol; available from Aldrich Chemical Company, Inc., Milwaukee, Wis.) was added, followed by finely ground potassium carbonate (1.54 g, 11.2 mmol). The mixture was heated overnight at 60 degrees, and it was then cooled and filtered. The solid was washed with acetone and the filtrate was concentrated to dryness. Ethyl acetate (100 mL) was added and the solution was washed twice with 2 M NaOH, with water, and with brine. The solution was dried (magnesium sulfate), filtered and evaporated to give the crude product. This was dissolved in acetone (approximately 25 mL) with warming, and water (approximately 20 mL) was added. An oil came out of solution and it crystallized. The mixture was heated to redissolve the solid and the solution was seeded with a crystal of the product to give crystals of the product. The recrystallization was repeated to give 6-(4-iodo-phenoxymethyl)-pyridine-2-carboxylic acid methyl ester (2.24 g, 62%) as a white crystalline solid. Mass spectrum m/z 370.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11](Cl)=[O:12])=[O:4].[CH:16]1[C:27]2[CH:26]=[CH:25][C:24]3[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=3[CH2:22][NH:21][C:20]=2[CH:19]=[CH:18][CH:17]=1.N1C=CC=CC=1>C(Cl)Cl>[CH:16]1[C:27]2[CH:26]=[CH:25][C:24]3[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=3[CH2:22][N:21]([C:11](=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:3](=[O:4])[C:2]([F:15])([F:14])[F:1])[C:20]=2[CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)CCCCCNC(=O)C(F)(F)F
Reactant: C1=Cc2ccccc2NCc2ccccc21
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(CCCCCNC(=O)C(F)(F)F)N1Cc2ccccc2C=Cc2ccccc21
Reaction time: 0.5 h
Yield: 70.7 %

Procedure:
6-(trifluoroacetamido)hexanoyl chloride (Clark et al., Chem. Soc. Perkin Trans. 1 2001:3312-3324) (0.984 g, 4.52 mmol) was added to a solution of 2 (0.75 g, 3.62 mmol) and pyridine (0.859 g, 10.86 mmol) in CH2Cl2 (approximately 10 ml) at room temperature, and stirred for 30 minutes. The reaction mixture was diluted with CH2Cl2 (approximately 20 mL), washed with water (2×30 mL), dried over anhydrous MgSO4 and the solvent was removed under reduced pressure. The residue was purified by chromatography (hexanes:ethyl acetate 2:3) to provide 1.064 g (2.56 mmol, 71%) of 3 as yellowish oil. 1H: δ 7.32-7.22 (m, 4H), 7.19-7.11 (m, 4H), 6.77 (d, J=13.2 Hz, 1H), 6.58 (d, J=13.2 Hz, 1H), 5.46 (d, J=14.8 Hz, 1H), 4.20 (d, J=14.8 Hz, 1H), 3.29-3.15 (m, 2H), 2.09-2.02 (m, 1H), 1.93-1.85 (m, 1H), 1.51-1.32 (m, 4H), 1.25-1.04 (m, 2H); 13C: 172.7, 157.5, 141.1, 136.1, 135.8, 134.8, 132.4, 131.8, 130.5, 128.5, 128.2, 128.1, 128.0, 127.3, 127.2, 117.5, 114.6, 54.8, 39.6, 34.3, 28.2, 25.9, 24.3; FIRMS (ESI+) m/z calcd for C23H24F3N2O2 [M+H]+ 417.1790. found 417.1783.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[CH2:7][C@H:8]([C:18]1[O:22][N:21]=[C:20]([CH2:23][N:24]([CH2:26][C:27](O)=[O:28])[CH3:25])[N:19]=1)[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:4])([CH3:3])[CH3:2].[NH:31]([CH3:33])[CH3:32].Cl>>[CH:12]1([CH2:11][CH2:10][CH2:9][C@@H:8]([C:18]2[O:22][N:21]=[C:20]([CH2:23][N:24]([CH2:26][C:27]([N:31]([CH3:33])[CH3:32])=[O:28])[CH3:25])[N:19]=2)[CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:30])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CNC
Reactant: CN(CC(=O)O)Cc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Agent: Cl
Product: CN(CC(=O)N(C)C)Cc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1

Procedure:
Method as for preparation 56 using [({5-[(1R)-1-(2-tert-butoxy-2-oxoethyl)-4-cyclohexylbutyl]-1,2,4-oxadiazol-3-yl}methyl)(methyl)amino]acetic acid (preparation 133) (725 mg, 1.71 mmol) and Me2NH.HCl (106 mg, 1.30 mmol) as starting materials.
Reaction SMILES: [O:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:10].[CH3:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18](Cl)=[O:19])[CH2:14][CH2:13]1.C(N(CC)CC)C>N1C=CC=CC=1>[CH3:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]([N:3]2[C:4]3=[N:5][CH:6]=[CH:7][CH:8]=[C:9]3[O:1][C:2]2=[O:10])=[O:19])[CH2:14][CH2:13]1
Reactant: CC1CCN(C(=O)Cl)CC1
Reactant: O=c1[nH]c2ncccc2o1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CC1CCN(C(=O)n2c(=O)oc3cccnc32)CC1

Procedure:
100 mg (0.735 mmol) of 3H-oxazolo[4,5-b]pyridin-2-one, 235 mg (1.45 mmol) of 4-methylpiperidine-1-carbonyl chloride and 101 μl (2.18 mmol) of triethylamine were stirred in 5 ml of pyridine at room temperature for 3 h. The reaction mixture was concentrated, and the residue was dissolved in water and extracted with ethyl acetate. The organic phase was concentrated and purified by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 6 mg (3%), M+H+: 262.12.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:16][C:17]([CH3:22])([CH3:21])[C:18](Cl)=[O:19].Cl>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:18](=[O:19])[C:17]([CH3:22])([CH3:21])[CH3:16])[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc(Cl)n1
Reactant: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)C(=O)Nc1cccc(Cl)n1
Temperature: 50 °C
Reaction time: 4 h
Yield: 92.3 %

Procedure:
A solution of 6-chloro-2-pyridinamine (13.776 g, 107 mmol) in toluene (100 ml) and triethylamine (16.28 ml, 118 mmol) at 50° C. under argon was treated with 2,2-dimethylpropanoyl chloride (13.81 ml, 112 mmol). The reaction was then stirred at 50° C. for 4 h and then at rt for 18 h. 2M HCl (200 ml) was then added and the mixture was extracted with diethyl ether (3×500 ml). The organic extracts were dried (MgSO4), filtered and evaporated to give the product as a brown solid (21.005 g, 92%).
Reaction SMILES: C([O-])(=O)C.[NH4+].[F:6][C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([F:16])[C:14]=1[F:15])[CH:10]=O.[N+:17]([CH3:20])([O-:19])=[O:18]>C(O)(=O)C>[F:6][C:7]1[CH:8]=[C:9](/[CH:10]=[CH:20]/[N+:17]([O-:19])=[O:18])[CH:12]=[C:13]([F:16])[C:14]=1[F:15]
Reactant: O=Cc1cc(F)c(F)c(F)c1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=[N+]([O-])/C=C/c1cc(F)c(F)c(F)c1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
Ammonium acetate (7.3 g) was added to a solution of 3,4,5-trifluorobenzaldehyde (12.6 g) and nitromethane (17.1 mL) in acetic acid (50 mL), and the reaction solution was stirred at 100° C. for three hours. The reaction solution was left to cool to room temperature and then concentrated under reduced pressure. Ethyl acetate and saturated sodium bicarbonate water were added to the residue, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane->heptane:ethyl acetate=9:1) to obtain 10.5 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: [CH:1]1([N:7]([C@H:29]2[CH2:34][CH2:33][C@H:32]([CH3:35])[CH2:31][CH2:30]2)[C:8](=[O:28])[NH:9][C:10]2[S:11][C:12]([S:15]([N:18](C)[CH2:19][C:20]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[O:21])(=[O:17])=[O:16])=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(N([C@H]2CC[C@H](C)CC2)C(=O)NC2SC(S(NCC(O)=O)(=O)=[O:51])=CN=2)CCCCC1.N1CCOCC1>>[N:22]1([C:20](=[O:21])[CH2:19][NH:18][S:15]([C:12]2[S:11][C:10]([NH:9][C:8]([N:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[C@H:29]3[CH2:30][CH2:31][C@H:32]([CH3:35])[CH2:33][CH2:34]3)=[O:28])=[N:14][CH:13]=2)(=[O:16])=[O:17])[CH2:23][CH2:24][O:51][CH2:26][CH2:25]1
Reactant: CCN(CC)C(=O)CN(C)S(=O)(=O)c1cnc(NC(=O)N(C2CCCCC2)[C@H]2CC[C@H](C)CC2)s1
Reactant: C[C@H]1CC[C@H](N(C(=O)Nc2ncc(S(=O)(=O)NCC(=O)O)s2)C2CCCCC2)CC1
Solvent: C1COCCN1
Product: C[C@H]1CC[C@H](N(C(=O)Nc2ncc(S(=O)(=O)NCC(=O)N3CCOCC3)s2)C2CCCCC2)CC1

Procedure:
The title compound was prepared in a similar manner to 2-({2-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazole-5-sulfonyl}-methyl-amino)-N,N-diethyl-acetamide using {2-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazole-5-sulfonylamino}-acetic acid and morpholine.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([OH:7])[C:4]2[NH:8][C:9]3[C:14]([C:3]=2[CH:2]=1)=[C:13]1[C:15]([NH:17][C:18](=[O:19])[C:12]1=[C:11]1[C:20]2[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[C:21]=2[NH:22][C:10]=31)=[O:16].C(=O)([O-])[O-].[K+].[K+].[CH2:34](Br)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.O>CN(C)C=O>[CH2:34]([O:27][C:23]1[C:21]2[NH:22][C:10]3[C:9]4[NH:8][C:4]5[C:3](=[CH:2][CH:1]=[CH:6][C:5]=5[O:7][CH2:14][C:3]5[CH:4]=[CH:5][CH:6]=[CH:1][CH:2]=5)[C:14]=4[C:13]4[C:15](=[O:16])[NH:17][C:18](=[O:19])[C:12]=4[C:11]=3[C:20]=2[CH:26]=[CH:25][CH:24]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: BrCc1ccccc1
Reactant: O=C1NC(=O)c2c1c1c3cccc(O)c3[nH]c1c1[nH]c3c(O)cccc3c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1NC(=O)c2c1c1c3cccc(OCc4ccccc4)c3[nH]c1c1[nH]c3c(OCc4ccccc4)cccc3c21
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.7 %

Procedure:
180.5 mg of BE-13793C (12,13-dihydro-1,11-dihydroxy-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7-(6H)-dione) was dissolved in 137 ml of N,N-dimethylformamide (DMF), 510 mg of potassium carbonate was added, and 170 μl of benzyl bromide was added under ice cooling. The reaction solution was stirred at room temperature for 2 hours and, after addition of 200 ml of water, extracted with 200 ml of ethyl acetate, and the extract was dried over sodium sulfate and concentrated under reduced pressure to give 1,11-dibenzyloxy-12,13-dihydro-5H-indolo[ 2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione (yield: 93.7%).
Reaction SMILES: [Na].F[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([OH:13])=[N:8][CH:9]=[N:10]2)=[CH:5][C:4]=1[N+:14]([O-:16])=[O:15].Cl.[CH3:18][OH:19]>>[CH3:18][O:19][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([OH:13])=[N:8][CH:9]=[N:10]2)=[CH:5][C:4]=1[N+:14]([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1cc2c(O)ncnc2cc1F
Reactant: CO
Agent: Cl
Agent: [Na]
Product: COc1cc2ncnc(O)c2cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 92 %

Procedure:
Sodium (92 mg, 4 mmol) was dissolved in methanol (4 mL) under nitrogen at 0° C. 7-Fluoro-6-nitroquinazolin-4-ol (418 mg, 2 mmol) was added. The mixture was refluxed for 3 h and cooled to room temperature and treated with 2N HCl to adjust its pH to 3-4. After the mixture was concentrated, the residue was diluted with ethyl acetate and washed with water twice. The organic layer was concentrated to give 405 mg (92%) of 7-methoxy-6-nitroquinazolin-4-ol.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([SH:22])=[CH:18][CH:17]=1.N1C=CC=CC=1>C(#N)C>[C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([S:22][C:19]2[CH:20]=[CH:21][C:16]([O:15][CH3:14])=[CH:17][CH:18]=2)=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(C(=O)Cl)cc1
Reactant: COc1ccc(S)cc1
Solvent: c1ccncc1
Solvent: CC#N
Product: COc1ccc(SC(=O)c2ccc(OC(C)=O)cc2)cc1
Reaction time: 2 h
Yield: 82.2 %

Procedure:
A solution of 4-acetoxybenzoyl chloride (7.06 g) in dry acetonitrile (15 ml) was added to a solution of 4-methoxythiophenol (5.00 g) in dry acetonitrile (60 ml), and the mixture cooled (ice-bath) and stirred whilst pyridine (2.83 ml) was added dropwise over 10 minutes. The solution was allowed to reach room temperature, stirred for a further 2 hours and the volatile solvents evaporated in vacuo. The residue was partitioned between ethyl acetate and water and the separated organic layer was washed successively with water and brine, dried over magnesium sulphate, and evaporated. Column chromatography of the crude material (silica; ethyl acetate/hexane mixtures as eluant) gave the pure thioester as a pale yellow foam (8.84 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH2:10][C:11]3[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][C:12]=3[O:21][CH3:22])[C:6]=2[CH:23]=1.N1C(C)=CC=CC=1C.Cl[C:33]([O:35][CH:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1)=[O:34]>ClCCl>[CH:36]1([O:35][C:33]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[N:9]=[CH:8][N:7]([CH2:10][C:11]4[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][C:12]=4[O:21][CH3:22])[C:6]=3[CH:23]=2)=[O:34])[CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: COC(=O)c1ccc(Cn2cnc3ccc(N)cc32)c(OC)c1
Reactant: O=C(Cl)OC1CCCC1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: COC(=O)c1ccc(Cn2cnc3ccc(NC(=O)OC4CCCC4)cc32)c(OC)c1
Reaction time: 24 h
Yield: 66.5 %

Procedure:
A solution of methyl 4-(6-aminobenzimidazol-1-ylmethyl)-3-methoxybenzoate (J) (0.63 g.) and 2,6-lutidine (0.36 ml.) in dichloromethane (10 ml.) was treated with cyclopentyl chloroformate (0.33 g.). After stirring for 24 hours the solution was diluted with dichloromethane. The mixture was washed successively with 20% w/v sodium hydroxide, water, and brine, then dried (MgSO4) and evaporated. The resultant residue was purified by flash chromatography on a 6×20 cm. silica gel column using 1:3 v/v hexane:ethyl acetate as the eluent to give the title compound (0.57 g., 93%); NMR: 1.7[m,8H, (CH2)4 ], 3.8(s,3H, OCH3), 3.9(s,3H, OCH3) 5.2(m,1H, CHO), 6.17-7.0(br m,3H), 7.5-7.8(br m,4H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([C@H:12]3[CH2:15][CH2:14][C@H:13]3[C:16](O)=[O:17])=O)=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:19].O.[NH2:21][NH2:22]>C(O)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[CH:12]4[CH:13]([C:16](=[O:17])[NH:21][N:22]=3)[CH2:14][CH2:15]4)=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:19]
Reactant: NN
Reactant: O=C1Cc2cc(C(=O)[C@H]3CC[C@H]3C(=O)O)ccc2N1
Solvent: CCO
Solvent: O
Product: O=C1Cc2cc(C3=NNC(=O)C4CCC34)ccc2N1
Yield: 92.1 %

Procedure:
5.22 g (0.02 mole) of cis-2-(indolin-2-on-5-oyl)-cyclobutanecarboxylic acid are refluxed with 1.1 g (0.022 mole) of hydrazine hydrate and 50 ml of ethanol for 11 hours. The product is filtered off under suction at room temperature and recrystallized from dimethylformamide/water to give 4.7 g (92%) of 2-(indolin-2-on-5-yl)-3,4-diazabicyclo[4.2.0]oct-2-en-5-one of melting point 309°-312° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:12])[CH:8]=2)[N:3]=1.[O:13]([CH2:20][CH2:21][NH2:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[Cl:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:22][CH2:21][CH2:20][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:11]=[CH:10]2
Reactant: Clc1ccc2nc(Cl)ccc2c1
Reactant: NCCOc1ccccc1
Product: Clc1ccc2nc(NCCOc3ccccc3)ccc2c1
Temperature: 120 °C
Yield: 72.2 %

Procedure:
A stirred mixture of 2,6-dichloro-quinoline (1.0 g, 5.1 mmol) and 2-phenoxyethylamine (1.5 g, 11 mmol) was heated in the microwave for 1 h at 120° C. Purification by flash chromatography on silica gel (ethyl acetate/heptane 100:0→70:30) yielded (6-chloro-quinolin-2-yl)-(2-phenoxy-ethyl)-amine as a light yellow oil (1.1 g, 73%), MS: m/e=299.3 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:12](=[O:18])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])=[C:6]([CH:11]=1)[N:7]([CH3:10])[CH:8]=O>COCCO>[F:1][C:2]1[CH:11]=[C:6]2[C:5]([C:12](=[O:18])[C:13]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:8][N:7]2[CH3:10])=[CH:4][CH:3]=1
Reactant: CN(C=O)c1cc(F)ccc1C(=O)CS(C)(=O)=O
Solvent: COCCO
Product: Cn1cc(S(C)(=O)=O)c(=O)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 5'-fluoro-N-methyl-2'-methylsulphonylacetylformanilide (0.20 g), prepared in a similar manner to that described in Example 11, in 2-methoxyethanol (25 ml) was heated to reflux. Heating under reflux at 127° was continued for 2 hours. The mixture was allowed to cool to ambient temperature and then evaporated in vacuo to give 7-fluoro-1-methyl-3-methylsulphonyl-4-quinolone, m.p. 233.5°-235° (0.19 g).
Reaction SMILES: [ClH:1].Cl.[N:3]1([C:8]2[CH:17]=[CH:16][C:11]([O:12][CH2:13][CH2:14][NH2:15])=[CH:10][CH:9]=2)[CH:7]=[CH:6][N:5]=[CH:4]1.[OH-].[Na+].[O:20]1[CH2:22][CH:21]1[CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])=[CH:27][CH:26]=1>CO.O>[ClH:1].[OH:20][CH:21]([CH2:22][NH:15][CH2:14][CH2:13][O:12][C:11]1[CH:16]=[CH:17][C:8]([N:3]2[CH:7]=[CH:6][N:5]=[CH:4]2)=[CH:9][CH:10]=1)[CH2:23][O:24][C:25]1[CH:26]=[CH:27][C:28]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])=[CH:29][CH:30]=1
Reactant: NCCOc1ccc(-n2ccnc2)cc1
Reactant: CS(=O)(=O)Nc1ccc(OCC2CO2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CS(=O)(=O)Nc1ccc(OCC(O)CNCCOc2ccc(-n3ccnc3)cc2)cc1
Reaction time: 0.25 h

Procedure:
To a solution of 2.3 g (0.008 mol) of 2-[4-(1H-imidazol-1-yl)phenoxy]ethanamine dihydrochloride in 100 ml of methanol add a solution of 0.66 g of sodium hydroxide in 5 mL of water. Stir for 15 minutes. Add 2.0 g (0.008 mol) of N-[4-(oxiranylmethoxy)phenyl]methanesulfonamide and reflux for 16 h. Monitor the progress of the reaction by thin-layer chromatography on silica gel (methylene chloride, methanol, triethylamine, 84:15:1). Remove the solvent in vacuo. Chromatograph the oil on 350 g of silica gel using amixture of methylene chloride:methanol:triethylamine (94:5:1). Combine the fractions containing residue and remove the solvent in vacuo. Dissolve theresidue in methanol and add a solution of hydrogen chloride in methanol. Remove the solvent in vacuo. Recrystallize the salt from acetonitrile:methanol to obtain the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15](=[O:16])[N:14]3[CH:17]=[CH:18][S:19][C:13]3=[N:12][C:11]=2[CH3:20])=[CH:6][CH:5]=1)[CH3:2].BrCC[CH2:24][C:25]#[N:26].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH3:20][C:11]1[N:12]=[C:13]2[S:19][CH:18]=[CH:17][N:14]2[C:15](=[O:16])[C:10]=1[C:7]1[CH:6]=[CH:5][C:4]([O:3][CH2:1][CH2:2][CH2:24][C:25]#[N:26])=[CH:9][CH:8]=1
Reactant: N#CCCCBr
Reactant: CCOc1ccc(-c2c(C)nc3sccn3c2=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1nc2sccn2c(=O)c1-c1ccc(OCCCC#N)cc1
Temperature: 80 °C
Yield: 56.7 %

Procedure:
To a solution of Step 1 intermediate, Intermediate 10 (350 mg, 1.355 mmol) in DMF (10 ml) was added 4-bromobutyronitrile (280 mg, 1.897 mmol) at room temperature followed by K2CO3 (560 mg, 4.065 mmol) and the reaction temperature was heated to 80° C. for 15.0 h overnight. The reaction mixture was diluted with ethyl acetate, washed with water and brine and purified by column chromatography to afford 250 mg the desired compound as a white solid; 1H NMR (300 MHz, CDCl3) δ 2.17 (s, 3H), 3.80-3.85 (m, 2H), 7.07-7.10 (m, 2H), 7.24-7.27 (m, 2H), 7.50 (d, J=4.8 Hz, 1H), 7.98 (d, J=4.5 Hz, 1H).
Reaction SMILES: C([S:14][C:15]1[N:19]([CH2:20][C:21]#[CH:22])[N:18]=[N:17][N:16]=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>>[CH2:20]([N:19]1[C:15]([SH:14])=[N:16][N:17]=[N:18]1)[C:21]#[CH:22]
Reactant: C#CCn1nnnc1SC(c1ccccc1)c1ccccc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: C#CCn1nnnc1S
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 59.3 %

Procedure:
A mixture of 5-benzhydrylthio-1-(2-propynyl)-1H-tetrazole (0.35 g), anisole (0.6 g) and trifluoroacetic acid (3.4 ml) was stirred for 30 minutes at 20° C. and then allowed to stand for 45 minutes. The reaction mixture was filtered and the filter cake was washed with isopropyl ether. The filtrate and the washing were combined and evaporated under reduced pressure. After the addition of the residue to a saturated aqueous solution of sodium bicarbonate precooled to 10° C., the resulting mixture was adjusted to pH 8.5 with 2N aqueous solution of sodium hydroxide and washed with ethyl acetate. The washed aqueous layer was adjusted to pH 2.5 with 10% hydrochloric acid under ice-cooling and then extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated to give 1-(2-propynyl)-1H-tetrazole-5-thiol (95 mg), which is decomposed from 60° to 71° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]#[N:10])=[C:4]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:3]=1.[CH2:19]([OH:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([O:26][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:5]([C:9]#[N:10])=[C:4]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:3]=1
Reactant: N#Cc1c(Cl)nc(N)nc1OCc1ccccn1
Reactant: OCc1ccccc1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(OCc2ccccc2)nc(N)nc1OCc1ccccn1

Procedure:
From 2-amino-4-chloro-6-(pyridin-2-ylmethoxy)-pyrimidine-5-carbonitrile, benzyl alcohol and DBU in DME. ES-MS m/e (%): 356 (MNa+, 50), 334 (M+H+, 100).
Reaction SMILES: CON(C)[C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:8][CH:7]=1)=[O:5].[CH2:18]([Mg]Br)[CH3:19]>O1CCCC1>[C:11]1([C:9]2[S:10][C:6]([C:4](=[O:5])[CH2:18][CH3:19])=[CH:7][N:8]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CON(C)C(=O)c1cnc(-c2ccccc2)s1
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Product: CCC(=O)c1cnc(-c2ccccc2)s1
Reaction time: 1 h
Yield: 92 %

Procedure:
To a solution of 0.32 g (1.3 mmol) of the above-prepared 2-phenyl-thiazole-5-carboxylic acid methoxy-methyl-amide in tetrahydrofuran at room temperature was added 0.34 g (2.6 mmol) of 1M ethyl magnesium bromide in tetrahydrofuran. The reaction mixture was allowed to stir for one hour. The reaction was quenched with aqueous ammonium chloride and partitioned with ethyl acetate. The organic phase was washed once with aqueous ammonium chloride, once with water, once with brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by chromatography on silica gel using 1:19 ethyl acetate:hexanes to give 0.26 g of the title compound (93%). 1H NMR (500 MHz, CDCl3) δ 8.36 (s, 1H) 8.0 (m, 2H) 7.49 (m, 3H) 2.98 (q, 2H) 1.27 (t, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:13][CH:12]([CH2:14][N:15]3[CH:19]=[CH:18][N:17]=[N:16]3)[O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1F.C(=O)([O-])[O-].[K+].[K+].[NH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:13][CH:12]([CH2:14][N:15]3[CH:19]=[CH:18][N:17]=[N:16]3)[O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1
Reactant: C1CNCCN1
Reactant: Fc1ccc(C2=NOC(Cn3ccnn3)C2)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Fc1cc(C2=NOC(Cn3ccnn3)C2)ccc1N1CCNCC1
Yield: 93 %

Procedure:
A mixture of (5RS)-3-(3,4-difluorophenyl)-5-(1,2,3-triazol-1-ylmethyl)-4,5-dihydroisoxazole (528 mg, 2 mM), potassium carbonate (414 mg, 3 mM), and piperazine (7.5 g) was heated under nitrogen at 130° for 4 hours. After cooling, the mixture was partitioned between water (150 ml) and ethyl acetate (150 ml). The organic extract was washed with sodium bicarbonate (75 ml), and brine (75 ml). After drying (magnesium sulfate) and evaporation, the desired product (614 mg) was obtained sufficiently pure without chromatography. MS (ESP): 331 (MH+) for C16H19FN6O NMR (DMSO-d6) δ: 2.81 (t, 4H); 2.97 (t, 4H); 3.20 (dd overlapped by H2O, 1H); 3.52 (dd, 1H); 4.58 (dd, 1H); 4.64 (dd, 1H); 5.08 (m, 1H); 7.02 (t, 1H); 7.30 (overlapping m, 2H); 7.70 (d, 1H); 8.11 (d, 1H); NH missing—exchanged.