Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:17][CH2:18][CH3:19])[C:5]1[C:10]([CH:11]([NH:15][CH3:16])[CH:12]([CH3:14])[CH3:13])=[CH:9][N:8]=[CH:7][N:6]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].C(#N)C.[C:29]1([CH2:35][C:36](Cl)=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O>[CH2:1]([O:3][CH:4]([O:17][CH2:18][CH3:19])[C:5]1[C:10]([CH:11]([N:15]([CH3:16])[C:36](=[O:37])[CH2:35][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:12]([CH3:13])[CH3:14])=[CH:9][N:8]=[CH:7][N:6]=1)[CH3:2]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CCOC(OCC)c1ncncc1C(NC)C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCOC(OCC)c1ncncc1C(C(C)C)N(C)C(=O)Cc1ccccc1
Yield: 70.3 %

Procedure:
8.3 g (0.031 mol) of [1-(4-diethoxymethylpyrimidin-5-yl)-2-methylpropyl]methylamine and 6.4 g (46 mmol) of potassium carbonate were added to 100 ml of acetonitrile, and then 5.8 g (0.038 mol) of phenylacetyl chloride was dropwise added at room temperature and reacted for 2 hours. After completion of the reaction, the product was poured into water and extracted with ethyl acetate. The organic layer was washed with an aqueous citric acid solution, water and an aqueous sodium chloride solution in this order, dried and concentrated, and the obtained oily product was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:5 to ethyl acetate), to obtain 8.4 g (yield: 70%) of N-[1-(4-diethoxymethylpyrimidin-5-yl)-2-methylpropyl]-N-methyl-2-phenyl acetamide as colorless viscous liquid (nD2=1.5253)
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[C:5]([CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=1)[CH2:6][NH:7][CH2:8][C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[Br:18].Cl[C:29]([O:31][CH3:32])=[O:30].C(N(CC)CC)C>C(Cl)Cl>[F:23][C:22]([F:25])([F:24])[C:20]1[CH:19]=[C:5]([CH:4]=[C:3]([C:2]([F:26])([F:1])[F:27])[CH:21]=1)[CH2:6][N:7]([CH2:8][C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[Br:18])[C:29](=[O:30])[O:31][CH3:32]
Reactant: O=[N+]([O-])c1ccc(Br)c(CNCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc([N+](=O)[O-])ccc1Br
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of [3,5-bis(trifluoromethyl)benzyl](2-bromo-5-nitrobenzyl)amine from Step C (0.47 g, 1.0 mmol) in methylene chloride (20 ml) at room temperature, methyl chloroformate (0.12 ml, 1.54 mmol) and triethylamine (0.29 ml, 2.05 mmol) were added. The solution was stirred at room temperature for 18 h. The solvent was removed under reduced pressure. The title compound was obtained by flash column chromatography using 1:9 EtOAc/hexane as the eluant. 1H NMR (CDCl3, 500 MHz) δ 8.11 (m, 1H), 8.02 (dd, J=9.0, 2.5 Hz, 1H), 7.81 (s, 1H), 7.74 (d, J=9.0 Hz, 1H), 7.70 (m, 1H), 7.65 (m, 1H), 4.67 (m, 4H), 3.89 (s, 3H).
Reaction SMILES: C(NC(C)C)(C)C.[CH2:8]([Li])[CH2:9][CH2:10][CH3:11].[CH3:13][O:14][C:15]1[CH:27]=[CH:26][C:18]([CH2:19][N:20]2[CH2:24]CC[C:21]2=[O:25])=[CH:17][CH:16]=1.ICC.[Cl-].[NH4+]>O1CCCC1>[CH2:10]([CH:9]1[CH2:8][CH2:24][N:20]([CH2:19][C:18]2[CH:26]=[CH:27][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)[C:21]1=[O:25])[CH3:11]
Reactant: COc1ccc(CN2CCCC2=O)cc1
Reactant: [Li]CCCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: CCI
Solvent: C1CCOC1
Product: CCC1CCN(Cc2ccc(OC)cc2)C1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of diisopropylamine (4.1 mL) in tetrahydrofuran (25 mL) was added dropwise n-butyllithium (1.6 M hexane solution, 18 mL) at −78° C. under nitrogen atmosphere, and the mixture was warmed to 0° C., and stirred for 30 min. The reaction mixture was cooled to −78° C., a solution of 1-(4-methoxybenzyl)pyrrolidin-2-one (5.0 g) obtained in Step A in tetrahydrofuran (25 mL) was added thereto, and the mixture was stirred at the same temperature for 1 hr. Iodoethane (2.9 mL) was added thereto, and the mixture was stirred overnight while it was allowed to be warmed. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (2.8 g).
Reaction SMILES: [CH:1]([NH:3][CH:4]([C:8]1([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[CH2:11][CH2:10][CH2:9]1)[CH2:5][CH2:6][CH3:7])=O.[CH3:20]COCC.Cl.C=O>CC(O)C.C(O)=O.O>[ClH:18].[CH3:1][N:3]([CH:4]([C:8]1([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[CH2:11][CH2:10][CH2:9]1)[CH2:5][CH2:6][CH3:7])[CH3:20]
Reactant: CCOCC
Reactant: CCCC(NC=O)C1(c2ccc(Cl)c(Cl)c2)CCC1
Agent: C=O
Agent: Cl
Solvent: O=CO
Solvent: O
Solvent: CC(C)O
Product: CCCC(N(C)C)C1(c2ccc(Cl)c(Cl)c2)CCC1

Procedure:
The product of Example 7 (8.3 g), diethyleneglycoldimethyl ether (50 ml), water (20 ml) and concentrated hydrochloric acid (20 ml) were mixed and heated under reflux for sixteen hours. The mixture was poured into water aqueous NaOH was added and the product extracted into ether. Evaporation gave a dark oil. A sample of this oil (7.9 g), water (0.7 ml) and formic acid (6.5 ml) were mixed and formaldehyde (6.5 ml) added. The mixture was heated under reflux for three hours and then concentrated hydrochloric acid (10 ml) and propan-2-ol (10 ml) were added. Evaporation to dryness gave N,N-dimethyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]butylamine hydrochloride (m.p. 195°-196°) as a white solid (Formula I R1 =propyl; R2 =H; R3, R4 =Me; R5 =4-Cl and R6 =3-Cl).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([NH:31][C@@H:32]2[C@@H:37]3[CH2:38][C@@H:34]([CH:35]=[CH:36]3)[C@@H:33]2[C:39]([NH2:41])=[O:40])=[C:11]2[N:17]=[C:16]([C:18]3C=CC(CN4CCOCC4)=C[CH:19]=3)[NH:15][C:12]2=[N:13][CH:14]=1.NC1C(N)=C(N[C@@H]2[C@@H]3C[C@@H](C=C3)[C@@H]2C(N)=O)C(Cl)=CN=1.[CH3:62][N:63]1[CH:67]=C(C=O)C=[N:64]1>>[Cl:8][C:9]1[C:10]([NH:31][C@@H:32]2[C@@H:37]3[CH2:38][C@@H:34]([CH:35]=[CH:36]3)[C@@H:33]2[C:39]([NH2:41])=[O:40])=[C:11]2[N:17]=[C:16]([C:18]3[CH:19]=[N:64][N:63]([CH3:67])[CH:62]=3)[NH:15][C:12]2=[N:13][CH:14]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4ccc(CN5CCOCC5)cc4)nc23)[C@H]2C=C[C@@H]1C2
Reactant: Cn1cc(C=O)cn1
Agent: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Solvent: O=C(O)C(F)(F)F
Product: Cn1cc(-c2nc3c(N[C@H]4[C@@H](C(N)=O)[C@@H]5C=C[C@H]4C5)c(Cl)cnc3[nH]2)cn1
Yield: 88 %

Procedure:
In the same fashion as for Compound III, (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide and 1-Methyl-1H-pyrazole-4-carbaldehyde were reacted to produce the title compound (88%). 1H NMR (d-chloroform): 15.26 (br s, 1H) 8.26 (d, J=8 Hz, 1H), 8.04 (s, 1H), 8.02 (s, 1H), 7.78 (s, 1H), 6.45 (m, 1H), 6.41 (m, 1H), 5.99 (s, 1H), 5.70 (s, 1H), 5.31 (t, J=8 Hz, 1H), 4.02 (s, 3H), 3.16 (s, 1H), 3.00 (s, 1H), 2.68 (d, J=8 Hz, 1H), 2.29 (d, J=9 Hz, 1H), 1.66 (d, J=10 Hz, 1H). MS: 385.06 (M+H). HPLC retention time: 1.90 minutes (G Method).
Reaction SMILES: C1(C2[C:8](=O)[C:9]([C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=3)=[C:10]([C:37]3[CH:42]=[CH:41][C:40]([C:43]4[CH:55]=[CH:54][C:53]5[C:52]6[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=6)[C:46]([CH2:59][CH2:60][CH3:61])([CH2:56][CH2:57][CH3:58])[C:45]=5[CH:44]=4)=[CH:39][CH:38]=3)[C:11]=2[C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:30]=[CH:29][C:28]4[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[C:21]([CH2:34][CH2:35][CH3:36])([CH2:31][CH2:32][CH3:33])[C:20]=4[CH:19]=3)=[CH:14][CH:13]=2)C=CC=CC=1.[C:69]([C:71]1[CH:76]=[CH:75][C:74]([C:77]2[CH:82]=[CH:81][CH:80]=[CH:79][N:78]=2)=[CH:73][CH:72]=1)#[CH:70]>C1(OC2C=CC=CC=2)C=CC=CC=1>[C:12]1([C:70]2[C:11]([C:12]3[CH:13]=[CH:14][C:15]([C:18]4[CH:30]=[CH:29][C:28]5[C:27]6[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=6)[C:21]([CH2:34][CH2:35][CH3:36])([CH2:31][CH2:32][CH3:33])[C:20]=5[CH:19]=4)=[CH:16][CH:17]=3)=[C:10]([C:37]3[CH:38]=[CH:39][C:40]([C:43]4[CH:55]=[CH:54][C:53]5[C:52]6[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=6)[C:46]([CH2:59][CH2:60][CH3:61])([CH2:56][CH2:57][CH3:58])[C:45]=5[CH:44]=4)=[CH:41][CH:42]=3)[C:9]([C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=3)=[CH:8][C:69]=2[C:71]2[CH:76]=[CH:75][C:74]([C:77]3[CH:82]=[CH:81][CH:80]=[CH:79][N:78]=3)=[CH:73][CH:72]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C#Cc1ccc(-c2ccccn2)cc1
Reactant: CCCC1(CCC)c2ccccc2-c2ccc(-c3ccc(C4=C(c5ccccc5)C(=O)C(c5ccccc5)=C4c4ccc(-c5ccc6c(c5)C(CCC)(CCC)c5ccccc5-6)cc4)cc3)cc21
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCCC1(CCC)c2ccccc2-c2ccc(-c3ccc(-c4c(-c5ccccc5)cc(-c5ccc(-c6ccccn6)cc5)c(-c5ccccc5)c4-c4ccc(-c5ccc6c(c5)C(CCC)(CCC)c5ccccc5-6)cc4)cc3)cc21
Temperature: 210 °C
Yield: 126.4 %

Procedure:
A solution of (10) (1.48 g, 1.67 mmol) and (3) (200 mg, 1.12 mmol) in diphenyl ether (3 mL) was deoxygenated and heated at 210° C. under argon for 3 hours. The crude product was purified by column chromatography over silica using dichloromethane: light petroleum (1:1) as the eluent. The main band was isolated and the solvent completely removed to give (11) (1.09 g, 95%).
Reaction SMILES: [CH2:1]([C:8]1[CH:12]=[CH:11][NH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:13]=[O:14]>C(=O)([O-])[O-].[K+].[K+].O1CCCC1>[CH2:1]([C:8]1[CH:12]=[CH:11][NH:10][C:9]=1[CH2:13][OH:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=O
Reactant: c1ccc(Cc2cc[nH]c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: OCc1[nH]ccc1Cc1ccccc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 97.2 %

Procedure:
2.18 g (13.9 mmole) of 3-benzylpyrrole, 0.42 g (13.9 mmole) of paraformaldehyde and 0.07 g (0.5 mmole) of anhydrous potassium carbonate are mixed and stirred at 50° C. for 4 hours in an atmosphere of nitrogen. Dry tetrahydrofuran is added to the reaction solution and filtered. The filtrate is concentrated to obtain 2.53 g of 3-benzyl-1-pyrrolylmethanol as a pale yellow liquid. Yield 97.3%. nD31.5 1.5837.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([S:12]([OH:15])(=[O:14])=O)[N:6]=1)=[O:4].S(Cl)(Cl)=O.[NH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>CN(C=O)C.C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([S:12]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)(=[O:14])=[O:15])[N:6]=1)=[O:4]
Reactant: C1CCNCC1
Reactant: COC(=O)c1ccc(C)c(S(=O)(=O)O)n1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C)c(S(=O)(=O)N2CCCCC2)n1
Temperature: 40 °C
Reaction time: 2 h
Yield: 12.1 %

Procedure:
5-Methyl-6-sulfo-pyridine-2-carboxylic acid methyl ester (340 mg, 1.47 mmol), thionyl chloride (CAN 7719-09-7, 1 mL) and 1 drop of DMF were added to methylene chloride (10 mL), and the mixture was stirred for 2 h at 40° C. The mixture was cooled to room temperature, and piperidine (CAN 110-89-4, 1.0 g, 12 mmol) in methylene chloride (10 mL) was added to the above mixture. The solvent was removed in vacuo, and the crude product was purified by prep-HPLC (eluting with 50% ethyl acetate in petroleum ether) to give the product (53 mg, 12%); MS (EI): m/e=299.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].Cl[C:26](Cl)([O:28][C:29](=[O:35])OC(Cl)(Cl)Cl)Cl.[CH2:37]([C:41]1[CH:46]=[CH:45]C(O)=[CH:43][CH:42]=1)[CH2:38][CH2:39][CH3:40].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:28][C:26]2[CH:45]=[CH:46][C:41]([CH2:37][CH2:38][CH2:39][CH3:40])=[CH:42][CH:43]=2)=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCCCc1ccc(O)cc1
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCc1ccc(OC(=O)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)c(C)c2C)cc1
Yield: 57 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 4-butylphenol (35 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (44 mg, yield 55%).
Reaction SMILES: [CH3:1][NH:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]3[CH:16]=[CH:15][N:14]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:10]=3[N:11]=[CH:12][N:13]=2)[CH2:4]1.Cl[C:26]1[CH:31]=[C:30]([CH3:32])[C:29]([N+:33]([O-:35])=[O:34])=[CH:28][N:27]=1.CCN(C(C)C)C(C)C.O>CN1C(=O)CCC1>[CH3:1][N:2]([C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]3[CH:16]=[CH:15][N:14]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:23])([CH3:22])[CH3:24])[C:10]=3[N:11]=[CH:12][N:13]=2)[CH2:4]1)[C:26]1[CH:31]=[C:30]([CH3:32])[C:29]([N+:33]([O-:35])=[O:34])=[CH:28][N:27]=1
Reactant: Cc1cc(Cl)ncc1[N+](=O)[O-]
Reactant: CN[C@@H]1CCN(c2ncnc3c2ccn3COCC[Si](C)(C)C)C1
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(N(C)[C@@H]2CCN(c3ncnc4c3ccn4COCC[Si](C)(C)C)C2)ncc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 86.3 %

Procedure:
A solution of (R)—N-methyl-1-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-amine (0.287 mmol), 2-chloro-4-methyl-5-nitropyridine (0.347 mmol), and DIPEA (1.435 mmol) in NMP (1.5 mL) was stirred at 200° C. for 30 minutes in a microwave reactor and then cooled to ambient temperature. The solution was poured into water, extracted with EtOAc, concentrated, and purified by column chromatography to give the title compound in 86.3% yield.
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][CH:14]1[O:18][CH2:17][CH2:16][O:15]1.[C:19](Cl)(=[O:23])[C:20]([CH3:22])=[CH2:21]>C(Cl)Cl>[C:19]([O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][CH:14]1[O:15][CH2:16][CH2:17][O:18]1)(=[O:23])[C:20]([CH3:22])=[CH2:21]
Reactant: OCCOCCC1OCCO1
Reactant: C=C(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OCCOCCC1OCCO1

Procedure:
The preparation was similar to that used for the preparation of the monomer designated III except that 22.0 g triethylamine, 32.4 g 2-[2(2-hydroxyethoxy)-ethyl]-1,3-dioxolane and 180 ml methylene chloride were added initially and 23.22 g methacryloyl chloride were added dropwise. The monomer was purified by distillation at 106° C. under 0.2 mm Hg pressure.
Reaction SMILES: [CH3:1][C:2]1[C:8]([N+:9]([O-])=O)=[CH:7][CH:6]=[CH:5][C:3]=1N.N([O-])=O.[Na+].C([O:19][CH2:20][CH3:21])(=O)C.[CH3:22]CCCCC>C(O)(=O)C.O>[NH2:9][C:8]1[CH:7]=[CH:6][CH:5]=[C:3]2[C:2]=1[CH2:1][C@H:20]([OH:19])[CH2:21][CH2:22]2
Reactant: CCCCCC
Reactant: Cc1c(N)cccc1[N+](=O)[O-]
Reactant: CCOC(C)=O
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Nc1cccc2c1C[C@H](O)CC2
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
2-methyl-3-nitro aniline (10 g, 0.005 mol) was taken in acetic acid (100 ml, 10 times) and cooled to 20° C. A solution of sodium nitrite (10 g, 0.14 mol, 2.25 eq) in water (25 ml) was added drop wise for 15 min at 20° C. The overall reaction mixture was stirred for 30 min at 20° C. and later stirred for 2 hrs at rt. Progress of the reaction was monitored by TLC (15% ethyl acetate/hexane, Rf˜0.2). On completion of the reaction, acetic acid was distilled off completely and the residue obtained was taken in cold water (200 ml). Solid thrown out was filtered and dried to yield the required product as an yellow colored solid (8.5 g, 68% yield).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([F:17])[C:8]([F:16])=[C:9]2[C:14]=1[N:13]=[C:12]([CH3:15])[CH:11]=[CH:10]2)=[O:4].O.[H][H]>C(O)(=O)C.[Pt]>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([F:17])[C:8]([F:16])=[C:9]2[C:14]=1[NH:13][CH:12]([CH3:15])[CH2:11][CH2:10]2)=[O:4]
Reactant: [H][H]
Reactant: COC(=O)c1cc(F)c(F)c2ccc(C)nc12
Agent: [Pt]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1cc(F)c(F)c2c1NC(C)CC2
Yield: 68.9 %

Procedure:
A solution of 8.0 g (33.7 mmol) of 5,6-difluoro-2-methylquinoline-8-carboxylic acid methyl ester (Example 33) in 100 mL of glacial acetic acid is treated with 2.15 g of platinum on carbon (0.8 g of active catalyst+62.8% water) and then shaken in a hydrogen atmosphere at temperatures of 24° C. to 29° C. and pressures of 23.9 to 46.6 psi for 3 hours. The catalyst is removed by filtration and the solvent is removed in vacuo at 50° C. The residue is triturated with water (50 mL) and extracted with dichloromethane (2×200 mL). The combined organic layers are stirred with 5% sodium bicarbonate solution, washed with water, dried (MgSO4), filtered and evaporated in vacuo. The residue is chromatographed over flash grade silica gel (230–400 mesh) eluting with dichloromethane to give 5.6 g of the title compound as a light yellow oil. 1H NMR (400 MHz, CDCl3): 7.66 (bs, 1H), 7.49 (m, 1H), 3.82 (s, 3H), 3.46 (m, 1H), 2.88 (m, 1H), 2.67 (m, 1H), 1.97 (m, 1H), 1.27 (d, 3H).
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:13])(=[O:12])[N:4]([CH3:14])[C:3]=1[C:15]([O:17]C)=O.[NH2:19][C:20]1[C:21](=[O:27])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1>C1(C)C(C)=CC=CC=1>[OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:12])(=[O:13])[N:4]([CH3:14])[C:3]=1[C:15]([NH:19][C:20]1[C:21](=[O:27])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:17]
Reactant: Nc1cccccc1=O
Reactant: COC(=O)C1=C(O)c2ccccc2S(=O)(=O)N1C
Solvent: Cc1ccccc1C
Product: CN1C(C(=O)Nc2cccccc2=O)=C(O)c2ccccc2S1(=O)=O
Reaction time: 15 h
Yield: 17 %

Procedure:
A solution of methyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide (3.0 g) and 2-amino-2,4,6-cycloheptatrien-1-one (1.6 g) in xylene (100 ml) is refluxed for 8 hours. The reaction mixture is then allowed to stand at room temperature for 15 hours. The crystals that have separated out are collected by filtration, washed with toluene and recrystallized from dimethylformamide to give 4-hydroxy-2-methyl-N-(1-oxo-2,4,6-cycloheptatrien-2-yl)-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide (0.68 g), m.p. 259°-261° C.
Reaction SMILES: C(OC(C(F)(F)F)=O)(C(F)(F)F)=O.[Cl:14][C:15]1[C:16]([OH:37])=[C:17]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35])[C:18]([OH:24])=[C:19]([CH:22]=[O:23])[C:20]=1[CH3:21].[CH3:38][C:39](O)([CH3:41])[CH3:40].C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[Cl:14][C:15]1[C:16]([OH:37])=[C:17]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][C:39]([CH3:41])([CH3:40])[CH3:38])=[O:35])[C:18]([OH:24])=[C:19]([CH:22]=[O:23])[C:20]=1[CH3:21]
Reactant: CC(C)(C)O
Reactant: Cc1c(Cl)c(O)c(CCCCCCCCCC(=O)O)c(O)c1C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: Cc1ccccc1
Product: Cc1c(Cl)c(O)c(CCCCCCCCCC(=O)OC(C)(C)C)c(O)c1C=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 16.8 %

Procedure:
TFAA (0.20 ml, 1.4 mmol) was added to a suspension of Compound 215-11-COOH (144 mg, 0.403 mmol) in toluene (5 ml) at 0° C., and the mixture was allowed to warm to room temperature with stirring for 30 minutes. After checking for complete dissolution of the raw material, the mixture was again cooled to 0° C. tBuOH (0.40 ml, 4.2 mmol) was added to the cooled mixture, which was allowed to warm to room temperature with stirring for 15 hours. A saturated aqueous NaHCO3 solution was added to the reaction solution, which was extracted with EtOAc twice after stirring for 5 minutes. The combined organic layer was washed with a saturated aqueous NaCl solution, and was dried over anhydrous Na2SO4. After evaporation of the solvent, the residue was purified by column chromatography on silica gel (Hexane:EtOAc=7:1 to 4:1) followed by PTLC (Hexane:EtOAc=7:1) to yield the target product (28 mg, 17%).
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH3:5].[NH:7]1[CH:11]=[CH:10][N:9]=[CH:8]1>CO.[OH-].[Na+]>[CH2:1]([N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: c1c[nH]cn1
Reactant: CCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCn1ccnc1
Temperature: 20 °C

Procedure:
n-Pentylbromide (30 ml; 0.24 mole) was added dropwise to a stirred solution of imidazole (13.6 g; 0.2 mole) in a mixture of methanol (30 ml) and sodium hydroxide solution (30 ml, 10M) maintained at 20° C. When the addition was complete the reaction mixture was stirred and refluxed for 24 hours. The solvent was evaporated, the residue extracted with chloroform (2×50 ml) and the solid remaining removed by filtration. The chloroform solution (filtrate) was dried over magnesium sulphate and concentrated to give a yellow oil which on purification gave 1-n-pentylimidazole as a colourless oil, b.p. 66°-68° C./0.15 mmHg.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([NH:7][CH3:8])=[CH:5][CH:4]=1)#[N:2].[C:11]1([N:17]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:18]([C:20]2[CH:21]=[CH:22][C:23]3[S:27][C:26]([CH2:28]OC)=[N:25][C:24]=3[CH:31]=2)=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>ClCCl.C(O)C>[C:11]1([N:17]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:18]([C:20]2[CH:21]=[CH:22][C:23]3[S:27][C:26]([CH2:28][N:7]([C:6]4[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[CH:4][CH:5]=4)[CH3:8])=[N:25][C:24]=3[CH:31]=2)=[O:19])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2sc(COC)nc2c1)c1ccccc1
Reactant: CNc1ccc(C#N)cc1
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)CCN(C(=O)c1ccc2sc(CN(C)c3ccc(C#N)cc3)nc2c1)c1ccccc1
Yield: 57 %

Procedure:
Prepared analogously to Example 9e from 4-cyano-N-methyl-aniline and 2-methoxymethyl-benzothiazole-5-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide. Yield: 57% of theory, Rf value: 0.46 (silica gel; dichloromethane/ethanol=19:1).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>ClCCl.O1CCCC1>[Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:9][CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][O:12]2)=[O:8])=[CH:5][CH:4]=1
Reactant: O=C(O)c1ccc(CBr)cc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(OC1CCCCO1)c1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 54.6 %

Procedure:
In a mixed solvent of dichloromethane and tetrahydrofuran was dissolved 5 g of p-bromomethylbenzoic acid, and 10 g of dihydropyran and 585 mg of pyridinium p-toluenesulfonate were added to the solution and the mixture was stirred at room temperature for 6 hours. The thus-obtained solution was washed with a saturated aqueous solution of NaHCO3 and a saturated aqueous solution of sodium chloride, dried on anhydrous magnesium sulfate and concentrated. The concentrate was recrystallized from a mixed solvent of n-hexane, ethyl acetate and chloroform to obtain 3.8 g of tetrahydropyranyl p-bromomethylbenzoate.