Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:11]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[NH:14][C:13]2=[O:23])=[CH:10][C:5]2[C:6]([CH3:9])=[N:7][O:8][C:4]=2[CH:3]=1.[C:24](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[F:1][C:2]1[C:11]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:21])([F:20])[F:22])[N:14]([CH3:24])[C:13]2=[O:23])=[CH:10][C:5]2[C:6]([CH3:9])=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Cc1noc2cc(F)c(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)cc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cc1noc2cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A mixture of 3-(6-fluoro-3-methyl-1,2-benzisoxazol-5-yl)-6-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione (3.00 g, 9.12 mmol) and potassium carbonate (2.52 g, 18.2 mmol) in N,N-dimethylformamide is stirred for 15 minutes, treated with methyl iodide (2.58 g, 18.2 mmol), stirred at room temperature overnight, and poured into an ice-water mixture. The resultant aqueous mixture is filtered to obtain a solid which is recrystallized from a methylene chloride/hexanes solution to give the title product as a white solid (mp 158-159° C.) which is identified by NMR spectral analyses.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OC=[C:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C:11]1=[O:16]>>[C:11]1(=[O:16])[C:10]2[NH:1][C:2]3[C:7](=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:15]=2[CH2:14][CH2:13][CH2:12]1
Reactant: Nc1ccccc1
Reactant: O=C1CCCCC1=CO
Product: O=C1CCCc2c1[nH]c1ccccc21

Procedure:
2,3,4,9-Tetrahydro-1H-carbazol-1-one was prepared from aniline (2.9 g, 31 mmol) and 2-(hydroxymethylene)cyclohexanone (3.5 g, 28 mmol) in a similar manner as described above to give 2.5 g (49%). of a brown solid. 1H-NMR (DMSO-d6): δ 11.6 (s, 1H), 7.66 (d, 1H), 7.38 (d, 1H), 7.30 (t, 1H), 7.07 (t, 1H), 2.90 (t, 2H), 2.56 (t, 2H), 2.15 (m, 2H); MS m/z 186 (M+1).
Reaction SMILES: CON(C)[C:4]([C:6]1[C:11](=[O:12])[C:10]([O:13][CH3:14])=[CH:9][N:8]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[N:7]=1)=[O:5].[CH3:22][Mg+].[Br-]>C1COCC1>[C:4]([C:6]1[C:11](=[O:12])[C:10]([O:13][CH3:14])=[CH:9][N:8]([C:15]2[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=2)[N:7]=1)(=[O:5])[CH3:22]
Reactant: COc1cn(-c2ccncc2)nc(C(=O)N(C)OC)c1=O
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: COc1cn(-c2ccncc2)nc(C(C)=O)c1=O
Temperature: -78 °C
Reaction time: 1 h
Yield: 26 %

Procedure:
To a solution of N,5-dimethoxy-N-methyl-4-oxo-1-pyridin-4-yl-1,4-dihydropyridazine-3-carboxamide (9.6 g, 33 mmol) in THF (100 mL) was added dropwise 1 M MeMgBr in THF (66 mL, 66 mmol) at −78° C. for 15 min. After stirring at −78° C. for 1 h, the mixture was quenched with 1 M HCl aqueous solution (70 mL). The mixture was warmed to room temperature, basified with 1 M NaOH aqueous solution, washed with AcOEt. The aqueous layer was extracted with CH2Cl2 (50 mL×4). The combined extract was dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound (2.1 g, 26% yield) as yellow crystals: 1H NMR (300 MHz, CDCl3): δ ppm 2.70 (3H, s), 3.98 (3H, s), 7.64 (2H, dd, J=4.7, 1.6 Hz), 8.04 (1H, s), 8.79 (2H, dd, J=4.7, 1.6 Hz).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:19](=O)[CH2:20][CH3:21])=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:23][OH:24].Cl.N1C=CC=CC=1>CCO>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:19](=[N:23][OH:24])[CH2:20][CH3:21])=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCC(=O)c1ccc(-c2ccccc2)c(-c2ccccc2)n1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CCC(=NO)c1ccc(-c2ccccc2)c(-c2ccccc2)n1

Procedure:
Following General Procedure P, 1-(5,6-diphenyl-pyridin-2-yl)-propan-1-one (Compound 76, 90 mg, 0.31 mmol), NH2OH—HCl (87 mg, 1.25 mmol) and pyridine (272 mg, 0.27 mmol) in EtOH (2 ml) were reacted to give title compound as a white solid.
Reaction SMILES: C(C1N=C(N2CCC(F)(F)C2)C2N=NN(CC)C=2N=1)(C)(C)C.[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:42][C:38]3([CH2:41][O:40][CH2:39]3)[CH2:37]2)[C:30]2[N:35]=[N:34][NH:33][C:31]=2[N:32]=1)([CH3:26])([CH3:25])[CH3:24].Cl.Cl[CH2:45][C:46]1[N:50]([CH3:51])[N:49]=[N:48][CH:47]=1>>[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:37][C:38]3([CH2:39][O:40][CH2:41]3)[CH2:42]2)[C:30]2[N:35]=[N:34][N:33]([CH2:45][C:46]3[N:50]([CH3:51])[N:49]=[N:48][CH:47]=3)[C:31]=2[N:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1nc(N2CC3(COC3)C2)c2nn[nH]c2n1
Reactant: Cn1nncc1CCl
Agent: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Agent: Cl
Product: Cn1nncc1Cn1nnc2c(N3CC4(COC4)C3)nc(C(C)(C)C)nc21

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-Butyl-7-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 5-(chloromethyl)-1-methyl-1H-1,2,3-triazole hydrochloride and isolated as white solid. MS (m/e): 370.2 (MH+).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([CH2:13][CH2:14][CH2:15][NH2:16])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[O:27][CH2:28][CH2:29]Cl>CS(C)=O.O>[C:7]1([CH2:13][CH2:14][CH2:15][NH:16][CH2:29][CH2:28][O:27][C:18]2[CH:19]=[CH:20][C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:17]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: ClCCOc1ccc2ccccc2c1
Reactant: NCCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: c1ccc(CCCNCCOc2ccc3ccccc3c2)cc1
Temperature: 150 °C

Procedure:
A mixture of anhydrous potassium carbonate (10 gm, in excess) and 3-phenylpropylamine (0.47 ml, 0.003 mole) was taken in dry DMSO (40 ml). Now 2-(2-naphthyloxy)-1-chloroethane (0.5 gm, 0.002 mole) was added in it. Reaction mixture was refluxed at 150° C. for 6 hrs and the reaction was completed as checked by TLC. Reaction mixture was poured in distilled water (60 ml) and extracted with ethyl acetate thrice. The organic layer was separated and concentrated to get oily compound which was later crystallized by benzene hexane to get N-(3-phenylpropyl)-(2-(naphthalen-2-yloxy)ethyl)amine, solid, m.p. 104° C., (yield 0.65 gm, 87.6%).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[CH:5]=[CH:4]1.Br[CH2:13][C:14]([O:16][CH3:17])=[O:15]>CN(C)C=O>[N:3]1([CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[CH:5]=[CH:4]1
Reactant: c1cnc2[nH]ccc2c1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)Cn1ccc2cccnc21

Procedure:
A procedure similar to that described in Preparation 12 was repeated, except that 1.90 g of sodium hydride (as a 55% by weight dispersion in mineral oil), 4.95 g of 7-azaindol, 100 ml of dimethylformamide and 4.2 ml of methyl bromoacetate were used, to give 7.70 g of the title compound having Rf=0.33 (on silica gel thin layer chromatography using a 2:1 by volume mixture of hexane and ethyl acetate as the developing solvent).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([CH3:13])[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.P(Cl)(Cl)(Cl)=O>C1C=CC=CC=1>[CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([CH3:13])[C:9]1=[N:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1CCN(Cc2ccccc2)C1=O
Reactant: Nc1ccccc1N1CCOCC1
Solvent: c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC1CCN(Cc2ccccc2)C1=Nc1ccccc1N1CCOCC1

Procedure:
In a similar manner to that described in Example 1, 1-benzyl-3-methyl-2-pyrrolidone (14.17 g) in benzene (80 ml) was reacted with 4-(2-aminophenyl)morpholine (8.9 g) in benzene (30 ml) in the presence of phosphorus oxychloride (6.86 ml) for 24 hours at 70° C. to give 4-[2-(1-benzyl-3-methyl-2-pyrrolidinylideneamino)phenyl]morpholine (m.p. 96°-97° C.) which was recrystallised from hexane.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH3:17])[CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=[N:4][C:3]=1[C:18]([NH2:20])=[O:19].[Br:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](OC)=O)=[CH:24][CH:23]=1>>[Br:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]2[NH:20][C:18](=[O:19])[C:3]3[N:4]=[N:5][N:6]([CH:7]([CH3:17])[CH2:8][CH2:9][CH2:10][C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:2]=3[N:1]=2)=[CH:24][CH:23]=1
Reactant: CC(CCCc1ccccc1)n1nnc(C(N)=O)c1N
Reactant: COC(=O)Cc1ccc(Br)cc1
Product: CC(CCCc1ccccc1)n1nnc2c(=O)[nH]c(Cc3ccc(Br)cc3)nc21

Procedure:
Analogously to the procedure of Example 1, the title compound is prepared from 1.0 g (3.8 mmol) of 5-amino-1-(1-methyl-4-phenyl-butyl)-1H-[1,2,3]triazole-4-carboxamide and 2.61 g (11.4 mmol) of methyl 4-bromophenylacetate.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)([CH3:13])[C:8]2=[O:12])=[CH:4][C:3]=1[OH:19].C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33].O>CN(C)C=O>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)([CH3:13])[C:8]2=[O:12])=[CH:4][C:3]=1[O:19][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]
Reactant: CCOC(=O)CCCCCBr
Reactant: CC1(C2CCCC2)Cc2cc(O)c(Cl)c(Cl)c2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCCCOc1cc2c(c(Cl)c1Cl)C(=O)C(C)(C1CCCC1)C2
Reaction time: 0.5 h

Procedure:
6,7-Dichloro-2-cyclopentyl-2,3-dihydro-5-hydroxy-2-methyl-1H-inden-1-one (12 g., 0.04 mole) is dissolved in dimethylformamide (50 ml.), treated with potassium carbonate (5.5 g., 0.04 mole) and heated and stirred on a steam bath for 30 minutes. Ethyl 6-bromohexanoate (8.9 g., 0.04 mole) is added dropwise with good stirring over 15 minutes, then the mixture is heated and stirred in a steam bath for two hours. The reaction mixture is poured into water (400 ml.) and extracted with ether (2×150 ml.) The either extract is dried over sodium sulfate, filtered and the ether removed at reduced pressure. The residue, which crystallizes upon standing, is recrystallized from a mixture of ether and petroleum ether to give ethyl 6-[(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy]hexanoate, 16 g., m.p. 69°-72° C.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[N:5][S:6][C:7]=1[NH:8][C:9](=[O:17])OC1C=CC=CC=1)#[N:2].[O:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][CH2:35][NH2:36])[CH2:29][CH2:28]1>O1CCOCC1>[C:1]([C:3]1[C:4]([C:18]2[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=2)=[N:5][S:6][C:7]=1[NH:8][C:9]([NH:36][CH2:35][CH2:34][CH2:33][N:30]1[CH2:31][CH2:32][O:27][CH2:28][CH2:29]1)=[O:17])#[N:2]
Reactant: NCCCN1CCOCC1
Reactant: N#Cc1c(-c2ccc([N+](=O)[O-])cc2)nsc1NC(=O)Oc1ccccc1
Solvent: C1COCCO1
Product: N#Cc1c(-c2ccc([N+](=O)[O-])cc2)nsc1NC(=O)NCCCN1CCOCC1
Temperature: 80 °C
Yield: 79.2 %

Procedure:
A mixture of phenyl (4-cyano-3-(4-nitrophenyl)isothiazol-5-yl)carbamate (37 mg, 0.10 mmol) and 3-morpholinopropylamine (0.021 mL, 0.14 mmol) in 0.8 mL dioxane was heated at 80° C. After 2 hours the reaction mixture was evaporated to a yellowish oily film. This material was then chromatographed eluting with EtOAc, then gradient 2% to 6% MeOH in EtOAc to give the title compound as a pale yellow solid (33 mg, 80%). 1H NMR (acetone) δ: 8.38-8.44 (m, 2H), 8.22-8.27 (m, 2H), 6.91 (t, J=5.4 Hz, 1H), 3.59-3.64 (m, 4H), 3.38-3.45 (m, 2H), 2.37-2.45 (m, 6H), 1.77 (quin, J=6.8 Hz, 2H)
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:5]=1[C:6]([OH:8])=O)([O-:3])=[O:2].[CH2:16]([NH:20][CH2:21][CH:22]([CH3:24])[CH3:23])[CH:17]([CH3:19])[CH3:18].P(Cl)(Cl)(Cl)=O.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[CH2:16]([N:20]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:6](=[O:8])[C:5]1[C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=[CH:12][C:4]=1[N+:1]([O-:3])=[O:2])[CH:17]([CH3:19])[CH3:18]
Reactant: O=C(O)c1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: CC(C)CNCC(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(C)CN(CC(C)C)C(=O)c1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Temperature: 50 °C
Yield: 64.8 %

Procedure:
To a slurry of 106.5 g of 2,6-dinitrobenzoic acid in 1000 ml of toluene was added with stirring 133.2 g of diisobutylamine. Next 44.9 g of phosphorus oxychloride was added dropwise at such a rate to maintain the temperature below 40° C. The mixture was heated to 50° C. for 12 hrs and poured into 500 ml of aqueous 5% NaHCO3 solution with stirring. The organic layer was separated, washed with 500 ml water, and the toluene removed under reduced pressure. The remaining solid was recrystallized from hot ethanol to give 105.2 g of N,N-diisobutyl-2,6-dinitrobenzamide, a yellow solid, mp 97°-99° C.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]([O:17][C:18](=[O:30])[CH:19]([C:25](OCC)=[O:26])[C:20](OCC)=[O:21])[CH3:16].[Sn](Cl)(Cl)(Cl)Cl>>[CH2:15]([O:17][C:18]([C:19]1[C:20](=[O:21])[O:14][C:10]2[C:11]([C:25]=1[OH:26])=[CH:12][CH:13]=[C:8]([O:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:9]=2)=[O:30])[CH3:16]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)OCC
Reactant: Oc1cccc(Oc2ccccc2)c1
Agent: Cl[Sn](Cl)(Cl)Cl
Product: CCOC(=O)c1c(O)c2ccc(Oc3ccccc3)cc2oc1=O
Temperature: 200 °C
Yield: 4.5 %

Procedure:
A mixture of 3-phenoxy-phenol (1.068 g, 5.73 mmol), 2-ethoxycarbonyl-malonic acid diethyl ester (3.65 mL, 17.2 mmol), and tin tetrachloride (14 μL, 0.11 mmol) was heated in a 200° C.-oil bath for 5 min; then cooled, the reaction mixture was directly purified on silica gel column chromatography (eluent: ethyl acetate in dichloromethane: 10% to 80%) to give the desired title product (84 mg, 4.4%). ESI (m/z): 327 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([CH2:6][NH:7][CH2:8][CH3:9])=[CH:4][CH:3]=1.C(N(C(C)C)C(C)C)C.Cl[C:22](=[O:44])[CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][O:33][C:34]2[CH:43]=[CH:42][CH:41]=[CH:40][C:35]=2[C:36]([O:38][CH3:39])=[O:37])=[CH:27][CH:26]=1>C(#N)C>[CH2:8]([N:7]([CH2:6][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:11][CH:10]=1)[C:22](=[O:44])[CH2:23][O:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:31][CH2:32][O:33][C:34]2[CH:43]=[CH:42][CH:41]=[CH:40][C:35]=2[C:36]([O:38][CH3:39])=[O:37])=[CH:29][CH:30]=1)[CH3:9]
Reactant: COC(=O)c1ccccc1OCCc1ccc(OCC(=O)Cl)cc1
Reactant: CCNCc1ccc(F)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCN(Cc1ccc(F)cc1)C(=O)COc1ccc(CCOc2ccccc2C(=O)OC)cc1
Reaction time: 0.5 h
Yield: 83.6 %

Procedure:
N-(4-Fluorobenzyl)ethanamine (0.114 g, 0.745 mmol) was dissolved in dry acetonitrile under N2 and N-ethyl-N,N-diisopropylamine (0.371 g, 2.867 nmol) was added. The mixture was stirred for 30 min and methyl 2-{2-[4-(2-chloro-2-oxoethoxy)phenyl]-ethoxy}benzoate (0.200 g, 0.573 mmol) was added. The solution was stirred overnight at room temperature. The crude was purified by flash chromatography (started with isocratic heptane/EtOAc 50/50 and then the EtOAc concentration was increased to 100%, (silica gel 60 0.004-0.063 mm). The product containing fractions were pooled and the EtOAc was removed by evaporation to give 0.223 g of methyl 2-[2-(4-{2-[ethyl(4-fluorobenzyl)amino]-2-oxoethoxy}phenyl)ethoxy]benzoate (yield 83.5%).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][CH:11]=[CH:10][C:6]=2[C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1.OS(O)(=O)=O.[CH3:22]O>>[CH:1]1([NH:4][C:5]2[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][CH:11]=[CH:10][C:6]=2[C:7]([O:9][CH3:22])=[O:8])[CH2:2][CH2:3]1
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1NC1CC1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc([N+](=O)[O-])c1NC1CC1

Procedure:
The crude 2-(cyclopropylamino)-3-nitrobenzoic acid (0.90 g, 4.1 mmol) was dissolved in MeOH (15 mL), and 2 mL H2SO4 (98%) was added. The mixture was heated to reflux for 18 h. The mixture was cooled, concentrated in vacuo, and purified by column chromatography on a silica gel column using DCM as eluent to give methyl 2-(cyclopropylamino)-3-nitrobenzoate: LC-MS (ESI) m/z 237.1 [M+H]+.
Reaction SMILES: [C:1]1([CH3:12])[C:2]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:12][C:1]1[C:2]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1ccccc1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1ccccc1CBr

Procedure:
A mixture of 100 g of ethyl o-toluate, 100 g of N-bromosuccinimide and 0.3 g of benzoyl peroxide in 1 liter of carbon tetrachloride is heated under reflux for 3 hours with stirring and filtered. The filtrate is washed with 3% aqueous sodium hydroxide and then with water, dried over magnesium sulfate and concentrated under reduced pressure to provide ethyl α-bromo-o-toluate as an oil.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:20]3[CH2:25][CH2:24]S[C:22]4[N:26]=[CH:27][C:28]([N:30]5[CH2:35][CH2:34][O:33][CH2:32][CH2:31]5)=[CH:29][C:21]3=4)=[C:7]([CH3:19])[C:8]([C:12]3[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][N:13]=3)=[N:9]2)=[CH:4][CH:3]=1.O.OO.[OH:39][S:40]([O-:42])=O.[Na+]>CCOC(C)=O.[O-][W]([O-])(=O)=O.[Na+].[Na+]>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:20]3[CH2:25][CH2:24][S:40](=[O:42])(=[O:39])[C:22]4[N:26]=[CH:27][C:28]([N:30]5[CH2:35][CH2:34][O:33][CH2:32][CH2:31]5)=[CH:29][C:21]3=4)=[C:7]([CH3:19])[C:8]([C:12]3[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][N:13]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccnc(-c2nc3cc(F)ccc3c(N3CCSc4ncc(N5CCOCC5)cc43)c2C)c1
Reactant: O=S([O-])O
Agent: O=[W](=O)([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccnc(-c2nc3cc(F)ccc3c(N3CCS(=O)(=O)c4ncc(N5CCOCC5)cc43)c2C)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 4-(1-(7-fluoro-3-methyl-2-(4-methylpyridin-2-yl)quinolin-4-yl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazin-7-yl)morpholine (45 mg, 0.09 mmol) in EtOAc (2.5 mL) was added disodium tungstate (30.4 mg, 0.092 mol) and water (0.5 mL). The reaction was cooled at 0° C. and then H2O2 (56.6 μL, 1.85 mmol, 30%) was added. The reaction was allowed to warm to rt for 1 h. After this time more disodium tungstate (10 mg) was added followed by H2O2 (0.5 mL, 30%) and the reaction was stirred at rt overnight. After this time the reaction was diluted with EtOAc (50 mL) and treated with a saturated aqueous solution of NaHSO3 (15 mL). The separated organic layer was washed with brine (15 mL), dried over MgSO4, filtered and evaporated in vacuo to give 1-(7-fluoro-3-methyl-2-(4-methyl-2-pyridinyl)-4-quinolinyl)-7-(4-morpholinyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazine 4,4-dioxide. 1H NMR (400 MHz, chloroform-d) δ ppm 8.59 (1H, d, J=4.7 Hz), 7.86-7.91 (2H, m), 7.70-7.77 (2H, m), 7.38 (1H, ddd, J=9.2, 8.0, 2.5 Hz), 7.25 (1H, dd, J=5.0, 0.9 Hz), 5.58 (1H, d, J=2.5 Hz), 4.18-4.27 (2H, m), 3.59-3.75 (6H, m), 2.84-3.02 (4H, m), 2.51 (3H, s), 2.44 (3H, s). Mass Spectrum (ESI) m/e=520.0 (M+1).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)/[C:5](=N/S(C2SC=CC=2)(=O)=O)/[CH:4]=[C:3]1[S:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].ClC1C(=O)C2C(=CC=CC=2)/C(=N/S(C2SC=CC=2)(=O)=O)/C=1.CCOC(C)=O.[N+:55]([C:58]1[CH:63]=[CH:62][C:61]([S:64]([NH2:67])(=[O:66])=[O:65])=[CH:60][CH:59]=1)([O-:57])=[O:56]>ClCCCl>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:67][S:64]([C:61]2[CH:60]=[CH:59][C:58]([N+:55]([O-:57])=[O:56])=[CH:63][CH:62]=2)(=[O:65])=[O:66])=[CH:4][C:3]=1[S:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)CSC1=C/C(=N\S(=O)(=O)c2cccs2)c2ccccc2C1=O
Reactant: NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: O=C1C(Cl)=C/C(=N\S(=O)(=O)c2cccs2)c2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CCOC(=O)CSc1cc(NS(=O)(=O)c2ccc([N+](=O)[O-])cc2)c2ccccc2c1O

Procedure:
5.2.25 Ethyl 2-(1-hydroxy-4-(4-nitrophenylsulfonamido)naphthalen-2-ylthio)acetate (9e) was prepared according to the procedure for 8a except using 4-nitrobenzenesulfonamide, 1,2-dichloroethane as solvent and applying 100° C. to the reaction. The reaction was worked up according to the procedure for 12a and the title compound was isolated from the product mixture by flash chromatography (EtOAc/Hex) affording 48 mg (10.4%) as a brown solid, m.p.: 143-145° C.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[CH2:12]([CH:14]1[O:16][CH2:15]1)Cl>>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[CH:5][C:6]([O:9][CH2:12][CH:14]2[CH2:15][O:16]2)=[CH:7][CH:8]=1
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: ClCC1CO1
Product: FC(F)(F)c1ccc(OCC2CO2)cc1

Procedure:
The title compound was prepared from 4-trifluromethyl-phenol and epichlorohydrin employing the procedures as set forth in Step 1 of Example 2.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6](F)[N:5]=[CH:4][N:3]=1.[CH2:10]([OH:14])[C:11]#[C:12][CH3:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:10]([O:14][C:6]1[C:7]([F:8])=[C:2]([F:1])[N:3]=[CH:4][N:5]=1)[C:11]#[C:12][CH3:13]
Reactant: Fc1ncnc(F)c1F
Reactant: CC#CCO
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC#CCOc1ncnc(F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.5 %

Procedure:
0.5 g of 4,5,6-trifluoropyrimidine, 0.31 g of 2-butyn-1-ol and 0.62 ml of triethylamine were added to 1 ml of toluene, then the mixture was stirred at room temperature for 1 hour. Then the reaction mixture was subjected to silica gel column chromatography to obtain 0.56 g of 4-(2-butynyloxy)-5,6-difluoropyrimidine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[C:9](OC)=[CH:8][C:7]([C:12]2[C:17]([CH2:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:20][CH3:21])=[N:6][CH:5]=1.O=P(Cl)(Cl)[Cl:25]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:22])[C:4]1[C:9]([Cl:25])=[CH:8][C:7]([C:12]2[C:17]([CH2:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:20][CH3:21])=[N:6][CH:5]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCc1cccc(CC)c1-c1cc(OC)c(C(=O)OC)cn1
Solvent: CN(C)C=O
Product: CCc1cccc(CC)c1-c1cc(Cl)c(C(=O)OC)cn1
Temperature: 80 °C

Procedure:
A mixture of 6-(2,6-diethyl-phenyl)-4-methoxy-nicotinic acid methyl ester (4.0 g, 13.4 mmol), DMF (10 mL) and POCl3 (10 mL) is heated at 80° C. overnight. The volatile material is removed in vacuo. Ice water, NaHCO3 and hexane (50 mL) are added to the residue. The organic layer is separated and the aqueous layer is extracted with hexane (2×30 mL). The combined organic layer is washed with water, dried, and concentrated. The crude product is purified by silica gel chromatography (1% MeOH in CH2Cl2) to give 4-chloro-6-(2,6-diethyl-phenyl)-nicotinic acid methyl ester. 1H NMR (CDCl3) 9.12 (s, 1H), 7.40 (s, 1H), 7.30 (d, 1H), 7.15 (d, 2H), 4.00 (s, 3H), 2.30 (q, 4H), 1.05 (t, 6H).
Reaction SMILES: [NH2:1][C@@H:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][OH:4].[Br:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH:14]=O.S([O-])([O-])(=O)=O.[Mg+2]>C(Cl)Cl.CCOCC>[Br:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1/[CH:14]=[N:1]/[C@@H:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][OH:4]
Reactant: O=Cc1ccccc1Br
Reactant: N[C@H](CO)c1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CCOCC
Product: OC[C@@H](/N=C/c1ccccc1Br)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79 %

Procedure:
To a stirred solution of (S)-(+)-2-amino-2-phenylethanol (271 mmol, 37.2 g) in methylene chloride (350 mL) was added 2-bromobenzaldehyde (271 mmol, 31.8 mL, 50.2 g) and anhydrous magnesium sulfate (50 g). The mixture stirred 3 h at room temperature then left to stand overnight. Filtered through dicalite and evaporated to dryness to give a pale yellow solid. This solid was stirred in dry ether (100 mL) for 30 min, then filtered, washed with ether, and dried in vacuo to give (S,E)-2-(2-bromobenzylideneamino)-2-phenylethanol (65.1 g) as a colourless solid.