Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:14]2[C:9](=[CH:10][C:11]([Cl:15])=[CH:12][CH:13]=2)[NH:8][N:7]=1)=[O:4].[NH:16]1[CH2:21][CH2:20][S:19][CH2:18][CH2:17]1>C(#N)C>[Cl:15][C:11]1[CH:10]=[C:9]2[C:14]([C:6]([NH:5][C:3](=[O:4])[CH2:2][N:16]3[CH2:21][CH2:20][S:19][CH2:18][CH2:17]3)=[N:7][NH:8]2)=[CH:13][CH:12]=1
Reactant: O=C(CCl)Nc1n[nH]c2cc(Cl)ccc12
Reactant: C1CSCCN1
Solvent: CC#N
Product: O=C(CN1CCSCC1)Nc1n[nH]c2cc(Cl)ccc12

Procedure:
The process is performed as in Example 75, starting with 500 mg of 2-chloro-N-(6-chloro-1H-indazol-3-yl)acetamide, 15 cm3 of acetonitrile and 0.62 cm3 of thiomorpholine. The reaction medium is refluxed for 2 hours, the precipitate formed is filtered off and the filtrate is concentrated to dryness under reduced pressure (2 kPa; 50° C.); the crude product obtained is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 2.5 cm), eluting with a cyclohexane/ethyl acetate mixture (50/50 by volume). The fractions containing the expected product are combined, evaporated under reduced pressure (2 kPa; 50° C.) and dried (90 Pa; 45° C.) to give 560 mg of N-(6-chloro-1H-indazol-3-yl)thiomorpholine-4-acetamide in the form of a pale yellow foam.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][NH:10][O:11][CH3:12].[F:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16](Cl)=[O:17]>ClCCl>[F:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([N:10]([O:11][CH3:12])[CH3:9])=[O:17]
Reactant: O=C(Cl)c1ccccc1F
Reactant: CNOC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1ccccc1F
Reaction time: 0.17 h
Yield: 674.6 %

Procedure:
Triethylamine (5.32 mL, 37.84 mmol) was added dropwise to a solution of N,O-dimethylhydroxylamine hydrochloride (2.768 g, 28.38 mmol) in anhydrous dichloromethane (45 mL) at 0° C. After stirring for 10 min, 2-fluorobenzoyl chloride (0.303 mL, 2.52 mmol) in anhydrous dichloromethane (15 mL) was added dropwise. The reaction mixture was returned to room temperature and stirred for 5 h. The reaction mixture was quenched with water (60 mL) and the products were extracted with dichloromethane (2×60 mL). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Purification using flash chromatography (silica gel, hexanes:ethyl acetate, gradient 93:7 to 60:40) afforded 2-Fluoro-N-methoxy-N-methyl-benzamide (3.116, 17 mmol) in a 90% yield.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:25]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccc2[nH]cc(C3CCN(CCc4ccccc4)CC3)c2n1
Product: O=C(Nc1ccc2[nH]cc(C3CCN(CCc4ccccc4)CC3)c2n1)c1ccccc1

Procedure:
Beginning with 0.015 gm (0.047 mMol) 5-amino-3-(1-(2-phenyleth-1-yl)piperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.007 mL (0.061 mMol) benzoyl chloride, the title compound was prepared essentially by the procedure described in Example 7.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C@@H:15]3[O:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]3)=[CH:11][CH:10]=2)=[O:7])=[N:2]1.[Cl:28][C:29]1[C:34](Cl)=[N:33][CH:32]=[CH:31][N:30]=1.C(=O)([O-])[O-].[K+].[K+].O>CC(N(C)C)=O>[Cl:28][C:29]1[C:34]([N:1]2[CH:5]=[CH:4][C:3]([C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([C@@H:15]4[O:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]4)=[CH:11][CH:10]=3)=[O:7])=[N:2]2)=[N:33][CH:32]=[CH:31][N:30]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(NC(=O)c3cc[nH]n3)cc2)C1
Reactant: Clc1nccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(NC(=O)c3ccn(-c4nccnc4Cl)n3)cc2)C1
Reaction time: 16 h
Yield: 41.2 %

Procedure:
(S)-tert-Butyl 2-(4-(1H-pyrazole-3-carboxamido)phenyl)morpholine-4-carboxylate (90 mg, 0.24 mmol) and 2,3-dichloropyrazine (43 mg, 0.29 mmol) were dissolved in dimethylacetamide (2 ml) and potassium carbonate (67 mg, 0.48 mmol) was added. The reaction mixture was placed on a Büchi shaker for 16 hours at 80° C. To complete the reaction an additional amount of 2,3-dichloropyrazine (10 mg) was added and heating was continued for another 2 h at 120° C. After cooling the mixture, water was added followed by extraction with ethyl acetate twice. The combined organic layers was dried over MgSO4 and evaporated. The crude material was purified by flash chromatography (silica gel, 10 g, 25% to 50% EtOAc in heptane) to yield an off-white gum (48 mg, 42%). MS (ISP): 429.3 (100%, [M−tBu+H]+), 485.4 (10%, [M+H]+).
Reaction SMILES: Cl([O-])(=O)(=O)=O.[CH:6]1[C:19]2[C:10](=[S+:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:9]=[CH:8][CH:7]=1.[C-:20]#[N:21].[K+]>O.C(Cl)Cl>[C:20]([CH:18]1[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[S:11][C:10]2[C:19]1=[CH:6][CH:7]=[CH:8][CH:9]=2)#[N:21]
Reactant: c1ccc2[s+]c3ccccc3cc2c1
Reactant: [C-]#N
Agent: [K+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: O
Solvent: ClCCl
Product: N#CC1c2ccccc2Sc2ccccc21
Reaction time: 1 h
Yield: 91.2 %

Procedure:
8.0 g (27.0 mmol) of thioxanthylium perchlorate [C. C. Price et al, J. Amer. Chem. Soc. 85, 2278 (1963)] are added-toi well-stirred mixture of 3.5 g (53.8 mmol) of potassium cyanide in 4 ml of water and 30 ml of methylene chloride under a nitrogen atmosphere. After one hour, the mixture is dried over potassium carbonate and filtered and the filtrate is concentrated on a vacuum rotary evaporator. Crystallization of the residue from isopropanol gives 5.5 g (91%) of 9-cyano-thioxanthene, melting point 103°-105° C., colourless needles (compound (103), Table 1).
Reaction SMILES: NC1([C:6]([NH:8][C:9]2[CH:10]=[N:11][C:12]([O:15][C:16]3[C:21]4[C:22]([CH3:26])([CH3:25])[CH2:23][O:24][C:20]=4[CH:19]=[CH:18][CH:17]=3)=[CH:13][CH:14]=2)=[O:7])CCC1.[NH2:27][C:28]1([C:31](NC2C=NC(OC3C4C(C)(C)COC=4C=CC=3)=CC=2)=[O:32])[CH2:30][CH2:29]1>>[CH3:25][C:22]1([CH3:26])[C:21]2[C:16]([O:15][C:12]3[N:11]=[CH:10][C:9]([N:8]4[C:31](=[O:32])[C:28]5([CH2:30][CH2:29]5)[NH:27][C:6]4=[O:7])=[CH:14][CH:13]=3)=[CH:17][CH:18]=[CH:19][C:20]=2[O:24][CH2:23]1
Reactant: CC1(C)COc2cccc(Oc3ccc(NC(=O)C4(N)CC4)cn3)c21
Reactant: CC1(C)COc2cccc(Oc3ccc(NC(=O)C4(N)CCC4)cn3)c21
Product: CC1(C)COc2cccc(Oc3ccc(N4C(=O)NC5(CC5)C4=O)cn3)c21
Yield: 49 %

Procedure:
The title compound (5 mg, 49% yield) was made in a similar fashion to the preparation of Example 11 replacing 1-amino-N-{6-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-3-pyridinyl}cyclobutanecarboxamide (Intermediate 70) with 1-amino-N-{6-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-3-pyridinyl}cyclopropanecarboxamide (Intermediate 73, 9 mg).
Reaction SMILES: SCC.[Cl-].[Al+3].[Cl-].[Cl-].C(OC([NH:15][C:16]1[C:21]([CH3:22])=[C:20]([F:23])[CH:19]=[CH:18][C:17]=1[O:24]C)=O)(C)(C)C>ClCCl>[NH2:15][C:16]1[C:21]([CH3:22])=[C:20]([F:23])[CH:19]=[CH:18][C:17]=1[OH:24]
Reactant: COc1ccc(F)c(C)c1NC(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCS
Solvent: ClCCl
Product: Cc1c(F)ccc(O)c1N
Temperature: 0 °C

Procedure:
To a mixture of mercaptoethane (56 ml) and dichloromethane (56 ml) was added aluminum chloride (22.4 g, 168 mmoles) under stirring at 0° C. To this was then added 2-(N-tert-butoxycarbonylamino)-4-fluoro-3-methylanisole (12.6 g, 56 mmoles) slowly at room temperature. Stirring continued for 11/2 hours. The reaction was quenched by adding ice and water and the solution acidified with 1N HCl. The organic substance was extracted with ethyl acetate (x3). The combined extracts were washed with NaHCO3 and with brine, dried over sodium sulfate and concentrated to give a solid. Recrystallization from chloroform gave 3.15 of pure title product; m.p. 118°-121° (dec).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[C:10]1[C:19]2[C:14](=[C:15]([CH3:20])[CH:16]=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:21][C:22]2[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=2)[N:11]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[C:19]3[C:14](=[C:15]([CH3:20])[CH:16]=[CH:17][CH:18]=3)[CH:13]=[C:12]([NH:21][C:22]3[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=3)[N:11]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(Nc2cc3c(C)cccc3c(Cl)n2)n[nH]1
Reactant: Oc1ccc(F)cc1
Product: Cc1cc(Nc2cc3c(C)cccc3c(Oc3ccc(F)cc3)n2)n[nH]1

Procedure:
Similar procedure as described in example 10 was used, starting from 4-fluoro-phenol and (1-chloro-5-methyl-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give [1-(4-fluoro-phenoxy)-5-methyl-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 349(MH+).
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:33]2[CH:34]=[C:35]3[C:39](=[CH:40][CH:41]=2)[C:38](=[O:42])[NH:37][CH2:36]3)O1>>[O:42]=[C:38]1[C:39]2[C:35](=[CH:34][C:33]([C:2]3[N:7]4[N:8]=[CH:9][N:10]=[C:6]4[C:5]([NH:11][CH:12]4[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]4)=[N:4][CH:3]=3)=[CH:41][CH:40]=2)[CH2:36][NH:37]1
Reactant: CC1(C)OB(c2ccc3c(c2)CNC3=O)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ncc(Br)n3ncnc23)CC1
Product: CC(C)(C)OC(=O)N1CCC(Nc2ncc(-c3ccc4c(c3)CNC4=O)n3ncnc23)CC1

Procedure:
Prepared from the product of Step 1 and Intermediate 4 (5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,3-dihydro-isoindol-1-one) using the procedure described in Example 1, Step 2. 1H-NMR (400 MHz, d6-DMSO) =1.45 (s, 9H), 1.61-1.65 (m; 2H), 1.88-1.95 (m, 2H), 2.82-2.99 (brm, 2H), 3.99-4.04 (m, 2H), 4.27-4.38 (brm, 1H), 4.50 (s, 2H), 7.81 (d, 1H, J=8), 7.92 (s, 1H), 8.03-8.11 (m, 2H), 8.18 (s, 1H), 8.63 (s, 1H), 8.67 (s, 1H). LCMS: Rt 3.07 min (98.3%), m/z (APCI) 450 (M+H)+.
Reaction SMILES: [C:1]([CH:24](O)[CH2:25][CH2:26][C:27](=[O:49])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]/[CH:39]=[CH:40]\[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[C:51]([OH:70])(=O)[CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58]/[CH:59]=[CH:60]\[CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH3:68].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1>[C:27]([CH2:26][CH:25]([C:51](=[O:70])[CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58]/[CH:59]=[CH:60]\[CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH3:68])[CH2:24][C:1](=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])(=[O:49])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]/[CH:39]=[CH:40]\[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Reactant: CCCCCCCC/C=C\CCCCCCCCCCCC(=O)CCC(O)C(=O)CCCCCCCCCCC/C=C\CCCCCCCC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Product: CCCCCCCC/C=C\CCCCCCCCCCCC(=O)CC(CC(=O)CCCCCCCCCCC/C=C\CCCCCCCC)C(=O)CCCCCCC/C=C\CCCCCCCC

Procedure:
A triacylglycerol containing oil having an EOE content of at least 50% based on total triacylglycerol composition can be chemically synthesized using 1,3 dihydroxyacetone and free erucic and oleic fatty acids as starting materials. Oils chemically synthesized as described herein have EOE contents of 80% or greater, and preferably greater than 90%. In the first step, 1,3 dihydroxyacetone dimer and erucic acid can be reacted in the presence of dicyclohexylcarbodiimide and 4-dimethylaminopyridine to form 1,3 dierucoylpropanone. The ketone group of 1,3 dierucoylpropanone can be reduced using, for example, sodium borohydride and water to form 1,3 dierucoylpropanol. EOE can be produced by reacting 1,3 dierucoylpropanol and oleic acid in the presence of dicyclohexylcarbodiimide and 4-dimethylaminopyridine to form 1,3 dierucoyl 2-oleoyl propane.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:27][N:28](C)[C:29](=O)OC(C)(C)C)=[CH:4][N:5]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:18]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.C(OCC)(=O)C.[ClH:43]>C(OCC)(=O)C.CC(O)C>[ClH:43].[F:1][C:2]1[C:3]([CH2:27][NH:28][CH3:29])=[CH:4][N:5]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([S:23]([CH3:26])(=[O:24])=[O:25])[CH:18]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: CN(Cc1cn(S(=O)(=O)c2cccc(S(C)(=O)=O)c2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CNCc1cn(S(=O)(=O)c2cccc(S(C)(=O)=O)c2)c(-c2cccnc2F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
To a solution of tert-butyl [(4-fluoro-5-(2-fluoropyridin-3-yl)-1-{[3-(methylsulfonyl)phenyl]sulfonyl}-1H-pyrrol-3-yl)methyl]methylcarbamate (504 mg) in ethyl acetate (3 mL) and 2-propanol (2 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (6 mL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from a mixed solvent of ethanol and water to give the title compound as a white solid (yield 358 mg, 78%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2([OH:26])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>O>[F:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:23]2[CH2:22][CH2:21][C:20]([C:17]3[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=3)([OH:26])[CH2:25][CH2:24]2)=[CH:7][CH:8]=1
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Reactant: Fc1ccc(OCCCCl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: OC1(c2ccc(Cl)cc2)CCN(CCCOc2ccc(F)cc2)CC1

Procedure:
A mixture of 2.83 g of 1-chloro-3-(p-fluorophenoxy)-propane, 3.18 g of 4-(p-chlorophenyl)-4-hydroxypiperidine, 0.8 g of sodium carbonate and 60 ml of dimethylformamide is heated at a temperature of 80° - 90°C for 10 hours. After cooling, the reaction mixture is poured into water. The precipitate is collected by filtration and dried to give 1-[3-(p-fluorophenoxy)-propyl]-4-(p-chlorophenyl)-4-hydroxypiperidine, M.P. 134 - 135°C. Recrystallization from benzene gives the purified product, M.P. 136° - 137°C.
Reaction SMILES: [CH2:1]([C:4]1[O:5][C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[C:8](=O)[CH:9]=1)[CH2:2][CH3:3].O>C(O)C.Cl.[Pd]>[CH2:1]([CH:4]1[CH2:9][CH2:8][C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[O:5]1)[CH2:2][CH3:3]
Reactant: CCCc1cc(=O)c2ccccc2o1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCCC1CCc2ccccc2O1

Procedure:
A solution of 44 g (234 mmol) of 2-propyl-1-benzopyran-4-one in 350 ml of ethanol and 125 ml of concentrated hydrochloric acid is hydrogenated for 8 hours under a pressure of 500 kPa, in the presence of 14 g of 10% palladium on carbon containing 50% of water. The mixture is then filtered and the filtrate is concentrated under reduced pressure. By chromatography of the residue on a silica column using dichloromethane, 26 g of product are obtained in oil form.
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][CH2:10][OH:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:13][C:14]([OH:16])=[O:15]>CN(C=O)C>[CH2:10]([O:11][CH2:13][C:14]([OH:16])=[O:15])[CH2:9][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: OCCc1ccccc1
Reactant: O=C(O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)COCCc1ccccc1
Reaction time: 0.17 h

Procedure:
NaH (6.87 g, 172 mmol) was added slowly to a solution of 2-phenylethanol ([60-12-8], 6.00 g, 5.88 ml, 49.1 mmol) in DMF (50 ml). The reaction mixture was heated and kept for 10 min at 60° C. Chloroacetic acid ([79-11-8], 8.12 g, 86 mmol) was added slowly and carefully (exothermic), and the mixture was kept for 1 h at 60° C. The mixture was poured on ice and extracted twice with diethyl ether. Then the water phase was acidified (HCl, pH˜3) and extracted twice with ethyl acetate. Phenethyloxy-acetic acid [81228-03-7] was obtained after drying (Na2SO4), and evaporation of the solvent. The compound was sufficiently pure for the next step without further purification.
Reaction SMILES: Cl.[CH2:2]([NH:14][NH2:15])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[OH-].[K+].[CH3:18][N:19]=[C:20]=[O:21]>C(OCC)C>[CH3:18][NH:19][C:20]([N:14]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[NH2:15])=[O:21]
Reactant: CCCCCCCCCCCCNN
Reactant: CN=C=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Product: CCCCCCCCCCCCN(N)C(=O)NC
Yield: 94.1 %

Procedure:
A stirred, degassed suspension of dodecylhydrazine hydrochloride (4.62 g, 0.017 mole) in diethyl ether (15 mL) was cooled under nitrogen and 4N aqueous potassium hydroxide (8.7 mL, 0.035 mole) was added. Stirring was continued as methyl isocyanate (0.97 g, 0.017 mole) in 5 mL diethyl ether was added dropwise. The mixture was filtered to yield 4.12 g (94.7%) N-methyl-1-dodecyl-hydrazinecarboxamide (m.p. 73°-75° C.). NMR analysis confirmed the structure.
Reaction SMILES: [C:1]([C:5]1[C:6]2[CH:7]=[C:8]([CH3:29])[C:9]([NH:17][C:18]3[CH:28]=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:19]=3)=[CH:10][C:11]=2[C:12]([CH3:16])([CH3:15])[CH2:13][CH:14]=1)([CH3:4])([CH3:3])[CH3:2].[CH:30](=O)[CH3:31]>>[CH2:30]([N:17]([C:9]1[C:8]([CH3:29])=[CH:7][C:6]2[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:14][CH2:13][C:12]([CH3:15])([CH3:16])[C:11]=2[CH:10]=1)[C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:27][CH:28]=1)[CH3:31]
Reactant: CC=O
Reactant: CCOC(=O)c1ccc(Nc2cc3c(cc2C)C(C(C)(C)C)=CCC3(C)C)cc1
Product: CCOC(=O)c1ccc(N(CC)c2cc3c(cc2C)C(C(C)(C)C)=CCC3(C)C)cc1
Yield: 62 %

Procedure:
Following General Procedure D, ethyl 4-[(5-tert-butyl-3,8,8-trimethyl-7,8-dihydronaphthalen-2-yl)amino]benzoate (Compound 56, 0.019 g, 0.05 mmol) was reacted with acetaldehyde (0.030 mL, 0.5 mmol) to give 0.013 g (62%) of the title compound as a clear oil.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([O-:9])=[O:8])=[CH:5][S:4][N:3]=1.[OH-].[Na+].Cl.[CH2:13]1COCC1.CO.O>>[CH2:1]([C:2]1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][S:4][N:3]=1)[CH3:13]
Reactant: C1CCOC1
Reactant: Cc1nscc1C(=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCc1nscc1C(=O)O
Temperature: 40 °C
Reaction time: 16 h

Procedure:
To a solution of 3-methylisothiazole-4-carboxylate (G-3) (4.73 g, 30.1 mmol) in THF-MeOH-H2O (2:1:1, 50 mL), NaOH (3.61 g, 90.3 mmol) is added and the resulting mixture is stirred at 40° C. for 16 h. The mixture is allowed to cool to RT and then acidified with concentrated HCl to adjust the pH to 2-3. The precipitate is collected by filtration, rinsed with water and dried in vacuo to afford the product, 3 ethylisothiazole-4-carboxylic acid (G-4).
Reaction SMILES: [CH3:1][N:2]1[C:12]([CH3:13])=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=2)[C:10](=[O:21])[C:4]([C:5]([O:7]CC)=[O:6])=[C:3]1[CH3:22].[OH-].[Na+]>CO.O>[CH3:1][N:2]1[C:12]([CH3:13])=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=2)[C:10](=[O:21])[C:4]([C:5]([OH:7])=[O:6])=[C:3]1[CH3:22]
Reactant: CCOC(=O)c1c(C)n(C)c(C)c(-c2ccc(Br)cc2)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1c(C(=O)O)c(=O)c(-c2ccc(Br)cc2)c(C)n1C

Procedure:
2.7 g. of crude ethyl 1,2,6-trimethyl-5-(4'-bromophenyl)-4-oxonicotinate was suspended in 27 g. of 5% NaOH in 1:1 methanol/water. The reaction mixture was refluxed for 21/2 hours, cooled and acidified. Filtration of the resulting solid provided 2.2 g of 1,2,6-trimethyl-5-(4-bromophenyl)-4-oxonicotinic acid. m.p. =228°-230° C. (decomposition).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([CH2:17][CH3:18])[C:14]2[C:9](=[CH:10][C:11]([F:15])=[CH:12][CH:13]=2)[NH:8][C:7]1=[O:16].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]2[CH2:31][CH2:30][N:29]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]3([CH2:17][CH3:18])[C:14]4[C:9](=[CH:10][C:11]([F:15])=[CH:12][CH:13]=4)[NH:8][C:7]3=[O:16])[CH2:28][CH2:27]2)=[CH:24][CH:25]=1
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: CCC1(CCCCCl)C(=O)Nc2cc(F)ccc21
Product: CCC1(CCCCN2CCN(c3ccc(Cl)cc3)CC2)C(=O)Nc2cc(F)ccc21

Procedure:
The title compound is prepared according to process H by applying processing method 1 starting from 3-(4-chlorobutyl)-3-ethyl-6-fluoro-1,3-dihydro-2H-indol-2-one and 1-(4-chloro-phenyl)-piperazine.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]1[NH:13][CH:14]=[CH:15][N:16]=1.Br[CH2:18][CH2:19]Br>>[N:16]1[CH:15]=[CH:14][N:13]2[C:12]=1[C:3]1[CH:4]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:10]=[CH:11][C:2]=1[O:1][CH2:19][CH2:18]2
Reactant: BrCCBr
Reactant: COC(=O)c1ccc(O)c(-c2ncc[nH]2)c1
Product: COC(=O)c1ccc2c(c1)-c1nccn1CCO2
Yield: 76 %

Procedure:
Following the procedure in Example 17, methyl 4-hydroxy-3-(1H-imidazol-2-yl)benzoate reacted with 1,2-dibromoethane to give methyl 5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylate. Yield 76%. MS (ESI+): 245.0. 1H NMR (400 MHz, CDCl3) δ 9.21 (d, J=2.2, 1H), 7.91 (dd, J=8.6, 2.2, 1H), 7.20 (t, J=4.8, 1H), 7.05 (d, J=8.6, 1H), 7.00 (d, J=0.8, 1H), 4.53-4.48 (m, 2H), 4.43-4.39 (m, 2H), 3.91 (d, J=5.9, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([O:19][S:20]([C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[C:11]([F:18])([F:17])[C:12]([O:14]CC)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OCC)(=O)C.Cl>C(OCC)(=O)C>[F:18][C:11]1([F:17])[CH:10]([O:19][S:20]([C:23]2[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=2)(=[O:21])=[O:22])[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[C:12]1=[O:14]
Reactant: CCOC(=O)C(F)(F)C(CNC(=O)OC(C)(C)C)OS(=O)(=O)c1ccc(C)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)OC2CN(C(=O)OC(C)(C)C)C(=O)C2(F)F)cc1
Reaction time: 3 h
Yield: 79.8 %

Procedure:
To a solution of ethyl 4-[(tert-butoxycarbonyl)amino]-2,2-difluoro-3-{[(4-methylphenyl)sulfonyl]oxy}butanoate (44.8 g) in ethyl acetate (50 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (100 mL), and the mixture was stirred for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was azeotropically distilled twice with toluene. The obtained mixture was dissolved in acetonitrile (20 mL), triethylamine (15.6 g) was added, and the mixture was stirred for 3 hr. Di-tert-butyl bicarbonate (33.6 g) and 4-dimethylaminopyridine (3.76 g) were added at room temperature and the mixture was stirred for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate, and washed with 1 mol/L hydrochloric acid. The separated aqueous layer was extracted again with ethyl acetate. Combined organic layers were washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=2:1) to give the title compound as a pale-yellow oil (yield 32.0 g, 80%).