Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC1C=CC(F)=C2C=1C=CCO2.[Br:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[O:21][CH2:22][C:23]#[CH:24]>>[Br:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[C:16]2[C:15]=1[O:21][CH2:22][CH:23]=[CH:24]2
Reactant: C#CCOc1ccc(F)cc1Br
Agent: Fc1ccc(F)c2c1C=CCO2
Product: Fc1cc(Br)c2c(c1)C=CCO2
Yield: 47 %

Procedure:
This compound was prepared analogously to 5,8-difluoro-2H-chromene but using (15 g, 65 mmol) of 2-bromo-4-fluoro-1-prop-2-ynyloxybenzene to give the title compound (7 g, 46%)
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=O)[O:8][C:4]=2[CH:3]=1.[Cl:12]C1C=CC=CC=1Cl>>[Cl:12][C:7]1[O:8][C:4]2[CH:3]=[C:2]([Cl:1])[CH:11]=[CH:10][C:5]=2[N:6]=1
Reactant: Clc1ccccc1Cl
Reactant: O=c1[nH]c2ccc(Cl)cc2o1
Product: Clc1ccc2nc(Cl)oc2c1

Procedure:
lf the process is carried out as in Example 1, but only 500 ml of o-dichlorobenzene is initially introduced, and the 6-chlorobenzoxazolin-2-one is metered in as a suspension in 500 ml of o-dichlorobenzene, then 2,6-dichlorobenzoxazole is obtained in the same yield and purity as in Example 1.
Reaction SMILES: [CH2:1]([NH:3][CH:4]1[CH2:9][CH2:8][S:7](=[O:11])(=[O:10])[C:6]2[S:12][C:13]([S:15]([NH2:18])(=[O:17])=[O:16])=[CH:14][C:5]1=2)[CH3:2].C(N(CC)CC)C.[C:26](Cl)(=[O:28])[CH3:27].C([O-])(O)=O.[Na+]>C1COCC1>[CH2:1]([N:3]([CH:4]1[CH2:9][CH2:8][S:7](=[O:10])(=[O:11])[C:6]2[S:12][C:13]([S:15]([NH2:18])(=[O:16])=[O:17])=[CH:14][C:5]1=2)[C:26](=[O:28])[CH3:27])[CH3:2]
Reactant: CCNC1CCS(=O)(=O)c2sc(S(N)(=O)=O)cc21
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCN(C(C)=O)C1CCS(=O)(=O)c2sc(S(N)(=O)=O)cc21
Reaction time: 2 h
Yield: 81.1 %

Procedure:
To a mixture of 4-(N-ethylamino)-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide-7,7-dioxide (1.2 g, 0.0035 mol) in THF (30 ml) and triethylamine (1.1 ml, 0.79 g, 0.0078 mol) under N2 was added dropwise at room temperature a solution of acetyl chloride (0.26 ml, 0.28 g, 0.0036 mol) in THF (15 ml). After 2 hours, the mixture was poured into a saturated solution of NaHCO3 and extracted with ethyl acetate (3x). The organic extracts were dried, filtered and concentrated to dryness to yield 1.0 g (83%) of product.
Reaction SMILES: [OH-:1].[Na+].[CH:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]2[C:15]([OH:16])=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[CH:17](Cl)(Cl)Cl.Cl>O.C(O)C>[C:6]1([CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[C:14]([CH:17]=[O:1])[C:15]=2[OH:16])[CH:5]=[CH:4][CH:3]=[CH:8][CH:7]=1
Reactant: [OH-]
Reactant: ClC(Cl)Cl
Reactant: Oc1ccccc1Cc1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=Cc1cccc(Cc2ccccc2)c1O
Temperature: 65 °C
Yield: 24 %

Procedure:
To a warm, stirred mixture of sodium hydroxide (8.0 g) in water (8.00 ml) was added a warmed solution of 2-hydroxydiphenylmethane (1), (4.9 g, 27 mmol) in ethanol (4 ml) and the mixture heated to 65° C. Chloroform (4.1 ml) was added down a water condensor and the resulting mixture began to reflux. After 1 h at reflux, the mixture was cooled in ice, acidified to pH 2 with 1N HCl and extracted with ethyl acetate (3×30 ml). The combined extracts were dried (Na2SO4) and the solvent removed to yield a dark brown gum. The product was eluted through a silica column, using 0-10% ethyl acetate in petroleum spirit to yield a yellow oil (1.33 g, 24%)
Reaction SMILES: [C:1]1([S:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH:24]4[CH2:28][CH2:27][NH:26][CH2:25]4)[CH:21]=3)[NH:16][N:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C=O.[C:31](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CC#N>[CH3:31][N:26]1[CH2:27][CH2:28][CH:24]([O:23][C:20]2[CH:21]=[C:22]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[C:14]3[S:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)(=[O:12])=[O:13])[CH2:25]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=S(=O)(c1cccc2ccccc12)c1n[nH]c2ccc(OC3CCNC3)cc12
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Product: CN1CCC(Oc2ccc3[nH]nc(S(=O)(=O)c4cccc5ccccc45)c3c2)C1
Reaction time: 3 h
Yield: 37.9 %

Procedure:
A solution of 3-(naphthalene-1-sulfonyl)-5-(pyrrolidin-3-yloxy)-1H-indazole (73.4 mg, 0.187 mmol) in CH3CN was treated with 37% aqueous formaldehyde (0.15 mL, 2.0 mmol) and sodium triacetoxyborohydride (92.1 mg, 0.435 mmol), stirred for 3 hours at ambient temperatures and partitioned in chloroform and 1.0 N sodium hydroxide. The phases were separated; the organic phase was washed with brine, treated with methanol to aid in solubility, dried over anhydrous magnesium sulfate and concentrated in vacuo. The resultant residue was purified by flash chromatography using 0.3% ammonium hydroxide/3.0% methanol in chloroform to give 5-(1-methyl-pyrrolidin-3-yloxy)-3-(naphthalene-1-sulfonyl)-1H-indazole as a light orange foam, 28.8 mg (37.9% yield). The foam was taken up in methanol and chloroform, treated with isopropanolic HCl and concentrated in vacuo at 84° C. for 14 hours to yield the title product as a light orange foam, 27.2 mg, Mass spectrum (+EI, [M+H]+) m/z 408. 1HNMR (500 MHz, DMSO-d6): δ14.20 (s, 1H), 10.38-10.60 (br, 1H), 8.74 (d, 1H, J=8.66 Hz), 8.54-8.56 (m, 1H), 8.28 (d, 1H, J=8.30 Hz), 8.03-8.05 (m, 1H), 7.71-7.75 (m, 1H), 7.56-7.65 (m, 3H), 7.28 (d, 1H, J=2.20 Hz), 7.12 (dd, 1H, J=9.15 Hz and 2.32 Hz), 5.22 (s, 1H), 3.31-3.74 (m*, 3H), 2.85 (s, 3H), 2.03-2.12 ppm (m, 1H). *Conformational isomers due to protonation of tertiary amine.
Reaction SMILES: [S:1]=[C:2]1[N:6]([CH2:7][CH2:8][C:9]#N)[C:5]2[CH:11]=[CH:12][CH:13]=[CH:14][C:4]=2[S:3]1.S(=O)(=O)(O)[OH:16].[OH2:20]>>[S:1]=[C:2]1[N:6]([CH2:7][CH2:8][C:9]([OH:16])=[O:20])[C:5]2[CH:11]=[CH:12][CH:13]=[CH:14][C:4]=2[S:3]1
Reactant: O=S(=O)(O)O
Reactant: N#CCCn1c(=S)sc2ccccc21
Reactant: O
Product: O=C(O)CCn1c(=S)sc2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 96 %

Procedure:
A stirred charge containing 44 g (0.2 mol) of 2-thioxo-3-benzothiazolinepropionitrile and 600 ml of 30% sulfuric acid (by volume) was heated at reflux (114°-116° C.) for 2 hours. After cooling to 25° C., 400 ml of water was added and stirring continued at 25°-30° C., for 15 minutes. The solid was collected by filtration, washed with water until neutral to litmus and air-dried at 50° C. The product, 2-thioxo-3(2H)-benzothiazolepropionic acid, m.p. 164°-165° C., was obtained in 96% yield, after recrystallization from NaOH/HCl, m.p. 167°-168° C.
Reaction SMILES: [CH2:1]([N:8]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:9]1[CH:10]=[CH:11][C:12]([CH:15]=O)=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][NH:25][CH2:26][CH2:27][OH:28].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C1COCC1.O.C(O)(=O)C>[CH2:1]([N:8]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:9]1[CH:10]=[CH:11][C:12]([CH2:15][N:25]([CH3:24])[CH2:26][CH2:27][OH:28])=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(N(Cc2ccccc2)Cc2ccccc2)cn1
Reactant: CNCCO
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CN(CCO)Cc1ccc(N(Cc2ccccc2)Cc2ccccc2)cn1
Reaction time: 3 h
Yield: 55.3 %

Procedure:
To a solution of 39 (600 mg, 2.0 mmol) in THF (25 mL) was added 2-(methyl amino) ethanol (224 mg, 3.0 mmol) and a catalytic amount of acetic acid (0.1 mL) and cooled to 0° C. Na(OAc)3BH (1 g, 5.0 mmol) was added portion wise and the reaction mixture allowed to warm and stired at rt for 3 h. The reaction mixture was neutralized by using NaHCO3 (aq), diluted with water (25 mL, 1:3 dilution), extracted with EtOAc (2×100 mL), the combined organic layers were washed with brine (20 mL), dried (Na2SO4) and evaporated. The crude compound was purified by column chromatography (neutral alumina, eluted with 5% MeOH/CHCl3) to obtain compound 40 (400 mg, 55%) as a brown solid. Rf: 0.3 (10% MeOH/CHCl3); (m/z): 362 [MH]+; 1H NMR (400 MHz, DMSO-d6) δ 7.91 (1H, d, J=2.8 Hz), 7.35-7.22 (10H, m), 7.12 (1H, d, J=8.8 Hz), 7.02 (1H, dd, J=2.8, 8.8 Hz), 4.72 (4H, s), 4.37 (1H, br s), 3.46-3.44 (4H, m), 2.40 (2H, t, J=6.4 Hz), 2.13 (3H, S).
Reaction SMILES: [CH:1]12[CH2:8][CH:7]=[CH:6][CH:5]1[CH:4]([C:9]([OH:11])=O)[CH2:3][CH:2]2[C:12]([OH:14])=O.C(OC(=O)C)(=O)C.[NH2:22][CH2:23][CH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][N:30]([C:33]2[N:38]=[CH:37][CH:36]=[CH:35][N:34]=2)[CH2:29][CH2:28]1.C1(C)C(C)=CC=CC=1>O>[N:34]1[CH:35]=[CH:36][CH:37]=[N:38][C:33]=1[N:30]1[CH2:31][CH2:32][N:27]([CH2:26][CH2:25][CH2:24][CH2:23][N:22]2[C:9](=[O:11])[CH:4]3[CH2:3][CH:2]([CH:1]4[CH2:8][CH:7]=[CH:6][CH:5]43)[C:12]2=[O:14])[CH2:28][CH2:29]1
Reactant: O=C(O)C1CC(C(=O)O)C2CC=CC12
Reactant: NCCCCN1CCN(c2ncccn2)CC1
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1C
Solvent: O
Product: O=C1C2CC(C(=O)N1CCCCN1CCN(c3ncccn3)CC1)C1CC=CC21
Reaction time: 24 h

Procedure:
Bicyclo[3.3.0]oct-6-ene-2,4-dicarboxylic acid (12.6 g., 67 mmol.) was converted to 4.24 g. of anhydride by treatment with excess acetic anhydride as in Example 1. In this instance, however, the anhydride was purified by extraction of the dark residual gum with hexane, filtration, and evaporation in vacuo. The anhydride was combined with 6.0 g. (24 mmols) of 1-(4-aminobutyl)-4-(2-pyrimidinyl)piperazine in 250 ml. of xylene and refluxed under N2 for 24 hours with water separation via a Dean-Stark trap. The supernatant liquid was removed at this point and replaced with an additional 150 ml. of xylene. Reflux under N2 was continued for 24 hours. The combined xylene solutions were then evaporated and the residue column chromatographed on 250 g. of silica gel with a gradient elution beginning with CHCl3 and ending with 10% CH3OH/CHCl3. The product-containing fractions were combined and evaporated and the residue crystallized from isopropanol with the addition of 4N HCl in isopropanol to give 3.25 g. of white solid title compound as the dihydrochloride salt, m.p. 232°-234° C.
Reaction SMILES: Cl.C(OC(=O)[NH:8][C@@H:9]1[CH2:15][CH2:14][C@@H:13]([CH3:16])[N:12]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)(=[O:19])=[O:18])[CH2:11][C@H:10]1[OH:26])(C)(C)C>O1CCOCC1.CO.C1(C)C=CC=CC=1>[NH2:8][C@@H:9]1[CH2:15][CH2:14][C@@H:13]([CH3:16])[N:12]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)(=[O:19])=[O:18])[CH2:11][C@H:10]1[OH:26]
Reactant: C[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](O)CN1S(=O)(=O)c1ccccn1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Solvent: CO
Product: C[C@@H]1CC[C@@H](N)[C@H](O)CN1S(=O)(=O)c1ccccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
HCl in dioxane (4.0 M, 10 ml) was added to a stirred solution. [(3R,4R,7R)-3-Hydroxy-7-methyl-1-(pyridine-2-sulfonyl)-azepan-4-yl]-carbamic acid tert-butyl ester (0.6 g, 1.55 mmol) in MeOH (10 ml). The reaction mixture was stirred for 1 h at RT, then was diluted with toluene (20 ml), concentrated in vacuo by rotary evaporation and was used in the next reaction without further purification (0.5 g, quantitative): Electrospray mass spec: M+H+=286.2.
Reaction SMILES: Cl.C(O)C.[NH2:5][C:6]([NH2:33])=[N:7][C:8]([C:10]1[CH:22]=[CH:21][C:20]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:23][CH2:24][O:25]CC3C=CC=CC=3)[C:12]=2[CH:11]=1)=[O:9]>[C].[Pd].C1COCC1>[NH2:33][C:6]([NH2:5])=[N:7][C:8]([C:10]1[CH:22]=[CH:21][C:20]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:23][CH2:24][OH:25])[C:12]=2[CH:11]=1)=[O:9]
Reactant: NC(N)=NC(=O)c1ccc2c3ccccc3n(CCOCc3ccccc3)c2c1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Product: NC(N)=NC(=O)c1ccc2c3ccccc3n(CCO)c2c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 46.5 %

Procedure:
A 1.0 ml portion of 1 M hydrochloric acid and 40 mg of 10% palladium-carbon were added to an ethanol 9 ml-THF 3 ml solution of 393 mg N-(diaminomethylene)-9-[2-(benzyloxy)ethyl]-9H-carbazole-2-carboxamide, followed by stirring at room temperature for 3 days under an atmosphere of hydrogen gas. After carrying out celite filtration by adding 1 M sodium hydroxide aqueous solution, the organic solvent was evaporated and the water layer was extracted with chloroform, followed by washing with saturated brine and drying with anhydrous magnesium sulfate. By evaporating the solvent, 140 mg of N-(diaminomethylene)-9-(2-hydroxyethyl)-9H-carbazole-2-carboxamide was obtained.
Reaction SMILES: C([O:3][C:4](=[O:47])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[C:11]([O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][C:31]2[CH:36]=[CH:35][C:34]([C:37](=[O:39])[CH3:38])=[C:33]([OH:40])[C:32]=2[CH2:41][CH2:42][CH3:43])[C:10]=1[CH2:44][CH2:45][CH3:46])C.C1(C)C=CC=CC=1.C(OCC)(=O)C>[OH-].[Na+].CO>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:47])=[O:3])=[C:10]([CH2:44][CH2:45][CH3:46])[C:11]=1[O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([C:37](=[O:39])[CH3:38])=[C:33]([OH:40])[C:32]=1[CH2:41][CH2:42][CH3:43])(=[O:17])[CH3:16]
Reactant: CCCc1c(OCCOCCOCCOCCOc2c(C(C)=O)ccc(OCCCC(=O)OCC)c2CCC)ccc(C(C)=O)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: Cc1ccccc1
Product: CCCc1c(OCCOCCOCCOCCOc2c(C(C)=O)ccc(OCCCC(=O)O)c2CCC)ccc(C(C)=O)c1O
Yield: 78.1 %

Procedure:
A solution of 2.30 g of 4-[4-acetyl-3-[2-[2-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]ethoxy]ethoxy]-2-propylphenoxy]butanoic acid ethyl ester in 17 ml of 1.0N sodium hydroxide and 50 ml of methanol was stirred at reflux for 7 hours. The methanol was removed in vacuo and the residue was acidified. The product was extracted with ether and the dried (magnesium sulfate) extract was concentrated in vacuo to an oil (2.40 g). Chromatography on 150 g of silica gel and elution with a solvent mixture of 5% acetic acid: 70% toluene: 25% ethyl acetate gave 1.72 g (78% yield) of 4-[4-acetyl-3-[2-[2-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]ethoxy]ethoxy]-2-propylphenoxy]butanoic acid as a viscous oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([O:11][CH3:12])=[CH:4][C:3]=1[N:13]1[CH2:18][CH2:17][CH:16]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH2:15][CH2:14]1.[CH3:25][S:26]([CH:29]=[CH2:30])(=[O:28])=[O:27].CS(C)=O>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([O:11][CH3:12])=[CH:4][C:3]=1[N:13]1[CH2:18][CH2:17][CH:16]([N:19]2[CH2:20][CH2:21][N:22]([CH2:30][CH2:29][S:26]([CH3:25])(=[O:28])=[O:27])[CH2:23][CH2:24]2)[CH2:15][CH2:14]1
Reactant: COc1cc(N2CCC(N3CCNCC3)CC2)c(Cl)cc1[N+](=O)[O-]
Reactant: C=CS(C)(=O)=O
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: COc1cc(N2CCC(N3CCN(CCS(C)(=O)=O)CC3)CC2)c(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.9 %

Procedure:
1-{1-[2-Chloro-5-(methyloxy)-4-nitrophenyl]-4-piperidinyl}piperazine (Example 112, step D) (0.050 g, 1.41 mmol) was taken up in THF (10 mL) and methylvinylsulfone (0.371 mL, 4.23 mmol) was added. DMSO was added to solubilize the starting material. Reaction was stirred overnight at rt. Reaction was not complete and over the next 3 days, 30 equivalents more methylvinylsulfone were added. Reaction was then stirred over the weekend. Poured reaction mixture onto prepackaged silica gel cartridge, dried by vacuum suction of air through cartridge and then flash chromatographed to give the title compound of step A (0.370 g, 57%). MS (M+H, ES+) 461.
Reaction SMILES: C1(C)C=CC=C([Cl:7])C=1.Cl.[C:10]([NH:14][CH2:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:26]=[C:27]([CH3:31])[CH:28]=[CH:29][CH:30]=2)=[C:20]([O:32][C:33]2[CH:34]=[C:35]([CH3:39])[CH:36]=[CH:37][CH:38]=2)[CH:19]=1)=[O:17])([CH3:13])([CH3:12])[CH3:11].Cl>>[ClH:7].[C:35]1([CH3:39])[CH:36]=[CH:37][CH:38]=[C:33]([O:32][C:20]2[CH:19]=[C:18]([CH:23]=[CH:22][C:21]=2[O:24][C:25]2[CH:26]=[C:27]([CH3:31])[CH:28]=[CH:29][CH:30]=2)[CH:16]([OH:17])[CH2:15][NH:14][C:10]([CH3:13])([CH3:12])[CH3:11])[CH:34]=1
Reactant: Cc1cccc(Cl)c1
Reactant: Cc1cccc(Oc2ccc(C(=O)CNC(C)(C)C)cc2Oc2cccc(C)c2)c1
Agent: Cl
Product: Cc1cccc(Oc2ccc(C(O)CNC(C)(C)C)cc2Oc2cccc(C)c2)c1

Procedure:
Following a procedure similar to that described above in Example 111 but using m-toluyl chloride instead of o-toluyl chloride, there was obtained 14 g. of 3,4-bis(m-toluyloxy)phenyl tert-butylaminomethyl ketone hydrochloride as a white crystalline solid which melted at 215°-218° C. When 19 g. of this hydrochloride (5 g. of which was obtained from a second run) was catalytically hydrogenated, using a procedure similar to that described above in Example 30B, there was obtained 3,4-bis(m-toluyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol hydrochloride which was converted to the free base and then to the methanesulfonate, a white crystalline solid which weighed 12.0 g. and melted at 135° C. (uncorr.).
Reaction SMILES: [CH2:1]([Si:4]([CH2:12][CH:13]=[CH2:14])([CH2:9][CH:10]=[CH2:11])[CH2:5][CH2:6][CH2:7]Br)[CH:2]=[CH2:3].C([O-])=[O:16].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:1]([Si:4]([CH2:12][CH:13]=[CH2:14])([CH2:9][CH:10]=[CH2:11])[CH2:5][CH2:6][CH2:7][OH:16])[CH:2]=[CH2:3]
Reactant: O=C[O-]
Reactant: C=CC[Si](CC=C)(CC=C)CCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Product: C=CC[Si](CC=C)(CC=C)CCCO

Procedure:
Triallyl (3-hydroxylpropyl) silane was prepared from triallyl-3-bromopropyl silane prepared in Example 7 via the formyloxypropyl intermediate. A 100 ml flask equipped with stir bar and reflux condenser was charged with 10.0 grams (36 millimoles) of triallyl 3-bromopropyl silane (prepared as described in Example 7), 4.90 grams (72 millimoles) sodium formate (commercially available from Aldrich Chemical Co. of Milwaukee, Wis.) and 0.60 grams of tetrabutyl ammonium bromide (commercially available from Aldrich Chemical Co.). The suspension was stirred at 110° C. for two days. The solution was then filtered and combined with equal volumes of deionized water and cyclohexane (commercially available as Omnisolve from E. Merck of Gibbstown, N.J.). The organic extract was flash chromatographed on silica using first cyclohexane, followed by 80/20 cyclohexane/acetone to collect the triallyl formyloxypropyl silane intermediate.
Reaction SMILES: Cl.[CH:2]1([C:5]2[N:10]=[CH:9][C:8]([C:11]3[CH:12]=[C:13]4[C:18](=[CH:19][N:20]=3)[CH2:17][NH:16][CH2:15][CH2:14]4)=[CH:7][CH:6]=2)[CH2:4][CH2:3]1.[CH3:21][C@@:22]1([CH2:29][S:30](Cl)(=[O:32])=[O:31])[C:26](=[O:27])[NH:25][C:24](=[O:28])[NH:23]1>CCOC(C)=O.CCOC(C)=O.CO>[CH:2]1([C:5]2[N:10]=[CH:9][C:8]([C:11]3[CH:12]=[C:13]4[C:18](=[CH:19][N:20]=3)[CH2:17][N:16]([S:30]([CH2:29][C@@:22]3([CH3:21])[NH:23][C:24](=[O:28])[NH:25][C:26]3=[O:27])(=[O:31])=[O:32])[CH2:15][CH2:14]4)=[CH:7][CH:6]=2)[CH2:4][CH2:3]1
Reactant: c1cc(C2CC2)ncc1-c1cc2c(cn1)CNCC2
Reactant: C[C@]1(CS(=O)(=O)Cl)NC(=O)NC1=O
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: C[C@]1(CS(=O)(=O)N2CCc3cc(-c4ccc(C5CC5)nc4)ncc3C2)NC(=O)NC1=O
Yield: 6.8 %

Procedure:
The title compound was prepared from 6-(6-cyclopropylpyridin-3-yl)-1,2,3,4-tetrahydro-2,7-naphthyridine hydrochloride (0.63 mmol) and [(4S)-4-methyl-2,5-dioxoimidazolidin-4-yl]methanesulfonyl chloride (0.70 mmol) following the general procedure of Example 1. Column chromatography with neat EtOAc and EtOAc-MeOH (9:1) as eluents gave 0.060 g of almost pure product. Recrystallisation from 99% EtOH gave 0.019 g (7.0%) of the title compound as white solid.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:10])[CH2:6][C:7]([CH3:9])=O)[CH2:3][CH2:2]1.[NH3:11]>C(O)C>[CH:1]1([NH:4][C:5](=[O:10])/[CH:6]=[C:7](\[NH2:11])/[CH3:9])[CH2:3][CH2:2]1
Reactant: N
Reactant: CC(=O)CC(=O)NC1CC1
Solvent: CCO
Product: C/C(N)=C/C(=O)NC1CC1
Reaction time: 8 h

Procedure:
Acetoacetic cyclopropylamide (209.4 g, 1.48 mole) is dissolved in ethanol (160 ml) and thereto is passed ammonia gas, while the temperature is controlled below 30° C. by cooling with a water bath. After passing ammonia gas for about 3 hours, yellow crystals precipitate. The reaction mixture is allowed to stand at 0° C. overnight. The precipitates are separated by filtration and washed with diethyl
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:34]=[CH:33][C:6]([C:7]([N:9]([C@@H:11]2[CH2:16][CH2:15][N:14]([C:17]([CH:19]3[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]3)=[O:18])[CH2:13][C@H:12]2[C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=2)[CH3:10])=[O:8])=[CH:5][CH:4]=1.[C:35](Cl)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([N:9]([C@@H:11]2[CH2:16][CH2:15][N:14]([C:17]([CH:19]3[CH2:24][CH2:23][CH2:22][N:21]([C:35]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[O:42])[CH2:20]3)=[O:18])[CH2:13][C@H:12]2[C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=2)[CH3:10])=[O:8])=[CH:33][CH:34]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CN(C(=O)c1ccc(Cl)cc1)[C@@H]1CCN(C(=O)C2CCCNC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Agent: Cl
Product: CN(C(=O)c1ccc(Cl)cc1)[C@@H]1CCN(C(=O)C2CCCN(C(=O)c3ccccc3)C2)C[C@H]1c1ccc(Cl)c(Cl)c1

Procedure:
Using the compound obtained in Example 542 and benzoyl chloride, and by the reaction and purification in the same manner as in Example 39, the title compound was obtained.
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].[OH:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([O:16][C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=2[C:12]([F:15])([F:14])[F:13])[CH:18]=1
Reactant: Oc1cccnc1
Reactant: COC(=O)c1ccc(F)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(Oc2cccnc2)c(C(F)(F)F)c1

Procedure:
2 mmol of methyl 4-fluoro-3-trifluoromethylbenzoate, 2 mmol of 3-hydroxypyridine and 4 mmol of K2CO3 were stirred at 110° C. for 1.5 h in 15 ml of DMF (anhydrous). The mixture was then poured onto 100 ml of water and extracted 3 times using 50 ml of EA each time. It was dried over Na2SO4, the solvent was removed in vacuo and the product was reacted further without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH2:7])=[CH:5][C:4]([CH2:8][CH:9]([CH3:11])[CH3:10])=[N:3]1.[CH3:12][O:13][CH2:14][CH2:15][O:16][C:17](=[O:32])[C:18](=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N+:29]([O-:31])=[O:30])[C:19]([CH3:21])=O>>[CH3:12][O:13][CH2:14][CH2:15][O:16][C:17]([C:18]1[CH:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[N+:29]([O-:31])=[O:30])[C:5]2[C:4]([CH2:8][CH:9]([CH3:11])[CH3:10])=[N:3][N:2]([CH3:1])[C:6]=2[NH:7][C:19]=1[CH3:21])=[O:32]
Reactant: COCCOC(=O)C(=Cc1ccccc1[N+](=O)[O-])C(C)=O
Reactant: CC(C)Cc1cc(N)n(C)n1
Product: COCCOC(=O)C1=C(C)Nc2c(c(CC(C)C)nn2C)C1c1ccccc1[N+](=O)[O-]

Procedure:
Starting from 1-methyl-3-(2-methylpropyl)-5-pyrazolamine and 2-methoxyethyl-2-(2-nitrobenzyliden)acetoacetate.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH:5]=[C:6]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:15]=1)[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:2].[C:26]1(=O)[CH:31]=[CH:30][C:29](=[O:32])[CH:28]=[CH:27]1>CC#N>[CH2:1]([O:3][C:4]([C:5]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([OH:32])[CH:30]=2)[N:13]([C:14]2[CH:19]=[CH:18][C:17]([N:20]([CH2:21][CH3:22])[CH2:23][CH3:24])=[CH:16][CH:15]=2)[C:6]=1[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:25])[CH3:2]
Reactant: CCOC(=O)C=C(CC(=O)OCC)Nc1ccc(N(CC)CC)cc1
Reactant: O=C1C=CC(=O)C=C1
Solvent: CC#N
Product: CCOC(=O)Cc1c(C(=O)OCC)c2cc(O)ccc2n1-c1ccc(N(CC)CC)cc1
Temperature: 4 °C
Reaction time: 24 h

Procedure:
A mixture of 3-(4-diethylaminophenylamino)pent-2-enedioic acid diethyl ester (11.9 g, 34.2 mmol, see step (a) above), 1,4-benzoquinone (4.62 g, 42.8 mmol) and anhydrous MeCN (70 mL) was stirred at 70° C. for 2 d and at 4° C. for 1 d. The solid was collected and recrystallized from MeCN. Yield 4.5 g (30%).