Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=O.[O:3]=[O+][O-].[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([O-:16])(=[O:15])=[O:14])=[CH:9][CH:8]=1.[C:17]1([CH:23]([O:30][C:31]([C@@H:33]2[N:38]3[C:39](=[O:42])[C@@H:40]([NH2:41])[C@H:37]3[S:36][CH2:35][C:34]2=C)=[O:32])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CSC>CO>[CH3:6][C:7]1[CH:8]=[CH:9][C:10]([S:13]([O-:16])(=[O:15])=[O:14])=[CH:11][CH:12]=1.[C:24]1([CH:23]([O:30][C:31]([CH:33]2[N:38]3[C:39](=[O:42])[C@@H:40]([NH2:41])[C@H:37]3[S:36][CH2:35][C:34]2=[O:3])=[O:32])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: C=C1CS[C@@H]2[C@H](N)C(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1
Reactant: O=[O+][O-]
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=O
Solvent: CO
Solvent: CSC
Product: N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(=O)CS[C@H]12
Temperature: -12 °C
Reaction time: 0.08 h

Procedure:
A stream of oxygen and ozone (containing 0.35 mmol of ozone per minute) is passed for 4 minutes through a solution, cooled to -60° C., of 0.553 g of the 4-methylphenylsulphonate of 7β-amino-3-methylene-cepham-4α-carboxylic acid diphenylmethyl ester in 50 ml of methanol. After a further 5 minutes, the pale blue-coloured solution is treated with 0.3 ml of dimethyl sulphide. The mixture is stirred for 15 minutes at -70° C., for one hour at -12° C. and for one hour in an ice bath and is then evaporated. The residue is taken up in a small amount of methylene chloride, diethyl ether is then added until the mixture turns cloudy, and the mixture is left to stand. The microcrystalline, reddish-coloured pulverulent precipitate is filtered off and yields the 4-methylphenylsulphonate of 7β-amino-cepham-3-one-4ξ-carboxylic acid diphenylmethyl ester which is mainly present in the enol form as the 4-methylphenylsulphonate of 7β-amino-3-cephem-3-ol-4-carboxylic acid diphenylmethyl ester, melting point=143° -145° C. (with decomposition); thin layer chromatogram (silica gel) Rf~0.28 (system: ethyl acetate/pyridine/water, 85:10:5); ultraviolet absorption spectrum (in ethanol): λmax =262 mμ (ε=3,050) and 282 mμ (ε=3,020); infrared absorption spectrum (in methylene chloride): characteristic bands at 5.58μ, 5.77μ (shoulder), 6.02μ and 6.22μ.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[NH:11][CH:10]([C:12]([OH:14])=O)[CH2:9][S:8]2)[CH:2]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[N:17][C:16]=1[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O.C(N(CC)CC)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[NH:11][CH:10]([C:12]([N:24]3[CH2:25][CH2:26][N:21]([C:16]4[N:15]=[CH:20][CH:19]=[CH:18][N:17]=4)[CH2:22][CH2:23]3)=[O:14])[CH2:9][S:8]2)[CH:2]=1
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: O=C(O)C1CSC(c2cccnc2)N1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(C1CSC(c2cccnc2)N1)N1CCN(c2ncccn2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(3-pyridyl)thiazolidine-4-carboxylic acid 2.1 g, 1-(2-pyrimidinyl)piperazine.2 hydrochyloride 2.2 g, triethylamine 1.8 g, 1-hydroxybenzotriazole 1.5 g and N,N-dimethylformamide 30 ml was added dicyclohexylcarbodiimide 2.0 g under cooling and the mixture was stirred overnight at room temperature. The resultant dicyclohexylurea was distilled off, ethyl acetate 100 ml and water 50 ml were added to the filtrate and the solution was basified by addition of potassium carbonate. The organic layer was separated and the aqueous layer extracted with ethyl acetate. The organic layer and extract were combined, washed successively with water and saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethanol to give 0.8 g of 1-[2-(3-pyridyl)thiazolidine-4-ylcarbonyl]-4-(2-pyrimidinyl)piperazine.
Reaction SMILES: [C:1]([C@@H:3]([NH:5][C:6](=[O:12])OC(C)(C)C)[CH3:4])#[N:2].[CH2:13]([O:20][C:21]1[CH:22]=[C:23]([CH:35]=[CH:36][CH:37]=1)[CH2:24][O:25][C:26]1[CH:34]=[CH:33][C:29](C(O)=O)=[CH:28][CH:27]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([O:20][C:21]1[CH:22]=[C:23]([CH:35]=[CH:36][CH:37]=1)[CH2:24][O:25][C:26]1[CH:27]=[CH:28][C:29]([C:6]([NH:5][C@H:3]([C:1]#[N:2])[CH3:4])=[O:12])=[CH:33][CH:34]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(O)c1ccc(OCc2cccc(OCc3ccccc3)c2)cc1
Reactant: C[C@@H](C#N)NC(=O)OC(C)(C)C
Product: C[C@@H](C#N)NC(=O)c1ccc(OCc2cccc(OCc3ccccc3)c2)cc1
Yield: 51.1 %

Procedure:
General procedures D and E were used to deprotect 0.45 mmols of (S)-tert-butyl 1-cyanoethylcarbamate and couple to 0.45 mmols of the acid 36. After purification by flash chromatography, 0.23 mmols of the title product was recovered. 1H NMR (500 MHz, CDCl3) δ 7.78-7.72 (m, 2H), 7.47-7.42 (m, 2H), 7.41-7.37 (m, 2H), 7.36-7.29 (m, 2H), 7.06 (s, 1H), 7.02 (s, 1H), 7.01-6.98 (m, 2H), 6.95 (dd, J=2.5, 8.2, 1H), 6.46 (s, 1H), 5.15 (dd, J=7.6, 14.9, 1H), 5.09 (s, 2H), 5.07 (s, 2H), 1.65 (d, J=7.2, 3H). 13C NMR (75 MHz, CDCl3) δ 191.04, 163.88, 159.36, 137.82, 136.98, 132.24, 130.09, 128.86, 128.29, 127.74, 120.05, 115.39, 114.79, 114.14, 70.25.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[N:13]1[C:35](=[O:36])[C:32]2[C:33]3[C:34]4[C:29](=[CH:30][CH:31]=2)[C:28]2[C:37]5[C:24]([C:25]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][OH:44])=[CH:26][CH:27]=2)=[CH:23][CH:22]=[CH:21][C:20]=5[C:19]=4[CH:18]=[CH:17][C:16]=3[C:14]1=[O:15])([CH3:3])[CH3:2].[C:45](Cl)(=[O:49])[C:46]([CH3:48])=[CH2:47]>>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[N:13]1[C:35](=[O:36])[C:32]2[C:33]3[C:34]4[C:29](=[CH:30][CH:31]=2)[C:28]2[C:37]5[C:24]([C:25]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][O:44][C:45](=[O:49])[C:46]([CH3:48])=[CH2:47])=[CH:26][CH:27]=2)=[CH:23][CH:22]=[CH:21][C:20]=5[C:19]=4[CH:18]=[CH:17][C:16]=3[C:14]1=[O:15])([CH3:2])[CH3:3]
Reactant: CC(C)c1cccc(C(C)C)c1N1C(=O)c2ccc3c4cccc5c(CCCCCCO)ccc(c6ccc(c2c36)C1=O)c54
Reactant: C=C(C)C(=O)Cl
Product: C=C(C)C(=O)OCCCCCCc1ccc2c3ccc4c5c(ccc(c6cccc1c62)c53)C(=O)N(c1c(C(C)C)cccc1C(C)C)C4=O
Yield: 81 %

Procedure:
Reduction of 2 g (3.2 mmol) of N-(2,6-diisopropylphenyl)-9-(6-acetoxy-1-hexynyl)perylene-3,4-dicarboximide (cf. Example 10, 1.) in accordance with the hydrogenation instructions indicated for alkynylperylenes in Liebigs Ann./Recueil 1997, 395-407 gave a quantitative yield of the corresponding acetoxyhexyl derivative, which could be hydrolyzed as per Example 10, 2. in 98% yield to N-(2,6-diisopropylphenyl)-9-(6-hydroxyhexyl)perylene-3,4-dicarboximide. This, when reacted with methacryloyl chloride in accordance with Example 10, 3., gave the desired product in 81% yield as a red, amorphous solid.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([OH:10])=[CH:4][C:3]=2[O:2]1.Br[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:14].C(=O)([O-])[O-].[Na+].[Na+].C(=O)([O-])[O-].[K+].[K+]>C1C=CC=CC=1>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([O:10][CH2:12][C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:14])=[CH:4][C:3]=2[O:2]1
Reactant: O=C(CBr)c1ccccc1
Reactant: Oc1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: c1ccccc1
Product: O=C(COc1ccc2c(c1)OCO2)c1ccccc1

Procedure:
A mixture of 25 g. (0.181 mole) of 3,4-methylenedioxyphenol, 36 g. (0.181 mole) of α-bromoacetophenone and 41.2 g. (0.40 mole) of sodium carbonate in 350 ml. of benzene is heated to its reflux temperature and maintained at reflux for 16 hours. To the mixture is added 50 g. of potassium carbonate, and the mixture is refluxed for an additional 7 days while collecting water in a Barrett water trap. The mixture is then diluted with a mixture of water and benzene. The benzene layer is washed with water, then cold 5 percent sodium hydroxide solution. A precipitate forms in the benzene layer. It is collected, rinsed with benzene and dried to provide a white powder which is recrystallized from ethanol to provide α-(3,4-methylenedioxyphenoxy)acetophenone, m.p. 123°-126° C.
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([N+:24]([O-:26])=[O:25])[CH:22]=3)[NH:17][CH:16]=2)=[CH:10][CH:9]=1.[C:27]([O:31][CH3:32])(=[O:30])[CH:28]=[CH2:29].O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCOCC1.CCOCC>[F:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([N+:24]([O-:26])=[O:25])[CH:22]=3)[N:17]([CH2:29][CH2:28][C:27]([O:31][CH3:32])=[O:30])[CH:16]=2)=[CH:12][CH:13]=1
Reactant: O=[N+]([O-])c1ccc2[nH]cc(Cc3ccc(F)cc3)c2c1
Reactant: C=CC(=O)OC
Agent: CC(C)(C)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CCOCC
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)CCn1cc(Cc2ccc(F)cc2)c2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 66 h
Yield: 65.5 %

Procedure:
Tetrabutylammonium bromide (0.262 g) and potassium t-butoxide (100 mg) wereadded to a stirred solution of 3-(4-fluorophenylmethyl)-5-nitro-1H-indole (2.20 g) and methyl acrylate (0.84 g) in dioxan (30 ml) and the solution was stirred at room temperature for 66 hours. Further quantities of methylacrylate (0.5 g), tetrabutylammonium bromide (262 mg) and potassium t-butoxide (100 mg) were added and stirring was continued for an additional 5 hours. The solution was poured into water and the mixture wasextracted twice with ether. The combined ether extracts were washed with water, dried (Na2SO4) and evaporated. The residue was chromatographed on silica gel using hexane/dichloromethane (1:4) as eluent. The product fractions were combined and evaporated to give the title compound as a gum (1.90 g). Found: C,64.43; H,4.39; N,7.65. C19H17FN2O4 requires: C,64.03; H,4.81; N,7.86%.
Reaction SMILES: CN(CC)C.O=[C:7]1[NH:13][C:12]2[CH:14]=[CH:15][CH:16]=[N:17][C:11]=2[N:10]2[CH2:18][CH2:19][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH:9]2[CH2:8]1.CO.[OH-].[Na+]>O1CCCC1.O>[N:17]1[C:11]2[N:10]3[CH2:18][CH2:19][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH:9]3[CH2:8][CH2:7][NH:13][C:12]=2[CH:14]=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCN2c3ncccc3NC(=O)CC2C1
Agent: CCN(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN2c3ncccc3NCCC2C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of alane-N,N-dimethylethylamine complex (0.5 M in toluene, 5.0 mL, 2.50 mmol) was added dropwise over 2 minutes to a solution of the product of Example 64A (506 mg, 1.59 mmol) in dry tetrahydrofuran (22 mL). The reaction was stirred at room temperature for 5 hours. Additional portions of alane-N,N-dimethylethylamine complex (0.5 M in toluene, 5.0 mL, 2.50 mmol) were added after 1 hour, and again after 4 hours. Methanol (10 mL) was added, followed after 10 minutes by water (20 mL) and 25% NaOH (3 mL). The mixture was stirred for 10 minutes, and the aqueous layer was separated and extracted with ethyl acetate (30 mL). The combined organic phases were washed with brine, dried (Na2SO4) and concentrated under vacuum. The residue was purified by chromatography (SiO2, eluted with ethyl acetate-ethanol, 90:10) to provide the title compound: 1H NMR (300 MHz, CDCl3) δ ppm 1.48 (s, 9H), 1.73-1.88 (m, 1H), 1.90-2.07 (m, 1H), 3.17-3.40 (m, 2H), 3.40-3.83 (m, 7H), 6.67 (dd, J=7.8, 4.8 Hz, 1H), 6.76 (d, J=7.8 Hz, 1H), 7.75 (dd, J=4.7, 1.7 Hz, 1H); MS (DCI) m/z 305 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C@@H:7]([N:11]1[CH2:16][CH2:15][N:14]([C:17]3([CH3:30])[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]3)[CH2:13][C@@H:12]1[CH3:31])[C@H:6]([O:32][CH2:33][CH3:34])[CH2:5]2.[ClH:35]>O1CCCC1.O1CCOCC1>[ClH:35].[ClH:35].[ClH:35].[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C@@H:7]([N:11]1[CH2:16][CH2:15][N:14]([C:17]3([CH3:30])[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]3)[CH2:13][C@@H:12]1[CH3:31])[C@H:6]([O:32][CH2:33][CH3:34])[CH2:5]2
Reactant: CCO[C@@H]1Cc2cc(Br)ccc2[C@H]1N1CCN(C2(C)CCN(C(=O)OC(C)(C)C)CC2)C[C@@H]1C
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CCO[C@@H]1Cc2cc(Br)ccc2[C@H]1N1CCN(C2(C)CCNCC2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 4-{(3S)-4-[(1R,2R)-5-bromo-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3-methylpiperazin-1-yl}-4-methylpiperidine-1-carboxylate (50 mg, 0.093 mmol) in tetrahydrofuran (3 mL) was added a 4.00 M solution of hydrogen chloride in 1,4-dioxane (3 mL). The reaction mixture was stirred at room temperature for 1 h. Evaporation under reduced pressure afforded the desired de-Boc product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:5]=[CH:6][CH:7]=1.[CH:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][C:26]=1[S:35](Cl)(=[O:37])=[O:36]>>[O:16]=[C:12]1[NH:11][C:10]2[C:17]3[C:22]([CH:23]=[CH:24][C:9]=2[N:8]([C:4]2[CH:3]=[C:2]([NH:1][S:35]([C:26]4[CH:27]=[CH:28][C:29]5[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=5)[CH:25]=4)(=[O:37])=[O:36])[CH:7]=[CH:6][CH:5]=2)[C:14](=[O:15])[CH2:13]1)=[CH:21][CH:20]=[CH:19][CH:18]=3
Reactant: Nc1cccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)c1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Product: O=C1CC(=O)N(c2cccc(NS(=O)(=O)c3ccc4ccccc4c3)c2)c2ccc3ccccc3c2N1
Yield: 100 %

Procedure:
By using 5-(3-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione obtained in Example 53, (1), and naphthalene-2-sulfonyl chloride, the title compound (yield 100%) was obtained in the same manner as that of Example 150.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]([CH3:11])[CH3:10])[CH:5]=[CH:4][C:3]=1[C:12](=O)[CH2:13][C:14]([C:16]1[C:17]([OH:37])=[C:18]([CH:26]2[CH2:30][CH2:29][N:28]([CH3:31])[CH:27]2[CH2:32][O:33]C(=O)C)[C:19]([O:24][CH3:25])=[CH:20][C:21]=1[O:22][CH3:23])=[O:15].C([O-])(O)=O.[Na+]>Cl>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]([CH3:11])[CH3:10])[CH:5]=[CH:4][C:3]=1[C:12]1[O:37][C:17]2[C:16]([C:14](=[O:15])[CH:13]=1)=[C:21]([O:22][CH3:23])[CH:20]=[C:19]([O:24][CH3:25])[C:18]=2[C@@H:26]1[CH2:30][CH2:29][N:28]([CH3:31])[C@H:27]1[CH2:32][OH:33]
Reactant: COc1cc(OC)c(C2CCN(C)C2COC(C)=O)c(O)c1C(=O)CC(=O)c1ccc(NC(C)C)cc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1cc(OC)c2c(=O)cc(-c3ccc(NC(C)C)cc3Cl)oc2c1[C@@H]1CCN(C)[C@H]1CO
Reaction time: 3 h

Procedure:
To a solution of n-BuLi (1.6 M in hexane, 2.22 mL, 3.56 mmol) in THF (10 mL), maintained at 0° C. under nitrogen atmosphere, hexamethyldisilazane (0.74 mL, 3.56 mmol) was added dropwise and stirred for 15 min. To this, a solution of the compound of example (59)(0.95 g, 1.78 mmol) in THF (5 mL) was added drop wise, maintaining the temperature at 0° C. After the addition, the reaction was allowed to warm to room temperature and stirred for 2.5 hrs. The reaction mixture was acidified with dilute HCl, and basified with 10% sodium bicarbonate to pH 8-9. The aqueous layer was extracted with chloroform (3×50 mL). The organic layer was washed with water (25 mL), brine (25 mL) and dried over anhydrous Na2SO4. The organic layer was concentrated under reduced pressure and dried under vacuum to yield acetic acid 3-{3-[3-(2-chloro-4-isopropylamino-phenyl)-3-oxo-propionyl]-2-hydroxy-4,6-dimethoxy-phenyl}-1-methyl-pyrrolidin-2-ylmethyl ester as a brown solid (0.95 g). This ester was dissolved in conc. HCl (5 mL) and stirred for 3 hrs. to effect cyclisation. At the end of 3 hrs, the reaction mixture was basified with solid NaHCO3 to pH 8-9. The aqueous layer was extracted with chloroform (3×25 mL) and washed with water (10 mL) and brine (10 mL). The organic layer was dried over anhydrous Na2SO4, concentrated under reduced pressure and dried over vacuum to yield the compound, (+)-trans-2-(2-chloro-4-isopropylaminophenyl)-8-(2-hydroxy methyl-1-methylpyrrolidin-3-yl)-5,7-dimethoxy-chromen-4-one, as a brown solid which was taken ahead without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][C@@H:20]([C:31]1[NH:35][C:34]2[CH:36]=[CH:37][C:38]([Cl:40])=[CH:39][C:33]=2[N:32]=1)[CH2:21][O:22][CH2:23][C:24]([O:26]C(C)(C)C)=[O:25].FC(F)(F)C(O)=O>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][C@@H:20]([C:31]1[NH:35][C:34]2[CH:36]=[CH:37][C:38]([Cl:40])=[CH:39][C:33]=2[N:32]=1)[CH2:21][O:22][CH2:23][C:24]([OH:26])=[O:25]
Reactant: CC(C)(C)OC(=O)COC[C@@H](Nc1ncnc2cc(C(=O)N3CCCC3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)COC[C@@H](Nc1ncnc2cc(C(=O)N3CCCC3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 8c from 6-chloro-4-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-2-(tert.-butyloxycarbonylmethoxy)-ethylamino]-7-(pyrrolidin-1-yl-carbonyl)-quinazoline and trifluoroacetic acid.
Reaction SMILES: [CH3:1][N:2]([CH3:34])[CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[CH:17]=[CH:16][C:15]([CH2:19][N:20]3[CH2:25][CH2:24][CH2:23][CH:22]([NH:26]C(=O)OC(C)(C)C)[CH2:21]3)=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2.[ClH:35]>O1CCOCC1>[ClH:35].[ClH:35].[CH3:34][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[CH:17]=[CH:16][C:15]([CH2:19][N:20]3[CH2:25][CH2:24][CH2:23][CH:22]([NH2:26])[CH2:21]3)=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2
Reactant: CN(C)CCCn1c2ccccc2c2cc(CN3CCCC(NC(=O)OC(C)(C)C)C3)ccc21
Agent: Cl
Solvent: C1COCCO1
Product: CN(C)CCCn1c2ccccc2c2cc(CN3CCCC(N)C3)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
A 50-mL round-bottom flask was charged with tert-butyl 1-((9-(3-(dimethylamino)propyl)-9H-carbazol-3-yl)methyl)piperidin-3-ylcarbamate (200 mg, 0.43 mmol, 1.00 equiv) and conc. HCl (1 mL) in 1,4-dioxane (3 mL). The resulting mixture was stirred at room temperature for 1 hour. Upon completion, the resulting mixture was concentrated on a rotary evaporator to give the crude that was re-crystallized from 1:1 CH3OH/ether affording 1-((9-(3-(dimethylamino)propyl)-9H-carbazol-3-yl)methyl)piperidin-3-amine dihydrochloride yellow solid (0.2 g, 98%). LCMS: [M+H]+: 365. 1H NMR (D2O, 300 MHz) δ 8.08-8.05 (m, 2H), 7.53-7.44 (m, 4H), 7.28-7.23 (m, 1H), 4.47 (br, 2H), 4.31 (t, 2H), 3.73 (br, 1H), 3.55-3.47 (m, 2H), 3.06-2.90 (m, 4H), 2.64 (s, 6H), 2.22-2.13 (m, 3H), 2.05-2.00 (m, 1H), 1.67-1.54 (m, 2H).
Reaction SMILES: C(OC([NH:8][C:9]1[CH:10]=[C:11]([C:16]([F:19])=[CH:17][N:18]=1)[C:12]([O:14][CH3:15])=[O:13])=O)(C)(C)C.Cl>>[NH2:8][C:9]1[CH:10]=[C:11]([C:16]([F:19])=[CH:17][N:18]=1)[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1cc(NC(=O)OC(C)(C)C)ncc1F
Agent: Cl
Product: COC(=O)c1cc(N)ncc1F
Temperature: 25 °C
Reaction time: 20 h
Yield: 82.2 %

Procedure:
A mixture of methyl 2-(tert-butoxycarbonylamino)-5-fluoroisonicotinate (1.80 g, 6.66 mmol) and hydrochloric acid (6N in ether, 40 ml, 240 mmol) is stirred for 20 hours at 25° C. The solvent is evaporated and the light brown slurry is diluted with ethyl acetate, cooled to 0° C. and adjusted to pH 8 with sat. aqueous sodium carbonate solution. The organic layer is washed with brine, dried with magnesium sulfate and the solvent is removed under reduced pressure affording methyl 2-amino-5-fluoroisonicotinate (932 mg, 82.2%) as a brown waxy solid. MS: m/z=171.0 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[N:14]=[C:15]([N:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)[C:4]=2[CH:3]=1.[CH2:23]([S:25]([OH:28])(=[O:27])=[O:26])[CH3:24]>CC(C)=O>[CH3:1][C:2]1[S:6][C:5]2[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[N:14]=[C:15]([N:16]3[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]3)[C:4]=2[CH:3]=1.[S:25]([CH2:23][CH3:24])([O-:28])(=[O:27])=[O:26]
Reactant: CCS(=O)(=O)O
Agent: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN(C)CC1
Solvent: CC(C)=O
Product: CCS(=O)(=O)[O-]
Reaction time: 3 h

Procedure:
To a solution of 5.0 g of olanzapine base in 150 ml acetone was added 1.76 g ethane sulfonic acid in 50 ml acetone at room temperature. Immediately a solid started to form. After stirring for 3 hours, the crystals were isolated by filtration and washed with 50 ml acetone. Yield: 6.59 g (97%).
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2].[CH:13]1([C:18](Cl)=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1.[OH-].[K+]>>[CH:1]([C:4]1[C:12]([C:18]([CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:19])=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2]
Reactant: O=C(Cl)C1CCCC1
Reactant: CC(C)c1cc2ccccn2n1
Agent: [K+]
Agent: [OH-]
Product: CC(C)c1nn2ccccc2c1C(=O)C1CCCC1
Temperature: 160 °C

Procedure:
A mixture of 5 g of 2-isopropylpyrazolo[1,5-a]pyridine and 5 ml of cyclopentylcarbonyl chloride was heated at 160° C. for 4.5 hours and, after cooling, poured into aqueous potassium hydroxide solution. The mixture was extracted with dichloromethane and the organic layer was dried over anhydrous sodium sulfate, concentrated to dryness. The residue was applied to a column of silica gel, eluting with ethyl acetate-hexane(1:9), to give 2.1 g of the title compound as colorless crystals, mp 106°-110° C.
Reaction SMILES: C(=O)([S:3][CH2:4][CH2:5][C@@:6]1([C:19]([N:21]2[CH2:30][CH2:29][C:28]3[N:27]=[CH:26][C:25]([C:31]([F:34])([F:33])[F:32])=[CH:24][C:23]=3[CH2:22]2)=[O:20])[CH2:10][C@H:9]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:8]=[CH:7]1)C.[OH-].[Na+]>CO>[SH:3][CH2:4][CH2:5][C@@:6]1([C:19]([N:21]2[CH2:30][CH2:29][C:28]3[N:27]=[CH:26][C:25]([C:31]([F:34])([F:33])[F:32])=[CH:24][C:23]=3[CH2:22]2)=[O:20])[CH2:10][C@H:9]([NH:11][C:12](=[O:13])[O:14][C:15]([CH3:16])([CH3:17])[CH3:18])[CH:8]=[CH:7]1
Reactant: CC(=O)SCC[C@]1(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)C=C[C@@H](NC(=O)OC(C)(C)C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H]1C=C[C@](CCS)(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)C1
Reaction time: 2 h

Procedure:
To a solution of the product of Step A (1.74 g, 3.39 mmol, 1 eq) in methanol (100 mL) at rt under Ar (degassed) was added 0.2 N NaOH (85 mL, 85 mmol, 5 eq) that was degassed by bubbling Ar through the solution prior to addition. After 2 hr, the methanol was concentrated, 6 N HCl was added until the solution was acidic, the aqueous was extracted with DCM, the organics combined, dried over MgSO4 and concentrated to afford the product of Step B which was used unpurified in the next step. Calculated for C22H28F3N3O3S: 494.2 (M+23). found: 494.1.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.C(N(CC)CC)C.[F:25][C:26]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:27]=1[CH:28]=[CH:29][C:30](O)=[O:31].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[F:25][C:26]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:27]=1[CH:28]=[CH:29][C:30]([NH:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:31]
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: O=C(O)C=Cc1cc(F)ccc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)C=Cc1cc(F)ccc1F
Yield: 90.6 %

Procedure:
The same procedures as in Example 2 were carried out from methyl L-tryptophanate hydrochloride (3.0 g), triethylamine (2.0 mL), 2,5-difluorocinnamic acid (2.6 g), WSC.HCl (2.7 g), and methylene chloride (80 mL), to give the captioned compound (4.1 g, 90%) as an oily product.
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4](=[O:22])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12]/[CH:13]=[CH:14]/[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[CH:7][CH:6]=1>CO.[OH-].[Na+]>[F:21][C:18]1[CH:17]=[CH:16][C:15](/[CH:14]=[CH:13]/[CH2:12][O:11][C:8]2[CH:9]=[CH:10][C:5]([C:4](=[O:22])[C:3]([OH:23])=[O:2])=[CH:6][CH:7]=2)=[CH:20][CH:19]=1
Reactant: COC(=O)C(=O)c1ccc(OC/C=C/c2ccc(F)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(=O)c1ccc(OC/C=C/c2ccc(F)cc2)cc1
Yield: 90 %

Procedure:
A mixture of (E)-4-[[3-(4-fluorophenyl)-2-propenyl]oxy]-alpha-oxobenzeneacetic acid methyl ester (0.5 g) in methanol and 0.5N sodium hydroxide (8 mL) was treated as in Example 19. Extraction provided solids which were crystallized from diethyl ether-hexane to give 0.43 g of colorless (E)-4-[[3-(4-fluorophenyl)-2-propenyl]oxy]-alpha-oxobenzeneacetic acid, mp 132°-133° C.