Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:8][CH2:7][C:6](=[O:9])[O:5][C:3]1=[O:4].[CH2:11]([OH:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CC(C)(CCC(O)=O)C(O)=O.OS(O)(=O)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[CH3:1][C:2]([CH3:10])([CH2:8][CH2:7][C:6]([O:18][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[C:3]([OH:5])=[O:4]
Reactant: CC1(C)CCC(=O)OC1=O
Reactant: OCc1ccccc1
Agent: CC(C)(CCC(=O)O)C(=O)O
Agent: CN(C)c1ccncc1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(CCC(=O)OCc1ccccc1)C(=O)O
Reaction time: 4 h
Yield: 73.6 %

Procedure:
To a mixture of 3 g (0.021 mol) of 2.2-dimethylglutaric anhydride, 2.0 ml (0.019 mol) of benzyl alcohol in 10 ml of CH2Cl2 was added 100 mg of DMAP and 3.4 ml of pyridine. The resulting solution was stired at room temperature for 4 h. After additional 2.2-dimethyl-glutaric acid (0.7 g, 4.9 mmol) was added, the mixture continued to be stirred overnight, then poured into 0.5M H2SO4 (aq.) solution and extracted with CH2Cl2. The organic layer was washed with brine, dried over Na2SO4 and filtered. Concentration followed by purification by flash chromatography on silica gel using EtOAc/hexane (1:1) as the irrigant gave 3.5 g of desired product in 66% yield and 1.2 g of isomer in 23% yield.
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.ClC1C=CC=C(C(OO)=O)C=1.[Br:23]C1C=C(SC)C(Cl)=NC=1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[Br:23][C:5]1[CH:6]=[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])[C:2]([Cl:1])=[N:3][CH:4]=1
Reactant: CSc1cc(Br)cnc1Cl
Reactant: CS(=O)(=O)c1cccnc1Cl
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)c1cc(Br)cnc1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 73 %

Procedure:
Using an analogous method to that described by Ponticello et al, J. Org. Chem., Vol. 44, No. 17, 1979, for the preparation of 2-chloro-3-methylsulfonylpyridine, a solution of 3-chloroperbenzoic acid (75% pure; 5 g, 22 mmol) in chloroform (50 mL) was added to a stirred solution of 5-bromo-2-chloro-3-methylthiopyridine (2.6 g, 10.9 mmol) in chloroform (50 mL) and the mixture was stirred at room temperature for 20 hours. The resultant solution was poured into a saturated aqueous sodium hydrogen carbonate solution. The organic phase was separated, washed twice with saturated aqueous sodium hydrogen carbonate solution and dried over sodium sulfate. The organic solvent was removed under reduced pressure and the residue was crystallised from a methanolic solution (20 mL). The resultant solid was filtered off and dried to afford 5-bromo-2-chloro-3-methylsulfonylpyridine (2.15 g, 73% yield); 1H NMR Spectrum: (CDCl3) 8.70 (1H, d); 8.59 (1H, d); 3.34 (3H, s); Mass Spectrum: M+H+ 270 and 272.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].[CH3:14][O:15][C:16]1[N:21]=[CH:20][C:19]([NH2:22])=[CH:18][C:17]=1[CH3:23].N1C=CC=CC=1>O1CCOCC1>[CH3:14][O:15][C:16]1[N:21]=[CH:20][C:19]([NH:22][S:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11])=[CH:18][C:17]=1[CH3:23]
Reactant: COc1ncc(N)cc1C
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: COc1ncc(NS(=O)(=O)c2ccccc2[N+](=O)[O-])cc1C
Yield: 76.3 %

Procedure:
The title compound (2.69 g, 8.32 mmol) was prepared from 2-nitrobenzenesulfonyl chloride (2.41 g, 10.9 mmol), 6-methoxy-5-methylpyridin-3-amine (1.66 g, 12.0 mmol) and pyridine (2.64 mL, 32.7 mmol) in 1,4-dioxane (25 mL) at rt using the methods of (IntA1), step 1.
Reaction SMILES: [C:1]1([OH:13])[CH:12]=[C:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH:5]=[C:3]([OH:4])[CH:2]=1.C(N)(C)(C)C.[CH3:19][C:20](=[CH:22][CH2:23][CH2:24][C:25](=[CH:27][CH:28]=O)[CH3:26])[CH3:21]>C1(C)C=CC=CC=1>[CH3:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]1[CH:5]=[C:3]([OH:4])[C:2]2[CH:28]=[CH:27][C:25]([CH2:24][CH2:23][CH:22]=[C:20]([CH3:21])[CH3:19])([CH3:26])[O:13][C:1]=2[CH:12]=1
Reactant: CCCCCc1cc(O)cc(O)c1
Reactant: CC(C)=CCCC(C)=CC=O
Solvent: Cc1ccccc1
Solvent: CC(C)(C)N
Product: CCCCCc1cc(O)c2c(c1)OC(C)(CCC=C(C)C)C=C2
Temperature: 25 °C

Procedure:
To a three-necked round bottomed flask (100 ml capacity), fitted with a dropping funnel and a condenser was added 5 g. olivetol (27.8 mmole) and 2.03 g. (2.96 ml., 27.8 mmole) t-butyl amine in 55 ml toluene and the mixture was heated to 50°-60° C., 4.23 g. (4.76 ml., 27.8 mmole) of citral was then added dropwise. The mixture was refluxed for 9 hours, after which time it was cooled to room temperature and the solvent evaporated to give 9.3 g. of crude reaction mixture. Gas chromatographic analysis of the reaction mixture showed 59.46% CBC (molar conversion), 5.04% cannabicitran and trace amount of iso-CBC.
Reaction SMILES: N12CCCN=C1CCCCC2.[Cl:12][C:13]1[C:22]([C:23]2[N:24]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:25]3[C:30]([CH:31]=2)=[CH:29][C:28]([CH2:32]O)=[CH:27][CH:26]=3)=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1.C1(P([N:55]=[N+:56]=[N-:57])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1>[N:55]([CH2:32][C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][CH:27]=1)[N:24]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:23]([C:22]1[C:13]([Cl:12])=[N:14][C:15]3[C:20]([CH:21]=1)=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:31]2)=[N+:56]=[N-:57]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)n1c(-c2cc3ccccc3nc2Cl)cc2cc(CO)ccc21
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)n1c(-c2cc3ccccc3nc2Cl)cc2cc(CN=[N+]=[N-])ccc21
Temperature: 23 °C
Reaction time: 20 h

Procedure:
1,8-diazabicyclo[5.4.0]undec-7-ene (0.400 mL, 2.69 mmol, 1.10 equiv) was added dropowise over 2 min to a solution of tert-butyl 2-(2-chloro-3-quinolinyl)-5-(hydroxymethyl)-1H-indole-1-carboxylate (7-2, 1.00 g, 2.45 mmol, 1 equiv) and diphenylphosphoryl azide (0.580 mL, 2.69 mmol, 1.10 equiv) in THF (20 mL) at 0° C. The resulting mixture was warmed to 23° C. and stirred for 20 h. The reaction mixture was partitioned between saturated sodium bicarbonate solution and ethyl acetate (2×75 mL). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (100% hexane, grading to 50% EtOAc in hexane) to afford tert-butyl 5-(azidomethyl)-2-2-chloro-3-quinolinyl)-1H-indole-1-carboxylate (7-3) as a colorless oil. 1H NMR (500 MHz, CDCl3) δ 8.34 (d, 1H, J=8.5 Hz), 8.19 (s, 1H), 8.08 (d, 1H, J=8.3 Hz), 7.88 (d, 1H, J=7.8 Hz), 7.79 (br t, 1H, J=8.1 Hz), 7.62 (br t, 1H, J=8.0 Hz), 7.58 (s, 1H), 7.36 (dd, 1H, J=8.6, 1.5 Hz), 6.68 (s, 1H), 4.46 (s, 2H), 1.27 (s, 9H).
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9](C)([CH3:11])[CH2:8][C:7]2NC=[C:4]([C:13]([OH:15])=O)[C:3]1=2.C(N(CC)CC)C.Cl[C:24]([O:26][CH2:27][CH3:28])=[O:25].FC1C=CC=CC=1N.Cl>CN(C)C=O>[O:1]=[C:2]1[C:3]2[C:4]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:13][O:15][C:7]=2[CH2:8][CH:9]([CH3:11])[CH2:10]1
Reactant: CC1(C)CC(=O)c2c(C(=O)O)c[nH]c2C1
Reactant: CCOC(=O)Cl
Agent: Cl
Agent: Nc1ccccc1F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1coc2c1C(=O)CC(C)C2
Reaction time: 0.75 h
Yield: 33 %

Procedure:
To a stirred solution of 4-oxo-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid (155 mg, 0.75 mmol) and triethylamine (209 μL, 1.5 mmol) in dimethylformamide (4 mL) at 0° C. was added ethyl chloroformate (143 μL, 1.5 mmol). After stirring an additional 45 minutes, 2-fluoroaniline (145 μL, 1.5 mmol) was added. The reaction mixture was stirred for 30 minutes, then poured into aqueous 3.6N hydrochloric acid and extracted 2× with ethyl acetate. The combined organic layers were washed with water, dried over magnesium sulfate, filtered, and concentrated in vacuo . To the residue was added aqueous 5N sodium hydroxide (5 mL) and ethyl alcohol (1 mL), and the mixture was heated at reflux for 30 minutes. After cooling in an ice water bath, the reaction mixture was acidified with hydrochloric acid, the precipitate was collected, rinsed with water, and dried to give 55 mg of N-(2-fluorophenyl)-4-oxo-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indole-3 oxamide (Compound 2).
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:36])[CH2:7][C:8]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=3)(=[O:27])=[O:26])=[CH:21][CH:20]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:35])[CH:14]=2)[CH:9]=1>C1COCC1.O>[Cl:35][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH2:7][C:6]([OH:36])=[O:5])[C:17]([CH3:18])=[C:16]2[C:19]1[CH:20]=[CH:21][C:22]([S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=2)(=[O:27])=[O:26])=[CH:23][CH:24]=1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(S(=O)(=O)c3cccc(Cl)c3)cc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(CC(=O)O)cc2ccc(Cl)cc2c1-c1ccc(S(=O)(=O)c2cccc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Lithium hydroxide monohydrate (0.007 g, 0.16 mmol) was added to a stirred solution of {6-chloro-4-[4-(3-chloro-benzenesulfonyl)-phenyl]-3-methyl-naphthalen-2-yl acetic acid methyl ester (0.020 g, 0.04 mmol) in a 3:1 THF—H2O mixture (4 mL). The reaction mixture was stirred for 16 hours at room temperature. The THF was distilled off under reduced pressure, and the crude residue was diluted with water, acidified [pH˜2] via the drop-wise addition of an aqueous solution of hydrochloric acid (6.0 N). The mixture was extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. Trituration with hexanes afforded {6-chloro-4-[4-(3-chloro-benzenesulfonyl)-phenyl]-3-methyl-naphthalen-2-yl acetic acid (0.018 g, 93%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.48 (br. s, 1 H) 8.20 (d, J=7.82 Hz, 2 H) 8.14 (s, 1 H) 8.06 (d, J=6.85 Hz, 1 H) 7.97 (d, J=8.80 Hz, 1 H) 7.91 (s, 1 H) 7.85 (d, J=8.20 Hz, 1 H) 7.73 (t, J=7.80 Hz, 1 H) 7.55 (d, J=7.83 Hz, 2 H) 7.48 (d, J=8.80 Hz, 1 H) 6.95 (s, 1 H) 3.84 (s, 2 H) 2.02 (s, 3 H) MS calcd. for C25H17Cl2O4S [(M−H)−] 483, obsd. 482.3.
Reaction SMILES: C([Mg]CCCC)CCC.C(NC(C)C)(C)C.[CH2:17]([N:24]1[C:28]2[C:29]([N:35]([CH3:37])[CH3:36])=[N:30][N:31]([CH3:34])[C:32](=[O:33])[C:27]=2[N:26]=[CH:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Cl:38]C(Cl)(Cl)C(Cl)(Cl)Cl.[Cl-].[NH4+]>O1CCCC1>[CH2:17]([N:24]1[C:28]2[C:29]([N:35]([CH3:37])[CH3:36])=[N:30][N:31]([CH3:34])[C:32](=[O:33])[C:27]=2[N:26]=[C:25]1[Cl:38])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CN(C)c1nn(C)c(=O)c2ncn(Cc3ccccc3)c12
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: CCCC[Mg]CCCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CN(C)c1nn(C)c(=O)c2nc(Cl)n(Cc3ccccc3)c12
Reaction time: 8 h
Yield: 51.7 %

Procedure:
1.15 ml of a 1 M tetrahydrofuran solution of dibutylmagnesium was added to a 2 ml tetrahydrofuran solution of 0.320 ml of diisopropylamine at room temperature under a nitrogen atmosphere, and the mixture was stirred for 8 hours. This solution was added to a 4 ml tetrahydrofuran solution of 0.162 g of 1-benzyl-7-dimethylamino-5-methyl-1,5-dihydroimidazo[4,5-d]pyridazin-4-one at room temperature under a nitrogen atmosphere, and the mixture was stirred at room temperature for 15 hours. Then, a 5 ml tetrahydrofuran solution of 0.540 g of hexachloroethane was added dropwise to the solution. After the mixture had been stirred for 4 hours, 30 ml of a 5% aqueous ammonium chloride solution was added thereto. The mixture was extracted with 100 ml of ethyl acetate. The organic layer was washed successively with 30 ml of water and 30 ml of a saturated sodium chloride solution, and dried over magnesium sulfate. The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 0.094 g of the title compound was obtained from the fraction eluted with ethyl acetate-hexane (2:1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]2[CH2:15][CH2:14][CH2:13][CH:12]2[CH2:16][C:17]([O-:19])=[O:18])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.CO.[OH-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]2[CH2:15][CH2:14][CH2:13][CH:12]2[CH2:16][C:17]([OH:19])=[O:18])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: COc1cc(OC)cc(N2CCCC2CC(=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc(OC)cc(N2CCCC2CC(=O)O)c1

Procedure:
A mixture of 53.6 g. (0.192 mole) methyl dl-2-[1-(3,5-dimethoxyphenyl)pyrrolidin-2-yl]acetate, 250 ml. methanol and 22.8 g. (0.57 mole) sodium hydroxide in 200 ml. water was stirred at room temperature for 2.5 hours. The methanol was evaporated and the aqueous residue cooled in ice. To this was added dropwise 48 ml. concentrated hydrochloric acid, the mixture extracted with 4×150 ml. methylene chloride, the extract washed with water, dried (MgSO4) and the solvent evaporated to afford 48.9 g. (96%) of product. 1H--NMR (CDCl3) ppm (delta): 3.80 (s, 6H, OCH3), 4.10 (m, 1H, N--CH), 5.82 (s, 3H, aromatic), 11.0 (s, 1H, COOH). Mass spectrum (m/e): 206 (base peak), 265 (M+).
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[CH2:12]O.P(Br)(Br)[Br:15]>C(OCC)C>[Br:15][CH2:12][C:3]1[C:4]([C:8]([F:11])([F:10])[F:9])=[N:5][N:6]([CH3:7])[C:2]=1[Cl:1]
Reactant: Cn1nc(C(F)(F)F)c(CO)c1Cl
Reactant: BrP(Br)Br
Solvent: CCOCC
Product: Cn1nc(C(F)(F)F)c(CBr)c1Cl
Temperature: -10 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
A solution of 8.3 g (38.7 mmoles) of (5-chloro-1-methyl-3-trifluoromethyl-1H-pyrazol-4-yl)-methanol dissolved in 100 ml of diethyl ether was cooled to −10° C. Thereto was added 12.6 g (46.4 mmoles) of phosphorus tribromide. The mixture was stirred at room temperature for 1 hour to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into ice water and extraction with diethyl ether was conducted. The resulting organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to reduced pressure distillation to remove the solvent contained therein, to obtain 10.7 g (yield: 99.9%) of 4-bromomethyl-5-chloro-1-methyl-3-trifluoromethyl-1H-pyrazole.
Reaction SMILES: [CH:1]1([CH2:6][OH:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>ClCCl>[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20]([O:7][CH2:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: OCC1CCCC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2CCCC2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 93.9 %

Procedure:
Cyclopentanemethanol p-toluenesulfonate was prepared by the following method: To a solution of cyclopentanemethanol (2.0 g, 20.0 mmol) and pyridine (2.9 ml, 36.3 mmol) in dichloromethane (20 ml) was added p-toluenesulfonyl chloride (3.46 g, 18.1 mmol). The mixture was stirred at room temperature for 24 h under nitrogen. The resulting mixture was washed with 2M hydrochloric acid and the aqueous layer separated and extracted with dichloromethane. The combined organics were dried over sodium sulphate and concentrated under reduced pressure to yield cyclopentanemethanol p-toluenesulfonate as a colourless oil (4.3 g, 17.0 mmol).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[C@H:11]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]([C:19]([O:21][CH3:22])=[O:20])=[C:9]([CH3:23])[NH:8][C:7]=1[CH2:24][O:25][CH2:26][CH2:27][NH2:28])=[O:5].C([O-])(=O)[C@@H]([C@H](C([O-])=O)O)O.[C:39]1([S:45]([OH:48])(=[O:47])=[O:46])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C(O)(C)C.O>[CH3:1][CH2:2][O:3][C:4]([C:6]1[CH:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=2[Cl:18])[C:10]([C:19]([O:21][CH3:22])=[O:20])=[C:9]([CH3:23])[NH:8][C:7]=1[CH2:24][O:25][CH2:26][CH2:27][NH2:28])=[O:5].[CH:42]1[CH:41]=[CH:40][C:39]([S:45]([OH:48])(=[O:47])=[O:46])=[CH:44][CH:43]=1
Reactant: CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)[C@H]1c1ccccc1Cl
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: O=S(=O)(O)c1ccccc1
Solvent: CC(C)O
Solvent: O
Product: CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Reaction time: 2 h
Yield: 84.6 %

Procedure:
68.8 gm (0.122 mole, 95;2% de) R (+) amlodipine hemi L(+) tartarate mono DMSO solvate prepared as per example 2 was suspended in aqueous isopropanol (70 ml IPA: 250 ml distilled water) and a solution of benzene sulfonic acid (19.35 gm of 90% cal grade, 0.110 mole) in 150 ml water was added. Th reaction mixture was stirred for 2 hrs and the slurry was filtered, washed with distilled water, hexane, the solid was dried under vac. at 40° C. till constant weight to give R(+) amlodipine besylate (63.4 gm, 84.6% yield) 99.3 ec by chiral HPLC.
Reaction SMILES: COC1C=C(OC)N=C(O[C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:21]=2[C:19](=O)[O:18][CH:17]3[OH:22])N=1.[CH:23]([Mg]Cl)=[CH2:24].Cl>O1CCCC1>[CH:23]([CH:19]1[C:21]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:17](=[O:22])[O:18]1)=[CH2:24]
Reactant: COc1cc(OC)nc(Oc2cccc3c2C(=O)OC3O)n1
Reactant: C=C[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: C=CC1OC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3.6 g of 7-[(4,6-dimethoxy-pyrimidin-2-yl)oxy]-3-hydroxyphthalide (see Example 84) are placed in 60 ml of absolute tetrahydrofuran at -45° C., and the solution is treated within 10 minutes with 18 ml of a 2M solution of vinylmagnesium chloride solution in tetrahydrofuran. The reaction solution is then stirred for approximately 16 hours at room temperature, a further 6 ml of vinylmagnesium chloride solution are added and the reaction solution is heated at reflux temperature for a further hour. When it has cooled, the reaction solution is acidified with 1N hydrochloric acid and freed of tetrahydrofuran in a rotary evaporator. The aqueous phase is then extracted with tert-butyl methyl ether, and the organic phase in washed and concentrated by evaporation under reduced pressure. Silica gel chromatography using ethyl acetate/n-hexane (2:3) as eluant yields pure 7-[4,6-dimethoxy-pyrimidin-2-yl)oxy]-3-vinyl-phthalide, m.p. 94°-97° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=2[C:11]([N:13]([CH3:15])C)=[O:12])[C:5]([Cl:20])=[CH:4][N:3]=1.[N:21]1([CH2:27][CH2:28][C:29]2[CH:30]=[C:31]([CH:33]=[CH:34][CH:35]=2)[NH2:32])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.Cl>C(O)(C)C>[Cl:20][C:5]1[C:6]([NH:8][C:9]2[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=2[C:11]([NH:13][C:15]2[CH:33]=[CH:34][CH:35]=[C:29]([CH2:28][CH2:27][N:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)[CH:30]=2)=[O:12])=[N:7][C:2]([NH:32][C:31]2[CH:33]=[CH:34][CH:35]=[C:29]([CH2:28][CH2:27][N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH:30]=2)=[N:3][CH:4]=1
Reactant: Nc1cccc(CCN2CCOCC2)c1
Reactant: CN(C)C(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Agent: Cl
Solvent: CC(C)O
Product: O=C(Nc1cccc(CCN2CCOCC2)c1)c1ccccc1Nc1nc(Nc2cccc(CCN3CCOCC3)c2)ncc1Cl
Temperature: 95 °C
Reaction time: 18 h
Yield: 9.7 %

Procedure:
2-[(2,5-Dichloro-4-pyrimidinyl)amino]-N,N-dimethylbenzamide (250 mg, 0.80 mmol), and 3-[2-(4-morpholinyl)ethyl]aniline (165 mg, 0.80 mmol) were combined in a vessel with 10 mL of isopropanol and 12N HCl (67 μL, 0.80 mmol). The vessel was sealed and heated with stirring at 95° C. for 18 h. The reaction mixture was concentrated to dryness. The crude product was purified by HPLC to afford the title compound as a white solid (25 mg, 6%): Mass (M+H)+=642, 644.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:20]([O:24][C:25](=[O:35])[NH:26][C:27]1[CH:32]=[CH:31][C:30]([CH:33]=O)=[CH:29][CH:28]=1)([CH3:23])([CH3:22])[CH3:21]>C(O)(=O)C.ClCCl>[F:19][C:16]([F:17])([F:18])[C:13]1[N:11]2[N:12]=[C:7]([N:1]3[CH2:2][CH2:3][N:4]([CH2:33][C:30]4[CH:29]=[CH:28][C:27]([NH:26][C:25](=[O:35])[O:24][C:20]([CH3:22])([CH3:21])[CH3:23])=[CH:32][CH:31]=4)[CH2:5][CH2:6]3)[CH:8]=[CH:9][C:10]2=[N:15][N:14]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: CC(C)(C)OC(=O)Nc1ccc(C=O)cc1
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Reaction time: 96 h
Yield: 52.1 %

Procedure:
A solution of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (0.079 g, 0.29 mmol) in a mixture of acetic acid and dichloromethane (1:9; 3 mL) was added to a mixture of (polystyrylmethyl)trimethylammonium cyanoborohydride (4.1 mmol/g, 0.097 g, 0.4 mmol) and N-(4-formylphenyl)carbamic acid tert-butyl ester (0.088.4 g, 0.4 mmol). The reaction mixture was shaken for 4 days and then filtered. The filtrate was evaporated and the and the involatile residue was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 21 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile as eluents to give tert-butyl 4-((4-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperazin-1-yl)methyl)phenylcarbamate (0.0722 g, 52%) as a white solid, which was used without further purification.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[C:9]([O:13][C:14]([CH:16]([C:28](=[O:30])[CH3:29])[CH:17]([CH:23]([O:26][CH3:27])[O:24][CH3:25])[CH2:18][C:19]([O:21][CH3:22])=[O:20])=[O:15])([CH3:12])([CH3:11])[CH3:10].[C:31](Br)#[C:32][CH2:33][CH2:34][CH3:35]>CC(C)=O>[C:28]([C:16]([C:14]([O:13][C:9]([CH3:11])([CH3:10])[CH3:12])=[O:15])([CH2:31][C:32]#[C:33][CH2:34][CH3:35])[CH:17]([CH:23]([O:24][CH3:25])[O:26][CH3:27])[CH2:18][C:19]([O:21][CH3:22])=[O:20])(=[O:30])[CH3:29]
Reactant: COC(=O)CC(C(OC)OC)C(C(C)=O)C(=O)OC(C)(C)C
Reactant: CCCC#CBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCC#CCC(C(C)=O)(C(=O)OC(C)(C)C)C(CC(=O)OC)C(OC)OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 1.38 g quantity of potassium carbonate and 308 mg of potassium iodide are placed into a reactor. Acetone (30 ml) and a solution of 450 mg of methyl 4-tert-butoxycarbonyl-3-dimethoxymethyl-5-oxohexanoate in 10 ml of acetone are further placed into the reactor. Subsequently 270 mg of pentynyl bromide is added to the mixture. The resulting mixture is stirred at room temperature for one hour and thereafter refluxed at 70° C. for 13 hours. On completion of the reaction, the mixture is cooled to room temperature, and the solids are separated off. The product is concentrated in a vacuum, and the residue purified by a silica gel column, giving methyl 4-acetyl-4-tert-butoxycarbonyl-3-dimethoxymethyl-6-nonynoate (compound (8), R1 =t-Bu, R2 =R3 =CH3) in a yield of 91%.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][N:12]=1)[C:6]([O:8][CH3:9])=[O:7].C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>ClCCl>[CH3:20][S:21]([O:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][N:12]=1)[C:6]([O:8][CH3:9])=[O:7])(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1ccnc(CO)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccnc(COS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.2 %

Procedure:
Methyl 2-(hydroxymethyl)isonicotinate (3.17 mmol, 0.530 g) and triethylamine (9.51 mmol, 1.322 mL, 0.963 g) were stirred in dichloromethane (20 mL) at 0° C. Methanesulfonyl chloride (4.76 mmol, 0.368 mL, 0.545 g) was added dropwise and the reaction stirred at room temperature for 1 hour. The reaction mixture was washed with water, dried over sodium sulfate and concentrated under vacuum to afford the title compound (686 mg). MS (ESI) m/z 246.4 [M+H]+