Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>CN(C)C=O.C(Cl)(Cl)(Cl)Cl>[CH2:5]([O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([Cl:3])=[O:21])=[CH:18][CH:17]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCCCOc1ccc(C(=O)O)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CCCCCCCCCCOc1ccc(C(=O)Cl)cc1

Procedure:
A 300 ml two-necked flask equipped with a stirrer and a reflux condenser was charged with 100 ml of carbon tetrachloride, 4.5 ml of thionyl chloride and 11.1 g of 4-n-decyloxybenzoic acid obtained by a conventional method, and heated under reflux together with one drop of dimethylformamide for 4 hours. Then, unreacted thionyl chloride was removed under reduced pressure to obtain 4-decyloxybenzoyl chloride as a colorless liquid.
Reaction SMILES: CN(C)C=O.[H-].[Na+].[C:8]([OH:11])(=[S:10])[CH3:9].CS(O[CH:17]1[CH2:21][CH2:20][N:19]([C:22](=[N:24][C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=2)=[O:26])[CH3:23])[CH2:18]1)(=O)=O>O>[C:8]([S:10][CH:17]1[CH2:21][CH2:20][N:19]([C:22](=[N:24][C:25]([O:27][CH2:28][C:29]2[CH:30]=[CH:31][C:32]([N+:35]([O-:37])=[O:36])=[CH:33][CH:34]=2)=[O:26])[CH3:23])[CH2:18]1)(=[O:11])[CH3:9]
Reactant: CC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)N1CCC(OS(C)(=O)=O)C1
Reactant: CC(O)=S
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)SC1CCN(C(C)=NC(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 0.17 h
Yield: 79.1 %

Procedure:
To 300 ml of anhydrous N,N-dimethylformamide were added 7.35 g of sodium hydride in the form of a 55% w/w/ dispersion in oil, followed by 12.5 g of thioacetic acid. The mixture was then stirred for 10 minutes, with ice-cooling, after which 40 g of 3-methanesulphonyloxy-1-(N-p-nitrobenzyloxycarbonylacetimidoyl)pyrrolidine were added. The mixture was then stirred for 3 hours at 65° C. After the reaction mixture had been allowed to cool, water was added and the mixture was extracted with ethyl acetate. The extract was washed with water and dried and then the solvent was distilled off under reduced pressure. The residue was purified by chromatography through a column of silica gel, eluted with a 2:1 by volume mixture of benzene and ethyl acetate, to give 30 g of the title compound.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=O)[NH:14][CH:13]=[C:12]2[F:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:23]>ClCCCl>[CH2:1]([S:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15]([Cl:23])=[N:14][CH:13]=[C:12]2[F:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]cc(F)c2cc(SCc3ccccc3)ccc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: Fc1cnc(Cl)c2ccc(SCc3ccccc3)cc12
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A vial was charged with 6-(benzylthio)-4-fluoroisoquinolin-1(2H)-one (0.083 g, 0.291 mmol) and DCE (1.454 ml). POCl3 (0.136 ml, 1.454 mmol) was added and the reaction was stirred overnight at 90° C. The reaction was quenched into ice water and extracted with ethyl acetate. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated to afford crude 6-(benzylthio)-1-chloro-4-fluoroisoquinoline as a light yellow solid. The material was carried forward without further purification. (ESI) 304.1 (M+H)+.
Reaction SMILES: P(=[S:5])([O-])([O-])[O-].[Na+].[Na+].[Na+].Cl.[OH:10][N:11]=[C:12]1[CH2:17][CH2:16][N:15]([C:18](=[NH:21])[CH2:19][Cl:20])[CH2:14][CH2:13]1.Cl>O>[ClH:20].[OH:10][N:11]=[C:12]1[CH2:17][CH2:16][N:15]([C:18](=[NH:21])[CH2:19][SH:5])[CH2:14][CH2:13]1
Reactant: N=C(CCl)N1CCC(=NO)CC1
Reactant: [O-]P([O-])([O-])=S
Agent: Cl
Agent: [Na+]
Solvent: O
Product: N=C(CS)N1CCC(=NO)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.6 %

Procedure:
1.77 g of trisodium phosphorothioate were added to an ice-cooled solution of 2.1 g of 2-(4-hydroxyiminopiperidin-1-yl)-2-iminoethylchloride hydrochloride in 12 ml of water, the mixture was stirred at room temperature for about one hour, 9.8 ml of 1N hydrochloric acid were then added, and the mixture was heated at 65° C. for 30 minutes. The reaction mixture was concentrated under reduced pressure, the concentrate was mixed with 9.8 ml of methanol, and insolubles were filtered off. The filtrate was concentrated under reduced pressure, ether was added to the concentrate, and the crystals which separated out were collected by filtration and washed with ether, giving 1.8 g of 2-(4-hydroxyiminopiperidin-1-yl)-2-iminoethylmercaptan hydrochloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][CH:17]([OH:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:12][CH2:11]2)=[CH:7][CH:6]=[CH:5][N:4]=1>C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[CH3:1][O:2][C:3]1[C:8]([CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][C:17](=[O:24])[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:12][CH2:11]2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: COc1ncccc1CN1CCC(CC(O)c2ccccc2)CC1
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: COc1ncccc1CN1CCC(CC(=O)c2ccccc2)CC1
Yield: 70.4 %

Procedure:
2.2 g of 1-[(2-methoxy-3-pyridyl)methyl]-4-(2-hydroxy-2-phenylethyl)piperidine and 8.6 g of manganese dioxide were suspended in 35 ml of toluene, and the mixture was heated under reflux for 2 hours. The reaction solution was filtered, and the filtrate was evaporated. Then, the residue was purified and separated by silica gel column chromatography (ethyl acetate), to give 1.54 g of the title compound as a pale yellow oil.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([CH3:4])=[CH2:3].C(C1C=CC(C)=C(O)C=1C(C)(C)C)(C)(C)C.[CH2:23]([OH:59])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][O:45][CH2:46][CH2:47][O:48][CH2:49][CH2:50][O:51][CH2:52][CH2:53][O:54][CH2:55][CH2:56][O:57][CH3:58].C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:59][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][O:45][CH2:46][CH2:47][O:48][CH2:49][CH2:50][O:51][CH2:52][CH2:53][O:54][CH2:55][CH2:56][O:57][CH3:58])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: COCCOCCOCCOCCOCCOCCOCCOCCOCCCCCCCCCCO
Reactant: C=C(C)C(=O)Cl
Agent: Cc1ccc(C(C)(C)C)c(C(C)(C)C)c1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)C(=O)OCCCCCCCCCCOCCOCCOCCOCCOCCOCCOCCOCCOC
Temperature: 25 °C
Reaction time: 12 h

Procedure:
1.87 g (0.018 mol) of methacrylyl chloride and a small amount of di-t-butylhydroxytoluene in methylene chloride are added to a solution of 8 g (0.0148 mol) of 11,14,17,20,23,26,29,32,35-Nonaoxahexatriacontan-1-ol and 1.82 g (0.018 mol) of triethylamine in 40 ml of methylene chloride at a temperature of -20° C. The mixture is stirred at room temperature for 12 hours, without cooling. The solvent is removed at room temperature and the crude product is worked up by flash chromatography over silica gel 60 (0.040-0.063 mm) using acetone/ether 50:50. The mobile phase is distilled off at room temperature and the product is obtained as a colorless liquid. 1HNMR: 1.2-1.8 ppm (m, 16H, (--CH2)8 --), 1.9 ppm (s, 1H, HO--), 3.4 ppm (s, 3H, --OCH3), 3.7 ppm (m, 34H, --(OCH2CH2)8 --O--),--(CH2)8 --CH2 --O--), 4.2 ppm (m, 2H, --COO--CH2 --CH 2 --), 5.5 ppm (s, 1H, H--CH=C(CH3)--COO--), 6.1 ppm (s, 1H, H--CH=C(CH3)--COO--). IR (film): 1700 cm-1 (C=O), 1620 cm-1 (C=C), 1110 cm-l (C--O).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH2:21][C@H:22]([CH:26]([CH3:28])[CH3:27])[C:23](O)=[O:24])[CH:19]=2)[CH:14]=[N:13]1>C1COCC1>[CH3:7][O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH2:21][C@H:22]([CH:26]([CH3:28])[CH3:27])[CH2:23][OH:24])[CH:19]=2)[CH:14]=[N:13]1
Reactant: COCCCn1ncc2ccc(C[C@@H](C(=O)O)C(C)C)cc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COCCCn1ncc2ccc(C[C@@H](CO)C(C)C)cc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 79.2 %

Procedure:
To a stirred suspension of LiAlH4 (40 mg, 1 mmol) in anhydrous THF (2 mL) under N2 at −78° C. was added dropwise a solution of (R)-2-((1-(3-methoxypropyl)-1H-indazol-6-yl)methyl)-3-methylbutanoic acid (150 mg, 0.5 mmol) in anhydrous THF (1 mL). The mixture was allowed to warm to rt and stirred for 24 h. TLC showed the starting material had been consumed. The mixture was cooled to 0° C., H2O (40 uL) was added dropwise, followed by 10% aq NaOH (40 uL). The mixture was filtered and the filtrate was evaporated. The residue was partitioned between EtOAc and water, and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated to give (R)-2-((1-(3-methoxypropyl)-1H-indazol-6-yl)methyl)-3-methylbutan-1-ol (115 mg, 79%). 1H NMR (400 MHz, CDCl3): 1.00 (m, 6H), 1.72 (m, 3H), 2.16 (m, 2H), 2.68 (m, 1H), 2.88 (m, 1H), 3.27 (m, 2H), 3.29 (s, 3H), 3.58 (m, 2H), 4.48 (m, 2H), 7.00 (m, 1H), 7.23 (m, 1H), 7.62 (m, 1H), 7.96 (m, 1H); MS: 291 (M++1)
Reaction SMILES: [CH:1]1([C:4]2[C:8]3[CH:9]=[CH:10][C:11]([OH:16])=[C:12]([CH2:13][CH2:14][CH3:15])[C:7]=3[O:6]N=2)[CH2:3][CH2:2]1.ClC1C=C(CC(OC)=[O:31])C=CC=1NCCCBr.C(=O)([O-])[O-].[Cs+].[Cs+].CCCCCC.C(OCC)(=O)C>CN(C=O)C.C(OCC)(=O)C>[CH:1]1([C:4]([C:8]2[CH:9]=[CH:10][C:11]([OH:16])=[C:12]([CH2:13][CH2:14][CH3:15])[C:7]=2[OH:6])=[O:31])[CH2:3][CH2:2]1
Reactant: COC(=O)Cc1ccc(NCCCBr)c(Cl)c1
Reactant: CCCc1c(O)ccc2c(C3CC3)noc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(O)ccc(C(=O)C2CC2)c1O
Temperature: 80 °C
Reaction time: 2 h
Yield: 128.1 %

Procedure:
To a solution of 3-cyclopropyl-6-hydroxy-7-propylbenz-[4,5]-isoxazole (34 mg, 0.156 mmole) and methyl 3-chloro-4-(3-bromopropylamino)phenylacetate (Example 21, Step C, 50 mg, 0.156 mmole) in DMF (0.70 mL) was added cesium carbonate (54 mg , 0.164 mmole), and the mixture stirred at 80° C. in a nitrogen atmosphere for 2 hours. The cooled mixture was dissolved in ethyl acetate and washed with water, brine, dried over magnesium sulfate and concentrated in vacuo to give an oil. Thin layer chromatography on silica gel eluting with hexane:ethyl acetate (2:1) afforded the title compound (44 mg).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[S:11])[CH2:5]2.Br[C:13]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH3:19])[C:14](OCC)=[O:15].[OH-].[Na+].Cl>CN(C=O)C.O>[OH:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[C:14](=[O:15])[C:13]([CH3:19])([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[S:11][C:6]3=[CH:5][C:4]=2[CH:3]=1
Reactant: Oc1ccc2c(c1)CC(=S)N2
Reactant: CCOC(=O)C(C)(Br)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(c2ccccc2)Sc2cc3cc(O)ccc3n2C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
To a solution (13 ml) of 1,3-dihydro-5-hydroxyindol-2-thione (1.26 g) and ethyl 2-bromo-2-phenylpropionate (1.88 g) in DMF, an aqueous 2N sodium hydroxide solution (7.3 ml) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water, made acidic by adding 6N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water, and a saturated aqueous sodium chloride solution, and was dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (diluting solvent: methylene chloride) to give 1.77 g (yield: 81/9 %) of 7-hydroxy-2-methyl-2-phenylthiazolo[3,2-a]indol-3(2H)-one.
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]#[C:17][Si](C)(C)C)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+]>CO.CCOCC>[CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]2[CH:11]=[CH:12][C:13]([C:16]#[CH:17])=[CH:14][CH:15]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: CCC[C@H]1CC[C@H](c2ccc(C#C[Si](C)(C)C)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CO
Product: C#Cc1ccc([C@H]2CC[C@H](CCC)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 3.8g of 1[-4-(trans-4-propylcyclohexyl)phenyl]-2-trimethylsilylacetylene, 0.4 g of potassium carbonate and 50 ml of methanol/ether (2:1) was stirred at room temperature for 1 hr. Then, the mixture was partitioned between water and ether and the organic phase was washed in succession with saturated sodium chloride solution and water, dried over magnesium sulfate, filtered over Celite and evaporated. After chromatography of the residue over 150 silica gel with cyclohexane 1.95 g of 4-(trans-4-propylcyclohexyl)phenylacetylene were obtained as a colourless solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24](=[O:26])[CH3:25])=[CH:20][CH:19]=1.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14](=[O:16])[NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24](=[O:26])[CH3:25])=[CH:20][CH:19]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: CC(=O)c1ccc(N)cc1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(NC(=O)C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.4 %

Procedure:
To a solution of piperidine-1,4-dicarboxylic acid 1-tert-butyl ester (1.69 g, 7.4 mmol) in DMF (20 ml) was added 1-(4-aminophenyl)ethanone (1 g, 7.4 mmol), NEM (0.852 g, 7.4 mmol) and TOTU (2.427 g, 7.4 mmol). The solution was stirred for 16 h at room temperature. The solvent was removed and the residue was dissolved in ethyl acetate (50 ml) and washed with saturated aqueous NaHCO3 solution (5 ml) and HCl (1 N, 10 ml). The organic phase was dried (MgSO4) and filtered. The solvent was removed to give 1.344 g (52%) of the title compound.
Reaction SMILES: [CH2:1]([SH:21])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH3:20].[H-].[Na+].Br[CH:25]([CH3:31])[C:26]([O:28][CH2:29][CH3:30])=[O:27].[NH4+].[Cl-]>CN(C=O)C.CCCCCCC>[CH2:1]([S:21][CH:25]([CH3:31])[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH3:20]
Reactant: CCOC(=O)C(C)Br
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCCS
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCCCCCC
Solvent: CN(C)C=O
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCCSC(C)C(=O)OCC
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 92.9 %

Procedure:
(5Z,8Z,11Z,14Z,17Z)-Icosa-5,8,11,14,17-pentaene-1-thiol (305 mg, 1.00 mmol) was added to a solution of NaH (60% in mineral oil, 44 mg, 1.10 mmol) in dry DMF (10 mL) held at 0° C. under inert atmosphere. After ten minutes ethyl bromopropionate (136 μL, 1.05 mmol) was added and the mixture was stirred for 1.5 hour at 0° C. The reaction mixture was added sat. aq. NH4Cl (20 mL) and heptane (50 mL). The phases were separated and the water phase extracted with heptane (2×25 mL). The combined organics were washed with brine (25 mL), dried (MgSO4), filtered and evaporated to give 376 mg of title compound as crude oil. Purification by flash chromatography on silica gel using gradient elution (starting pure heptane and increasing stepwise to heptane:EtOAc 95:5) afforded 318 mg (79% yield) of the title compound as oil.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:8]([C:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:25])=[CH:9][C:10]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:11]([CH:15]=2)[C:12](O)=[O:13])[CH:4]=[N:3]1.C(N(C(C)C)CC)(C)C.[CH3:41][C:42]1[C:46]([NH2:47])=[CH:45][O:44][N:43]=1.ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CN(C)C=O>[CH3:41][C:42]1[C:46]([NH:47][C:12](=[O:13])[C:11]2[CH:15]=[C:7]([C:5]3[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=3)[C:8]([C:24]([N:26]3[CH2:27][CH2:28][O:29][CH2:30][CH2:31]3)=[O:25])=[CH:9][C:10]=2[O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:45][O:44][N:43]=1
Reactant: Cn1cc(-c2cc(C(=O)O)c(OCc3ccccc3)cc2C(=O)N2CCOCC2)cn1
Reactant: Cc1nocc1N
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nocc1NC(=O)c1cc(-c2cnn(C)c2)c(C(=O)N2CCOCC2)cc1OCc1ccccc1
Reaction time: 18 h

Procedure:
To a solution of 5-(1-methyl-1H-pyrazol-4-yl)-4-(4-morpholinylcarbonyl)-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 26; 44 mg, 0.10 mmol) in N,N-dimethylformamide (5 ml) was added diisopropylethylamine (0.04 ml, 0.21 mmol), 3-methyl-4-isoxazolamine (20.48 mg, 0.21 mmol), 1-hydroxy-7-azabenzotriazole (21.32 mg, 0.16 mmol) and EDC (34.0 mg, 0.18 mmol). The reaction was stirred for 18 hours and then the solvent was removed in vacuo. The residue was purified by MDAP to yield the title compound as a white solid. 43 mg.
Reaction SMILES: [C:1]([NH:5][C:6]1[C:7]([CH3:27])=[N:8][C:9]2[C:14]([N:15]=1)=[C:13]([C:16]1[NH:20][C:19]([CH:21]3[CH2:23][CH2:22]3)=[C:18]([C:24]([OH:26])=O)[CH:17]=1)[CH:12]=[CH:11][CH:10]=2)([CH3:4])([CH3:3])[CH3:2].CC[N:30](C(C)C)C(C)C.N.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(Cl)Cl>[C:1]([NH:5][C:6]1[C:7]([CH3:27])=[N:8][C:9]2[C:14]([N:15]=1)=[C:13]([C:16]1[NH:20][C:19]([CH:21]3[CH2:22][CH2:23]3)=[C:18]([C:24]([NH2:30])=[O:26])[CH:17]=1)[CH:12]=[CH:11][CH:10]=2)([CH3:2])([CH3:4])[CH3:3]
Reactant: Cc1nc2cccc(-c3cc(C(=O)O)c(C4CC4)[nH]3)c2nc1NC(C)(C)C
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1nc2cccc(-c3cc(C(N)=O)c(C4CC4)[nH]3)c2nc1NC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.9 %

Procedure:
A mixture of 5-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-2-cyclopropyl-1H-pyrrole-3-carboxylic acid (418c) (0.15 g, 0.412 mmol), 0-(-7-azabenzotriazol-1-yl)-n,′n,′n,′n′-tetramethyluronium-hexafluorophosphate (GenScript Corporation, 0.196 g, 0.514 mmol), DIPEA (Sigma Aldrich, 0.179 ml, 1.029 mmol), in DMF (2.058 mL) was stirred at RT for 5 min before addition of ammonia (2.0 M solution in MeOH, 0.412 mL, 0.823 mmol). Reaction mixture was stirred at RT overnight. Additional aliquots of HATU and DIPEA were added to the reaction mixture which was stirred at RT overnight. Reaction mixture was diluted with DCM and washed with water and brine to remove DMF. Purification by Biotage (0-10% MeOH/DCM) produced 5-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-2-cyclopropyl-1H-pyrrole-3-carboxamide (418) (0.028 g, 0.078 mmol, 19% yield). 1H NMR (300 MHz, MeOH-d4) δ ppm 0.82-0.92 (m, 2H) 0.98-1.08 (m, 2H) 1.65 (s, 9H) 2.30-2.45 (m, 1H) 2.57 (s, 3H) 6.93-6.99 (m, 1H) 7.26-7.39 (m, 1H) 7.56-7.65 (m, 1H) 7.75-7.85 (m, 1H). m/z (ESI, +ve) 364.1 (M+H).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][C@@H:6]([OH:8])[C@H:5]([C:9]([CH3:11])=[CH2:10])[CH2:4][CH2:3]1.CC(=CCCC(CC=O)C)C>>[CH3:1][CH:2]1[CH2:7][CH:6]([OH:8])[CH:5]([C:9]([CH3:11])=[CH2:10])[CH2:4][CH2:3]1
Reactant: C=C(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Agent: CC(C)=CCCC(C)CC=O
Product: C=C(C)C1CCC(C)CC1O
Yield: 95.1 %

Procedure:
In Example 15, isopulegol was synthesized in the same manner as in Example 1, except for replacing d-citronellal with 5.00 g of dl-citronellal. As a result, dl-isopulegol was obtained in a yield of 95.1%, and the ratio of dl-isopulegol to other isomers was 99.4/0.6.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:16][C:15](=[O:17])[C:9]3([CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)[N:8]=[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:6]=2[CH:24]=1.C(O)(C)C.Cl.[H][H]>CO.[Pt]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:16][C:15](=[O:17])[C:9]3([CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)[NH:8][CH:7]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:6]=2[CH:24]=1
Reactant: [H][H]
Reactant: O=C1Nc2ccc(Cl)cc2C(c2ccccc2)=NC12CCNCC2
Agent: [Pt]
Agent: Cl
Solvent: CC(C)O
Solvent: CO
Product: O=C1Nc2ccc(Cl)cc2C(c2ccccc2)NC12CCNCC2

Procedure:
4.0 g (0.012 mole) of 7-chloro-5-phenyl-spiro[1H-1,4-benzodiazepine-3,4'-piperidin]-2(3H)-one are hydrogenated in 160 ml of methanol with the addition of 10 ml of a 30% strength isopropanol/HCl solution in the presence of platinum at 25° C. in the course of 3 hours, until the calculated amount of hydrogen has been taken up. After filtration, the solvent is distilled off, the residue is rendered alkaline with aqueous concentrated ammonia solution and the base is extracted by shaking with methylene chloride. The organic phase is washed with water, dried over Na2SO4 and concentrated and the residue is chromatographed on silica gel 60 (Merck); eluting agent: methylene chloride/methanol/25% strength aqueous ammonia solution (14:2.5:0.5).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[C:5]([F:16])=[CH:4][N:3]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[NH2:22]>>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([NH:22][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=3)[C:5]([F:16])=[CH:4][N:3]=2)[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]
Reactant: COc1ccc(N)cc1OC
Reactant: Oc1cccc(Nc2nc(Cl)ncc2F)c1
Product: COc1ccc(Nc2ncc(F)c(Nc3cccc(O)c3)n2)cc1OC

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine with 3,4-dimethoxyaniline gave N2-(3,4-dimethoxyphenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 7.90 (d, 1H, J=6.6 Hz), 7.59 (bs, 1H), 7.30 (s, 1H), 7.20-7.10 (m, 2H), 7.00-6.75 (m, 4H), 6.59 (bd, 1H, J=7.8 Hz), 3.87 (s, 3H), 3.84 (s, 3H); 19F NMR (CDCl3): −47229; LCMS: ret. time: 17.77 min.; purity: 78%; MS (m/e): 357 (MH+).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][SH:3].[H-].[Na+].[CH:9](Br)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O1CCCC1>[C:10]1([CH:9]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[S:3][CH2:2][C:1]([O:5][CH3:6])=[O:4])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)CS
Reactant: BrC(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)CSC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 15 %

Procedure:
To a solution of methyl thioglycolate (5.95 g, 56 mmol) in 225 mL of tetrahydrofuran is added sodium hydride (2.5 g of 60% NaH in oil, 62.5 mmol). The mixture is stirred at room temperature for 10 minutes. Benzhydryl bromide (Aldrich of Milwaukee, Wis.; hereinafter "Aldrich") (15.3 g, 62 mmol) is added and the reaction mixture is stirred at room temperature for 3 days and then concentrated in vacuo. The residue is taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate, 10% aqueous citric acid, and brine and then dried over magnesium sulfate. Chromatography on silica gel, eluting with 4% ethyl acetate in hexane provides methyl [[(diphenyl)methyl]thio]acetate as a colorless oil in 15% yield.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:13]([O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1)[CH3:14]>>[Cl:1][C:2]1[N:11]=[C:10]([NH:20][C:19]2[CH:21]=[CH:22][C:16]([O:15][CH2:13][CH3:14])=[CH:17][CH:18]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: CCOc1ccc(N)cc1
Product: CCOc1ccc(Nc2nc(Cl)nc3ccccc23)cc1

Procedure:
The title compound was prepared from 2,4-dichloroquinazoline and 4-ethoxyaniline by a procedure similar to Example 28 (32%). 1H NMR (CDCl3): 7.81 (m, 1H), 7.65 (m, 1H), 7.32 (m, 2H), 7.03 (m, 1H), 6.73 (m, 3H), 4.09 (q, J=7.2, 2H), 1.49 (t, J=7.2, 3H).