Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.ClC([O:14][C:15]1C=CC=CC=1)=O.O.[NH2:22][NH2:23].Cl>C(#N)C.O.N1C=CC=CC=1>[C:6]([C:5]1[CH:9]=[CH:10][C:2]([NH:1][C:15](=[O:14])[NH:22][NH2:23])=[CH:3][CH:4]=1)([OH:8])=[O:7]
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: NN
Agent: Cl
Solvent: CC#N
Solvent: O
Solvent: c1ccncc1
Product: NNC(=O)Nc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 27 g of p-aminobenzoic acid in 100 ml of acetonitrile was slowly added drop-wise 25 ml of phenyl chloroformate under ice-cooling, followed by stirring at room temperature for 2 hours. To the solution was further added 16 ml of pyridine at room temperature, followed by stirring for 1 hour. After completion of the reaction, the reaction solution was poured into 1 l of ice-water to precipitate while crystals. The crystals were collected by filtration, washed twice with 50 ml of water, and dried to obtain 47 g of phenyl 4-carboxycarbanilide. Subsequently, the crystals were slowly added to a solution of 62 g of hydrazine hydrate (80%) in 50 ml of water while ice-cooling, and the mixture was stirred at room temperature for 3 hours. The reaction solution was adjusted to a pH of about 1 by addition of 100 ml of concentrated hydrochloric acid under ice-cooling to precipitate white crystals. The thus formed crystals were collected by filtration, washed once with 20 ml of water and then twice with 50 ml of methanol, and dried to obtain 29 g of 4-(4-carboxyphenyl)semicarbazide (melting point: 254-257° C.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:18][CH2:17][C:16]3([CH2:23][CH2:22][CH2:21][CH:20](C(O)=O)[CH2:19]3)[C:15]2=[O:27])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].NC1CC[N:32]([C:35]([O:37][C:38]([CH3:41])(C)C)=[O:36])CC1.C(N(CC)CC)C.C(O)[C:50]1[CH:55]=[CH:54]C=[CH:52][CH:51]=1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:18][CH2:17][C:16]3([CH2:23][CH2:22][CH2:21][CH:20]([NH:32][C:35]([O:37][CH2:38][C:41]4[CH:54]=[CH:55][CH:50]=[CH:51][CH:52]=4)=[O:36])[CH2:19]3)[C:15]2=[O:27])[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCC3(CCCC(C(=O)O)C3)C2=O)CC1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(N2CCC3(CCCC(NC(=O)OCc4ccccc4)C3)C2=O)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 54 %

Procedure:
Using the same experimental procedures described in the synthesis of intermediate 10, 2-(1-tert-Butoxycarbonyl-piperidin-4-yl)-1-oxo-2-aza-spiro[4.5]decane-7-carboxylic acid (mixture of cis and trans diastereomers) was made from 7.40 mmol of 1-(2-oxo-ethyl)-cyclohexane-1,3-dicarboxylic aid diethyl ester and 7.40 mmol of 4-amino-1-Boc-piperidine. 2-(1-tert-Butoxycarbonyl-piperidin-4-yl)-1-oxo-2-aza-spiro[4.5]decane-7-carboxylic acid (1.24 g, 3.25 mmol) was dissolved in toluene (20.0 mL), triethylamine (0.54 mL, 3.90 mmol) was added, followed by the addition of diphenylphosphonic azid (0.70 mL, 3.25 mmol). The mixture was stirred at rt for 1.5 hrs, and then heated at 90° C. for 2 hrs. Benzyl alcohol (2.0 mL, 19.5 mmol) was added, and the mixture was heated at 90° C. overnight. The mixture was cooled down, concentrated under reduce pressure to afford 0.85 g (54%) of the title compound which is a mixture of two diastereomers (cis/trns: 1/1; under LC-MS method C, the first peak with RT of 1.56 min was assigned as cis, and the second peak with RT of 1.59 min was assigned as trans.). ESI-MS m/z: 486 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[CH2:8][CH2:9][CH3:10])[CH2:3][C:4](O)=O.C(OC(=O)C)(=[O:19])C.[CH:24]([OH:26])=[O:25]>>[CH3:4][CH:3]([C:24]([OH:26])=[O:25])[N:2]([CH:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[CH2:8][CH2:9][CH3:10])[CH:1]=[O:19]
Reactant: CC(=O)OC(C)=O
Reactant: O=CO
Reactant: CCCC(C1CCCCC1)N(C)CC(=O)O
Product: CCCC(C1CCCCC1)N(C=O)C(C)C(=O)O
Yield: 94.9 %

Procedure:
A solution of 45 parts of methyl N-(1-cyclohexylbutyl)glycine in 50 parts of acetic acid, anhydride and 300 parts of formic acid was stirred for 14 hours at room temperature. The reaction mixture was evaporated and the residue was taken up in dichloromethane. The organic layer was washed with water and a sodium carbonate solution, dried, filtered and evaporated. The residue was crystallized from a mixture of 2,2'-oxybispropane and petroleum ether. The product was filtered off and dried, yielding 48 parts (94.9%) of methyl N-(1-cyclohexylbutyl)-N-formylglycine as a residue (int. 4).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4]([NH2:9])=[N:5][CH:6]=[CH:7][CH:8]=1.Cl[CH2:11][CH:12]=O.C(=O)(O)[O-].[Na+]>C(O)C>[OH:1][CH2:2][C:3]1[C:4]2[N:5]([CH:11]=[CH:12][N:9]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=CCCl
Reactant: Nc1ncccc1CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: OCc1cccn2ccnc12
Yield: 129.1 %

Procedure:
A mixture of 2.92 g (23 mmole) of 3-hydroxymethyl-2-pyridinamine, 6.15 g (35 mmole) of chloroacetaldehyde, and 2.0 g (35 mmole) of sodium bicarbonate in 100 ml of ethanol was heated at reflux for 1.5 hours. The mixture was filtered and the filtrate was concentrated in vacuo to a solid. Recrystallization from diethyl ether yielded 4.4 g of 8-hydroxymethylimidazo[1,2-a]pyridine, as confirmed by the nmr and infrared spectra. A mixture of 683 mg (3.8 mmole) of 2-mercapto-5-methoxybenzimidazole and 700 mg (3.8 mmole) of 8-hydroxymethylimidazo[1,2-a]pyridine was dissolved in 3 ml of 30% hydrogen bromide in acetic acid and heated on a steam bath. After being cooled to room temperature, the mixture was partitioned between 5% aqueous sodium hydroxide and dichloromethane. The organic layer was dried over sodium sulfate, filtered, and concentrated to yield the title compound as an oil. Structure assignment was supported by the nmr and infrared spectra.
Reaction SMILES: [NH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)[NH2:2].C([O:14][C:15](=O)[CH2:16][C:17]([CH3:19])=O)C>>[CH3:19][C:17]1[CH2:16][C:15](=[O:14])[N:1]([C:3]2[CH:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:10][CH:11]=2)[N:2]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: NNc1ccc(C(=O)O)cc1
Product: CC1=NN(c2ccc(C(=O)O)cc2)C(=O)C1

Procedure:
From the reaction of p-hydrazinobenzoic acid and ethylacetoacetate, 4-(4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)-benzoic acid is obtained. Subsequent reaction with 2-propoxyaniline yields 4-(4,5-dihydro-3-methyl-5-oxo-4-(2-propoxyanilinomethylene)-1H-pyrazol-1-yl)-benzoic acid, Mp 259.6° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([OH:8])[CH:7]=1.[C:10]([C:12]1([C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=2)[C:18](O)=[O:19])[CH2:14][CH2:13]1)#[N:11].C(Cl)(=O)C(Cl)=O.C(=O)([O-])O.[Na+]>O.O1CCCC1.CN(C)C=O>[C:10]([C:12]1([C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=2)[C:18]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([OH:8])[CH:7]=2)=[O:19])[CH2:13][CH2:14]1)#[N:11]
Reactant: Cc1ccc(N)cc1O
Reactant: N#CC1(c2cccc(C(=O)O)c2)CC1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)c2cccc(C3(C#N)CC3)c2)cc1O
Yield: 87.5 %

Procedure:
Using 5-amino-2-methylphenol (6.00 g, 48.5 mmol), 3-(1-cyanocyclopropyl)benzoic acid (6.00 g, 48.5 mmol) produced in Example A1(iii), oxalyl chloride (6.40 mL, 73.0 mmol), N,N-dimethylformamide (40 μL), tetrahydrofuran (250 mL), sodium hydrogencarbonate (6.20 g, 73.0 mmol) and water (60 mL) as starting materials, and in the same manner as in Example A32(i), the title compound (12.4 g, 87%) was obtained as a white powder. The title compound was washed with a mixed solvent of ethyl acetate and hexane.
Reaction SMILES: C(O[C:4](=[C:7]([C:10]#[N:11])[C:8]#[N:9])[CH2:5][CH3:6])C.[C:12]([O:16][CH2:17][CH3:18])(=[O:15])[CH2:13][SH:14].C([O-])(=O)C.[K+].O>C(O)C>[CH2:17]([O:16][C:12]([C:13]1[S:14][C:4]([CH2:5][CH3:6])=[C:7]([C:8]#[N:9])[C:10]=1[NH2:11])=[O:15])[CH3:18]
Reactant: CCOC(CC)=C(C#N)C#N
Reactant: CCOC(=O)CS
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1sc(CC)c(C#N)c1N
Temperature: 60 °C

Procedure:
Add 2-(1-ethoxy-propylidene)-malononitrile, prepared in preparation 38, (230.0 g, 1531 mmol) in ethanol (1.3 L) stir with overhead stirring under nitrogen at rt and add ethyl thioglycolate (168.8 mL, 1531 mmol) and potassium acetate (225.4 g, 2297 mmol). Heat the resulting red mixture at 60° C. for 2 h. Add water (300 mL) and cool the mixture to 5° C. for 1 h. Collect the precipitate that forms by filtration, wash with 20-25% water/ethanol, and dry at rt for 3 d affording the title compound as light orange needles: 1H NMR (DMSO-d6) δ 6.76 (bs, 2H), 4.18 (q, J=7.1, 2H), 2.86 (q, J=7.5, 2H), 1.223 (t, J=7.1, 3H), 1.220 (t, J=7.5, 3H); 13C NMR (DMSO-d6) 163.8, 163.7, 153.7, 112.9, 100.0, 96.3, 60.0, 23.2, 14.3, 14.2.
Reaction SMILES: FC(F)(F)C(O)=O.C(O[C:13]([N:15](C)[NH:16][C:17]([CH:19]1[C:24](=O)[C@:23]2([CH3:29])[C:26]([CH3:28])([CH3:27])[C@H:20]1[CH2:21][CH2:22]2)=[O:18])=O)(C)(C)C>ClCCl>[CH3:13][N:15]1[C:24]2[C@:23]3([CH3:29])[C:26]([CH3:28])([CH3:27])[C@@H:20]([CH2:21][CH2:22]3)[C:19]=2[C:17](=[O:18])[NH:16]1
Reactant: CN(NC(=O)C1C(=O)[C@@]2(C)CC[C@@H]1C2(C)C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1[nH]c(=O)c2c1[C@@]1(C)CC[C@@H]2C1(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 63.1 %

Procedure:
Trifluoroacetic acid (15.7 mL) was added to a solution of N-methyl-N′-((1S,4S)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl)-hydrazinecarboxylic acid tert-butyl ester (6.13 g, 18.9 mmol) in dichloromethane (15.7 mL) at 0° C. The reaction mixture was stirred at 0° C. for 30 min, at room temperature for 1 h, and then heated at reflux for 6 h. Following overnight stirring at room temperature, the solvent was evaporated. The residue was taken up in dichloromethane (100 mL) and washed with water (2×100 mL) and brine (100 mL), dried (sodium sulfate), filtered, evaporated and purified using a Biotage system eluting with 2% methanol/dichloromethane to give (4R,7S)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (2.46 g, 63%) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[N+:9]([C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1)([O-:11])=[O:10].C(COC)OC.C([O-])(O)=O.[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[Cl:8][C:6]1[CH:7]=[C:2]([C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:9]([O-:11])=[O:10])[CH:17]=2)[N:3]=[CH:4][N:5]=1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: Clc1cc(Cl)ncn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=[N+]([O-])c1cccc(-c2cc(Cl)ncn2)c1
Yield: 86.1 %

Procedure:
4,6-Dichloropyrimidine (5.58 g, 37.4 mmol) and 3-nitrophenylboronic acid (5.00 g, 27.2 mmol) were added to a stirred mixture of dimethoxyethane (112 mL) and water (17 mL), followed by the addition of NaHCO3 (6.28 g, 75 mmol) and (PPh3)2PdCl2 (0.787 g, 1.12 mmol) herein, and the reaction mixture was refluxed for 8 h. The solvent was removed under reduced pressure. The residue was taken up in CH2Cl2 (100 mL), and the resulting solution washed with water, dried over anhydrous K2CO3, filtered and the solvent removed under reduced pressure. The crude product was purified by column chropatography on silica (eluent CH2Cl2) to yield 4-chloro-6-(3-nitro-phenyl)-pyrimidine (5.52 g; 86%) as yellowish solid.
Reaction SMILES: [CH2:1]([N:8]([CH3:17])[C:9]1[N:14]=[C:13]([NH2:15])[N:12]=[C:11](Cl)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18](#[N:20])C>[C-]#N.C([N+](CCCC)(CCCC)CCCC)CCC.CCOC(C)=O>[NH2:15][C:13]1[N:14]=[C:9]([N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH3:17])[N:10]=[C:11]([C:18]#[N:20])[N:12]=1
Reactant: CC#N
Reactant: CN(Cc1ccccc1)c1nc(N)nc(Cl)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [C-]#N
Solvent: CCOC(C)=O
Product: CN(Cc1ccccc1)c1nc(N)nc(C#N)n1
Reaction time: 1 h

Procedure:
To N-Benzyl-6-chloro-N-methyl-[1,3,5]triazine-2,4-diamine (Intermediate 34, 350 mg, 1.40 mmol) was added tetra n-butylammonium cyanide (1.15 g, 4.28 mmol) and anhydrous acetonitrile (15 mL). The reaction mixture was stirred at 50 C for 1 h, diluted with EtOAc (20 mL), extracted with water (2×10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to furnish the desired product, which was used directly without further purification (327 mg, 97%). Method C HPLC-MS: MH+ requires m/z=241. Found: m/z=241, Rt=1.29 min (86%).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9](C#N)[C:10]([C:12]2[CH:13]=[N:14][C:15]([CH3:18])=[CH:16][CH:17]=2)=[O:11])=[CH:5][CH:4]=1.Cl.N>C(O)(=O)C>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([C:12]2[CH:13]=[N:14][C:15]([CH3:18])=[CH:16][CH:17]=2)=[O:11])=[CH:7][CH:8]=1
Reactant: CSc1ccc(C(C#N)C(=O)c2ccc(C)nc2)cc1
Agent: Cl
Agent: N
Solvent: CC(=O)O
Product: CSc1ccc(CC(=O)c2ccc(C)nc2)cc1

Procedure:
A mixture of 8.0 g (28 mmol) of 3-[2-(4-(methylthio)phenyl)-2-cyanoacetyl](6-methyl)pyridine, 20 ml of acetic acid and 60 ml of concentrated hydrochloric acid was heated at 95° C. to 100° C. for 1.5 h. The orange solution was cooled and adjusted to pH 10 using concentrated ammonia solution. The resulting yellow-beige suspension was filtered and the residue was washed with water and dried. This gave 5.35 g (74.3) of the title product in the form of a yellow solid.
Reaction SMILES: [C:1]1([C:11]([OH:13])=O)[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:14]([O:16][C:17]([C:19]1([NH2:29])[CH2:28][C:22]2=[C:23]([CH3:27])[S:24][C:25]([CH3:26])=[C:21]2[CH2:20]1)=[O:18])[CH3:15].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:14]([O:16][C:17]([C:19]1([NH:29][C:11]([C:1]2[C:10]3[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=3[CH:4]=[CH:3][CH:2]=2)=[O:13])[CH2:20][C:21]2=[C:25]([CH3:26])[S:24][C:23]([CH3:27])=[C:22]2[CH2:28]1)=[O:18])[CH3:15]
Reactant: O=C(O)c1cccc2c1CCCC2
Reactant: CCOC(=O)C1(N)Cc2c(C)sc(C)c2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C1(NC(=O)c2cccc3c2CCCC3)Cc2c(C)sc(C)c2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.4 %

Procedure:
To a solution of 5,6,7,8-tetrahydro-naphthalene-1-carboxylic acid (500 mg, 2.84 mmol), 5-amino-1,3-dimethyl-5,6-dihydro-4H-cyclopenta[c]thiophene-5-carboxylic acid ethyl ester (816 mg, 3.41 mmol), HATU (1.62 g, 4.26 mmol) in anhydrous DMF (15 mL) is added DIPEA (704 μL, 4.26 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (50 mL) and washed with water (1×10 mL) and brine (2×10 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (115 g silica gel, gradient elution: 5-50% EtOAc in heptane) to give a pure product (74) as white solid (1.10 g, 97%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[C:7]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[CH3:19].[H-].[Na+].I[CH2:23][CH2:24][CH3:25]>>[F:1][C:2]1[C:10]2[C:6](=[C:7]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=3[CH3:19])[N:8]([CH2:23][CH2:24][CH3:25])[N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(-c2n[nH]c3c(F)cccc23)c(C)c1
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Product: CCCn1nc2c(F)cccc2c1-c1ccc(OC)cc1C
Yield: 45.8 %

Procedure:
Prepared according to Method D step B from 7-fluoro-3-(4-methoxy-2-methylphenyl)-1H-indazole (0.150 g, 0.52 mmol), sodium hydride (60% in oil, 0.025 g, 1.04 mmol) and 1-iodopropane (0.075 mL, 0.7 mmol) to give the title compound (0.071 g) as a white solid.
Reaction SMILES: [N:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1O)=[O:2].C1(N)CCCCC1>>[CH2:4]1[CH2:5][CH2:6][CH2:7][CH2:12][CH:3]1[NH2:1].[N:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1)=[O:2]
Reactant: O=Nc1c(O)ccc2ccccc12
Solvent: NC1CCCCC1
Product: O=Nc1cccc2ccccc12

Procedure:
The starting 2-cyclohexylamine-1-nitrosonaphthalene is prepared by reacting 1-nitroso-2-naphthol with cyclohexylamine according to the procedure described in the second part of example 12.
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH:13]1([SH:18])[CH2:17][CH2:16][CH2:15][CH2:14]1>>[C:1](=[O:12])([S:18][CH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCC/C=C/C(=O)O
Reactant: SC1CCCC1
Product: CCCCCCC/C=C/C(=O)SC1CCCC1

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and cyclopentanethiol as starting materials to give the aimed compound.
Reaction SMILES: C[C@H](CCCC1C=CC=CC=1)C(OCC)=O.[CH3:17][C@@H:18]([CH2:28][CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:19](=[O:27])[CH2:20][P:21](=[O:26])([O:24][CH3:25])[O:22][CH3:23]>>[CH3:17][C@H:18]([CH2:28][CH2:29][CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:19](=[O:27])[CH2:20][P:21](=[O:26])([O:24][CH3:25])[O:22][CH3:23]
Reactant: COP(=O)(CC(=O)[C@@H](C)CCCc1ccccc1)OC
Agent: CCOC(=O)[C@H](C)CCCc1ccccc1
Product: COP(=O)(CC(=O)[C@H](C)CCCc1ccccc1)OC
Yield: 66 %

Procedure:
(R)-(−)-Dimethyl (3-methyl-2-oxo-6-phenylhexyl)phosphonate was prepared from 14mc(i) (93 mg) in the same manner (S)-(+)-dimethyl (3-methyl-2-oxo-6-phenylhexyl)phosphonate was prepared from 14mb(i) as described above. The residue was purified by silica gel chromatography. Elution with ethyl acetate-heptane (70:30 v/v) afforded the title compound (83 mg, 66%) as a colorless oil; TLC Rf 0.22 (solvent system: 70:30 v/v ethyl acetate-heptane); HPLC retention time 12.36 min, 5μ Chiralpak OJ-H 4.6×250 mm, at ultraviolet wavelength of 210 nm, 90:10:0.1 heptane-ethanol:acetic acid) 1 mL/min, chiral purity 100% (R); MS (ESI−) m/z 297.1 (M−H)−; 1H NMR (CDCl3) δ 7.29 (d, J=6.51 Hz, 2H,), 7.22-7.16 (m, 3H), 3.77 (d, J=11.35 Hz, 3H), 3.78 (d, J=11.35 Hz, 3H), 3.13 (d, J=1.83 Hz, 1H), 3.08 (d, J=1.83 Hz, 1H), 2.78 (d, J=6.96 Hz, 1H), 2.67-2.56 (m, 2H), 1.61-1.52 (m, 3H), 1.45-1.32 (m, 1H), 1.11 (d, J=6.96 Hz, 3H); [α]Tλ=α/cl, [α]21.9D=−0.080/(0.01742 g/1.5 mL)(0.5)=−13.78° (c=1.16, CHCl3).
Reaction SMILES: [CH2:1]([NH:8][C:9](=[C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:18](=[O:19])[O:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.[Na].[ClH:28]>O1CCOCC1.O>[Cl-:28].[CH2:1]([NH:8][CH:9]([CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:18](=[O:19])[O:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cl
Reactant: O=C1OC(=C(NCc2ccccc2)c2ccccc2)c2ccccc21
Agent: B
Agent: [Na]
Solvent: C1COCCO1
Solvent: O
Product: O=C1OC(C(NCc2ccccc2)c2ccccc2)c2ccccc21
Product: [Cl-]
Temperature: 25 °C
Yield: 65 %

Procedure:
4.90 g (0.015 mole) of α-benzylamino-benzylidenephthalide (R = C6H5 ; R' = H; R" =C6H5CH2 ; X = H) is dissolved in 40 ml of absolute dioxane, and dry hydrogen chloride is bubbled through the solution. 10 to 15 minutes of this procedure causes the dioxane solution to grow turbid, with fine crystals precipitating out. 2.84 g (0.075 mole) of sodium boron hydride is added to this suspension. The solution is maintained at room temperature for 2 days, after which the excess of the reducing agent is decomposed with weak hydrochloric acid, the acid solution is diluted with a triple amount of water, neutralized with alkali hydroxide and extracted with ether. The ether extract is dried over magnesium sulfate, filtered off and saturated with dry hydrogen chloride. The resultant white precipitate is filtered off to yield 3.60 g (65%) of 1-benzylamino-1-phthalidyl-1-phenylmethane chloride. Crystallization from absolute methanol with absolute ether added yields 3.10 g (56% of the theoretical) of a product with a melting point of 255° to 257° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:16]([F:17])=[CH:15][C:12]([CH:13]=O)=[CH:11][C:10]=1[F:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([CH:24]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:21][CH2:22][CH3:23])=[O:20]>C1COCC1>[CH2:22]([O:21][C:19](=[O:20])/[CH:24]=[CH:13]/[C:12]1[CH:15]=[C:16]([F:17])[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:10]([F:18])[CH:11]=1)[CH3:23]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cc(F)c(OCc2ccccc2)c(F)c1
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1cc(F)c(OCc2ccccc2)c(F)c1
Reaction time: 1 h
Yield: 78.1 %

Procedure:
4-Benzyloxy-3,5-difluoro-benzaldehyde (1.2 g, 4.83 mmol) obtained in Step B and carbethoxymethylene triphenylphosphorane (2.0 g, 5.78 mmol) was dissolved in THF (10 mL), and the solution was stirred at 65˜75° C. for 1 hour. After the termination of the reaction, the reactant was cooled and concentrated under reduced pressure. The residue was purified by column chromatography (eluent, EtOAc/Hex=1/10) to obtain the title compound (1.2 g, 78%).
Reaction SMILES: O[C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2.[C:12]([OH:16])(=[O:15])[CH:13]=[CH2:14].C1(C)C=CC(S(O)=O)=CC=1.COC1C=CC(O)=CC=1>C1(C)C=CC=CC=1>[C:12]([OH:16])(=[O:15])[CH:13]=[CH2:14].[CH:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2
Reactant: OC12CC3CC(CC(C3)C1)C2
Agent: C=CC(=O)O
Agent: COc1ccc(O)cc1
Agent: Cc1ccc(S(=O)O)cc1
Solvent: Cc1ccccc1
Product: C1C2CC3CC1CC(C2)C3

Procedure:
To 200 ml of toluene were added 0.1 mole of 1-hydroxyadamantane, 0.2 mole of acrylic acid, 0.06 mole of p-toluene sulfinic acid and 0.2 mole of p-methoxyphenol, and the resultant mixture was stirred at the reflux temperature to esterify reacted while collecting the provided water to the point where the amount of produced water reached the theoretical amount. The reaction product was neutralized by 10 parts by weight of sodium hydroxide solution, and the precipitate produced was separated by filtration, and the toluene was distilled off under reduced pressure. The resultant crude product was recrystalized from n-hexane to obtain an adamantane monoacrylate.
Reaction SMILES: C[O:2][C:3](=[O:35])[CH:4]([CH3:34])[C:5]([NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([O:15][C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([S:23]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)(=[O:25])=[O:24])[CH:17]=2)=[C:10]([CH3:33])[CH:9]=1)=[O:6].[OH-].[Na+]>O.CO.CCOC(C)=O>[F:32][C:29]1[CH:30]=[CH:31][C:26]([S:23]([C:18]2[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=2[OH:22])[O:15][C:11]2[C:12]([CH3:14])=[CH:13][C:8]([NH:7][C:5](=[O:6])[CH:4]([CH3:34])[C:3]([OH:35])=[O:2])=[CH:9][C:10]=2[CH3:33])(=[O:25])=[O:24])=[CH:27][CH:28]=1
Reactant: COC(=O)C(C)C(=O)Nc1cc(C)c(Oc2ccc(O)c(S(=O)(=O)c3ccc(F)cc3)c2)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: Cc1cc(NC(=O)C(C)C(=O)O)cc(C)c1Oc1ccc(O)c(S(=O)(=O)c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-{4-[3-(4-Fluoro-benzenesulfonyl)-4-hydroxy-phenoxy]-3,5-dimethyl-phenyl}-2-methyl-malonamic acid methyl ester (155 mg, 0.31 mmol) in H2O/MeOH (1/1, 4 mL) was added 1N NaOH (0.6 mL, 0.6 mmol). After stirring at room temperature for 1 h, the solution was diluted with EtOAc (15 mL) and extracted with 0.1 N NaOH (3×10 mL). The combined basic extracts were acidified with 1M HCl and extracted with EtOAc (3×15 mL). The organic extracts were combined, washed with brine, dried and concentrated to give the title compound of Step B and Example 4-4 (131 mg) as a solid. 1H NMR (400 MHz, CD3OD) δ 7.98-7.95 (m, 2H), 7.35 (s, 2H), 7.27-7.22 (m, 3H), 6.93-6.90 (dd, 1H), 6.80 (d, 1H), 3.57-3.52 (q, 1H), 2.05 (s, 6H), 1.41 (d, 3H). MS (ES31) Calc: 487.1, Found: 485.9 (M−1).