Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:16])=[N:8][C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])=[N:10][CH:11]=1)=[O:5])[CH3:2].[CH2:17](OC(C1C(O)=NC(CC)=NC=1)=O)[CH3:18].[H-].[Na+]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:16][CH2:17][CH3:18])=[N:8][C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc(C(C)(C)C)nc1O
Reactant: CCOC(=O)c1cnc(CC)nc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(C(C)(C)C)nc1OCC
Temperature: 0 °C
Reaction time: 2 h
Yield: 30 %

Procedure:
A solution of 4-hydroxy-2-tert-butyl-pyrimidine-5-carboxylic acid ethyl ester (3 g, 13.377 mmol, prepared in an analogous manner as described for the preparation of 2-ethyl-4-hydroxy-pyrimidine-5-carboxylic acid ethyl ester, Dostert, P. et al. Eur. J. Med. Chem. 1982, 17, 437-444) in dimethylformamide (10 mL) was added slowly to the suspension of sodium hydride (800 mg, 60% in mineral oil, Aldrich) in dimethylformamide cooled to 0° C. After the addition, the ice-bath was removed and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was stirred at room temperature for 4 h then quenched with saturated solution of ammonium chloride. It was extracted with ethyl acetate (2×). The organic extracts were washed with brine (1×), dried over anhydrous sodium sulfate and concentrated. Purification of the crude residue by flash column chromatography (120 g of silica gel, eluting with a gradient of 5-60% ethyl acetate in hexane gave 4-ethoxy-2-tert-butyl-pyrimidine-5-carboxylic acid ethyl ester (1.12 g, 30%).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[N:8]=[CH:7][C:6]([CH2:9][NH:10][C:11]2[C:12]3[CH2:20][NH:19][CH2:18][CH2:17][C:13]=3[N:14]=[CH:15][N:16]=2)=[CH:5][CH:4]=1.F[C:24]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][C:25]=1[C:26]#[N:27].C(#N)C.C(N(CC)C(C)C)(C)C>C(Cl)(Cl)Cl>[F:33][C:32]([F:34])([F:35])[C:29]1[CH:30]=[CH:31][C:24]([N:19]2[CH2:18][CH2:17][C:13]3[N:14]=[CH:15][N:16]=[C:11]([NH:10][CH2:9][C:6]4[CH:7]=[N:8][C:3]([C:2]([F:21])([F:1])[F:22])=[CH:4][CH:5]=4)[C:12]=3[CH2:20]2)=[C:25]([CH:28]=1)[C:26]#[N:27]
Reactant: FC(F)(F)c1ccc(CNc2ncnc3c2CNCC3)cn1
Reactant: N#Cc1cc(C(F)(F)F)ccc1F
Solvent: CC#N
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc(C(F)(F)F)ccc1N1CCc2ncnc(NCc3ccc(C(F)(F)F)nc3)c2C1

Procedure:
A 2 mL microwave vial was charged with N-((6-(trifluoromethyl)pyridin-3-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine (40 mg, 0.13 mmol), 2-fluoro-5-(trifluoromethyl)benzonitrile (150 mg, 0.78 mmol), acetonitrile (0.4 mL) and N,N-diisopropylethylamine (68 μL, 0.39 mmol). The mixture was subjected to microwave irradiation at 200° C. for 2 h. The mixture was diluted with chloroform (7 mL), and washed with 0.1 M NaH2PO4 (10 mL), dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column to yield a pale brown solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[C:18]2[CH2:21][CH2:22][CH2:23][CH2:24][C:17]=2[C:16]1=[O:25].[C:26]1([CH:32]([NH2:34])[CH3:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)=[CH:4][C:3]=1[NH:15][C:16](=[O:25])[C:17]1[CH2:24][CH2:23][CH2:22][CH2:21][C:18]=1[C:19]([NH:34][CH:32]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:33])=[O:20]
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Reactant: CC(N)c1ccccc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CC(NC(=O)C1=C(C(=O)Nc2cc(OC3CCCC3)c(Cl)cc2F)CCCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.2 %

Procedure:
N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide (1.00 g, 2.75 mmol), (±)-1-phenylethylamine (0.433 g, 3.57 mmol), triethylamine (0.310 g, 3.06 mmol) and benzene (25 ml) as a solvent were placed into a round bottom flask (50 cc) and stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. The crystals were washed with hexane and dried to obtain N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-(1-phenylethyl)-3,4,5,6-tetrahydrophthalamide as white crystals (1.069 g, 80.0% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([CH3:8])[CH:7]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[CH2:36]([O:38][C:39]([C:41]1([CH3:45])[CH2:44][CH2:43][NH:42]1)=[O:40])[CH3:37]>C1COCC1.C(Cl)Cl>[CH2:36]([O:38][C:39]([C:41]1([CH3:45])[CH2:44][CH2:43][N:42]1[C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[CH:3]=1)=[O:40])[CH3:37]
Reactant: CCOC(=O)C1(C)CCN1
Reactant: Cc1cc(C)cc(CC(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOC(=O)C1(C)CCN1C(=O)Cc1cc(C)cc(C)c1
Temperature: 20 °C
Reaction time: 15 h

Procedure:
To a solution of (3,5-dimethyl-phenyl)-acetic acid (1 eq.) in either DCM or THF was added HOBt (1.1 eq.), EDC.HCl (1.5 eq.). Then, 2-methyl-azetidine-2-carboxylic acid ethyl ester hydrochloride, Intermediate 13 (1 eq.) and TEA (4 eq.) were added. The reaction was stirred at 20° C. for 15 h. The crude was concentrated under reduced pressure and partitioned between a saturated aqueous solution of NaHCO3 and EtOAc. The aqueous layer was extracted three times with EtOAc. The organic layers were combined, washed with water then with brine, dried over MgSO4, filtered and concentrated under reduced pressure to afford 1-[2-(3,5-dimethyl-phenyl)-acetyl]-2-methyl-azetidine-2-carboxylic acid ethyl ester.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[O:8][CH2:7][C@H:6]([NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5][CH2:4]1.[C:17]([O:20][CH2:21][CH:22]=O)(=[O:19])[CH3:18].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCl>[C:17]([O:20][CH2:21][CH2:22][NH:1][CH2:2][C@H:3]1[O:8][CH2:7][C@H:6]([NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5][CH2:4]1)(=[O:19])[CH3:18]
Reactant: CC(=O)OCC=O
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](CN)OC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)OCCNC[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.2 %

Procedure:
The compound (500 mg, 2.17 mmol) obtained in Step 3 above was dissolved in dichloromethane (10 ml), 2-oxoethyl acetate (243 mg, 2.39 mmol) was added and the resulting mixture was stirred at room temperature for 1 hour. Then sodium triacetoxyborohydride (920 mg, 4.34 mmol) was added and the resulting mixture was stirred at room temperature for 3 hours. After reaction, saturated sodium bicarbonate solution (50 ml) was added and the resulting mixture was further stirred for 1 hour. The reaction mixture was diluted with dichloromethane and the organic layer was washed with brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue obtained was purified by silica gel column chromatography [chloroform:methanol=40:1→20:1 (v/v)] to give 544 mg (64%) of the title compound as a colorless oil.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:20]1[N:25]=[CH:24][CH:23]=[CH:22][N:21]=1>>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:20]2[N:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Clc1ncccn1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Product: c1cnc(NCCCOc2cccc(CN3CCCCC3)c2)nc1

Procedure:
3-[3-(Piperidinomethyl)phenoxy]propylamine (2.0 g) and 2-chloropyrimidine (0.92 g) were fused at 160° C. for one hour. The reaction mixture was worked-up in a manner similar to that of Example 3 to give the title compound as an oil. This was treated with oxalic acid to give 2-[3-[3-(piperidinomethyl)phenoxy]propylamino]pyrimidine dioxalate (0.8 g), m.p. 181°-3° C. (recrystallised from methanol).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C@@H:5]1[C:10]2[CH:11]=[C:12]([C:15]#[N:16])[CH:13]=[CH:14][C:9]=2[O:8][C:7]([CH3:18])([CH3:17])[C@H:6]1[OH:19].CS[C:22](SC)=[N:23][C:24]#[N:25]>C1(C)C=CC=CC=1>[C:15]([C:12]1[CH:13]=[CH:14][C:9]2[O:8][C:7]([CH3:17])([CH3:18])[C@@H:6]([OH:19])[C@H:5]([N:4]3[CH2:3][CH2:2][NH:1][C:22]3=[N:23][C:24]#[N:25])[C:10]=2[CH:11]=1)#[N:16]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](NCCN)[C@@H]1O
Reactant: CSC(=NC#N)SC
Solvent: Cc1ccccc1
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](N2CCNC2=NC#N)[C@@H]1O
Yield: 98.1 %

Procedure:
A mixture of trans-4-(2-aminoethylamino)-6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol (D3) (0.39g) and dimethyl N-cyanodithioiminocarbonate (0.158g) was heated under reflux in toluene (30 ml) for 71 h. The solvent was evaporated in vacuo, and the residue column chromatographed (Kieselgel 60, gradient elution: 2-7% methanol-chloroform) giving the title compound as a white solid (0.33g). Recrystallisation from ethyl acetate-ether gave a sample of m.p. 257°-260° C.
Reaction SMILES: ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.[Cl:13][C:14]1[C:19]([F:20])=[CH:18][CH:17]=[C:16]([Cl:21])[C:15]=1[C@H:22]([O:24][C:25]1[C:26]2[O:34][CH:33]=[C:32]([C:35]3[CH2:36][CH2:37][NH:38][CH2:39][CH:40]=3)[C:27]=2[CH:28]=[N:29][C:30]=1[NH2:31])[CH3:23].CCN(C(C)C)C(C)C.[N:50]1([C:56](OC(C)(C)C)=[O:57])[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1>C(Cl)Cl>[NH2:31][C:30]1[N:29]=[CH:28][C:27]2[C:32]([C:35]3[CH2:36][CH2:37][N:38]([C:56]([N:50]4[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]4)=[O:57])[CH2:39][CH:40]=3)=[CH:33][O:34][C:26]=2[C:25]=1[O:24][C@@H:22]([C:15]1[C:16]([Cl:21])=[CH:17][CH:18]=[C:19]([F:20])[C:14]=1[Cl:13])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: C[C@@H](Oc1c(N)ncc2c(C3=CCNCC3)coc12)c1c(Cl)ccc(F)c1Cl
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H](Oc1c(N)ncc2c(C3=CCN(C(=O)N4CCNCC4)CC3)coc12)c1c(Cl)ccc(F)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of triphosgene (4 mg, 0.01 mmol) in DCM (0.8 mL) was cooled to 0° C. A solution of 7-[(R)-1-(2,6-dichloro-3-fluorophenyl)-ethoxy]-3-(1,2,3,6-tetrahydropyridin-4-yl)-furo[3,2-c]pyridin-6-ylamine (10.0 mg, 0.0237 mmol), DIPEA (0.04 mL, 0.2 mmol) and DCM was added, and the mixture was allowed to warm to rt. A solution of tert-butyl 1-piperazinecarboxylate (8.82 mg, 0.0474 mmol) in DCM was then added, and the mixture was stirred at rt for 30 min. The material was transferred to a separatory funnel and washed with sat. aq. NaHCO3. The organic layer was concentrated in vacuo, redissolved in dioxane and transferred to a sealed tube. 4 M HCl in 1,4-dioxane (0.2 mL) was added, and the solution was heated to 50° C. for 3 h. The material was concentrated in vacuo and redissolved in DMF (0.5 mL). The solution was purified by HPLC. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a brown solid. 1H NMR (CD3OD, 400 MHz): δ=1.89 (d, J=6.8 Hz, 3H), 2.56 (br, s, 2H), 3.21-3.29 (m, 4H), 3.44-3.52 (m, 4H), 3.56 (t, J=5.8 Hz, 2H), 4.08 (d, J=2.5 Hz, 2H), 6.26 (br, s, 1H), 6.50 (q, J=6.7 Hz, 1H), 7.22 (t, J=8.7 Hz, 1H), 7.40 (dd, J=9.0, 4.9 Hz, 1H), 7.66 (s, 1H), 8.19 (s, 1H). MS (ES+): m/z 534.14 [MH+]. HPLC: tR=2.16 min (ZQ2, polar—5 min).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:27]>C1COCC1.CN(C=O)C.O>[CH2:1]([N:8]([CH3:27])[CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCC(CCNCc2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: CN(CCC1CCN(C(=O)OC(C)(C)C)CC1)Cc1ccccc1
Reaction time: 0.5 h
Yield: 34 %

Procedure:
At 0° C., a solution of tert-butyl 4-(2-(benzylamino)ethyl)piperidine-1-carboxylate (400 mg, 1.25 mmol, 1 eq) in THF (10 ml) was added dropwise to a suspension of NaH (110 mg, 2.74 mmol, 1.3 eq, 60% in mineral oil) in DMF (4 ml), and stirring was carried out for 30 min. Then a solution of iodomethane (93 μl, 1.5 mmol, 1.2 eq) in THF (2 ml) was added dropwise at 0° C., and stirring was carried out for 2 h at RT. After monitoring by thin-layer chromatography, the reaction mixture was diluted with water (5 ml) and extracted with ethyl acetate (2×50 ml). The combined organic phases were washed with water and sat. NaCl solution (in each case 50 ml), dried over sodium sulfate and concentrated under reduced pressure. After purification by column chromatography (silica gel, 60% ethyl acetate in hexane), a light-yellow solid was obtained. Yield: 34% (140 mg, 0.42 mmol).
Reaction SMILES: Br[C:2]1[C:3]([F:22])=[C:4]([F:21])[CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:7]2=[O:20].[CH2:23]([Sn](CCCC)(CCCC)C#CC)[CH2:24][CH2:25]C>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:12]1([N:10]2[C:11]3[C:6](=[CH:5][C:4]([F:21])=[C:3]([F:22])[C:2]=3[C:23]#[C:24][CH3:25])[C:7](=[O:20])[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9]2)[CH2:14][CH2:13]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(Br)c(F)c(F)cc2c1=O
Reactant: CC#C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC#Cc1c(F)c(F)cc2c(=O)c(C(=O)OCC)cn(C3CC3)c12
Yield: 30.7 %

Procedure:
7.5 g of ethyl 8-bromo-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate, 9.1 g of 1-tributylstannyl-prop-1-ine and 1.16 g of tetrakis(triphenylphosphine)palladium(0) are refluxed for 8 hours in 80 ml of absolute toluene under a nitrogen atmosphere. The solid which crystallises out at -18° C. is filtered off with suction and dried. 2.05 g of ethyl 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-8-(propin-1-yl)-3-quinolinecarboxylate are obtained (31% of theory).
Reaction SMILES: [NH2:1][C:2]1[C:3](C(O)=O)=[N:4][C:5]([C:14]2[CH:19]=[CH:18][C:17](=[O:20])[N:16]([CH:21]([CH3:23])[CH3:22])[N:15]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1>ClC1C=CC=CC=1Cl>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:5]([C:14]2[CH:19]=[CH:18][C:17](=[O:20])[N:16]([CH:21]([CH3:23])[CH3:22])[N:15]=2)=[N:4][CH:3]=1
Reactant: CC(C)n1nc(-c2nc(C(=O)O)c(N)nc2-c2ccccc2)ccc1=O
Solvent: Clc1ccccc1Cl
Product: CC(C)n1nc(-c2ncc(N)nc2-c2ccccc2)ccc1=O
Yield: 93.7 %

Procedure:
A suspension of 3-amino-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-5-phenyl-2-pyrazinecarboxylic acid (250 mg) in o-dichlorobenzene (1.25 ml) was refluxed for 2 hours. After cooling, IPE (2.5 ml) was added to the reaction mixture to yield a precipitate. The precipitate was collected by filtration to give 6-(5-amino-3-phenyl-2-pyrazinyl)-2-isopropyl-3(2H)-pyridazinone as a solid (205 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[O:3]1.[CH3:17][C:18]1([CH2:22]O)[CH2:21][O:20][CH2:19]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH3:8][C:6]1([CH3:7])[C:2]([CH3:16])([CH3:1])[O:3][B:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:17][C:18]3([CH3:22])[CH2:21][O:20][CH2:19]3)=[CH:11][CH:10]=2)[O:5]1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Reactant: CC1(CO)COC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1(COc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)COC1
Temperature: 30 °C
Reaction time: 0.25 h
Yield: 86.5 %

Procedure:
A vial was charged with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (220 mg, 1.00 mmol), (3-methyloxetan-3-yl)methanol (122 mg, 1.20 mmol), triphenylphosphine (353 mg, 1.50 mmol) and tetrahydrofuran (2 mL). The mixture was stirred at 30° C. for 15 min under nitrogen atmosphere. To the mixture was added Diisopropyl azodicarboxylate (300 mg, 1.50 mmol). The mixture was purged with nitrogen and heated to 50° C. for 17 hrs. The mixture was diluted with ethyl acetate and washed with brine. The organic layer was dried (sodium sulfate) and concentrated to give crude product (900 mg) as yellow gum, which was purified through flash column chromatography to give the title compound (263 mg, 87%) as white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([C:12](=[O:14])[CH3:13])=[CH:9][CH:8]=[CH:7]2.[BH4-].[Na+].CC(C)=O>C(O)C>[OH:14][CH:12]([C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[C:2]([OH:1])=[CH:3][CH:4]=[CH:5]2)[CH3:13]
Reactant: CC(=O)c1cccc2cccc(O)c12
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCO
Product: CC(O)c1cccc2cccc(O)c12
Reaction time: 0.5 h
Yield: 95.1 %

Procedure:
1040 g of 8'-hydroxy-1'-acetonaphthone was dissolved in 8.5 liters of ethanol, to which 131 g of sodium borohydride was added while ice-cooling in order not to allow the temperature of the reaction solution to exceed 30° C. After agitation for 30 minutes at room temperature, excess sodium borohydride was decomposed with 1 liter of acetone. The reaction solution was concentrated under reduced pressure, after which 4 liters of 1N hydrochloric acid was added, followed by extraction with ethyl acetate. The resultant organic phase was washed with a saturated saline solution to remove the excess acid. After drying with anhydrous magnesium sulfate, the solvent was distilled off and a small amount of hexane was added to the resultant residue for crystallization. The crystals were collected by filtration to obtain 1000 g of the captioned compound as light brown crystals.
Reaction SMILES: N[C:2]1C(N)=C(C)C=CC=1.NC(N)=O.[C:14](=[O:28])([O:16][C:17]1[CH:23]=[C:22]([O:24][C:25](=[O:27])[NH2:26])[CH:21]=[CH:20][C:18]=1C)[NH2:15]>>[C:25](=[O:27])([O:24][C:22]1[CH:21]=[CH:20][CH:18]=[C:17]([O:16][C:14](=[O:28])[NH2:15])[C:23]=1[CH3:2])[NH2:26]
Reactant: Cc1ccc(OC(N)=O)cc1OC(N)=O
Reactant: Cc1cccc(N)c1N
Agent: NC(N)=O
Product: Cc1c(OC(N)=O)cccc1OC(N)=O

Procedure:
Then, this reaction may be carried out, for example, by charging the mixed diaminotoluene, urea and/or N-unsubstituted carbamic acid ester, alcohol, if necessary, a catalyst and a reaction solvent, in a reaction vessel under the above-described conditions, and stirring or mixing the charged mixture. Tolylene dicarbamate containing 2,4-tolylene dicarbamate and 2,6-tolylene dicarbamate is produced as a main product.
Reaction SMILES: [Na+].[CH2:2]([P:4]([OH:11])([CH2:6][CH2:7][C:8]([O-:10])=[O:9])=[O:5])[CH3:3].S(=O)(=O)(O)O>>[CH2:2]([P:4]([OH:11])([CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:5])[CH3:3]
Reactant: CCP(=O)(O)CCC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCP(=O)(O)CCC(=O)O
Yield: 97.8 %

Procedure:
In the aqueous solution of 420 g (2 mol) of 3-(ethylhydroxyphosphinyl)propionic acid sodium salt (produced as in Example 12) is rendered acidic with about 196 g of concentrated sulfuric acid and the water is distilled off in vacuo. The residue was taken up in tetrahydrofuran and extracted. The insoluble salts were filtered off. The solvent of the filtrate was removed in vacuo and the residue was recrystallized from acetone to obtain 325 g (98% of theory) of 3-(ethylhydroxyphosphinyl)-propionic acid as colorless solid.
Reaction SMILES: [OH:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH:12]1C=C(O)C(O)=CC=1>>[C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[C:10]2[O:11][CH2:12][O:1][C:2]=12)([OH:6])=[O:5]
Reactant: O=C(O)c1cccc(O)c1O
Reactant: Oc1ccccc1O
Product: O=C(O)c1cccc2c1OCO2

Procedure:
By substituting pyrocatechoic acid (ie., 2,3-dihydroxybenzoic acid) for the pyrocatechin of Example 1, and otherwise following the procedure described therein, the product 1-carboxy-methylenedioxybenzene is obtained.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:7]=[C:8]([Sn](CCCC)(CCCC)CCCC)[CH:9]=[CH:10][C:11]=1[CH2:12][O:13][C:14](=[O:16])[CH3:15])(=[O:3])[CH3:2].Br[C:31]1[N:32]=[C:33]([N:41]2[CH2:46][CH2:45][N:44]([CH2:47][CH3:48])[CH2:43][CH2:42]2)[C:34]2[C:39]([CH:40]=1)=[CH:38][CH:37]=[CH:36][CH:35]=2>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:47]([N:44]1[CH2:43][CH2:42][N:41]([C:33]2[C:34]3[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH:40]=[C:31]([C:8]3[CH:9]=[CH:10][C:11]([CH2:12][O:13][C:14](=[O:16])[CH3:15])=[C:6]([CH2:5][O:4][C:1](=[O:3])[CH3:2])[CH:7]=3)[N:32]=2)[CH2:46][CH2:45]1)[CH3:48]
Reactant: CCN1CCN(c2nc(Br)cc3ccccc23)CC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(COC(C)=O)c(COC(C)=O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Product: CCN1CCN(c2nc(-c3ccc(COC(C)=O)c(COC(C)=O)c3)cc3ccccc23)CC1
Yield: 94.4 %

Procedure:
3,4-Bis(acetoxymethyl)tributylstannylbenzene (1.91 g) and 3-bromo-1-(4-ethylpiperazin-1-yl)isoquinoline (1.00 g) were heated under reflux overnight in the presence of tetrakistriphenylphosphinepalladium(0) (0.14 g) in xylene in nitrogen atmosphere. After cooling, the reaction solution was diluted with ethyl acetate and filtered. The filtrate was extracted with 2N hydrochloric acid, and the resulting aqueous layer was washed with ethyl acetate, adjusted to pH 10 with a 8N aqueous solution of sodium hydroxide, and then extracted with ethyl acetate. The extract was washed with a 10% aqueous solution of sodium carbonate and brine, and dried over magnesium sulfate. The solvent was evaporated, to give a mixture (1.36 g) of 1-(4-ethylpiperazin-1-yl)-3-[3,4-bis(acetoxymethyl)phenyl]isoquinoline as a brown viscous oil and the starting material.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[S:30][C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[N:28][C:27]=1[CH3:37])[CH2:6][O:7][C:8]1[C:12]([CH:13]=O)=[CH:11][N:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]=1.[CH2:38](P(=O)(OCC)OCC)[P:39](=[O:46])([O:43][CH2:44][CH3:45])[O:40][CH2:41][CH3:42].CN(C)C=O.[H-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[S:30][C:29]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[N:28][C:27]=1[CH3:37])[CH2:6][O:7][C:8]1[C:12](/[CH:13]=[CH:38]/[P:39](=[O:46])([O:43][CH2:44][CH3:45])[O:40][CH2:41][CH3:42])=[CH:11][N:10]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:9]=1
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1sc(-c2ccccc2)nc1C
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2sc(-c3ccccc3)nc2C)c(OC)c1)OCC
Reaction time: 15 h
Yield: 59.4 %

Procedure:
To a mixture of 3-({3-methoxy-4-[(4-methyl-2-phenyl-1,3-thiazol-5-yl)methoxy]benzyl}oxy)-1-phenyl-1H-pyrazole-4-carbaldehyde (0.60 g), tetraethyl methylenediphosphonate (0.37 g) and N,N-dimethylformamide (20 mL) was added sodium hydride (60% in oil, 0.060 g) at room temperature, and the mixture was stirred at the same temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give diethyl (E)-2-[3-({3-methoxy-4-[(4-methyl-2-phenyl-1,3-thiazol-5-yl)methoxy]benzyl}oxy)-1-phenyl-1H-pyrazol-4-yl]ethenylphosphonate as colorless crystals (0.45 g, yield 58%) from a fraction eluted with ethyl acetate-hexane (5:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 113-114° C.