Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH:4]([NH:10][C:11](=[O:13])[CH3:12])[CH:5]([OH:9])[CH2:6][O:7][CH3:8].C(Cl)Cl.C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>CO>[CH3:1][O:2][C:3](=[O:14])[C:4]([NH:10][C:11](=[O:13])[CH3:12])=[C:5]([O:9][S:26]([CH3:25])(=[O:28])=[O:27])[CH2:6][O:7][CH3:8]
Reactant: CS(=O)(=O)Cl
Reactant: COCC(O)C(NC(C)=O)C(=O)OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: COCC(OS(C)(=O)=O)=C(NC(C)=O)C(=O)OC

Procedure:
A solution consisting of 20.5 g (0.1 mol) of alcohol 8, 1 l of methylene chloride, and 20.5 ml of triethylamine was cooled to 0° under an argon atmosphere. Methanesulfonyl chloride (8.5 ml) was added dropwise with stirring. The resultant solution was maintained at 0° for 1/2 hr. Methanol (0.4 ml) was added, and the solvent was removed in vacuo (35°). The white solid residue was triturated with ethyl acetate and the extract filtered through a column containing silica gel (200 g). The fractions containing product (as determined by thin layer chromatography) were concentrated in vacuo yielding 2-acetamido-3-mesyloxy-4-methoxy-butenoic acid methyl ester (9) as a partially crystalline residue. Crystallization from ethyl acetate/petroleum ether (bp 35°-60°) gave one of the diastereomers as a white crystalline solid: mp 101.5°-104.5°; NMR (CDCl3) δ 6.4 (broad d, 1H, NH), 5.2 (m, 1H, CH2CH), 5.0 (m, 1H, CHNH), 3.8 (s, 3H, CH3O2C--), 3.6 (m, 2H, CH3OCH2 --), 3.3 (s, 3H, CH3OCH2 --), 3.0 (s, 3H, CH3SO 3 --), 2.0 (s, 3H, CH3CONH--). (Calcd. for C9H17NO7S: C, 38.16; H, 6.05; N, 4.94; S, 11.31. Found: C, 38.34; H, 6.21; N, 4.92; S, 11.27).
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([C:13]2[NH:14][C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[C:17]([C:22](=[O:34])[NH:23][C:24]2[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=2)[CH:16]=3)=[C:8]([CH3:35])[CH:7]=1.O.[OH-].[Li+].C1COCC1.CO.O.Cl>O>[CH3:12][C:10]1[CH:11]=[C:6]([CH2:5][CH2:4][C:3]([OH:36])=[O:2])[CH:7]=[C:8]([CH3:35])[C:9]=1[C:13]1[NH:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([C:22](=[O:34])[NH:23][C:24]1[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=1)[CH:16]=2
Reactant: COC(=O)CCc1cc(C)c(-c2cc3ccc(C(=O)Nc4ccc5ccccc5n4)cc3[nH]2)c(C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1cc(CCC(=O)O)cc(C)c1-c1cc2ccc(C(=O)Nc3ccc4ccccc4n3)cc2[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 3-{3,5-dimethyl-4-[6-(quinolin-2-ylcarbamoyl)-1H-indol-2-yl]-phenyl}-propionic acid methyl ester (100 mg, 210 μmol) and lithium hydroxide monohydrate (26 mg, 620 μmol) in 5:5:2 THF/MeOH/H2O (10 mL) was stirred at ambient temperature for 18 h. The solution was concentrated to remove the organic solvents, then was diluted with water and neutralized with one equivalent of 1N HCl. The mixture was stirred vigorously for 30 min and the precipitate was filtered and washed with water. The solid was triturated with water and refiltered, then dried at 50° C. under reduced pressure to give the title compound. 1H NMR (DMSO-d6, 400 MHz): δ 12.15 (s, broad, 1H), 11.56 (s, 1H), 10.99 (s, 1H), 8.39 (s, 2H), 8.16 (s, 1H), 7.95 (d, J=7.4 Hz, 1H), 7.88 (d, J=8.3 Hz, 1H), 7.79 (dd, J=8.3, 1.4 Hz, 1H), 7.73 (m, 1H), 7.63 (d, J=8.2 Hz, 1H), 7.52 (t, J=7.1 Hz, 1H), 7.06 (s, 2H), 6.41 (d, J=1.4 Hz, 1H), 2.82 (t, J=7.4 Hz, 2H), 2.57 (t, J=7.6 Hz, 2H), 2.11 (s, 6H). MS (m/z) 464.3 (M+1); Retention time=1.36 min (Method 10).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.[CH3:34][N:35]1[CH:40]=[CH:39][C:38](OS(C(F)(F)F)(=O)=O)=[CH:37][C:36]1=[O:49]>>[CH3:1][O:2][CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:38]3[CH:39]=[CH:40][N:35]([CH3:34])[C:36](=[O:49])[CH:37]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: COC[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)C(=O)O1
Reactant: Cn1ccc(OS(=O)(=O)C(F)(F)F)cc1=O
Product: COC[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(-c3ccn(C)c(=O)c3)cc2)C(=O)O1

Procedure:
The title compound was prepared from (R)-6-(methoxymethyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and trifluoro-methanesulfonic acid 1-methyl-2-oxo-1,2-dihydro-pyridin-4-yl ester following a procedure analogous to that described in Example 76. Mass spectrum (ESI+): m/z=433 [M+H]+.
Reaction SMILES: [N:1]([C@@H:4]1[CH2:6][C@H:5]1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[C:2]=[O:3].[N:13]12[CH2:20][CH2:19][CH:16]([CH2:17][CH2:18]1)[CH:15]([OH:21])[CH2:14]2>>[C:7]1([C@@H:5]2[CH2:6][C@H:4]2[NH:1][C:2](=[O:3])[O:21][CH:15]2[CH:16]3[CH2:19][CH2:20][N:13]([CH2:18][CH2:17]3)[CH2:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: OC1CN2CCC1CC2
Reactant: O=C=N[C@@H]1C[C@H]1c1ccccc1
Product: O=C(N[C@@H]1C[C@H]1c1ccccc1)OC1CN2CCC1CC2
Yield: 28 %

Procedure:
Using general procedure A, (+/−) ((1S,2R)-2-isocyanatocyclopropyl)benzene (117 uL, 0.780 mmol) and quinuclidin-3-ol gave (+/−) quinuclidin-3-yl (1R,2S)-2-phenylcyclopropylcarbamate (63 mg, 28%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.30-7.05 (m, 5H), 5.43 (br s, 1H), 4.77 (br s, 1H), 3.23 (dd, J=9.0, 14.0 Hz, 1H), 2.97-2.65 (m, 6H), 2.15-1.12 (m, 8H) ppm. 13C NMR (100 MHz, CDCl3) δ 157.1, 140.7, 140.2, 128.5, 126.8, 126.3, 71.5, 55.7, 47.5, 46.6, 32.7, 25.6, 25.2, 24.5, 19.5, 16.2 ppm. Purity: >99.9% UPLCMS (210 nm); retention time 0.67 min; (M+1) 287.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH:12]=[C:11](I)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>O1CCOCC1.O.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>[CH2:1]([N:8]1[C:13](=[O:14])[CH:12]=[C:11]([C:20]2[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: O=c1cc(I)cnn1Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: O=c1cc(-c2ccc(F)cc2)cnn1Cc1ccccc1
Temperature: 100 °C

Procedure:
2-Benzyl-5-iodopyridazine-3(2H)-one (5.0 g, 16 mmol), 4-fluorophenyl boronic acid (2.91 g, 20.8 mmol), Pd(Ph3P)4 (0.93 g, 0.80 mmol), and potassium carbonate (6.64 g, 48.1 mmol) were combined in dioxane (120 ml) and Water (40 ml). The reaction mixture was refluxed at 100° C. for 3 h, cooled to room temperature, and poured into ethyl acetate (200 mL) and water (200 mL). The mixture was extracted with ethyl acetate (3×200 mL). The combined organics were washed with water, dried (sodium sulfate), concentrated, and purified by flash chromatography to afford the title compound as a white solid. 1H NMR (500 MHz, CD3SOCD3) δ 8.38 (d, 1H); 7.25-7.92 (m, 10H); 5.27 (s, 2H). LRMS (APCI) calc'd for (C17H14FN2O) [M+H]+, 281.1. found 281.1.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[K+].[Cl-].[NH4+:17]>CS(C)=O>[N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([NH2:17])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc2ccccc12
Reactant: [NH4+]
Agent: [Cl-]
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Nc1ccc([N+](=O)[O-])c2ccccc12
Reaction time: 1 h

Procedure:
3.5 g of 1-nitronaphthalene and 3.3 g of N,N-tetramethylenethiocarbamoylsulphenamide, dissolved in 15 ml of dimethyl sulphoxide, are added dropwise to a vigorously stirred suspension of 6 g of potassium hydroxide in 50 ml of dimethyl sulphoxide, the temperature being kept at 20° to 25° C. When the addition has ended the mixture is stirred for a further 60 minutes, poured into 400 ml of a saturated aqueous ammonium chloride solution and extracted with methylene chloride. After drying and removing the solvent, 4-nitro-1-naphthylamine is obtained with a melting point of 190° to 192° C. The yield is 2.9 g (77%). 1Nitro-2-napthylamine is additionally obtained in a yield of about 2%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].Cl.[OH:13][NH2:14].C([O-])([O-])=O.[Na+].[Na+]>C(O)C.O>[OH:13][N:14]=[CH:7][C:6]1[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1cccc(C=NO)c1
Reaction time: 1 h
Yield: 90.7 %

Procedure:
3-Nitrobenzaldehyde (3.00 g, 19.9 mmol) and hydroxyamine HCl (1.79 g, 25.8 mmol) were dissolved in 60 mL of ethyl alcohol/water (1/1, v/v) solution. While stirring the reaction mixture, Na2CO3 (2.74 g, 25.8 mmol) was added slowly at below 0. The reaction was continued for 1 hr in an oil bath preheated to 60-65. After the reaction was completed, 3.0 g (92%) of the target product was obtained by extracting with ethyl acetate, drying over anhydrous MgSO4 and removing the solvent under reduced pressure.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30]([OH:32])=O)[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[CH3:63][O:64][C:65]1[CH:71]=[C:70]([N:72]2[CH2:77][CH2:76][O:75][CH2:74][CH2:73]2)[CH:69]=[CH:68][C:66]=1[NH2:67]>>[CH3:63][O:64][C:65]1[CH:71]=[C:70]([N:72]2[CH2:73][CH2:74][O:75][CH2:76][CH2:77]2)[CH:69]=[CH:68][C:66]=1[NH:67][C:30]([CH:20]1[NH:19][CH:18]([CH2:33][C:34]([CH3:35])([CH3:37])[CH3:36])[C:17]2([C:12]3[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=3)[NH:15][C:16]2=[O:38])[CH:21]1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=1[F:29])=[O:32]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Reactant: COc1cc(N2CCOCC2)ccc1N
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(N2CCOCC2)ccc1NC(=O)C1NC(CC(C)(C)C)C2(C(=O)Nc3cc(Cl)ccc32)C1c1cccc(Cl)c1F
Yield: 46.1 %

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.25 g, 0.43 mmol), was reacted with diisopropylethylamine (0.29 g, 2.2 mmol), diphenylphosphinic chloride (0.21 g, 0.89 mmol), then reacted with 2-methoxy-4-morpholinoaniline (Bionet) (0.14 g, 0.67 mmol) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (2-methoxy-4-morpholin-4-yl-phenyl)-amide as a light yellow solid (Yield 0.13 g, 46%).
Reaction SMILES: [C:1]([O:6]CC1OC1)(=[O:5])[C:2]([CH3:4])=[CH2:3].C[N:12](CCCCCCCCCCCC)C.C1(C=CC(O)=CC=1)O.CC(C)=O>CS(C)=O>[C:1]([NH2:12])(=[O:6])[CH:2]=[CH2:3].[C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: CCCCCCCCCCCCN(C)C
Reactant: C=C(C)C(=O)OCC1CO1
Agent: Oc1ccc(O)cc1
Solvent: CC(C)=O
Solvent: CS(C)=O
Product: C=C(C)C(=O)O
Product: C=CC(N)=O
Yield: 6304.1 %

Procedure:
After 20 g of the obtained prepolymers were dissolved in 62 g of dimethyl sulfoxide, 6.71 g of glycidyl methacrylate, 504 mg of N,N-dimethyldodecylamine (catalyst), and 62.4 mg of hydroquinone (polymerization inhibitor) were added. The obtained solution was allowed to react for 7 hours at 140° C. in a nitrogen atmosphere. Acetone was added to the resultant solution to precipitate a polymer. The polymer was sufficiently washed to obtain 23.4 g of terminal methacrylate acrylamide macromonomer (weight average molecular weight: 1,400). It was confirmed that a polymerizable group was introduced into the terminal because H1-NMR(D20) 6.12, 5.70 ppm methacryloyl group olefin peak, and the acid value (0.057meq/g) decreased.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1)=[O:5].C(N(CC)CC)C.[N:27]1[CH:28]=[CH:29][N:30]2[CH2:36][C:35]3[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=3[NH:33][CH2:32][C:31]=12>C(Cl)Cl>[N:27]1[CH:28]=[CH:29][N:30]2[CH2:36][C:35]3[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=3[N:33]([C:11]([C:10]3[CH:14]=[CH:15][C:7]([NH:6][C:4](=[O:5])[C:3]4[CH:16]=[CH:17][CH:18]=[CH:19][C:2]=4[CH3:1])=[CH:8][CH:9]=3)=[O:12])[CH2:32][C:31]=12
Reactant: c1ccc2c(c1)Cn1ccnc1CN2
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3nccn3Cc3ccccc32)cc1
Temperature: 0 °C
Reaction time: 0.05 h

Procedure:
To a mixture of 1.37 g (5 mmol) of 4-[(2-methylbenzoyl)amino]benzoyl chloride in 15 ml of methylene chloride, cooled to 0° C. is added 1.5 ml of triethylamine. After stirring for 3 minutes, 5 mmol of 10,11-dihydro-5H-imidazo[2,1-c][1,4]benzodiazepine in 5 ml of methylene chloride is added. The cooling bath is removed and after about 30 minutes a complete solution is obtained. The reaction mixture is allowed to stir at room temperature for 1 hour and the volatiles are concentrated in vacuo. The residue is dissolved in 100 ml of ethyl acetate and washed with water, 2N citric acid, and brine. The solution is dried with Na2 SO4 and the volatiles concentrated in vacuo to give the desired product as a solid.
Reaction SMILES: [C:1]([NH:11][CH2:12][C:13]([OH:15])=O)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[CH:31]([NH2:34])([CH3:33])[CH3:32]>C1COCC1>[CH2:4]([O:3][C:1](=[O:2])[NH:11][CH2:12][C:13](=[O:15])[NH:34][CH:31]([CH3:33])[CH3:32])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: CC(C)N
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(C)NC(=O)CNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98 %

Procedure:
To a solution of N-Cbz-glycine (20.9 g, 100 mmol) in THF (400 mL) at 0° C. was added N-methylmorpholine (NMM) (12.1 mL, 110 mmol) and i-butylchloroformate (13 mL, 100 mmol). The resultant mixture was stirred at 0° C. for 2 min and then i-propylamine (9.4 mL, 110 mmol) was added. The reaction mixture was warmed to room temperature and stirred at this temperature for 16 h. The mixture was filtered through a pad of CELITE™ and concentrated in vacuo. The crude residue was dissolved in ethyl acetate (500 mL) and washed with 1N HCl (aq.) (1×100 mL), sat. NaHCO3 (aq.) (1×100 mL) and brine (1×100 mL). The organic layer was dried (MgSO4), filtered and concentrated in vacuo to afford (isopropylcarbamoylmethyl)carbamic acid benzyl ester as a white solid (24.5 g, 98 mmol, 98%) which was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:9]=[CH:8][N:7]=1)=[O:5])[CH3:2].ClC(Cl)C.[BH4-].[Na+].Cl>C(O)C>[OH:13][CH2:12][C:10]1[CH:9]=[CH:8][N:7]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:11]=1.[OH:3][CH2:4][C:6]1[CH:11]=[C:10]([CH:9]=[CH:8][N:7]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)c1ccnc(C(=O)OCC)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(Cl)Cl
Product: CCOC(=O)c1cc(CO)ccn1
Product: CCOC(=O)c1ccnc(CO)c1
Reaction time: 1 h

Procedure:
To 5 g of diethylpyridine-2,4-dicarboxylate were added 50 ml of ethanol and 50 ml of dichloroethane, followed by ice-cooling. 932 mg of sodium borohydride was added portionwise thereto, followed by stirring for 1 hour under ice-cooling, and further at room temperature for 15 hours. After ice-cooling the reaction solution, 5 ml of 6 M hydrochloric acid was added thereto, followed by stirring for 5 minutes and concentrating. A saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extracting with chloroform-isopropanol (10:1) and drying over anhydrous magnesium sulfate. After concentrating under reduced pressure, the residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to obtain 0.7 g of ethyl 4-(hydroxymethyl)pyridine-2-carboxylate (Production Example 53-1) and 1.6 g of ethyl 2-(hydroxymethyl)isonicotinate (Production Example 53-2), respectively.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH2:9][C:10]1[C:11]([NH2:24])=[N:12][C:13]([S:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:14][CH:15]=1.C(N(CC)CC)C.[C:32](Cl)(Cl)=[O:33].O>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:9][C:10]2[C:11](=[N:12][C:13]([S:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:14][CH:15]=2)[NH:24][C:32]1=[O:33]
Reactant: O=C(Cl)Cl
Reactant: Nc1nc(SCc2ccccc2)ncc1CNc1ccccc1Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1Nc2nc(SCc3ccccc3)ncc2CN1c1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.8 %

Procedure:
To a stirred solution, cooled to −10° C., of 5-(2-chlorophenyl) aminomethyl-4-amino-2-benzylthiopyrimidine (4.3 g, 12.1 mmol) in 100 mL of tetrahydrofuran was added triethylamine (3.1 mL, 22.2 mmol). This solution was then treated dropwise with a solution of phosgene (6.15 mL of 20% solution in toluene; 11.8 mmol). After stirring for 30 minutes, additional triethylamine (1.0 mL, 7.1 mmol) was added followed by phosgene (2.0 mL of 20% solution in toluene; 3.8 mmol). The reaction was warmed to room temperature, treated with 0.5 mL water and stirred for 30 minutes. The reaction was then filtered and the mother liquor was concentrated and stirred with dichloromethane. The product was then collected by vacuum filtration and dried in vacuo to give 3.83 g of 3-(2-chlorophenyl)-7-benzylthio-3,4-dihydropyrimido-[4,5-d]pyrimidin-2(1H)-one as a white solid (sulfide 8.1).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]([Cl:8])=[O:7])[N:3]=[CH:2]1.[NH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[C:12]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[N:11]=1>>[ClH:8].[NH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[C:12]([N:24]2[CH2:29][CH2:28][N:27]([C:6]([C:4]3[N:3]=[CH:2][S:1][CH:5]=3)=[O:7])[CH2:26][CH2:25]2)[N:11]=1
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Reactant: O=C(Cl)c1cscn1
Product: COc1cc2nc(N3CCN(C(=O)c4cscn4)CC3)nc(N)c2cc1OC
Product: Cl

Procedure:
The title compound was prepared from thiazole-4-carbonyl chloride (1.02 g.) and 4-amino-6,7-dimethoxy-2-(1-piperazinyl)quinazoline (2.00 g.) following previously described procedures. The product had a m.p. of 274°-277° C. with decomposition.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:4]=1[NH:10][NH2:11].C(O[CH:15]=[C:16]([C:19]#[N:20])[C:17]#[N:18])C>>[NH2:20][C:19]1[N:10]([C:4]2[C:5]([F:9])=[CH:6][CH:7]=[CH:8][C:3]=2[Cl:2])[N:11]=[CH:15][C:16]=1[C:17]#[N:18]
Reactant: NNc1c(F)cccc1Cl
Reactant: CCOC=C(C#N)C#N
Agent: Cl
Product: N#Cc1cnn(-c2c(F)cccc2Cl)c1N
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
(2-Chloro-6-fluorophenyl)hydrazine hydrochloride (CAS no. 529512-79-6) (5 g, 25.38 mmol) was partitioned between EtOAc (100 mL) and NaOH (2M, aq) (40 mL). The organic layer separated and washed with water (50 mL), brine (50 mL), dried (MgSO4), filtered and concentrated. The resultant oil was suspended in MeOH (50 mL) under nitrogen at -5° C. 2-(Ethoxymethylene)malononitrile (3.10 g, 25.38 mmol) added portionwise over 5 mins and the mixture stirred at ˜0° C. for 30 mins. The reaction mixture was allowed to warm to room temperature and then heated at reflux under nitrogen for 2 hours. The reaction mixture was allowed to cool and evaporated to dryness to afford the product (3.52 g) which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH:7]2[CH2:8][CH:3]1[CH2:4][CH2:5][CH:6]2[CH2:9][CH:10]=[O:11].[CH3:13][C:14](C)([O-])[CH3:15].[K+].C(Cl)C=C>CN(C=O)C>[CH3:1][C:2]1([CH3:12])[CH:7]2[CH2:8][CH:3]1[CH2:4][CH2:5][CH:6]2[CH:9]([CH2:15][CH:14]=[CH2:13])[CH:10]=[O:11]
Reactant: CC1(C)C2CCC(CC=O)C1C2
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C=CCCl
Product: C=CCC(C=O)C1CCC2CC1C2(C)C
Yield: 17.2 %

Procedure:
In a procedure similar to Example 6, 100 g of 6,6-dimethylbicyclo[3.1.1]hept-2-yl acetaldehyde at a purity of 98.3% (0.59 mole) in 50 ml of DMF, 82 g of potassium t-butoxide (0.69 mole) in 300 ml of DMF, and 55 g of allyl chloride in 50 ml of DMF (0.78 mole) were reacted in the usual way to afford 110.5 g of crude product composed of 36% starting material, 31% O-alkylate and 21% C-alkylate. The product was heated at 165°-185° C. for 6 hours. The crude aldehyde, 105.6 g, was distilled to afford 21.4 g of purified product (17% yield). A major impurity in the crude was the dialkylation product. BP product 114° C./1.2 mmHg; 1H-NMR (300 MHz), δ 1.05 (3H, s), 1.21 (3H, s), 1.3-2.6 (12H, m), 5.01 (2H, m), 5.7 (1H, m), 9.47 (1H, m); 13C-NMR (75 MHz), spectra consistent with assigned structures; IR (Neat), 2970, 2700, 1730, 1640, 1450, 1370, 910 cm-1 ; MS (m/e), 205 (M+ -1), 191, 175, 163, 122, 107, 93, 41 (Base);
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH:21](=O)[CH2:22][CH3:23].[NH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26]1.[OH-].[Na+]>O1CCOCC1.C(O)(=O)C.C(OCC)C>[NH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([CH:21]([N:12]2[CH2:11][CH2:10][N:9]([CH:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:14][CH2:13]2)[CH2:22][CH3:23])=[CH:26]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: Clc1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: CCC=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CCC(c1c[nH]c2ccccc12)N1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 11.3 %

Procedure:
A solution of 2.0 grams (0.006 mole) of N-[(4-chlorophenyl)(phenyl)-methyl]piperazine and 0.5 mL (0.007 mole) of propionaldehyde in 8.0 mL of dioxane and 8.0 mL of glacial acetic acid was stirred and cooled in an ice bath. To this a solution of 0.7 gram (0.006 mole) of indole in 10.0 mL of dioxane was added dropwise during a 15 minute period. Upon completion of the addition the reaction mixture was allowed to warm to ambient temperature, where it stirred for about 18 hours, after which the reaction mixture was poured into a mixture of diethyl ether and aqueous 5% sodium hydroxide. The ether layer was separated and washed with water and then with an aqueous saturated sodium chloride solution. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to an oil, which was subjected to column chromatography on silica gel. Elution was accomplished with pure hexane, followed by diethyl ether/hexane mixtures and then pure diethyl ether. The product-containing fractions were combined and concentrated under reduced pressure, yielding 0.3 gram of N-[1-(indol-3yl)propyl]-N′-[(4chlorophenyl)-(phenyl)methyl]piperazine. The NMR spectrum was consistent with the proposed structure.