Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[S:13](=[O:15])(=[O:14])[N:12]([CH3:16])[C:11]([C:17]([O:19]C)=O)=[C:10]([OH:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:22][C:23]1[CH:27]=[C:26]([CH3:28])[O:25][N:24]=1.C(OC(C)C)(C)C.C(O)=O.C(OC(C)C)(C)C.CC(C)=O>>[CH2:1]([N:8]1[S:13](=[O:14])(=[O:15])[N:12]([CH3:16])[C:11]([C:17]([NH:22][C:23]2[CH:27]=[C:26]([CH3:28])[O:25][N:24]=2)=[O:19])=[C:10]([OH:21])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(N)no1
Reactant: COC(=O)C1=C(O)CN(Cc2ccccc2)S(=O)(=O)N1C
Solvent: O=CO
Solvent: CC(C)OC(C)C
Solvent: CC(C)=O
Product: Cc1cc(NC(=O)C2=C(O)CN(Cc3ccccc3)S(=O)(=O)N2C)no1
Yield: 59 %

Procedure:
The synthesis is effected analogously to Example 1 using in each case 1 equivalent of methyl 6-benzyl-5,6-dihydro-4-hydroxy-2-methyl-1,1-dioxo-2H-1,2,6-thiadiazine-3-carboxylate and 3-amino-5-methylisoxazole. Chromatography over silica gel using a mixture of diisopropyl ether/formic acid=100/1 or recrystallisation from a diisopropyl ether/acetone mixture gives the title compound in a yield of 59%.
Reaction SMILES: [C:1]1([C:7]2[O:8][CH:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:10]([OH:13])[CH2:11][N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[F:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1.O>O1CCCC1>[F:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([O:13][CH:10]2[CH:9]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[O:8][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[N:12][CH2:11]2)=[O:31])=[CH:25][CH:24]=1
Reactant: OC1CN=C(c2ccccc2)OC1c1ccccc1
Reactant: O=C=Nc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1ccc(F)cc1)OC1CN=C(c2ccccc2)OC1c1ccccc1
Reaction time: 0.5 h
Yield: 34.1 %

Procedure:
A solution of (5RS, 6SR)-2,6-diphenyl-5,6-dihydro-4H-1,3-oxazin-5-ol (1.52 g) in anhydrous tetrahydrofuran (10 cc) is added at a temperature in the region of 20° C. to an oily suspension (50% by weight; 0.31 g), maintained under an argon atmosphere, of sodium hydride in anhydrous tetrahydrofuran (20 cc). The mixture is stirred for 30 minutes at the same temperature. A solution of 4-fluorophenyl isocyanate (0.9 g) in anhydrous tetrahydrofuran (10 cc) is then added dropwise and stirring is continued for 4 hours at a temperature in the region of 20° C. Distilled water (25 cc) is then added and the mixture is extracted with dichloromethane (3×50 cc). The organic phases are combined, washed with distilled water (3×20 cc), dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. The residue is purified by chromatography on silica (0.063-0.2 mm; 50 g) contained in a column 2 cm in diameter [eluent: ethyl acetate/cyclohexane (3:7 by volume)], collecting 20-cc fractions. Fractions 3 to 5 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallization in diisopropyl ether, (5RS, 6SR)-5-(4-fluorophenylcarbamoyloxy)-2,6-diphenyl-5,6-dihydro-4H-1,3-oxazine (0.8 g), m.p. 158° C., is obtained.
Reaction SMILES: N1(C(N)=O)CC[O:4]CC1.[Cl:10][C:11]1[C:12]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:13][C:14]([O:21][CH3:22])=[C:15]([CH2:17][C:18]([OH:20])=S)[CH:16]=1>C(O)(=O)C.Cl.O>[Cl:10][C:11]1[C:12]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:13][C:14]([O:21][CH3:22])=[C:15]([CH2:17][C:18]([OH:4])=[O:20])[CH:16]=1
Reactant: NC(=O)N1CCOCC1
Reactant: COc1cc(N2CCCCC2)c(Cl)cc1CC(O)=S
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(N2CCCCC2)c(Cl)cc1CC(=O)O

Procedure:
A solution of 11.07 g (30 mmole) of 5-chloro-2-methoxy-4-(piperidin-1-yl)-phenylthioacetic acid morpholinamide in 120 ml of glacial acetic acid and 30 ml of concentrated hydrochloric acid is boiled under reflux for 22 hours. The reaction mixture is cooled, diluted with water and extracted with methylene chloride. The combined methylene chloride phases are washed with water, dried over sodium sulphate and concentrated by evaporation in a vacuum rotary evaporator. Chromatography over silica gel with chloroform/methanol (19:1) yields 5-chloro-2-methoxy-4-(piperidin-1-yl)-phenylacetic acid which after recrystallisation with methylene chloride/hexane melts at 120°-122°.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][C:14]1[N:15]([C:39]2[CH:40]=[CH:41][C:42]3[O:46][CH:45]([CH3:47])[CH2:44][C:43]=3[CH:48]=2)[C:16](=[O:38])[C:17]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=3)=[CH:26][CH:25]=2)=[C:18]([CH2:20][CH2:21][CH3:22])[N:19]=1>O.C(OCC)(=O)C>[CH3:13][C:14]1[N:15]([C:39]2[CH:40]=[CH:41][C:42]3[O:46][CH:45]([CH3:47])[CH2:44][C:43]=3[CH:48]=2)[C:16](=[O:38])[C:17]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]3[NH:3][C:4](=[O:7])[O:5][N:37]=3)=[CH:28][CH:29]=2)=[C:18]([CH2:20][CH2:21][CH3:22])[N:19]=1
Reactant: CCCc1nc(C)n(-c2ccc3c(c2)CC(C)O3)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: CCCc1nc(C)n(-c2ccc3c(c2)CC(C)O3)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 32.9 %

Procedure:
A mixture of hydroxylammonium chloride (1.20 g), sodium hydrogen carbonate (1.8 g) and dimethyl sulfoxide (7 mL) was stirred at 40° C. for 30 min, 4′-{[2-methyl-1-(2-methyl-2,3-dihydro-1-benzofuran-5-yl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1.0 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (7 mL), N,N′-carbonyldiimidazole (0.35 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.32 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.37 g, 48%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-])=O.[H][H].[CH3:11][CH2:12][O:13][C:14]([CH:16]1[C:21](=O)[CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:15]>C(O)C.[Pd]>[NH:6]1[CH:5]=[C:4]([NH:1][CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21][CH:16]2[C:14]([O:13][CH2:12][CH3:11])=[O:15])[CH:8]=[N:7]1
Reactant: [H][H]
Reactant: CCOC(=O)C1CCCCC1=O
Reactant: O=[N+]([O-])c1cn[nH]c1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1CCCCC1Nc1cn[nH]c1
Yield: 88.9 %

Procedure:
A solution of 4-nitropyrazole (5.2 g, 0.046 mole) in ethanol (150 ml) was hydrogenated over a 10% Pd/C catalyst (0.5 g) at atmospheric temperature and pressure until the uptake of hydrogen ceased. The catalyst was filtered off and the filtrate treated with ethyl 2-cyclohexanonecarboxylate (7.3 ml, 0.046 mole), before evaporating to dryness. A few drops of concentrated hydrochloric acid (0.1 ml) were added to the yellow oil, which was then heated on the steam bath under nitrogen for 10 minutes. The mixture was dissolved in ethyl acetate, washed with aqueous sodium hydrogen carbonate solution and water, then dried (MgSO4) and concentrated to leave a yellow solid. This was recrystallised from ether/60°-80° petroleum ether to give the title compound as a white solid (9.7 g, 90%), m.p. 92°-94° C. Found: C, 61.20; H, 7.35; N, 18.00% C12H17N3O2 requires C, 61.25; H, 7.30; N, 17.85%
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(O)(=O)C.[NH2:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=1[N:23]1[CH:27]=[CH:26][CH:25]=[CH:24]1>C(O)C>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2([NH:15][C:16]3[C:17](=[CH:18][CH:19]=[C:20]([CH3:22])[CH:21]=3)[N:23]3[CH:24]=[CH:25][CH:26]=[C:27]23)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: Cc1ccc(-n2cccc2)c(N)c1
Reactant: CC(=O)N1CCC(=O)CC1
Solvent: CCO
Solvent: CC(=O)O
Product: CC(=O)N1CCC2(CC1)Nc1cc(C)ccc1-n1cccc12
Reaction time: 24 h

Procedure:
8.46 g (0.06 mole) of 1-acetyl-4-piperidone and 3 ml. of glacial acetic acid are added to a solution of 12.0 g (0.06 mole) of 1-(2-amino-4-methyl-phenyl)pyrrole [Example 16(b)] in 160 ml. of absolute ethanol. The solution is refluxed under nitrogen with stirring for 24 hours and cooled. A solid precipitates and is filtered. The solid is recrystallized from absolute ethanol to give white crystals, m.p. 212°-213° C. of 1'-acetyl-4,5-dihydro-7-methylspiro[pyrrolo(1,2-a)quinoxaline-4,4'-piperidine].
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:25]#[N:26])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[NH2:27][C:28]([CH3:34])([CH3:33])[CH2:29][C:30]([OH:32])=[O:31].C[O-].[Na+].Cl>CC(N(C)C)=O.O>[C:25]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:16][C:17]3[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=3)[CH:9]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:27][C:28]([CH3:34])([CH3:33])[CH2:29][C:30]([OH:32])=[O:31])=[O:4])[N:6]=1)#[N:26]
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccc(OC)cc3)ccc2c1O
Reactant: CC(C)(N)CC(=O)O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1ccc(Oc2ccc3c(O)c(C(=O)NC(C)(C)CC(=O)O)nc(C#N)c3c2)cc1
Yield: 21.7 %

Procedure:
A mixture of 1-cyano-4-hydroxy-7-(4-methoxy-phenoxy)-isoquinoline-3-carboxylic acid methyl ester (100 mg) and 3-amino-3-methyl-butyric acid (100 mg) and NaOMe (45 mg) in DMA (1.5 mL) was microwaved at 150° C. for 3 h. The mixture was cooled, diluted with water, acidified with 2 M HCl solution, solids were collected with filtration, washed with water, air dried then the residue was further column purified to give the desired product (27 mg). LC MS ESI+: 436 (M+1)+.
Reaction SMILES: [C:1]1([CH:11]2[CH2:16][CH2:15][N:14](C(OCC(Cl)(Cl)[Cl:22])=O)[CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1>C(O)(=O)C.[Zn]>[ClH:22].[C:1]1([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(OCC(Cl)(Cl)Cl)N1CCC(c2cccc3ccccc23)CC1
Agent: [Zn]
Solvent: CC(=O)O
Product: Cl
Product: c1ccc2c(C3CCNCC3)cccc2c1
Yield: 73.4 %

Procedure:
A solution of 4-(1-naphthyl)-1-(2,2,2-trichloroethoxycarbonyl)piperidine (0.85 g, 2.2 mmol) and a powdered zinc (0.80 g, 1.2 mmol) in acetic acid (22 mL) was stirred at room temperature overnight. After filtrating the reaction mixture through Celite, the filtrate was concentrated, and a saturated aqueous sodium hydrogencarbonate was then added to pH of 10, and the resulting mixture was extracted with chloroform. After drying over anhydrous sodium sulfate, the chloroform layer was concentrated, and the resulting crude product was purified by column chromatography on a silica gel (silica gel NH-DM 1020 produced by Fuji Silysia Chemical Ltd., eluent; chloroform) to afford a free form of the title compound (0.4 g) as a pale yellow oil. After adding hydrochloric acid/methanol, a solution of the free form (0.4 g) in methanol was cooled to afford the title compound (0.36 g, yield: 66%) as white crystals.
Reaction SMILES: [CH:1]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:2]=1[C:3]1[N:13]3[C@@H:14]([CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:15][O:16][CH2:17][C:12]3=[N:11][C:4]=1[CH:5]=[N:6]2.ClC1C=C(C=CC=1)C(OO)=[O:32].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[O-:32][N+:6]1[C:7]2[C:2](=[CH:1][CH:10]=[CH:9][CH:8]=2)[C:3]2[N:13]3[C@@H:14]([CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:25])[CH3:24])[CH2:15][O:16][CH2:17][C:12]3=[N:11][C:4]=2[CH:5]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)NC[C@H]1COCc2nc3cnc4ccccc4c3n21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC[C@H]1COCc2nc3c[n+]([O-])c4ccccc4c3n21
Reaction time: 2 h
Yield: 99.6 %

Procedure:
tert-Butyl (11S)-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-11-ylmethylcarbamate (1.62 g, 4.58 mmol) was dissolved in 40 mL of CH2Cl2 and treated with 3-chloroperoxybenzoic acid (MCPBA) (1.23 g, 77% maximum purity). After stirring for 2 hours, the reaction mixture was treated with 40 mL of 2% Na2CO3 solution and 40 mL of CH2Cl2 and the layers were separated. The aqueous layer was then extracted with CH2Cl2 (3×20 mL). The combined organic layers were washed with 10 mL of brine. The organic portion was then dried over Na2SO4, filtered and concentrated under reduced pressure to give tert-butyl [(11S)-5-oxido-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-11-yl]methylcarbamate (1.69 g) as a crusty, off-white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][CH2:7][CH2:6][C:5]2=[O:13].N1C=CN=C1.[CH:19]([Si:22](Cl)([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])([CH3:21])[CH3:20].O>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][Si:22]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:19]([CH3:21])[CH3:20])[O:8][CH2:7][CH2:6][C:5]2=[O:13]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: Cc1cc2c(cc1O)OCCC2=O
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc2c(cc1O[Si](C(C)C)(C(C)C)C(C)C)OCCC2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A mixture of 6-methyl-7-hydroxychroman-4-one (the compound of Preparation 32, 1.50 g, 8.42 mmol), imidazole (1.15 g, 16.9 mmol), and triisopropylsilyl chloride (2.0 mL, 9.2 mmol) in dimethylformamide (30 mL) was stirred overnight at ambient temperature. The reaction was poured into water and extracted with ether (2×). The combined organic layer was washed with 1 N lithium chloride (2×), dried over magnesium sulfate, and concentrated to afford 3.01 g (100%) of 6-methyl-7-triisopropylsilyloxychroman-4-one as a dull yellow oil which had: NMR δ7.64 (s, 1 H), 6.30 (s, 1 H), 4.45 (t, J=6.4 Hz, 2 H), 2.70 (t, J=6.4 Hz, 2 H), 2.14 (s, 3 H), 1.40-1.25 (m, 3 H), 1.09 (d, J=7.3 Hz, 18 H). The product also had a small silyl impurity and residual dimethylformamide present but was suitable for subsequent reaction.
Reaction SMILES: [CH2:1]([Li])CCC.CCCCCC.[F:12][C:13]([F:23])([F:22])[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][N:15]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.O>[F:12][C:13]([F:23])([F:22])[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[CH2:1])=[CH:16][N:15]=1
Reactant: [Li]CCCC
Reactant: O=Cc1ccc(C(F)(F)F)nc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: C=Cc1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of methyltriphenylphosphonium bromide (24.4 g, 68.4 mmol) in THF (150 mL) at −78° C. under an atmosphere of nitrogen was added 2.5 M of n-butyllithium in hexane (27 mL, 67.5 mmol) during a period of 12 mins. The reaction was warmed to room temperature to give a deep red ylide solution. To the ylide solution, cooled in ice, was introduced a solution of 6-(trifluoromethyl)nicotinaldehyde (10 g, 57 mmol) in THF (50 mL). The reaction mixture was warmed to room temperature and stirred for 3 hours. The result suspension was heated to 60° C. over 30 minutes and then stirred at 60° C. for 1 hour. After cooling, the mixture was diluted with water (400 mL), and extracted with EtOAc. The organic layer was washed with brine, dried (MgSO4), and concentrated. The residue was purified by silica gel column (0-10% EtOAc/hexane) to afford title compound.
Reaction SMILES: [OH2:1].C[CH:3]([CH2:7][CH2:8][CH2:9][CH:10]([CH3:15])[CH2:11][CH2:12][CH:13]=[O:14])[CH2:4]C=O.[C:16]([OH:19])(=[O:18])[CH3:17]>>[CH3:4][CH:3]([CH2:7][CH2:8][CH2:9][CH:10]([CH3:15])[CH2:11][CH2:12][C:13]([OH:1])=[O:14])[CH2:17][C:16]([OH:19])=[O:18]
Reactant: O
Reactant: CC(CC=O)CCCC(C)CCC=O
Reactant: CC(=O)O
Product: CC(CCCC(C)CC(=O)O)CCC(=O)O
Temperature: 50 °C
Reaction time: 3 h
Yield: 61 %

Procedure:
A 5-L pressure reaction vessel was charged with 0.19 g of Cu(OCOCH3)2 (H2O) and 1.5 L of acetic acid, and the vessel was pressurized to 7 atm with air and then warmed to 50° C. While air was introduced at a rate of 240 L/hr, a mixture of 750 g of 3,7-dimethyldecanedial and 750 mL of acetic acid was fed thereto over a period of 3 hours. After completion of the feed, the reaction was conducted for an additional 6 hours at the same temperature and pressure. The reaction vessel was cooled, the gas therein was purged and then the reaction mixture was taken out. This mixture was heated at 110° C. for 1 hour under nitrogen atmosphere. The acetic acid was distilled off under a reduced pressure and the residual liquid was distilled to give 3,7-dimethyldecanedioic acid as an almost colorless clear liquid having a boiling point of 175° to 180° C. at 0.80 mmHg. The yield was 61% (435 g). Instrumental-analysis data are shown below.
Reaction SMILES: [CH:1]1[C:6]([C:7]([NH:9][C@H:10]([C:16]([OH:18])=[O:17])[CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[O:8])=[CH:5][CH:4]=[C:3]([NH:19][CH2:20][C:21]2[CH:26]=[C:25]3[C:27]([NH2:32])=[N:28][C:29]([NH2:31])=[N:30][C:24]3=[N:23][CH:22]=2)[CH:2]=1.C=O.[C:35]([BH3-])#N.[Na+]>CS(C)=O.O>[CH3:35][N:19]([C:3]1[CH:2]=[CH:1][C:6]([C:7]([NH:9][CH:10]([C:16]([OH:18])=[O:17])[CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[O:8])=[CH:5][CH:4]=1)[CH2:20][C:21]1[CH:26]=[C:25]2[C:27]([NH2:32])=[N:28][C:29]([NH2:31])=[N:30][C:24]2=[N:23][CH:22]=1
Reactant: [BH3-]C#N
Reactant: Nc1nc(N)c2cc(CNc3ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc3)cnc2n1
Agent: C=O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CN(Cc1cnc2nc(N)nc(N)c2c1)c1ccc(C(=O)NC(CCC(=O)O)C(=O)O)cc1
Yield: 85 %

Procedure:
Reductive alkylation of diethyl p-aminobenzoyl-L-glutamate) (VI; R=H; R1 =C2H5) with III (Y=CHO) and hydrogen in 70% acetic acid containing Raney nickel gave a 32% yield of 5-deazaaminopterin diethyl ester. Saponification of the ester groups in a mixture of dimethyl sulfoxide-water at ambient temperature gave an 87% yield of 5-deazaaminopterin (II, R=H). Methylation of the latter compound was accomplished by treatment of II (R=H) with formaldehyde and sodium cyanoborohydride in aqueous solution at pH 6.4 to give an 85% yield of 5-deazamethotrexate, (II, R=CH3). The structure of II (R=CH3) was established as described hereinafter in Example 8C by oxidation with alkaline potassium permanganate to give the previously prepared 2-amino-4(3H)oxopyrido[2,3-d]pyrimidine-6-carboxylic acid (VIII), which indicated that methylation had occurred either on the 4- or 10-amino group. Methylation of the 4-amino group was eliminated from consideration by alkaline hydrolysis of the 4-amino group to give 5-deaza-10-methylfolic acid (I, R=CH3).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].Br[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([CH3:21])[CH:15]=1>>[ClH:11].[Cl:11][C:8]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:2](=[NH:1])[N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([CH3:21])[CH:15]=2)[CH:9]=1
Reactant: Cc1cc(CBr)ccc1F
Reactant: NC(=O)c1cc(Cl)cnc1N
Product: Cc1cc(Cn2cc(Cl)cc(C(N)=O)c2=N)ccc1F
Product: Cl

Procedure:
According to the method of Example 171, 2-amino-5-chloronicotinamide was reacted with 4-(bromomethyl)-1-fluoro-2-methylbenzene to give the title compound.