Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]([NH2:7])(=[NH:6])[CH:3]([CH3:5])[CH3:4].[CH3:8][O:9][C:10](OC)=[N:11][C:12]#[N:13].[OH-].[Na+]>>[NH2:13][C:12]1[N:7]=[C:2]([CH:3]([CH3:5])[CH3:4])[N:6]=[C:10]([O:9][CH3:8])[N:11]=1
Reactant: CC(C)C(=N)N
Reactant: COC(=NC#N)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1nc(N)nc(C(C)C)n1
Temperature: 25 °C
Yield: 61.2 %

Procedure:
Cool the isobutyramidine hydrochloride solution in an ice bath. Charge 8 gm. (0.07 mole) dimethyl (N-cyanoimido)carbonate to the solution, followed by 5.8 gm. (0.073 mole) 50% NaOH, added dropwise. Stir while letting the mixture warm to room temperature for one hour. Remove the methanol by vacuum stripping, and slurry the resulting solids in75 ml. water. Cool and filter. Upon drying, 7.2 gm. (61.2%) 2-amino-4-isopropyl-6-methoxy-s-triazine is obtained, mp 116°-117° C.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:15]([CH2:16][O:17][Si](C(C)(C)C)(C)C)[O:14][CH:11](OC)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N:29]1[C:34](=[O:35])[C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][NH:31][C:30]1=[O:40])(C)C.C(O)C>C(Cl)Cl>[CH2:1]([O:8][C@@H:9]1[C@@H:15]([CH2:16][OH:17])[O:14][C@@H:11]([N:31]2[CH:32]=[C:33]([C:36]([F:38])([F:39])[F:37])[C:34](=[O:35])[NH:29][C:30]2=[O:40])[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)n1c(=O)[nH]cc(C(F)(F)F)c1=O
Reactant: COC1C[C@H](OCc2ccccc2)[C@@H](CO[Si](C)(C)C(C)(C)C)O1
Solvent: ClCCl
Solvent: CCO
Product: O=c1[nH]c(=O)n([C@H]2C[C@H](OCc3ccccc3)[C@@H](CO)O2)cc1C(F)(F)F
Temperature: 5 °C

Procedure:
To a stirred mixture of 3.5 g (0.01 mole) of methyl 3-O-benzyl-5-O-(t-butyldimethylsilyl)-2-deoxyribofuranoside and 3.4 g (0.01 mole) of Bis-(trimethylsilyl-5-trifluoromethyluracil in 30 ml of methylene chloride at <5° C. was added a solution of 2.9 g (0.011 mole) of stannic chloride in 5 ml of methylene chloride at ca. 0.25 ml/min. The clear yellow solution was stirred for an additional one and one-half hours at 5° C. during which time the color darkened and a fine precipitate formed. Anhydrous ethanol (11 ml) was then added to the mixture. After warming to ambient temperature, the mixture was filtered removing only a small amount of a solid material. The solvent was then removed under vacuum. The dark residual oil was triturated (3×50 ml) with hexane. The residue was taken up in 100 ml of ethyl acetate, washed with 100 ml of cold saturated sodium bicarbonate solution forming an emulsion. This was vacuum filtered and the filtrate layers separated. The organic phase was washed (2×100 ml) with DI water, dried (Na2SO4), filtered, and the solvent removed under vacuum affording 1.0 g of a thick yellow oil. This material was chromatographed on 75 cc of silica gel eluting with ethyl acetate/hexane (1:1). From early eluting fractions, 150 mg (0.39 mmole, 3.9%) of crude beta-anomer of the title product was obtained with 200 mg (0.52 mmole, 5.2%) of the alpha-anomer being found in later eluting fractions. The products were identified by thin layer chromatography and 1H NMR analysis.
Reaction SMILES: [OH:1][CH:2]1[C:10]2[C:5](=[C:6]([CH:11]([CH3:16])[C:12]([O:14]C)=[O:13])[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[OH-].[Li+]>O1CCCC1.C(OCC)(=O)C.CCCCCC>[OH:1][CH:2]1[C:10]2[C:5](=[C:6]([CH:11]([CH3:16])[C:12]([OH:14])=[O:13])[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1
Reactant: COC(=O)C(C)c1cccc2c1CCC2O
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C(=O)O)c1cccc2c1CCC2O
Temperature: 25 °C
Reaction time: 5 h
Yield: 85.3 %

Procedure:
Methyl 2-(1-hydroxy-2,3-dihydro-1H-inden-4-yl)propanoate (2 g, 0.0091 mol) was dissolved in tetrahydrofuran (18 mL). Lithium hydroxide solution (18 mL, 0.018 mol, 1M) was added to it and the reaction mixture was stirred at ambient temperature for 5 hours. TLC (in 60% ethyl acetate in hexane, Rf=0.1) showed complete consumption of starting material. Tetrahydrofuran was removed under reduced pressure and the residue was diluted with water (100 mL). The aqueous part was washed with ethyl acetate (2×100 mL) and acidified with hydrochloric acid (1N, 25 mL). The compound was extracted with ethyl acetate (3×50 mL). The combined organic part was washed with water (2×50 mL) and brine (100 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford desired compound (1.6 g, 85% yield).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11]1>>[Cl:1][C:2]1[N:7]=[C:6]([C:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:10][CH:11]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: Fc1cnc(Cl)nc1Cl
Product: Fc1cnc(Cl)nc1-c1c[nH]c2ccccc12

Procedure:
Starting materials: 2,4-dichloro-5-fluoropyrimidine and 1H-indole. m/z 248.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]2[CH:11]=[C:10]3[NH:19][CH2:20][CH2:21][S:22][C:9]3=[CH:8][C:7]=2[N:6]=1)([CH3:3])[CH3:2].C(O[CH:26](O)[C:27]([F:30])([F:29])[F:28])C.[BH3-]C#N.[Na+]>C(O)(C(F)(F)F)=O>[CH:1]([O:4][C:5]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]2[CH:11]=[C:10]3[N:19]([CH2:26][C:27]([F:30])([F:29])[F:28])[CH2:20][CH2:21][S:22][C:9]3=[CH:8][C:7]=2[N:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1cc(C(F)(F)F)c2cc3c(cc2n1)SCCN3
Reactant: CCOC(O)C(F)(F)F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Oc1cc(C(F)(F)F)c2cc3c(cc2n1)SCCN3CC(F)(F)F
Yield: 55.9 %

Procedure:
This compound was prepared according to General Method 7 (EXAMPLE 5) from 2,3-dihydro-7-isopropoxy-9-(trifluoromethyl)-1H-[1,4]thiazino[3,2-g]quinoline (11 mg, 0.034 mmol), trifluoroacetaldehyde ethyl hemiacetal (49 mg, 0.34 mmol) and NaBH3CN (14 mg, 0.22 mmol) in 0.7 mL TFA to afford 7.8 mg (56%) of 2,3-dihydro-7-isopropoxy-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]thiazino[3,2-g]quinoline, a yellow oil, after flash chromatography (9:1 hexanes:EtOAc). Data for 2,3-dihydro-7-isopropoxy-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]thiazino[3,2-g]quinoline: 1H NMR (400 MHz, CDCl3) δ 7.62 (s, 1H), 7.21 (broad s, 1H), 7.03 (s, 1H), 5.46 (hept, 1H, J=6.1), 3.97 (q, 2H, J=8.8), 3.77-3.83 (m, 2H), 3.08-3.14 (m, 2H), 1.38 (d, 6H, J=6.1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([CH2:11][OH:12])[N:10]=2)[CH:7]=1.CC1(C)N([O])C(C)(C)CCC1.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1.COC(C)(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([CH:11]=[O:12])[N:10]=2)[CH:7]=1
Reactant: OCc1nc2ncc(Cl)cn2n1
Agent: CC1(C)CCCC(C)(C)N1[O]
Solvent: Ic1ccccc1
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=Cc1nc2ncc(Cl)cn2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (6-chloro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methanol (9.86 g, 53.4 mmol), TEMPO (626 mg, 4.01 mmol), iodobenzene diacetate (18.9 g, 58.76 mmol) in CH2Cl2 (75 mL) was stirred at room temperature for 2 hours. Once the reaction was deemed complete, methyl-tert-butyl ether (50 mL) was added slowly to precipitate the product. as a while solid (8.72 g, 90%). 1H NMR (300 MHz, CDCl3) δ: 8.93 (d, J=2.45 Hz, 1 H), 8.99 (d, J=2.64 Hz, 1 H), 10.25 (s, 1H). MS (APCI): 183.0, 185.0 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([NH2:18])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].[N+:19]([C:22]1[CH:23]=[C:24]2[C:29](=O)[O:28][C:26](=[O:27])[C:25]2=[CH:31][CH:32]=1)([O-:21])=[O:20]>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:18]2[C:29](=[O:28])[C:24]3[C:25](=[CH:31][CH:32]=[C:22]([N+:19]([O-:21])=[O:20])[CH:23]=3)[C:26]2=[O:27])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: CCOc1cc(C(N)CS(C)(=O)=O)ccc1OC
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Product: CCOc1cc(C(CS(C)(=O)=O)N2C(=O)c3ccc([N+](=O)[O-])cc3C2=O)ccc1OC
Temperature: 25 °C
Reaction time: 0.1 h
Yield: 86.5 %

Procedure:
A stirred mixture of 1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethylamine (1.0 g, 3.7 mmol) and 4-nitrophthalic anhydride (706 mg, 3.66 mmol) was heated to melt for 6 min. The mixture was allowed to cool to room temperature. Chromatography of the resulting oil gave 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-5-nitro-isoindoline-1,3-dione as a solid (1.42 g, 87% yield): mp, 255.0-256.0° C.; 1H NMR (CDCl3); δ 1.47 (t, J=7 Hz, 3H, CH3), 2.91 (s, 3H, CH3), 3.71 (dd, J=4.2, 14.3 Hz, 1H, CHH), 3.85 (2, 3H, CH3), 4.10 (q, J=7 Hz, 2H, CH2), 4.59 (dd, J=11.1, 14.1, Hz, 1H, CHH), 5.94 (dd, J=4.1, 10.9 Hz, 1H, NCH), 6.82-6.86 (m, 2H, Ar), 7.09-7.14 (m, 2H, Ar), 8.01-8.04 (m, 1H, Ar), 8.56-8.65 (m, 1H, Ar), 13C NMR (CDCl3) δ 14.67, 41.61, 49.16, 53.99, 55.96, 64.54, 111.48, 112.39, 118.98, 120.48, 124.79, 128.73, 129.39, 133.06, 136.03, 148.71, 149.92, 151.79, 165.56, 165.74; Anal Calcd for C20H20NO8S: C, 53.57; H, 4.50; N, 6.23. Found: C, 53.59; H, 4.58; N, 5.88.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]=[C:8]=[O:9])[CH:2]=1.[Cl:10][C:11]1[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]2[C:12]=1[CH2:13][CH2:14][NH:15]2>>[Cl:10][C:11]1[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]2[C:12]=1[CH2:13][CH2:14][N:15]2[C:8](=[O:9])[NH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: O=C=Nc1cccnc1
Reactant: Clc1ccc2c(c1Cl)CCN2
Product: O=C(Nc1cccnc1)N1CCc2c1ccc(Cl)c2Cl

Procedure:
The title compound was prepared as in the method of (Example 2) from 3-pyridylisocyanate and 4,5-dichloroindoline (D32) to give (E16) (0.5 g, 25%) m.p. >240° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4]([NH2:9])=[N:5][CH:6]=[CH:7][CH:8]=1.Br[CH:11]([C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)[CH:12]=O.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[OH:1][CH2:2][C:3]1[C:4]2[N:5]([CH:12]=[C:11]([C:14]3[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=3)[N:9]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1ncccc1CO
Reactant: O=CC(Br)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(-c2cn3cccc(CO)c3n2)cc1
Yield: 70.3 %

Procedure:
A mixture of 16.0 g (80 mmole) of 1-bromo-4-nitrobenzene, 11.2 ml (ca. 120 mmole) of ethyl vinyl ether, 179.2 mg of lead(II) acetate, 484 mg of tri-o-tolylphosphine, and 22 ml (ca. 160 mmole) of triethylamine was placed in a bomb, purged with nitrogen, and heated at 100° for eight hours. The reaction mixture was partitioned between diethyl ether and water and clarified by filtration. The organic layer was washed with water, dried over magnesium sulfate, filtered, and concentrated in vacuo. Chromatography of the residue on silica gel (using toluene-hexane as eluant) yielded three principle components (in order of elution): 2.1 g of 4-(1-ethoxyvinyl)nitrobenzene, 3.0 g of the cis isomer of 4-(2-ethoxyviny)nitrobenzene, and 7.2 g of the trans isomer of 4-(2-ethoxyvinyl)nitrobenzene. A solution of 3.0 g (15 mmole) of 4-(2-ethoxyvinyl)nitrobenzene (as a mixture of cis and trans isomers) in 30 ml of diethyl ether was cooled to - 15°. Bromine (2.48 ml, ca. 15 mmole) was added dropwise as the temperature was maintained at or below -10°. The reaction mixture was poured into 50 ml of water containing 5 g of sodium bicarbonate. After two hours of stirring, the mixture was allowed to separate into layers. The organic layer was washed with water, dried over sodium sulfate, filtered, and concentrated in vacuo to yield 3.9 g of 2-bromo-2-(4-nitrophenyl)acetaldehyde as an oil. A mixture of 1.98 g (15 mmole) of 3-hydroxymethyl-2-pyridinamine and 3.9 g (15 mmole) of 2-bromo-2-(4-nitrophenyl)acetaldehyde was warmed to initiate an exothermic reactiion. After cooling, the mixture was shaken with aqueous potassium carbonate and dichloromethane. The solid was collected, washed with water and dichloromethane, and air dried to yield 2.84 g of 8-hydroxymethyl-2-(4-nitrophenyl)imidazo[1,2-a]pyridine, as confirmed by the nmr and infrared spectra. The title compound (100 mg) was prepared by the method described in Example 6 using 1.4 g (5.2 mmole) of 8-hydroxymethyl-2-(4-nitrophenyl)imidazo[1,2-a]pyridine instead of 8-hydroxymethylimidazo[1,2-a]pyridine. Structure assignment was supported by the nmr and infrared spectra and by elemental analysis.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[CH:9]=[N:10][C:11]([N:18]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:12]([N+:15]([O-])=O)[C:13]=1[NH2:14])=[O:7])[CH3:4]>CO.ClCCl.O.[Ni](Cl)Cl>[CH2:3]([O:5][C:6]([C:8]1[CH:9]=[N:10][C:11]([N:18]([CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[C:12]([NH2:15])[C:13]=1[NH2:14])=[O:7])[CH3:4]
Reactant: CCOC(=O)c1cnc(N(Cc2ccccc2)Cc2ccccc2)c([N+](=O)[O-])c1N
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: CCOC(=O)c1cnc(N(Cc2ccccc2)Cc2ccccc2)c(N)c1N
Reaction time: 0.5 h
Yield: 24.1 %

Procedure:
Sodium borohydride (151 mg, 4.1 mmol) was added to a solution of nickel (II) chloride hydrate (261 mg, 1.1 mmol) in MeOH (26 mL). After 30 min. at room temperature, a solution of 4-amino-6-bis(phenylmethyl)amino-5-nitro-pyridine-3-carboxylic acid ethyl ester (0.9 g, 2.2 mmol) in dichloromethane (5 mL) was added followed by the addition of sodium borohydride (353 mg). The mixture was stirred over night then filtered through a layer of silica gel. The organic was diluted with dichloromethane, washed with brine and dried over sodium sulfate. The organics were filtered, concentrated and purified by column chromatography (dichloromethane:methanol, 20:1). 11 was obtained as a white solid (200 mg). 1H NMR (400 MHz, d6-DMSO) δ: 1.26 (t, J=7.1 Hz, 3H), 4.21 (s, 4H), 4.22 (q, J=7.1 Hz, 2H), 4.52 (s, 2H), 6.73 (s, 2H), 7.14–7.31 (m, 10H), 8.01 (s, 1H). ESIMS, M/Z, 377 (M+1)+.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4](/[CH:7]=[CH:8]/[CH2:9][O:10][C@@H:11]2[O:16][C@H:15]([CH2:17][OH:18])[C@@H:14]([OH:19])[C@H:13]([OH:20])[C@H:12]2[OH:21])=[CH:3][CH:2]=1.Cl[C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1>[Cl-].[Zn+2].[Cl-]>[CH:1]1[CH:2]=[CH:3][C:4](/[CH:7]=[CH:8]/[CH2:9][O:10][C@@H:11]2[O:16][C@H:15]([CH2:17][OH:18])[C@@H:14]([OH:19])[C@H:13]([OH:20])[C@H:12]2[OH:21])=[CH:5][CH:6]=1.[C:26]1([OH:29])[CH:27]=[CH:28][CH:23]=[CH:24][CH:25]=1
Reactant: Oc1ccc(Cl)cc1
Agent: OC[C@H]1O[C@@H](OC/C=C/c2ccccc2)[C@H](O)[C@@H](O)[C@@H]1O
Agent: [Cl-]
Agent: [Zn+2]
Product: Oc1ccccc1

Procedure:
After having added 0.4 part of zinc chloride, 302 parts of colophony are slowly heated to 100° C. together with 128 parts of 4-chlorophenol, while passing nitrogen through the mixture, and said temperature is maintained for 2 hours. Subsequently the temperature is increased to 200° to 210° C., until after about 1 hour the reaction product is free from halogen. After cooling there is obtained a clear rosin having a softening point of about 105° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[N:6][C:5]=1Cl.[Na].[C:14](O)(=[O:16])C>CO.C(OCC)(=O)C.O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[N:6][C:5]=1[O:16][CH3:14]
Reactant: CC(=O)O
Reactant: COC(=O)c1ccc(C)nc1Cl
Agent: [Na]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc(C)nc1OC
Temperature: 25 °C

Procedure:
To a stirred solution of 2-chloro-6-methyl-nicotinic acid methyl ester (10.4 g, 56.52 mmol) in MeOH under nitrogen is added a solution of sodium (2.58 g, 113.04 mmol) in methanol (80.0 mL) (sodium metal is dissolved in methanol under a nitrogen atmosphere) at room temperature. The reaction mixture is refluxed overnight. The reaction is cooled to room temperature and the pH is adjusted to pH=7 with acetic acid. The reaction mixture is diluted with ethyl acetate (100 mL) and water (30 mL). The organic layer is separated and the aqueous layer is extracted with ethyl acetate (2×75 mL). The combined organic extracts are dried over Na2SO4, filtered, and concentrated to give crude product. Yield: 7.25 g (71%). 1H NMR (400 MHz, CDCl3), δ8.066-8.047 (d, J=7.6 Hz, 1H), 6.782-6.764 (d, J=7.2 Hz, 1-1H), 4.029 (s, 3H), 3.879 (s, 3H), 2.483 (s, 3H); ES/MS m/z 182.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[NH:7][C:6](=[O:8])[CH:5](C(OC)=O)[C:4](=[O:13])[CH2:3]1.O>Cl.C(#N)C>[CH3:1][C:2]1([CH3:14])[NH:7][C:6](=[O:8])[CH2:5][C:4](=[O:13])[CH2:3]1
Reactant: COC(=O)C1C(=O)CC(C)(C)NC1=O
Agent: Cl
Solvent: CC#N
Solvent: O
Product: CC1(C)CC(=O)CC(=O)N1
Yield: 39.2 %

Procedure:
A mixture of methyl 6,6-dimethylpiperidine-2,4-dione-3-carboxylate (26.3 g), water (30 ml) and concentrated hydrochloric acid (3 drops) in acetonitrile (300 ml) was heated at reflux for 4 hours. The cooled solution was evaporated under reduced pressure and the residue recrystallised from water (50 ml) to give 6,6-dimethylpiperidine-2,4-dione (7.3 g), mp 183°-184° C., as a cream crystalline solid.
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:12]([CH2:14][NH2:15])[OH:13].C([O-])(O)=O.[Na+].C(OCC)(=O)C>O>[CH2:1]([O:8][C:9]([NH:15][CH2:14][CH2:12][OH:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(NCCO)OCc1ccccc1
Reaction time: 0.5 h
Yield: 76 %

Procedure:
Benzylchloroformate (44.95 kg, 263.5 mol, 1.0 eq.) was added over a 2 hour period at room temperature to a solution of ethanolamine (16.1 kg, 263.5 mol, 1.0 eq.) in water (34 gal). After stirring for 30 minutes, this was added to a cold (5-10° C.) solution of NaHCO3 (33.2 kg, 395.25 mol, 1.5 eq) in H2O (330 L) over a 30 min period and then allowed to stir at room temperature overnight. Ethyl acetate (22 gal) was added, the layers separated, and the aqueous layer extracted again with 22 gal. ethyl acetate. The combined organic extracts were concentrated under vacuum to a volume of 10 gal, and the remainder displaced with isopropyl ether. The resulting slurry was stirred and cooled to +10° C. for 2 hours, then filtered. The solids were washed with isopropyl ether and vacuum dried to give the title compound(39.1 kg, 71.1%). mp 61-63° C. NMR (300 MHz, d6 -DMSO): δ=7.50-7.37 (m, 5H), 7.37-7.16 (m, 1H), 5.05 (s, 2H), 4.70-4.63 (m, 1H), 3.46-3.37 (m, 2H), 3.13-3.03 (m, 2H).
Reaction SMILES: [CH3:1][C:2]([N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:8])[C:3](OCC)=[O:4].[H-].[H-].[H-].[H-].[Li+].[Al+3].CO>C1COCC1.O>[CH3:1][C:2]([N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:8])[CH2:3][OH:4]
Reactant: CCOC(=O)C(C)(C)N1CCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(CO)N1CCCC1
Temperature: 50 °C
Reaction time: 18 h
Yield: 62.1 %

Procedure:
Ethyl 2-methyl-2-pyrrolidin-1-ylpropanoate (0.6162 g, 3.3308 mmol) was taken up in dry THF (5 mL). A 1M solution of LAH in THF (3.7 mL, 3.6639 mmol) was added drop wise. The reaction was warmed to 50° C. and stirred for 18 h. Cooleed to 0° C. in an ice bath and methanol (5 mL) was added slowly. The reaction was diluted with water (50 mL) and extracted with Et2O (2×50 mL). The organics were concentrated by blowing a slow stream of N2 over the flask to give 0.3578 g (2.0682 mmol, 62%) of the product as a light brown oil. 1H NMR (CDCl3) δ 3.22 (s, 2H), 2.61 (bs, 4H), 1.79 (bs, 4H), 1.01 (s, 6H).
Reaction SMILES: CC(C)([O-])C.[K+].C(O)(C)(C)C.[Cl:12][C:13]1[N:22]=[CH:21][C:20]2[NH:19][CH2:18][C@H:17]3[CH2:23][O:24][CH2:25][CH2:26][N:16]3[C:15]=2[N:14]=1.Br[CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>CN(C=O)C.O>[Cl:12][C:13]1[N:22]=[CH:21][C:20]2[N:19]([CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:18][C@H:17]3[CH2:23][O:24][CH2:25][CH2:26][N:16]3[C:15]=2[N:14]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Clc1ncc2c(n1)N1CCOC[C@@H]1CN2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1C[C@H]2COCCN2c2nc(Cl)ncc21
Yield: 55.2 %

Procedure:
Potassium tert-butoxide in tert-BuOH (1M, 2.65 mL, 2.65 mmol) was added to a solution of (S)-2-chloro-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x4, 500 mg, 2.206 mmol) in DMF (5 mL) at 0° C. The resultant mixture was stirred at room temperature for 30 minutes. tert-Butyl 2-bromoacetate (0.421 mL, 2.87 mmol) was added to the reaction mixture at 0° C. The resultant mixture was stirred at room temperature for 1 hour. After addition of water, the resultant mixture was extracted with EtOAc. The extract was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified via flash column chromatography (gradient 20-80% EtOAc/hexane) to afford the title compound as an off-white solid (415 mg, 55.2%). 1H NMR (400 MHz, CDCl3) δ ppm 1.46 (s, 9H), 3.00-3.10 (m, 1H), 3.15-3.28 (m, 2H), 3.37 (dd, J=11.37, 8.84 Hz, 1H), 3.52-3.62 (m, 1H), 3.64-3.75 (m, 2H), 3.86-4.06 (m, 3H), 4.52 (dd, J=13.77, 1.89 Hz, 1H), 7.22 (s, 1H); ESI-MS m/z [M+H]+ calc'd for C15H21ClN4O3, 341.14. found 341.2.
Reaction SMILES: [C:1]([CH:3]1[C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:7]=2[CH2:6][CH2:5][CH2:4]1)#[N:2].[OH2:18]>>[C:1]([CH:3]1[C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:7]=2[CH2:6][CH2:5][CH2:4]1)(=[O:18])[NH2:2]
Reactant: CCOC(=O)c1cccc2c1CCCC2C#N
Reactant: O
Product: CCOC(=O)c1cccc2c1CCCC2C(N)=O

Procedure:
To 500 g. of polyphosphoric acid is added 22.4 g. of ethyl 1-cyano-1,2,3,4-tetrahydro-5-naphthoate and the mixture is stirred at 90°-100°C for 2 hours. Then, 1 l. of water is added, followed by cooling. The resultant crystals are collected by filtration, washed with water and recrystallized from ethanol. The procedure gives ethyl 1-carbamoyl-1,2,3,4-tetrahydro-5-naphthoate, melting point: 159.5°-161.5°C.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: C1CNCCN1
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Solvent: O
Product: O=C(O)c1cn(C2CC2)c2cc(N3CCNCC3)c(F)cc2c1=O
Yield: 95.2 %

Procedure:
26.5 parts by weight of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are introduced into a solution of 26.7 parts by weight of piperazine in 200 parts by volume of water, which is heated to reflux. The mixture is kept under reflux for 90 minutes and then cooled. The precipitate is separated off, washed with water and dried. 31.5 parts by weight (95.2% of theory) of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid are obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[O:10][CH2:11][O:12][CH3:13].[Li]CCCC.[I:19]I>C1COCC1>[I:19][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[O:10][CH2:11][O:12][CH3:13]
Reactant: COCOc1cc(OC)ccc1Br
Reactant: II
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCOc1cc(OC)ccc1I
Temperature: 23 °C
Reaction time: 0.08 h
Yield: 83.6 %

Procedure:
To a stirred solution of 2-bromo-5-methoxy-1-methoxymethoxybenzene (1.04 g, 4.23 mmol) in THF (13 mL) at −95° C. (hexanes/N2) was added n-BuLi (1.6 M in hexanes, 2.91 mL, 4.65 mmol) and the resulting solution was stirred for 5 min. To this solution was then added by syringe a solution of I2 (1.28 g, 5.07 mmol) in THF (8.5 mL) until a yellow color persisted. The solution was then permitted to warm to 23° C. and concentrated in vacuo. The residue was purified by flash chromatography (SiO2, petroleum ether:Et2O 8:1) to provide 2-iodo-5-methoxy-1-methoxymethoxybenzene as a pale-orange oil (1.04 g, 84%). See also Tsukayama, M., 1997.