Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC1NC(C(N)=O)=NC=1.[N+:10](=[C:12]1[NH:16][CH2:15][N:14]=[C:13]1[C:17]([NH2:19])=[O:18])=[N-:11].[CH3:20][N:21]=[C:22]=[O:23]>ClCCl>[CH3:20][N:21]1[N:11]=[N:10][C:12]2[N:16]([CH:15]=[N:14][C:13]=2[C:17]([NH2:19])=[O:18])[C:22]1=[O:23]
Reactant: CN=C=O
Reactant: [N-]=[N+]=C1NCN=C1C(N)=O
Agent: NC(=O)c1ncc(N)[nH]1
Solvent: ClCCl
Product: Cn1nnc2c(C(N)=O)ncn2c1=O

Procedure:
In this process, 5-amino-1H-imidazole-carboxamide (A) is converted into 5-diazo-1H-imidazole-4-carboxamide (B), which is then cyclized with methylisocyanate in dichloromethane to provide a high yield of clinical-grade Temozolomide. However, this process requires isolation of the unstable and potentially dangerous 5-diazo-1H-imidazole-4-carboxamide (B). Moreover, methylisocyanate is a difficult reagent to handle and ship, especially on the industrial scale, and indeed is better avoided in industrial manufacture. Furthermore, the cycloaddition of methylisocyanate requires a very long reaction time: Table I in J. Med. Chem. 1984, 27, 196-201, suggests 20 days.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]1.[CH2:7]([O:14][C:15](Cl)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:7]([O:14][C:15]([N:1]1[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]1)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: OC1CCNC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(OCc1ccccc1)N1CCC(O)C1

Procedure:
30 g of 3-pyrrolidinol was dissolved in 500 ml of chloroform, to which 53 ml of triethylamine was added, followed by gradually dropping 52 ml of benzyloxycarbonyl chloride at room temperature. After completion of the reaction, the reaction solution was poured into water and extracted with chloroform. The solvent was distilled off under reduced pressure and the resultant residue was purified by column chromatography (eluting solvent: hexane-ethyl acetate) to obtain 70.67 g of the intended compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH2:3]1.[N+:13]([O-])([OH:15])=[O:14]>S(=O)(=O)(O)O>[N+:13]([C:7]1[CH:6]=[C:5]2[C:10]([CH2:11][C:2]([CH3:12])([CH3:1])[CH2:3][NH:4]2)=[CH:9][CH:8]=1)([O-:15])=[O:14]
Reactant: CC1(C)CNc2ccccc2C1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CC1(C)CNc2cc([N+](=O)[O-])ccc2C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 59.1 %

Procedure:
1,2,3,4-Tetrahydro-3,3-dimethylquinoline (51 mg, 0.32 mmol) was dissolved in sulfuric acid (0.5 mL) and the temperature lowered to 0° C. To this solution 90% fuming nitric acid (14 mL, 0.32 mmol) was added slowly and the mixture stirred at 0° C. for 1 h, then warmed to rt. The reaction mixture was then poured onto 1 g of ice and extracted with dichloromethane (2×5 mL). The organic phase was washed with saturated aqueous NaHCO3 (3 mL) and concentrated in vacuo to a reddish residue that was subjected to chromatography (silica gel, hexanes/ethyl acetate, 85:15) which afforded 39 mg (58%) of 7-nitro-1,2,3,4-tetrahydro-3,3-dimethylquinoline. Data for 7-nitro-1,2,3,4-tetrahydro-3,3-dimethylquinoline: 1H NMR (400 MHz, CDCl3) 7.40 (dd, J=8.3, 2.1, 1H), 7.29 (d, J=1.8, 1H), 7.01 (d, J=8.3H, 1H), 4.25 (s, 1H), 2.98 (s, 2H), 2.54 (s, 2H), 1.01 (s, 6H).
Reaction SMILES: Cl.[CH2:2]([NH2:4])[CH3:3].O=[C:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1.C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[CH2:2]([NH:4][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)[CH3:3]
Reactant: CCN
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCNC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 2 h
Yield: 70 %

Procedure:
Ethylamine HCl (6.14 g, 75.376 mmol, 1.5 eq) and tert-butyl 4-oxopiperidine-1-carboxylate (10.0 g, 50.25 mmol, 1.0 eq) were dissolved in MeOH (200 ml); acetic acid (0.2 ml) was added and stirring was carried out for 2 hours at RT. NaBH3CN (6.3 g, 100.50 ml, 2.0 eq) was then added in portions at 0° C. and the mixture was stirred for 14 hours at RT. The reaction mixture was concentrated and the residue was taken up in sat. sodium hydrogen carbonate solution (150 ml) and extracted with DCM (2×400 ml). The combined org. phases were washed with sat. NaCl solution (200 ml), dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 1% MeOH in DCM). Yield: 70% (8.0 g, 35.08 mmol)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([Cl:9])[N:3]=1.[OH-].[NH4+:11]>CC(C)=O>[NH2:11][C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([Cl:9])[N:3]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CC(C)=O
Product: Nc1nc(Cl)nc(Cl)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2,4,6-Trichloro-1,3,5-triazine (XVIII) (10.0 g, 55 mmol) was dissolved in acetone (80 mL) and poured into ice-water (80 mL) to form a very fine suspension. To this mixture, 1 N ammonium hydroxide solution (108 mL, 109.4 mmol) was added at 0° C. The reaction was stirred for 30 min at ambient temperature and for additional 60 min at 25° C. The precipitate was filtered off, washed with water (3×25 mL). After drying over calcium chloride under high vacuum, 6-amino-2,4-dichloro-[1,3,5]triazine (XXXVII) was isolated as white powder (7.4 g, 82% yield). LCMS (ESI) m/z=165 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C@H:4]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH:5][C:6](=[O:10])[C@H:7]([CH3:9])[NH2:8].C(N[C@H:27]([C:29]([OH:31])=O)[CH3:28])(OC(C)(C)C)=O.CO[C:34](=O)[C@H:35]([CH2:37][C:38]1C=C[CH:41]=[CH:40][CH:39]=1)N>CO.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:18])[C@H:4]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH:5][C:6](=[O:10])[C@H:7]([CH3:9])[NH:8][C:29](=[O:31])[CH2:27][CH2:28][CH:34]=[CH:35][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)N
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: ClCCl
Solvent: CO
Product: CCCCCC=CCCC(=O)N[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC

Procedure:
Following General Procedure A and using N-(L-alaninyl)-L-phenylalanine methyl ester (prepared by coupling N-BOC-L-alanine (Sigma) and L-phenylalanine methyl ester (Sigma) using General Procedure A, followed by removal of the BOC-group using General Procedure Y) and dec-4-enoic acid (prepare from ethyl dec-4-enoate (ICM) using General Procedure N), the title compound was prepared as a solid (mp=115.5-117.5° C.). The reaction was monitored by tlc (Rf=0.52 in 50% EtOAc/hexanes; 0.60 in 10% CH3OH/CH2Cl2) and the product was purified by flash chromatography using 10% CH3OH/CH2Cl2 as the eluent.
Reaction SMILES: S(=O)(=O)(O)O.[B-](F)(F)(F)F.[Na+].[O:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>>[CH3:13][CH2:14][CH2:15][CH2:16][O:12][C@H:15]([CH2:16][OH:12])[CH2:14][CH3:13]
Reactant: C1CCOC1
Agent: F[B-](F)(F)F
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCCCO[C@@H](CC)CO

Procedure:
In the same reaction apparatus as in Example 4, a mixture of 50 g of 25% fuming sulfuric acid and 1.75 g of sodium borofluoride was dropwise added to 250 g of tetrahydrofuran at 0° C. over a period of one hour, and they were subjected to reaction at the same temperature for 2 hours. The final conversion was 66%, and the reaction system was solidified to form a wax-like mass. This product was then treated similarly to Example 4 to obtain colorless PTMG. The results of the analyses of the thus obtained PTMG and the catalytic efficiency α were as shown in Table 1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:30].O.CCOCC.C[N:38]1CCCC1=O>>[NH2:38][C:16]1[N:17]=[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])[C:13]2[CH:12]=[CH:11][C:10](=[O:30])[N:9]([C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[F:8])[C:14]=2[N:15]=1
Reactant: CN1CCCC1=O
Reactant: CS(=O)(=O)c1nc(-c2ccccc2F)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Solvent: O
Solvent: CCOCC
Product: Nc1nc(-c2ccccc2F)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reaction time: 1 h
Yield: 53 %

Procedure:
To a solution of 8-(2,6-difluoro-phenyl)-4-(2-fluoro-phenyl)-2-methanesulfonyl-8H-pyrido[2,3-d]pyrimidin-7-one (432 mg, 1 mmol) in 1-methyl-2-pyrrolidinone (5 mL) was added NaNH2 (195 mg, 5 mmol, 5 eq) and the mixture was heated to 50°. After 1 h, H2O (20 mL) was added then Et2O (20 mL). The layers were separated. The organic layer was washed with satd aq NaCl, dried (MgSO4), filtered and solvent was removed in vacuo. The yellow residue was then purified by Flash chromatography to afford 2-amino-8-(2,6-difluoro-phenyl)-4-(2-fluoro-phenyl)-8H-pyrido[2,3-d]pyrimidin-7-one (100 mg, 53% yield). 1H-NMR (CDCl3) δ 5.51 (br s, 2H), 6.42 (d, 1H, J=9.8 Hz), 7.08 (m, 2H), 7.30 (m, 2H), 7.50 (m, 4H), LC MS (m/e)=369 (MH+). Rt=1.77 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[N:11]=[C:12]2[C:22]3[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=3[NH:16][C:13]2=[N:14][CH:15]=1.C1CCCCC=1>[Pd].C1(C)C=C(C)C=C(C)C=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[N:11]=[C:12]2[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[NH:16][C:13]2=[N:14][CH:15]=1
Reactant: COc1ccc(F)c(-c2cnc3[nH]c4c(c3n2)CCCC4)c1
Agent: [Pd]
Solvent: Cc1cc(C)cc(C)c1
Solvent: C1=CCCCC1
Product: COc1ccc(F)c(-c2cnc3[nH]c4ccccc4c3n2)c1
Temperature: 200 °C

Procedure:
A sealed tube containing 2-(2-Fluoro-5-methoxyphenyl)-6,7,8,9-tetrahydro-indolo[2,3-b]-pyrazine (46 mg, 0.155 mmol), cyclohexene (10 equiv., 0.157 mL, 1.55 mmol), Pd black (35 mg) and mesitylene (10 mL) was heated to 200° C. in an oil bath and the contents stirred via a magnetic stir bar. The progress of the reaction was monitored by intermittently opening the cooled tube and taking out an aliquot for TLC analysis (30% ethyl acetate/hexanes eluent; the aromatized product has a slightly larger Rf value than that of the starting material). Upon completion of the reaction, the mixture was filtered through celite and the mesitylene removed using a high vacuum rotary evaporator. Recrystallization from hexanes/ethyl acetate afforded 2-(2-Fluoro-5-methoxyphenyl)-5H-indolo[2,3-b]-pyrazine (Compound 2) as an off-white solid.
Reaction SMILES: F[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)=O.O.[NH2:20][NH2:21]>CN(C1C=CN=CC=1)C>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[C:3]3[C:2](=[C:7]([CH3:8])[CH:6]=[CH:5][CH:4]=3)[NH:21][N:20]=2)=[CH:12][CH:13]=1
Reactant: NN
Reactant: COc1ccc(C(=O)c2cccc(C)c2F)cc1
Agent: CN(C)c1ccncc1
Solvent: O
Product: COc1ccc(-c2n[nH]c3c(C)cccc23)cc1
Yield: 48.5 %

Procedure:
Prepared according to Method D Step A from (2-Fluoro-3-methylphenyl)-(4-methoxyphenyl)-methanone (3.6 g, 14.7 mmol), hydrazine hydrate (4.3 mL, 140 mmol) and DMAP (1.8 g, 14.7 mmol) to give the product (1.7 g) as a yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH:4]([OH:6])[CH3:5].[Cl:8][C:9]1[CH:14]=[C:13](Cl)[N:12]=[C:11]([S:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=2[F:25])[N:10]=1.FC1C(F)=CC=CC=1CSC1N=C(NS(N2CCC2)(=O)=O)C=C(OC(CO)CO)N=1.[H-].[Na+]>C1COCC1>[Cl:8][C:9]1[N:10]=[C:11]([S:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=2[F:25])[N:12]=[C:13]([O:6][CH:4]([CH3:5])[CH2:3][N:2]([CH3:7])[CH3:1])[CH:14]=1
Reactant: CC(O)CN(C)C
Reactant: Fc1cccc(CSc2nc(Cl)cc(Cl)n2)c1F
Agent: O=S(=O)(Nc1cc(OC(CO)CO)nc(SCc2cccc(F)c2F)n1)N1CCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(CN(C)C)Oc1cc(Cl)nc(SCc2cccc(F)c2F)n1

Procedure:
The subtitle compound was prepared according to the procedure outlined in Example 41 step i) using 1-dimethylamino-2-propanol (80 mg), 4,6-Dichloro-2-[(2,3-difluorobenzyl)thio]pyrimidine (the product of Example 1 step (0.25 g) and 60% sodium hydride (30 mg) in THF (2 mL) at room temperature for 2d to give the subtitle compound as a pale yellow gum. Yield: 0.29 g.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:3][CH:4]=1
Reactant: Cc1ccc(Br)nc1
Reactant: OB(O)c1ccccc1
Product: Cc1ccc(-c2ccccc2)nc1

Procedure:
Synthesized using 2-bromo-5-methyl-pyridine (2.92 g, 16.95 mmol) and phenylboronic acid (3.09 g, 25.4 mmol) according to Method C. Crude product was purified by flash chromatography on silica-gel using a mixture of hexane/ethyl acetate (8:1) as eluent. White solid. Yield: 1.99 g, 70%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=2.38 (s, 3H), 7.37-7.43 (m, 1H), 7.44-7.51 (m, 2H), 7.54-7.60 (m, 1H), 7.60-7.67 (m, 1H), 7.95-8.00 (m, 2H), 8.51-8.55 (m, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=18.1, 120.0, 126.7, 128.6, 128.7, 131.5, 137.3, 139.4, 150.1, 154.8; (ESI): m/z=169.97 [M+H]+.
Reaction SMILES: S(=O)(=O)(O)O.[OH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([OH:21])=[O:20])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.O.[CH3:23]O>C1COCC1>[CH3:23][O:20][C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:10]2[CH:9]=[CH:8][C:7]([OH:6])=[CH:12][CH:11]=2)=[CH:14][CH:15]=1)=[O:21]
Reactant: O=C(O)c1ccc(-c2ccc(O)cc2)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(-c2ccc(O)cc2)cc1
Yield: 86 %

Procedure:
Concentrated sulfuric acid (approximately 4 ml) was carefully added to a solution of 4′-hydroxy-4-biphenylcarboxylic acid (Aldrich) (8.20 g, 38.3 mmol) in 1 liter of methanol. The reaction mixture was refluxed for three days and the solvent was evaporated. The resulting solid was filtered, washed with water, and recrystallized as follows. The crude solid was dissolved in a minimum amount of hot THF, and approximately three equivalents of methanol was added to the solution. The solution was brought to a boil, and water was added with vigorous stirring until the solution remained cloudy. After cooling, the tan precipitate was filtered, washed with cold ethanol, and air dried to yield 7.57 g (86%) of a tan solid.
Reaction SMILES: Cl.[NH:2]=[C:3]1[CH:8]=[CH:7][N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[CH:4]1.[C:15]([Cl:20])(=[O:19])[CH:16]([CH3:18])[CH3:17]>>[ClH:20].[C:15]([N:2]=[C:3]1[CH:8]=[CH:7][N:6]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:5]=[CH:4]1)(=[O:19])[CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)C(=O)Cl
Reactant: N=c1ccn(-c2ccccc2)nc1
Agent: Cl
Product: CC(C)C(=O)N=c1ccn(-c2ccccc2)nc1
Yield: 67 %

Procedure:
5.0 g (21.4 millimoles) of 1,4-dihydro-4-imino-1-phenylpyridazine hydrochloride in 20 ml of isobutyryl chloride were refluxed for 20 hours, while stirring. The mixture was cooled and then filtered under suction, and the residue was washed with acetone and recrystallized from ethanol/methyl tert.-butyl ether. 4.5 g (67% of theory) of 1,4-dihydro-4-isobutyrylimino-1-phenylpyridazine hydrochloride were isolated as colorless crystals of melting point 240°-242° C.
Reaction SMILES: [N:1]1([CH2:6][C:7]#[C:8][C@H:9]2[CH2:13][CH2:12][CH2:11][N:10]2C(OC(C)(C)C)=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)C.[ClH:24]>CO>[ClH:24].[ClH:24].[NH:10]1[CH2:11][CH2:12][CH2:13][C@@H:9]1[C:8]#[C:7][CH2:6][N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C#CCN1CCCC1
Agent: Cl
Solvent: CO
Solvent: CCO
Product: C(#C[C@H]1CCCN1)CN1CCCC1
Temperature: 80 °C

Procedure:
A mixture of 7.0 g of (R)-2-[3-(1- pyrrolidinyl)-1-propynyl]-1-pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester, 61 ml of ethanol and 61 ml of 2N hydrochloric acid is heated at 80° C. for one hour. The reaction is concentrated in vacuo and the residue is extracted with methylene chloride. The aqueous layer is concentrated in vacuo, made basic with 10N sodium hydroxide and extracted with methylene chloride. The methylene chloride solution is dried over sodium sulfate, filtered and concentrated in vacuo. The residue is dissolved in methanol, treated with an excess of methanolic hydrogen chloride and precipitated with the addition of diethyl ether. The dihydrochloride is recrystallized from hot methanol to give pure product, mp 198°-200° C. with decomposition, [α]D26° =+21°±1 (C=1.012%, methanol).
Reaction SMILES: N#N.[C:3]([O:15]C)(=[O:14])[C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10]C)=[O:9])=[CH:6][CH:5]=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][N:26]2[CH2:31][CH2:30][N:29]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:28][CH2:27]2)=[C:21]([OH:39])[C:20]=1[O:40][CH3:41].C([Sn](=O)CCCC)CCC>CO>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][N:26]2[CH2:27][CH2:28][N:29]([CH2:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH2:30][CH2:31]2)=[C:21]([OH:39])[C:20]=1[O:40][CH3:41].[C:3]([O-:15])(=[O:14])[C:4]1[CH:13]=[CH:12][C:7]([C:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(C(=O)OC)cc1
Agent: CCCC[Sn](=O)CCCC
Agent: COc1ccc(CN2CCN(Cc3ccccc3)CC2)c(O)c1OC
Agent: N#N
Solvent: CO
Product: O=C([O-])c1ccc(C(=O)[O-])cc1

Procedure:
Into a 4-necked, 1-liter flask fitted with a mechanical thermometer, N2 ebulator, and steam jacketed column packed with Berl Saddles and topped with a Dean-Stark trap and condenser are charged dimethyl terephthalate (220 grams, 1.14 moles), BHDP (300 grams, 1.36 moles) and dibutyltin oxide (1.4 grams). The mixture is heated at 180°-190° C. for 5.5 hours. A conversion of 9% percent is effected based upon methanol distilled overhead. The solid yellow glass (viscosity 40,000 cp at 220° F.) has an average molecular weight of 2,060, an acid number of 1.2, and a hydroxyl number of 51.3.
Reaction SMILES: [O:1]=[C:2]1[CH2:5][CH:4]([CH2:6][CH2:7][C:8]([OH:10])=O)[CH2:3]1.[C:11]([C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[C:17]([N+:22]([O-:24])=[O:23])[CH:16]=1)([CH3:14])([CH3:13])[CH3:12].N1C=CC=CC=1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>O1CCOCC1.CCOC(C)=O>[C:11]([C:15]1[CH:21]=[CH:20][C:18]([NH:19][C:8](=[O:10])[CH2:7][CH2:6][CH:4]2[CH2:3][C:2](=[O:1])[CH2:5]2)=[C:17]([N+:22]([O-:24])=[O:23])[CH:16]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)c1ccc(N)c([N+](=O)[O-])c1
Reactant: O=C(O)CCC1CC(=O)C1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)(C)c1ccc(NC(=O)CCC2CC(=O)C2)c([N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 7 h
Yield: 84.7 %

Procedure:
3-(3-Oxocyclobutyl)propanoic acid (10) (1.610 g, 11.3 mmol) and 4-tert-butyl-2-nitroaniline (11) (2.000 g, 10.3 mmol) were dissolved in 1,4-dioxane (20 ml) and pyridine (2.6 ml, 30.9 mmol) and T3P (50% solution in EtOAc) (9.1 ml, 15.5 mmol) was added at r.t. The reaction was heated to 100° C. and left for 7 hrs. The reaction was cooled to r.t., diluted with EtOAc (20 ml) and washed with 2M NaOH (2×20 ml), 2M HCl (20 ml), brine (20 ml), dried over MgSO4 and concentrated in vacuo to give the crude product. The product was purified by silica flash column chromatography using between 100% heptanes to 40% EtOAc:60% heptanes as eluent to give 12 as a yellow oil (2.776 g, 85%): MS (ESI+) for C17H22N2O4 m/z 319.25 [M+H]+, 341.00 [M+Na]+; LC purity 99% (UV) (ret. time, 2.11 min); 1H NMR (500 MHz, CDCl3) δ 10.28 (s, 1H), 8.66 (d, J=8.9 Hz, 1H), 8.20 (d, J=2.3 Hz, 1H), 7.70 (dd, J=8.9, 2.3 Hz, 1H), 3.30-3.12 (m, 2H), 2.86-2.69 (m, 2H), 2.50 (ddd, J=30.3, 14.9, 7.6 Hz, 3H), 2.07 (q, J=7.6 Hz, 2H), 1.34 (s, 9H).
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.O>C(Cl)Cl>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[N:7]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: C1COCCN1
Solvent: ClCCl
Solvent: O
Product: Clc1nc(Cl)nc(N2CCOCC2)n1
Reaction time: 0.33 h
Yield: 27.9 %

Procedure:
Cyanuric chloride (10.0 g, 54.2 mmol, 1.0 eq.) was dissolved in methylene chloride (60 ml) and morpholine (4.70 ml, 54.2 mmol, 1.0 eq.) was slowly added (drop by drop) to the reaction mixture at −50° C., stirred for 20 minutes at the same temperature and poured into water. After extraction with methylene chloride and ethyl acetate (2×), the organic layers were dried over MgSO4 and concentrated. Further purification was done by flash chromatography (1:1 hexane/ethyl acetate) to yield the title compound as a colorless solid (3.56 g, 28%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]([OH:15])=O)[C@@H:10]([CH3:12])[OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:17]([O:24][NH2:25])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[CH2:17]([O:24][NH:25][C:13](=[O:15])[C@H:9]([C@@H:10]([CH3:12])[OH:11])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: NOCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)NOCc1ccccc1
Reaction time: 26 h
Yield: 55.6 %

Procedure:
A solution of 8.76 g of t-butoxycarbonyl threonine and the free amine from 6.4 g of O-benzylhydroxylamine HCl (ethyl acetate-sodium bicarbonate liberation) in 100 ml of tetrahydrofuran was treated with 6.12 g of N-hydroxybenzotriazole and 8.24 g of dicyclohexylcarbodiimide in 20 ml of tetrahydrofuran. The mixture was stirred under nitrogen for 26 hours, filtered, and evaporated in vacuo. The residue was chromatographed on a 300 g silica gel column (elution with chloroform and chloroform/ethyl acetate (3:1) yielding 7.2 g of compound. Crystallization from ether-hexane gave 4.18 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[I:11]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Clc1ncnc2[nH]ccc12
Solvent: ClC(Cl)Cl
Product: Clc1ncnc2[nH]cc(I)c12
Temperature: 25 °C
Yield: 82.3 %

Procedure:
To a stirred solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (30 g/0.02 mol) dissolved in 80 mL of chloroform was added 4.5 grams (0.02 mol) of N-iodosuccinimide and the resulting mixture heated at reflux for 1 hour. After cooling to room temperature, the percipitate was removed by flitration and dried under reduced pressure affording 4.6 grams (82%) of the title compound.
Reaction SMILES: [F:1][CH:2]([F:14])[O:3][C:4]1[CH:9]=[C:8]([F:10])[C:7]([CH2:11]O)=[C:6]([F:13])[CH:5]=1.C(O)(=O)C.C(OCC)C.C(=O)([O-])O.[Na+].[BrH:29]>>[Br:29][CH2:11][C:7]1[C:8]([F:10])=[CH:9][C:4]([O:3][CH:2]([F:14])[F:1])=[CH:5][C:6]=1[F:13]
Reactant: OCc1c(F)cc(OC(F)F)cc1F
Reactant: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOCC
Product: Fc1cc(OC(F)F)cc(F)c1CBr
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.76 g of [4-(difluoromethoxy)-2,6-difluorophenyl]methanol (3.62 mmol, 1 eq.) were dissolved in 1.72 ml of 33% hydrogen bromide in glacial acetic acid (9.97 mmol, 2.75 eq.) and stirred at room temperature for 2 hours. 25 ml of diethyl ether were added and the mixture was stirred at room temperature for 15 min. The reaction mixture was added dropwise to 80 ml of aqueous saturated sodium hydrogen carbonate solution and stirred again at room temperature for 15 min. The separated aqueous layer was extracted twice with diethyl ether. The combined organic layers were washed with brine, dried over a silicone filter and concentrated in vacuo to yield 991 mg (3.56 mmol, 98.4%) of the analytically pure target compound.