Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](=[O:36])[C:8]2[CH:13]=[N:12][C:11]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]([CH3:24])[CH3:23])[CH:16]=3)=[N:10][C:9]=2[N:25]([C:27]2[CH:28]=[C:29]3[C:33](=[CH:34][CH:35]=2)[CH2:32][CH2:31][CH2:30]3)[CH:26]=1)=O)C.[CH3:37][NH2:38]>CO>[CH3:37][NH:38][C:4]([C:6]1[C:7](=[O:36])[C:8]2[CH:13]=[N:12][C:11]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]([CH3:23])[CH3:24])[CH:16]=3)=[N:10][C:9]=2[N:25]([C:27]2[CH:28]=[C:29]3[C:33](=[CH:34][CH:35]=2)[CH2:32][CH2:31][CH2:30]3)[CH:26]=1)=[O:3]
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(Nc3cccc(CN(C)C)c3)ncc2c1=O
Reactant: CN
Solvent: CO
Product: CNC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(Nc3cccc(CN(C)C)c3)ncc2c1=O
Temperature: 80 °C
Reaction time: 16 h
Yield: 15.3 %

Procedure:
2-(3-Dimethylaminomethyl-phenylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (15 mg, 0.032 mmol) was dissolved in MeOH (1 mL) and methylamine (1 mL of 1.0 M solution in THF, 1.0 mmol) was added and the reaction mixture was heated at 80° C. After 16 h, the solution was cooled to rt and purified by preparative HPLC (C-18 column, 32 mL/min 5-100% MeCN/H2O gradient over 15 min) and lyophilized to provide 2.3 mg of 2-(3-dimethylaminomethyl-phenylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methylamide. 1H NMR (TFA salt) (400 MHz, CDCl3) δ (ppm): 9.51 (s, 1H), 9.35 (s, 1H), 8.75 (s, 1H), 7.01-7.50 (m, 7H), 3.90 (br s, 2H), 2.90-3.02 (m, 7H), 2.60 (s, 6H), 2.11-2.19 (m, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C27H28N6O2: 468.23, Found: 469.1 (M+H).
Reaction SMILES: [N:1]1([CH2:10][C:11]2[N:15]3[CH2:16][CH2:17][O:18][C:19]4[CH:24]=[CH:23][C:22](Br)=[CH:21][C:20]=4[C:14]3=[N:13][C:12]=2[C:26]([NH2:28])=[O:27])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.BrC1C=CC2OCCN3C(CN4C=CN=C4C)=C(C(N)=O)N=C3C=2C=1.N1C2C=CC=CC=2NC=1.[CH3:63][C:64]([OH:68])([C:66]#[CH:67])[CH3:65]>>[N:1]1([CH2:10][C:11]2[N:15]3[CH2:16][CH2:17][O:18][C:19]4[CH:24]=[CH:23][C:22]([C:67]#[C:66][C:64]([OH:68])([CH3:65])[CH3:63])=[CH:21][C:20]=4[C:14]3=[N:13][C:12]=2[C:26]([NH2:28])=[O:27])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: NC(=O)c1nc2n(c1Cn1cnc3ccccc31)CCOc1ccc(Br)cc1-2
Reactant: C#CC(C)(C)O
Agent: Cc1nccn1Cc1c(C(N)=O)nc2n1CCOc1ccc(Br)cc1-2
Agent: c1ccc2[nH]cnc2c1
Product: CC(C)(O)C#Cc1ccc2c(c1)-c1nc(C(N)=O)c(Cn3cnc4ccccc43)n1CCO2
Yield: 35 %

Procedure:
Similar to as described in General Procedure G, 3-((1H-benzo[d]imidazol-1-yl)methyl)-10-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide (prepared similarly as described in the synthesis of 10-bromo-3((2-methyl-1H-imidazol-1-yl)methyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide replacing 2-methylimidazole with benzimidazole) was reacted with 2-methylbut-3-yn-2-ol to give the titled compound as an off-white solid (28 mg, 35%).
Reaction SMILES: Cl.[NH2:2][OH:3].[OH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH3:12])=[CH:7][CH:6]=1.C(C1C=CC=CC=1)(=O)C>N1C=CC=CC=1>[OH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[N:2][OH:3])[CH3:12])=[CH:7][CH:6]=1
Reactant: NO
Reactant: CC(=O)c1ccc(O)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(=O)c1ccccc1
Product: CC(=NO)c1ccc(O)cc1

Procedure:
1.1 equivalents of hydroxylamine hydrochloride are added to a solution of para-hydroxyacetophenone in pyridine (16% dilution). The reaction mixture is maintained at reflux until the starting acetophenone has disappeared, and is then poured into ice-cold water. The medium is extracted with ethyl acetate. After drying, the organic phase is removed and the corresponding oxime is obtained quantitatively. The elemental analysis is in accordance with the structure.
Reaction SMILES: COC1C=CC(C[N:8]2[C:16]3([CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]3)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:29])=CC=1.C(O)(C(F)(F)F)=O>>[NH:19]1[CH2:20][CH2:21][C:16]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:29])[NH:8]2)[CH2:17][CH2:18]1
Reactant: COc1ccc(CN2C(=O)c3ccccc3C23CCN(C(=O)OC(C)(C)C)CC3)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C1NC2(CCNCC2)c2ccccc21

Procedure:
Tert-butyl 2-(4-methoxybenzyl)-3-oxospiro[isoindoline-1,4′-piperidine]-1′-carboxylate (50 mg, 0.12 mmol, 1.0 equiv) and TFA (7 mL) were heated to 75° C. for 19 h. After this time LC-MS showed removal of the Boc- and p-methoxybenzyl groups. The mixture was concentrated to leave crude spiro[isoindoline-1,4′-piperidin]-3-one which was used directly.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([I:32])=[CH:28][C:27]=2[F:33])=[C:4]([CH:12]=[C:13](/[CH:16]=[N:17]/[O:18][CH2:19][CH2:20][C:21](=[O:24])NC)[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6].ClC(Cl)C(O)=O>ClCCl>[F:1][C:2]1[C:3]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([I:32])=[CH:28][C:27]=2[F:33])=[C:4]([CH:12]=[C:13]([CH2:16][N:17]2[C:21](=[O:24])[CH2:20][CH2:19][O:18]2)[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6]
Reactant: CNC(=O)CCO/N=C/c1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Agent: O=C(O)C(Cl)Cl
Solvent: ClCCl
Product: O=C(NOCCO)c1cc(CN2OCCC2=O)c(F)c(F)c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 96.7 %

Procedure:
To (E)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-methylcarbamoyl-ethoxyimino)-methyl]-benzamide (9.60 g, 15.54 mmol) were added sequentially dichloromethane (300 ml) and borane-pyridine complex (11.70 ml, 115.80 mmol) to give a suspension. This mixture was stirred at room temperature, and dichloroacetic acid (9.51 ml, 115.80 mmol) was added dropwise thereto over 10 minutes. After the mixture was stirred at room temperature for 13 hours, dichloromethane was removed under reduced pressure with a rotary evaporator, and the resultant residue was diluted with 1,2-dichloroethane (300 ml). This mixture was stirred at 60° C. for 6 hours, diluted with ethyl acetate, and washed sequentially with 0.1 M aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (8.28 g, 90% yield).
Reaction SMILES: [CH:1]1([N:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]2=[O:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)C.[Pd]>[CH:1]1([N:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]2=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=c1c2ccccc2ccn1C1CCCCC1
Agent: [Pd]
Solvent: CCO
Product: O=C1c2ccccc2CCN1C1CCCCC1
Reaction time: 3.5 h
Yield: 83.3 %

Procedure:
The compound (200 mg) obtained in step (c) just above was dissolved in a mixed solution (10.7 ml) of ethanol concentrated hydrochloric acid=15:1. 10% Pd—C (60 mg) was added to the solution, followed by hydrogenation for 3.5 hr. Pd—C was removed by filtration through Celite. The filtrate was concentrated under the reduced pressure. Water was then added the residue. The mixture was extracted with ethyl acetate. The organic layer was then dried over anhydrous magnesium sulfate. The solvent was then removed by distillation to give 2-cyclohexyl-3,4-dihydro-2H-isoquinolin-1-one (168 mg).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[O:9][CH:8]([C:14]([F:17])([F:16])[F:15])[C:7]([C:18]([OH:20])=[O:19])=[CH:6]2)[CH3:2].S(Cl)([Cl:24])(=O)=O>ClCCl.C(O)(=O)C.[Zn]>[Cl:24][C:11]1[C:12]([OH:13])=[C:3]([CH2:1][CH3:2])[CH:4]=[C:5]2[C:10]=1[O:9][CH:8]([C:14]([F:15])([F:16])[F:17])[C:7]([C:18]([OH:20])=[O:19])=[CH:6]2
Reactant: CCc1cc2c(cc1O)OC(C(F)(F)F)C(C(=O)O)=C2
Reactant: O=S(=O)(Cl)Cl
Agent: [Zn]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCc1cc2c(c(Cl)c1O)OC(C(F)(F)F)C(C(=O)O)=C2
Temperature: 25 °C
Reaction time: 24 h
Yield: 18.2 %

Procedure:
To a mixture of 1.0 g (3.4 mmol) of 6-ethyl-7-hydroxy-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid in anhydrous dichloromethane (30 mL) was added 4.2 mL (1.0 M in DCM, 22 mmol) sulfuryl chloride dropwise. The resulting mixture was stirred at room temperature for 24 h. The sample was concd and the residue dissolved in 30 mL of acetic acid, followed by addition of 0.5 g granular Zn. The mixture was stirred at room temperature for 3 h, filtered and the filtrate evaporated. The residue was purified by chromatography to afford 0.20 g (18%) of a white solid: 1H NMR(CDCl3/400 MHz) 7.79 (s, 1H), 7.26 (s, 1H), 5.77 (q, J=6.8 Hz, 1H), 2.63(q, J=7.6 Hz, 2H), 1.21(t, J=7.6 Hz, 3H). MS (ESI+) 323.0 (M+1, 100).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([Cl:17])[CH:10]=2)[C:5]([F:18])=[CH:4][N:3]=1.[OH:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23]>>[Cl:17][C:11]1[CH:10]=[C:9]([NH:8][C:6]2[C:5]([F:18])=[CH:4][N:3]=[C:2]([NH:23][C:22]3[CH:24]=[CH:25][CH:26]=[C:20]([OH:19])[CH:21]=3)[N:7]=2)[CH:14]=[CH:13][C:12]=1[O:15][CH3:16]
Reactant: COc1ccc(Nc2nc(Cl)ncc2F)cc1Cl
Reactant: Nc1cccc(O)c1
Product: COc1ccc(Nc2nc(Nc3cccc(O)c3)ncc2F)cc1Cl

Procedure:
In a like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-N4-(3-chloro-4-methoxyphenyl)-5-fluoro-4-pyrimidineamine and 3-hydroxyaniline were reacted to produce N4-(3-chloro-4-methoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 7.91 (d, 1H, J=5.4 Hz), 7.71 (d, 1H, J=2.4 Hz), 7.58 (dd, 1H, J=3.0 and 9.0 Hz), 7.15 (t, 1H, J=8.4 Hz), 7.06 (d, 1H, J=8.7 Hz), 6.92 (td, 1H, J=1.8 and 9.9 Hz), 6.88 (t, 1H, J=1.8 Hz), 6.61 (ddd, 1H, J=1.2, 2.4, and 8.1 Hz), 3.89 (s, 3H); 19F NMR (282 MHz, CD3OD): −46612; LCMS: purity: 98%; MS (m/e): 362 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]([NH:11][C:12](=[O:14])[CH3:13])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[F:16][C:17]1[CH:22]=[C:21]([CH:23]=[CH2:24])[CH:20]=[CH:19][C:18]=1[C:25]1[S:26][C:27]2[C:32]([N:33]=1)=[CH:31][CH:30]=[C:29]([C:34]1([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH2:36][CH2:35]1)[N:28]=2>CS(C)=O>[C:12]([NH:11][C:5]([CH2:24][CH2:23][C:21]1[CH:20]=[CH:19][C:18]([C:25]2[S:26][C:27]3[C:32]([N:33]=2)=[CH:31][CH:30]=[C:29]([C:34]2([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)[CH2:35][CH2:36]2)[N:28]=3)=[C:17]([F:16])[CH:22]=1)([C:4]([O:3][CH2:1][CH3:2])=[O:15])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:14])[CH3:13]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: C=Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Solvent: CS(C)=O
Product: CCOC(=O)C(CCc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1)(NC(C)=O)C(=O)OCC
Temperature: 35 °C
Reaction time: 2 h

Procedure:
A slurry of CsCO3 (0.420 g, 1.29 mmol) and acetamidomalonic acid diethyl ester (0.560 g, 2.58 mmol) in 6 mL DMSO under argon was allowed to stir for 2 h. 2-(2-Fluoro-4-vinylphenyl)-5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine (0.400 g, 1.07 mmol) was added as a solid and the reaction mixture sealed and heated to 35° C. for 3 h. The clear, red reaction mixture was quenched with ice and 1N aq. HCl until acidic, and partitioned between water and EA. The organic layer was washed with water, brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The material was treated with DCM and passed through a Redi-Sep® pre-packed silica gel column (40 g) using 0-60% EtOAc/hexane. The product-containing fractions were concentrated to afford diethyl 2-acetamido-2-(2-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)ethyl)malonate as a white solid. MS (ESI) m/z: calculated: 589.2; Observed: 590.1 (M++1).
Reaction SMILES: [N:1]1([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH2:24]([O:27][C:28](Cl)=[O:29])[CH2:25][CH3:26]>ClCCl>[CH2:10]([O:9][C:7]([N:1]1[CH2:6][CH2:5][N:4]([C:28]([O:27][CH2:24][CH2:25][CH3:26])=[O:29])[CH2:3][CH2:2]1)=[O:8])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCCOC(=O)Cl
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCOC(=O)N1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 15.0 g benzyl 1-piperazinecarboxylate in 100 ml dichloromethane were added 20.7 ml triethylamine. The solution was cooled to 0° C. and 8.4 ml propylchloroformate added dropwise at this temperature. After stirring for 1 h the reaction mixture was diluted with dichloromethane and washed with 0.1 M HCl and saturated NaHCO3. The crude product obtained after evaporation of the solvent was purified by flash chromatography on silica using an ethyl acetate/heptane gradient. Yield: 19.3 g.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=[O:9].[C:13]1(=[O:23])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[N:15][NH:14]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[O:23]=[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[N:15][N:14]1[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=[O:9]
Reactant: O=c1[nH]ncc2ccccc12
Reactant: O=Cc1cccc(OCCBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cccc(OCCn2ncc3ccccc3c2=O)c1
Temperature: 80 °C
Reaction time: 5 h
Yield: 90 %

Procedure:
A mixture of 3-(2-bromoethoxy)benzaldehyde (6.00 g), 1(2H)-phthalazinone (4.21 g), potassium carbonate (7.24 g) and N,N-dimethylformamide (40 ml) was stirred at 80° C. for 5 hours. After cooling, the reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated to obtain 3-[2-[1-oxo-2(1H)-phthalazinyl]ethoxy]benzaldehyde (6.94 g, yield 90%) as colorless crystals. This was recrystallized from acetone-hexane. Melting point: 110–111° C.
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]([C:16]([OH:18])=[O:17])=[CH:10]2)#[N:6].[CH2:19](O)[CH3:20]>>[C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10]2)#[N:6]
Reactant: CCO
Reactant: N#Cc1ccc2[nH]c(C(=O)O)cc2c1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cc2cc(C#N)ccc2[nH]1

Procedure:
Thionyl chloride (1 mL) was added to a solution of 5-cyano-1H-indole-2-carboxylic acid (D20) (1.1 g) in ethanol (120 mL) at RT. The resulting solution was heated to reflux and stirred when refluxing for 20 hours. Another portion of thionyl chloride (0.5 mL) was added. The reaction mixture was refluxed for 2 hours. The solvent was evaporated to afford ethyl 5-cyano-1H-indole-2-carboxylate (D21) (0.9 g) as a light green solid. MS (ES): C12H10N2O2 requires 214; found 215.2 (M+H+)
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([C:19]([OH:21])=O)[NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:23][NH:24][O:25][CH3:26].CN1CCOCC1>C(Cl)Cl>[CH2:1]([O:8][CH2:9][C@@H:10]([C:19]([N:24]([O:25][CH3:26])[CH3:23])=[O:21])[NH:11][C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CON(C)C(=O)[C@H](COCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 18 h

Procedure:
To a solution of O-benzyl-N-(tert-butoxycarbonyl)serine (5.9 g, 20.0 mmol) in CH2Cl2 (20 mL) was added N,O-dimethylhydroxylamine hydrochloride (1.95 g, 20.0 mmol) followed by N-methylmorpholine (2.20 mL, 19.98 mmol). The mixture was cooled to 0° C. and treated with a 1 M solution of N,N-dicyclohexylcarbodiimide in CH2Cl2 (20.0 mL, 20.0 mmol). The mixture was allowed to warm to ambient temperature while stirring under inert atmosphere for 18 h. The mixture was filtered, washing the solid residue with excess CH2Cl2, and the filtrate was concentrated in vacuo. The resulting oil was suspended in EtOAc, stirred for 20 min, and filtered once more, washing with EtOAc. The filtrate was concentrated to an orange oil which was purified by silica gel chromatography (20% to 60% EtOAc/hexanes) to afford the title compound as a colorless oil. 1H NMR (500 MHz, CDCl3) δ 7.35-7.25 (m, 5H), 5.44 (d, J=8.4 Hz, 1H), 4.88 (d, J=3.2 Hz, 1H), 4.53 (dd, J=12.4, 28.8 Hz, 2H), 3.71 (s, 3H), 3.69-3.64 (m, 2H), 3.21 (s, 3H), 1.44 (s, 9H). ES MS (M+1−100, for loss of BOC group)=239.2.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:8]([C:11]1[N:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13]([C:19]([F:22])([F:21])[F:20])[N:12]=1)=[C:9]=[O:10]>C(Cl)Cl>[CH3:18][O:17][C:15]1[CH:14]=[C:13]([C:19]([F:20])([F:22])[F:21])[N:12]=[C:11]([NH:8][C:9]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:10])[N:16]=1
Reactant: COc1cc(C(F)(F)F)nc(N=C=O)n1
Reactant: Oc1ccccc1
Solvent: ClCCl
Product: COc1cc(C(F)(F)F)nc(NC(=O)Oc2ccccc2)n1
Reaction time: 16 h
Yield: 86.6 %

Procedure:
4.2 g of phenol (45 mmol) were added at 25° C. to a solution of 9.9 g of 2-isocyanato-4-methoxy-6-trifluoromethylpyrimidine (45 mmol) in 50 ml of methylene chloride. Stirring was carried out for 16 hours at 25° C., the methylene chloride was distilled off under reduced pressure and the residue was stirred vigorously with 100 ml of a diisopropyl ether/hexane mixture (v/v 1:20), whereupon crystallization occurred. The product was filtered off with suction and dried under reduced pressure from a water pump at 50° C. The title compound (12.2 g; 87% of theory) was obtained as colorless crystals of melting point 85°-88° C.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[C:6]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH:5]=1)([O-:3])=[O:2].[C:21]1([N:27]=[C:28]=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH:8][C:28]([NH:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:29])=[C:6]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH:5]=1)([O-:3])=[O:2]
Reactant: O=C=Nc1ccccc1
Reactant: Nc1ccc([N+](=O)[O-])cc1NS(=O)(=O)c1ccccc1
Product: O=C(Nc1ccccc1)Nc1ccc([N+](=O)[O-])cc1NS(=O)(=O)c1ccccc1

Procedure:
N-(4-Nitro 2-(phenylsulfonylamino)phenyl)-N′-phenyl urea was prepared from 4-nitro 2-(phenylsulfonylamino) aniline (82 mg) and phenyl isocyanate (33 mg) by method A. The reaction was cooled and then partitioned between saturated ammonium chloride and 9:1 methylene chloride and methanol. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/hexanes) to afford desired (30.8 mg, 26%). EI-MS m/z 413 (M+H)+
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[CH3:14][O:15][N:16]=[C:17]([C:34](=[O:37])[CH2:35][Br:36])[C:18]([NH:20][CH:21]1[C:32](=[O:33])[N:23]2[CH:24]([C:29]([OH:31])=[O:30])[CH:25](O)[CH2:26][S:27][C@H:22]12)=[O:19].CO>C1(OC)C=CC=CC=1.CN(C)C=O.O1CCCC1>[CH3:14][O:15][N:16]=[C:17]([C:34](=[O:37])[CH2:35][Br:36])[C:18]([NH:20][CH:21]1[C:32](=[O:33])[N:23]2[C:24]([C:29]([OH:31])=[O:30])=[CH:25][CH2:26][S:27][C@H:22]12)=[O:19]
Reactant: CON=C(C(=O)CBr)C(=O)NC1C(=O)N2C(C(=O)O)C(O)CS[C@H]12
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CO
Product: CON=C(C(=O)CBr)C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12
Reaction time: 4 h
Yield: 85.6 %

Procedure:
Trifluoroacetic anhydride (1 ml.), anisole (1 drop) and dimethylformamide (1 drop) were added to a solution of 7-(2-methoxyimino-3-oxo-4-bromobutyramido)-3-hydroxycepham-4-carboxylic acid (syn isomer, 1 g.) in dry tetrahydrofuran (3 ml.) and stirred for 4 hours. After adding methanol (0.3 ml.) into the resultant solution, the solution was stirred for an hour and concentrated in vacuo. The residue was pulverized with diisopropyl ether. The precipitates were collected by filtration and dried over phosphorus pentoxide to give 7-(2-methoxyimino-3-oxo-4-bromobutyramido)-3-cephem-4-carboxylic acid (syn isomer, 0.82 g).
Reaction SMILES: CC(=C)C.[O:5]1[CH2:10][CH2:9][N:8]([C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]2[CH:25]=[CH:24][C:23]([CH2:26][N:27]3[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[CH:31]([CH3:38])[CH2:30][CH:29]([NH:39][C:40](=[O:50])[CH2:41][C:42]([NH:45][CH2:46][C@H:47]([OH:49])[CH3:48])([CH3:44])[CH3:43])[C:28]3=[O:51])=[CH:22][CH:21]=2)=[O:12])[CH2:7][CH2:6]1.C([O:54]CC)C>>[O:5]1[CH2:10][CH2:9][N:8]([C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]2[CH:25]=[CH:24][C:23]([CH2:26][N:27]3[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[CH:31]([CH3:38])[CH2:30][CH:29]([NH:39][C:40](=[O:50])[CH2:41][C:42]([NH:45][CH2:46][C@H:47]([OH:49])[CH2:48][OH:54])([CH3:43])[CH3:44])[C:28]3=[O:51])=[CH:22][CH:21]=2)=[O:12])[CH2:7][CH2:6]1
Reactant: CCOCC
Reactant: CC1CC(NC(=O)CC(C)(C)NC[C@@H](C)O)C(=O)N(Cc2ccc(-c3ccccc3NC(=O)N3CCOCC3)cc2)c2ccccc21
Agent: C=C(C)C
Product: CC1CC(NC(=O)CC(C)(C)NC[C@H](O)CO)C(=O)N(Cc2ccc(-c3ccccc3NC(=O)N3CCOCC3)cc2)c2ccccc21

Procedure:
Reaction of isobutylene with N-chlorosulfonylisocyanate 57 in diethyl ether gives the azetidinone derivative 58. Removal of the chlorosulfonyl group with aqueous sodium sulfite followed by reaction with di-t-butyl-dicarbonate gives the BOC-protected intermediate 60. Alkaline hydrolysis gives the protected amino acid derivative 61 in good overall yield.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH3:11][NH:12][CH3:13]>>[CH3:11][N:12]([CH3:13])[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CNC
Product: CN(C)c1ccc([N+](=O)[O-])cn1
Yield: 98 %

Procedure:
2-Chloro-5-nitropyridine (1.58 g, 10 mM) was treated with a 33% w/w solution of dimethylamine in methylated spirit (18 ml, 100 mM). An exothermic reaction ensued, with formation of a yellow solid. After 0.5 h the solid was filtered off. The filtrate was evaporated and the residue was combined with the yellow solid, and all material was dissolved in dichloromethane. This solution was washed with water and brine, dried and evaporated, to give the title compound (1.64 g; 98%), m.p. 146°-149° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C:5]([CH3:25])([CH3:24])[CH2:6][CH2:7][CH2:8][CH2:9][C:10](=[CH2:23])[CH2:11][CH2:12][CH2:13][CH2:14][C:15]([CH3:22])([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH3:2].B.CSC.[OH:31]O.[OH-].[Na+]>C1COCC1>[CH2:1]([O:3][C:4](=[O:26])[C:5]([CH3:24])([CH3:25])[CH2:6][CH2:7][CH2:8][CH2:9][CH:10]([CH2:23][OH:31])[CH2:11][CH2:12][CH2:13][CH2:14][C:15]([CH3:22])([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH3:2]
Reactant: C=C(CCCCC(C)(C)C(=O)OCC)CCCCC(C)(C)C(=O)OCC
Reactant: OO
Agent: B
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CSC
Product: CCOC(=O)C(C)(C)CCCCC(CO)CCCCC(C)(C)C(=O)OCC
Reaction time: 6 h
Yield: 75 %

Procedure:
Into a stirred solution of 2,2,12,12-tetramethyl-7-methylene-tridecanedioic acid diethyl ester (3.7 g, 10 mmol) in anhydrous THF (50 mL) was added borane-methyl sulfide complex (2.0 M in THF, 6 mL, 12 mmol) at room temperature and the solution was stirred for 6 h under argon atmosphere. Hydrogen peroxide (50 wt. % solution in water, 9 mL, 144 mmol) and an aqueous solution of sodium hydroxide (30 mL, 2.5 M, 75 mmol) were slowly introduced at 0-5° C. The reaction mixture was stirred for an additional h at room temperature and then extracted with dichloromethane (3×100 mL). The combined organic layers were dried over sodium sulfate, filtered, evaporated, and purified by column chromatography on silica (hexanes:ethyl acetate=95:5, then 90:10) to furnish the product (2.9 g, 77%) as an oil. 1H NMR (300 MHz, CDCl3/TMS): δ (ppm): 4.11 (q, 4H, J=7.0 Hz), 3.51 (d, 2H, J=5.4 Hz), 1.60-1.16 (m, 18H), 1.25 (t, 6H, J=7.0 Hz), 1.15 (s, 12H). 13C NMR. (75 MHz, CDCl3/TMS): δ (ppm): 178.0, 65.3, 60.1, 42.0, 40.6, 40.4, 30.7, 27.2, 25.4, 25.1, 14.2. HRMS (LSIMS, nba): Calcd. for C22H43O5 (MH+): 387.3110. found 387.3108.