Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C:17]2[CH:45]=[CH:44][C:20]([C:21]([NH:23][C:24]3[CH:25]=[C:26]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH:27]=[CH:28][C:29]=3[NH:30]C(=O)OC(C)(C)C)=[O:22])=[CH:19][CH:18]=2)[CH2:13]1)(C(C)(C)C)(C)C>C(O)(C(F)(F)F)=O.O.CCOC(C)=O>[NH2:30][C:29]1[CH:28]=[CH:27][C:26]([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)=[CH:25][C:24]=1[NH:23][C:21](=[O:22])[C:20]1[CH:44]=[CH:45][C:17]([N:14]2[CH2:15][CH2:16][C@H:12]([NH:11][CH2:10][CH2:9][OH:8])[CH2:13]2)=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)cc1NC(=O)c1ccc(N2CC[C@H](NCCO[Si](C)(C)C(C)(C)C)C2)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(-c2ccccc2)cc1NC(=O)c1ccc(N2CC[C@H](NCCO)C2)cc1
Yield: 81.6 %

Procedure:
A solution of 443 (0.13 g, 0.206 mmol) in TFA (0.392 mL) and water (0.021 mL) was stirred for 2 h at room temperature. The solvent was evaporated and the residue obtained was dissolved in EtOAc, washed with sat NaHCO3 and sat NaCl. The organic layer was dried with MgSO4, filtered and concentrated to a brown solid. Trituration in Et2O generated the title compound 444 as a beige powder (70 mg, 82% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:19])([C@H:16]([OH:18])[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(OCC)(=O)C.ClCCl.C(N(CC)CC)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:19])([C@H:16]([O:18][S:21]([CH3:20])(=[O:23])=[O:22])[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: C[C@@H](O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C[C@@H](OS(C)(=O)=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
(2R,3R)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2,3-butanediol (1.25 g) was dissolved in a mixture of ethyl acetate (40 ml) and dichloromethane (10 ml), to which triethylamine (0.84 ml) and methanesulfonyl chloride (0.48 ml) were added under ice-cooling. The resultant solution was stirred for 30 minutes at room temperature. After adding ethyl acetate, the reaction mixture was washed with water, dried over anhydrous magnesium sulfate and concentrated to obtain (2R,3R)-2-(2,4-difluorophenyl)-3-methanesulfonyloxy-1-(1H-1,2,4-triazol-1-yl)-2-butanol as an oil. Thus obtained compound was dissolved in methanol (40 ml), to which sodium methylate methanolic solution (1.16 ml, 28%) was added under ice-cooling. The resultant solution was stirred for 30 minutes at room temperature. The reaction mixture was concentrated to about 10 ml under reduced pressure, and the residue was extracted with ethyl acetate (100 ml). The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate and distilled off the solvent under reduced pressure. The residue was subjected to a silica gel column chromatography (ethyl acetate- dichloromethane=4:l) for purification and then recrystallized from a mixture of ethyl acetate and hexane to give (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(1H-1,2,4-triazol-1-yl)methyl]oxirane (520 mg) as colorless needles.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[C:9]([S:23][CH3:24])[N:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[N:11]=[C:5]2[N:4]([CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:3]1=[O:30].OO.C(O)(=[O:35])C>C(Cl)Cl.CC#N>[CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[C:9]([S:23]([CH3:24])=[O:35])[N:10]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([S:19]([CH3:22])(=[O:20])=[O:21])=[CH:17][CH:18]=3)[N:11]=[C:5]2[N:4]([CH2:25][C:26]([CH3:27])([CH3:29])[CH3:28])[C:3]1=[O:30]
Reactant: CSc1c2c(=O)n(C)c(=O)n(CC(C)(C)C)c2nn1Cc1ccc(S(C)(=O)=O)cc1
Reactant: CC(=O)O
Agent: OO
Solvent: ClCCl
Solvent: CC#N
Product: Cn1c(=O)c2c(S(C)=O)n(Cc3ccc(S(C)(=O)=O)cc3)nc2n(CC(C)(C)C)c1=O
Temperature: 25 °C
Yield: 58.5 %

Procedure:
5-methyl-2-(4-(methylsulfonyl)benzyl)-3-(methylthio)-7-neopentyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (11.4 mg, 0.022 mmol) is dissolved in CH2Cl2 (200 μL) and CH3CN (100 μL), and then 30% H2O2 aqueous solution (75 μL, 0.66 mmol) is added, followed by acetic acid (6.6 mg, 0.11 mmol). The reaction mixture is stirred at room temperature over a weekend, and then purified by a semi-preparative HPLC to give 6 mg of product as white solids. MS (ESI) m/z 467.1 [M+H]+.
Reaction SMILES: COC1C=CC(C[N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([O:19][C:20]4[CH:21]=[CH:22][C:23]([F:27])=[C:24]([NH2:26])[CH:25]=4)[N:14]=3)[CH:10]=[N:9]2)=CC=1.C(O)(C(F)(F)F)=O>ClCCl>[NH:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([O:19][C:20]3[CH:21]=[CH:22][C:23]([F:27])=[C:24]([NH2:26])[CH:25]=3)[N:14]=2)[CH:10]=[N:9]1
Reactant: COc1ccc(Cn2cc(-c3ccnc(Oc4ccc(F)c(N)c4)n3)cn2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1cc(Oc2nccc(-c3cn[nH]c3)n2)ccc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 42.5 %

Procedure:
To a solution of 5-(4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyrimidin-2-yloxy)-2-fluorobenzenamine (50 mg, 0.13 mmol) in dichloromethane (3 mL) was added TFA (0.3 mL) at 0° C. and the reaction stirred at RT for 12 h. The solvent was removed in vacuo, the residue was washed with ether and treated with saturated ammonia solution. The solid was collected via filtration and dried under vacuum to give 5-(4-(1H-pyrazol-4-yl)pyrimidin-2-yloxy)-2-fluorobenzenamine (15 mg, 43% yield). 1H NMR (300 MHz, MeOD) δ 8.44 (d, J=5.1 Hz, 1H), 8.23 (br s, 2H), 7.40 (d, J=5.4, 1H), 7.02 (dd, J=10.8, 8.7 Hz, 1H), 6.73 (dd, J=2.7, 7.2 Hz, 1H), 6.50 (m, 1H); MS (ESI) m/z: 272.2 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH3:14])[CH3:2].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[S:27][C:28]([CH2:32][CH2:33]O)=[C:29]([CH3:31])[N:30]=2)=[CH:22][CH:21]=1.C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:33][CH2:32][C:28]2[S:27][C:26]([C:23]3[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=3)=[N:30][C:29]=2[CH3:31])=[CH:9][C:8]=1[CH3:14])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1C)OCC
Reactant: Cc1nc(-c2ccc(Cl)cc2)sc1CCO
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CCOC(=O)C(Cc1ccc(OCCc2sc(-c3ccc(Cl)cc3)nc2C)cc1C)OCC

Procedure:
In analogy to the procedure described in example 10 c], [rac]-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethyl ester (example 10 b]) was reacted with 2-[2-(4-chloro-phenyl)-4-methyl-thiazol-5-yl]-ethanol in the presence of tributylphosphine and N,N,N′,N′-tetramethyl azodicarboxamide to yield [rac]-3-(4-{2-[2-(4-chloro-phenyl)-4-methyl-thiazol-5-yl]-ethoxy}-2-methyl-phenyl)-2-ethoxy-propionic acid ethyl ester as colorless liquid.
Reaction SMILES: [I:1][C:2]1[CH:12]=[CH:11][C:5]([C:6](OCC)=[O:7])=[CH:4][N:3]=1.[BH4-].[Na+].O>C(O)C.C(OCC)C>[I:1][C:2]1[N:3]=[CH:4][C:5]([CH2:6][OH:7])=[CH:11][CH:12]=1
Reactant: CCOC(=O)c1ccc(I)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Solvent: O
Product: OCc1ccc(I)nc1
Temperature: 6 °C
Reaction time: 1 h
Yield: 68.1 %

Procedure:
40 g (145 mmol) of ethyl 6-iodonicotinate diluted in 400 mL of ethanol are added dropwise to a solution at 0° C. of 27.3 g (−722 mmol) of sodium borohydride in 270 mL of ethanol. For the addition, the temperature of the reaction mixture is maintained from 2 and 6° C., and then at 0° C. for 1 hour and at room temperature for 20 hours. The reaction is worked up by addition of 200 mL of water, and a white precipitate forms. The reaction mixture is filtered off; the filtrate is evaporated under vacuum to give the product in the form of a yellow paste. The product is placed in 300 mL of diethyl ether and then filtered to give 23.2 g (68%) of (6-iodopyrid-3-yl)methanol in the form of a pale yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][O:10][C:9]2=[O:19])[C:5]([F:20])=[CH:4][N:3]=1.[CH:21]1([C@@H:24]([NH2:26])[CH3:25])[CH2:23][CH2:22]1.CCN(C(C)C)C(C)C>CS(C)=O.O>[CH:21]1([C@@H:24]([NH:26][C:2]2[N:7]=[C:6]([N:8]3[C@@H:12]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH2:11][O:10][C:9]3=[O:19])[C:5]([F:20])=[CH:4][N:3]=2)[CH3:25])[CH2:23][CH2:22]1
Reactant: C[C@H](N)C1CC1
Reactant: O=C1OC[C@H](c2ccccc2)N1c1nc(Cl)ncc1F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: C[C@H](Nc1ncc(F)c(N2C(=O)OC[C@@H]2c2ccccc2)n1)C1CC1
Temperature: 127.5 °C
Yield: 55.8 %

Procedure:
A mixture of (S)-3-(2-chloro-5-fluoropyrimidin-4-yl)-4-phenyloxazolidin-2-one (40 mg, 0.136 mmol), (S)-1-cyclopropylethanamine (34.8 mg, 0.409 mmol), Hunig's Base (0.119 mL, 0.681 mmol) in DMSO (0.4 mL) was heated under argon at 105-115° C. for ˜18 hrs (alternative: 120-135° C. for ˜90 min). Then mixture was allowed to cool to room temperature. The mixture was diluted with DMSO and water (˜10 vol. % of DMSO), filtered through a syringe filter and purified by reverse phase HPLC. Selected fractions were collected and lyophilized providing (S)-3-(2-((S)-1-cyclopropylethylamino)-5-fluoropyrimidin-4-yl)-4-phenyloxazolidin-2-one (26 mg) as a white solid as its trifluoroacetic acid salt.
Reaction SMILES: [C:1]12([C:14]([OH:16])=[O:15])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][C:3]([C:11]([OH:13])=[O:12])([CH2:4]3)[CH2:2]1)[CH2:8]2.I[CH:18]([CH3:20])[CH3:19].N1(C2CCCCCCCCCC2)CCCN=CCC[CH2:24][CH2:23][CH2:22]1>C(#N)C.C(OCC)(=O)C>[C:1]12([C:14]([O:16][CH:23]([CH3:24])[CH3:22])=[O:15])[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][C:3]([C:11]([O:13][CH:18]([CH3:20])[CH3:19])=[O:12])([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: CC(C)I
Reactant: O=C(O)C12CC3CC(C1)CC(C(=O)O)(C3)C2
Reactant: C1=NCCCN(C2CCCCCCCCCC2)CCCCC1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)OC(=O)C12CC3CC(C1)CC(C(=O)OC(C)C)(C3)C2
Temperature: 25 °C

Procedure:
Diisopropyl 1,3-adamantanedicarboxylate is prepared by way of the following procedure. A 50 mL round bottom flask equipped with magnetic stir bar is charged with 1,3-admantanedicarboxylic acid (2.76 g, 12.3 mmol), 2-iodopropane (3.07 mL, 30.8 mmol) and 1,8-diazabicycloundec-7-ene (4.60 mL, 30.8 mmol) in 25 mL acetonitrile. The mixture is heated to reflux overnight and cooled to room temperature. The reaction is diluted with 100 mL of ethyl acetate and washed with saturated NH4Cl/1N HCl, water, saturated sodium bicarbonate, and then brine. The organic layer is dried over sodium sulfate. After filtration, the filtrate is concentrated, and the residue is dried in vacuo. The crude product is further purified by distillation in vacuo to yield the product as a white liquid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[N:6][CH:7]=1.[CH2:12](O)[CH3:13]>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[N:6][CH:7]=1
Reactant: O=C(O)Cc1cncc(Br)c1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1cncc(Br)c1
Temperature: 25 °C

Procedure:
15 drops of concentrated sulfuric acid are added to 5.0 g (23.1 mmol) of (5-bromopyridin-3-yl)acetic acid in 30 ml of ethanol, and the mixture is heated under reflux for 16 h. After cooling to RT, the mixture is concentrated under reduced pressure and the residue is taken up in ethyl acetate and washed with semiconcentrated sodium bicarbonate solution. The organic phase is dried over sodium sulfate, filtered and concentrated under reduced pressure.
Reaction SMILES: [N:1]([CH:4]([C:9]1[CH:14]=[CH:13][C:12]([S:15][CH2:16][CH2:17][CH3:18])=[CH:11][CH:10]=1)[C:5]([CH3:8])([CH3:7])[CH3:6])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.Cl>C1COCC1.CO>[CH3:6][C:5]([CH3:7])([CH3:8])[CH:4]([C:9]1[CH:10]=[CH:11][C:12]([S:15][CH2:16][CH2:17][CH3:18])=[CH:13][CH:14]=1)[NH2:1]
Reactant: CCCSc1ccc(C(N=[N+]=[N-])C(C)(C)C)cc1
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCCSc1ccc(C(N)C(C)(C)C)cc1
Temperature: 50 °C
Yield: 90.9 %

Procedure:
To a stirred solution of 1-(1-azido-2,2-dimethylpropyl)-4-(propylthio)benzene (282 mg, 1.07 mmol) in THF (8 ml) were added triphenylphosphine (842 mg, 3.21 mmol) and water (2 ml). The mixture was heated at 50° C. for 18 hours then allowed to cool to room temperature. Methanol (10 ml) was added and the mixture was passed through an SCX cartridge, which had been pre-treated with HCl in MeOH, eluting first with several column lengths of methanol to remove the triphenylphosphine oxide, then with 2M solution of ammonia in methanol to elute the product. The appropriate fractions were evaporated to give the title product as a pale yellow oil (231 mg). 1H NMR 3 (CDCl3) 7.27-7.19 (4H, m), 3.67 (1H, s), 2.89 (2H, t, J=7.3 Hz), 1.72-1.62 (2H, m), 1.02 (3H, t, J=7.3 Hz), 0.89 (9H, s).
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]1[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][C:6]2[NH:7][C:8](=[O:25])[CH2:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[C:22]([CH2:23]O)=[CH:21][N:20]=[N:19]4)[CH:13]=3)=[N:11][C:5]=2[CH:4]=1.O=S(Cl)Cl.[CH:37]1([NH2:40])[CH2:39][CH2:38]1>>[CH:37]1([NH:40][CH2:23][C:22]2[N:18]([C:14]3[CH:13]=[C:12]([C:10]4[CH2:9][C:8](=[O:25])[NH:7][C:6]5[CH:26]=[C:27]([C:28]([F:29])([F:31])[F:30])[C:3]([N:2]([CH3:32])[CH3:1])=[CH:4][C:5]=5[N:11]=4)[CH:17]=[CH:16][CH:15]=3)[N:19]=[N:20][CH:21]=2)[CH2:39][CH2:38]1
Reactant: NC1CC1
Reactant: CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2
Solvent: O=S(Cl)Cl
Product: CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3nncc3CNC3CC3)c1)=N2

Procedure:
The title compound was prepared from 7-dimethylamino-4-[3-(5-hydroxymethyl-[1,2,3]triazol-1-yl)-phenyl]-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 17) (444 mg, 1.0 mmol) by treatment with SOCl2 (3 eq.) and cyclopropyl amine (10 eq.) as described in Example 45. Obtained as a yellow solid (248 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][CH2:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][C:3]=1[N:22]1[C:26]2=[N:27][C:28]([C:32]#[N:33])=[CH:29][C:30]([CH3:31])=[C:25]2[NH:24][C:23]1=[O:34].[Cl-].[NH4+].[N-:37]=[N+:38]=[N-:39].[Na+].O>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][CH2:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][C:3]=1[N:22]1[C:26]2=[N:27][C:28]([C:32]3[NH:39][N:38]=[N:37][N:33]=3)=[CH:29][C:30]([CH3:31])=[C:25]2[NH:24][C:23]1=[O:34]
Reactant: Cc1cc(C#N)nc2c1[nH]c(=O)n2-c1cc(S(=O)(=O)N2CCCCc3ccccc32)ccc1Cl
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(-c2nnn[nH]2)nc2c1[nH]c(=O)n2-c1cc(S(=O)(=O)N2CCCCc3ccccc32)ccc1Cl
Temperature: 60 °C
Reaction time: 1 h
Yield: 64.6 %

Procedure:
To a solution of 3-[2-chloro-5-(2,3,4,5-tetrahydro-1H-1-benzoazepin-1-ylsulfonyl)-phenyl]-5-cyano-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (47 mg) in N,N-dimethylformamide (1.5 mL) were added ammonium chloride (0.1 g) and sodium azide (0.12 g), and the mixture was stirred at 60° C. for 1 hour, and then stirred at 120° C. for 3 hours. The reaction mixture was cooled to room temperature, and diluted with ethyl acetate. To the mixture was added water, and the organic layer was separated. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residual solids were suspended in a mixed solvent (n-hexane/ethyl acetate=3/1), and collected by filtration. The collected solids were dried under reduced pressure to give the title compound (33 mg).
Reaction SMILES: [C:1]1([CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:8][C:9]([CH2:11][N:12]2[CH2:15][CH:14]([NH2:16])[C:13]2=[O:17])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:24]([CH2:31][C:32](Cl)=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>C1COCC1.O>[C:18]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][C:9]([CH2:11][N:12]2[CH2:15][CH:14]([NH:16][C:32](=[O:33])[CH2:31][O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:13]2=[O:17])=[O:10])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NC1CN(CC(=O)OC(c2ccccc2)c2ccccc2)C1=O
Reactant: O=C(Cl)COc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(COc1ccccc1)NC1CN(CC(=O)OC(c2ccccc2)c2ccccc2)C1=O

Procedure:
For example, N-(diphenylmethoxycarbonylmethyl)-3-amino- 2-azetidinone is reacted in THF-water with phenoxyacetyl chloride in the presence of triethylamine to provide N-(diphenylmethoxycarbonylmethyl)-3-phenoxyacetamido-2-azetidinone. Treatment of the product with trifluoroacetic acid in the presence of anisole removes the diphenylmethyl ester group to provide the N-(carboxymethyl)azetidinone.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]([O:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[N:21]=[C:20]([CH3:23])[CH:19]=[CH:18]2)[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Se](=O)=[O:25]>O1CCOCC1.O>[Si:1]([O:8][CH2:9][C@H:10]([O:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[N:21]=[C:20]([CH:23]=[O:25])[CH:19]=[CH:18]2)[CH3:11])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=[Se]=O
Reactant: Cc1ccc2cccc(O[C@H](C)CO[Si](C)(C)C(C)(C)C)c2n1
Solvent: C1COCCO1
Solvent: O
Product: C[C@H](CO[Si](C)(C)C(C)(C)C)Oc1cccc2ccc(C=O)nc12
Yield: 83.9 %

Procedure:
To a solution of (R)-8-(1-(tert-butyldimethylsilyloxy)propan-2-yloxy)-2-methylquinoline (0.33 g, 1.0 mmol) in dioxane (40 mL) and water (0.4 mL) was added selenium dioxide (0.13 g, 1.2 mmol) and the resultant mixture heated at reflux for 1 hour. The cooled reaction mixture was filtered through a plug of Celite® to remove solids, rinsing with dichloromethane and the filtrate was concentrated under reduced pressure. The residue was purified by normal phase chromatography on silica gel (10% ethyl acetate/hexanes) providing the title compound (0.29 g, 84%).
Reaction SMILES: [CH3:1][N:2]([CH2:34][C@H:35]([OH:44])[C@@H:36]([OH:43])[C@H:37]([OH:42])[C@H:38]([OH:41])[CH2:39][OH:40])[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19](=[O:33])[C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=4)=[C:22]([CH3:32])[CH:21]=3)[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].C(N(CC)C(C)C)(C)C.[C:54](OCC)(=[O:56])C>ClCCl>[C:26]1([C:23]2[CH:24]=[CH:25][C:20]([C:19]([N:10]3[C:11]4[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=4[CH2:13][N:14]4[C:5]([C:3]([N:2]([CH2:34][C@@H:35]([C@@H:36]5[C@@H:37]([C@H:38]([OH:41])[CH2:39][OH:40])[O:42][C:54](=[O:56])[O:43]5)[OH:44])[CH3:1])=[O:4])=[CH:6][CH:7]=[C:8]4[CH2:9]3)=[O:33])=[CH:21][C:22]=2[CH3:32])[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=1
Reactant: CCOC(C)=O
Reactant: Cc1cc(C(=O)N2Cc3ccc(C(=O)N(C)C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO)n3Cc3ccccc32)ccc1C1=CCCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(C(=O)N2Cc3ccc(C(=O)N(C)C[C@H](O)[C@H]4OC(=O)O[C@@H]4[C@H](O)CO)n3Cc3ccccc32)ccc1C1=CCCCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
10-(4-Cyclohex-1-en-1-yl-3-methyl-benzoyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid methyl-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxy-hexyl]-amide of Example 5 (0.190 g, 0.315 mmol), and N,N-diisopropylethylamine (0.110 mL, 0.315 mmol) were dissolved in anhydrous dichloromethane (6.3 mL) and the solution cooled to 0° C. N,N′-Carbonyldiimidazole (0.051 g, 0.315 mmol) was added and the reaction stirred at 0° C. for 1 hour, then warmed to room temperature and stirring continued for 12 hours. The solution was diluted with ethyl acetate and washed with water, 0.1 N hydrochloric acid and brine. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated. Purification of the residue by flash column chromatography on silica gel eluting with ethyl acetate, afforded 0.140 g of the title compound as a white, partially crystalline solid, m.p. 166-175° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([O:9][CH3:10])[CH:3]=1.[CH3:11][C:12]1[N:13]=[CH:14][S:15][C:16]=1[CH2:17][CH2:18]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:18][CH2:17][C:16]2[S:15][CH:14]=[N:13][C:12]=2[CH3:11])=[C:4]([O:9][CH3:10])[CH:3]=1
Reactant: Cc1ncsc1CCO
Reactant: COc1cc(Br)ccc1O
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc(Br)ccc1OCCc1scnc1C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of 4-bromo-2-methoxy-phenol (50.8 mg, 0.25 mmol), 2-(4-methyl-thiazol-5-yl)-ethanol (49.5 mg, 0.25 mmol) and polymer-supported triphenyl phosphine (250 mg, 0.75 mmol) in THF (2.5 mL) was stirred at room temperature for 20 minutes. DBAD (86.3 mg, 0.375 mmol) was added and the mixture was stirred overnight at room temperature. The reaction mixture was filtered through Celite®, rinsing with THF and methanol. The filtrate was concentrated, diluted with ethyl acetate, washed with water and brine, dried (MgSO4), filtered and concentrated. The concentrate was purified by column chromatography on silica gel (10 to 20% ethyl acetate in hexane) to give the title compound. MS (ESI) m/e 329 (M+H)+; 1H NMR (300 MHz, DMSO-d6) □ 8.82 (s, 1H), 7.12 (d, J=2.4 Hz, 1H), 7.03 (dd, J=8.5, 2.4 Hz, 1H), 6.91 (d, J=8.5 Hz, 1H), 4.10 (t, J=6.4 Hz, 2H), 3.77 (s, 3H), 3.20 (t, J=6.4 Hz, 2H), 2.35 (s, 3H).
Reaction SMILES: [OH-].[Na+].[C:3]1([SH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:11][CH2:12][CH2:13][Cl:14]>O>[C:3]1([S:9][CH2:11][CH2:12][CH2:13][Cl:14])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Sc1ccccc1
Reactant: ClCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: ClCCCSc1ccccc1

Procedure:
To a solution containing 1.1 mole sodium hydroxide in 500 ml water are added 1 mole thiophenol and 2 moles 1-bromo-3-chloro-propane. The mixture is then refluxed for 30 hours, with vigorous stirring. After cooling, the resulting material is extracted with methylene chloride. After washing with dilute lye, and then with water, the solvent is evaporated in vacuo. The product, 3-phenylthio-1-chloropropane, distills at 138°-140° C. under 13 mm Hg.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([I:10])[C:7]([NH2:11])=[C:6]([NH2:12])[CH:5]=1.[CH:14](OC)(OC)OC>C1COCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]([I:10])[C:7]2[N:11]=[CH:14][NH:12][C:6]=2[CH:5]=1)=[O:13]
Reactant: COC(=O)c1cc(N)c(N)c(I)c1
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(I)c2nc[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.1 %

Procedure:
To a solution of 3,4-diamino-5-iodo-benzoic acid methyl ester (1.68 g, 5.75 mmol) in THF (20 mL) was added trimethyl orthoformate (1.26 mL, 11.5 mmol) and 4-toluenesulfonic acid (11 mg, 0.057 mmol). The mixture was stirred at room temperature overnight, then partitioned between ethyl acetate and water. The organic layer was separated, dried over MgSO4, filtered and concentrated under reduced pressure to give 783 mg (45%) of 7-Iodo-3H-benzoimidazole-5-carboxylic acid methyl ester, MS (M+H)=303.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([N:10]2[CH2:17][CH:16]3[CH:12]([CH2:13][N:14]([CH3:18])[CH2:15]3)[CH2:11]2)[CH:7]=[CH:6][C:5]=1[N+:19]([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:19][C:5]1[CH:6]=[CH:7][C:8]([N:10]2[CH2:11][CH:12]3[CH:16]([CH2:15][N:14]([CH3:18])[CH2:13]3)[CH2:17]2)=[CH:9][C:4]=1[C:3]([NH:2][CH3:1])=[O:22]
Reactant: CNC(=O)c1cc(N2CC3CN(C)CC3C2)ccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CNC(=O)c1cc(N2CC3CN(C)CC3C2)ccc1N
Yield: 101.7 %

Procedure:
N-methyl-5-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-2-nitrobenzamide (Intermediate 13A) (900 mg, 2.96 mmol) was dissolved in ethanol (140 mL). The resulting solution was hydrogenated using the H-cube at 40° C. under 30 bar pressure of hydrogen, with a flow rate of 1 mL per minute through a 10% palladium on charcoal cartridge. The reaction mixture was concentrated to afford 2-amino-N-methyl-5-(5-methylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)benzamide, (824 mg, 3.01 mmol).