Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9](CC2C=CC(OC)=CC=2OC)[C:8](=[O:23])[C:7]1=[O:24])=[N+:2]=[N-:3].FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>>[N:1]([CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][NH:9][C:8](=[O:23])[C:7]1=[O:24])=[N+:2]=[N-:3]
Reactant: COc1ccc(CN2CCN(CCN=[N+]=[N-])C(=O)C2=O)c(OC)c1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: [N-]=[N+]=NCCN1CCNC(=O)C1=O
Yield: 89.7 %

Procedure:
A mixture of 3.65 g of 1-(2-azidoethyl)-4-(2,4-dimethoxybenzyl)-2,3-dioxopiperazine, 14.6 ml of trifluoroacetic acid and 7.3 ml of anisole was refluxed for 2 hours. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent; chloroform: methanol=20:1) to obtain 1.8 g of 1-(2-azidoethyl)-2,3-dioxopiperazine as an oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([CH3:10])[CH:3]=1.C(NC(C)C)(C)C.[CH3:18][Si:19]([C:22]#[CH:23])([CH3:21])[CH3:20]>C1(C)C=CC=CC=1.[Cu](I)I>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:23]#[C:22][Si:19]([CH3:21])([CH3:20])[CH3:18])=[CH:3][C:4]=1[CH3:10]
Reactant: C#C[Si](C)(C)C
Reactant: COc1ccc(Br)cc1C
Agent: I[Cu]I
Solvent: Cc1ccccc1
Solvent: CC(C)NC(C)C
Product: COc1ccc(C#C[Si](C)(C)C)cc1C
Temperature: 45 °C

Procedure:
A solution of 4-bromo-1-methoxy-2-methylbenzene (6.702 g) in toluene was treated with tetrakis(triphenylphosphie)palladium (0) (1.15 g), followed by diisopropylamine (23 mL), trimethylsilyl acetylene (4.7 mL) and copper iodide (I) (0.127 g). The reaction was heated at 45° C. in nitrogen atmosphere overnight and evaporated to dryness. The resultant residue was applied on a large silica pad and eluted with hexane:ethyl acetate (2:1). The elute was evaporated to dryness to give the silane intermediate as a brown oil (7.167 g). The compound was characterized by LCMS analysis. LCMS Conditions: HP 1100 HPLC system; Waters Xterra MS C18, 2 mm (i.d.)×50 mm (length), 3.5 um column, set at 50° C.; Flow rate 1.0 mL/min; Solvent A: 0.02% NH4OH in water; Solvent B 0.02% NH4OH in ACN; Gradient: Time O: 10% B; 2.5 min 90% B; 3 min 90% B; Sample concentration: ˜2.0 mM; Injection volume: 5 uL; Detection: 220 nm, 254 nm DAD
Reaction SMILES: [CH3:1][C:2]([CH3:18])([O:4][C:5]([NH:7][C@@H:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][C@@H:9]1[OH:17])=[O:6])[CH3:3].C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl>[CH3:3][C:2]([CH3:18])([O:4][C:5]([NH:7][C@@H:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][C@@H:9]1[O:17][S:27]([CH3:26])(=[O:29])=[O:28])=[O:6])[CH3:1]
Reactant: CC(C)(C)OC(=O)N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H]1c2ccccc2C[C@@H]1OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.7 %

Procedure:
Cis-1-[(1,1-Dimethylethoxy)carbonylamino]-2-hydroxyindan (Method 5; 14.0 g, 56.2 mmol) was dissolved in DCM (200 ml) and triethylamine (11.8 ml, 84.3 mmol). Methanesulfonyl chloride (7.1 g, 61.9 mmol) dissolved in DCM (20 ml) was added and the mixture stirred at room temperature for 3 hours. The mixture was evaporated and EtOAc (250 ml) added. After washing with water and drying over magnesium sulphate the organic solution was evaporated to yield Cis-1-[(1,1-dimethylethoxy)carbonylamino]-2-methanesulphonyloxyindan (9.7 g, 98%) as a white solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)=[CH:15][C:14]([C:27]([F:30])([F:29])[F:28])=[N:13]2)=[CH:8][CH:7]=1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[OH:3][CH2:4][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([C:17]3[CH:18]=[CH:19][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:21][CH:22]=3)=[CH:15][C:14]([C:27]([F:28])([F:29])[F:30])=[N:13]2)=[CH:8][CH:7]=1
Reactant: CCOC(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(S(C)(=O)=O)cc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(CO)cc2)cc1
Temperature: 55 °C
Reaction time: 2 h
Yield: 59.9 %

Procedure:
A mixture of 1-[4-(ethoxycarbonyl)phenyl]-5-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)pyrazole (2.4 g) and lithium aluminum hydride (0.25 g) in tetrahydrofuran (20 ml) was stirred at 55° C. for 2 hours. The reaction was quenched with methanol and water, and the mixture was filtered. The filtrate was concentrated and the residue was dissolved in a mixture of ethyl acetate and tetrahydrofuran. The solution was washed with water, dried, and evaporated. The residue was purified by column chromatography on silica gel eluting with a mixture of chloroform and methanol (20:1) to give a white powder of 1-[4-(hydroxymethyl)phenyl]-5-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)pyrazole (1.3 g).
Reaction SMILES: [O:1]([C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH:19]=O)[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[CH:9]=O.[C:26]([NH:29][NH2:30])([NH2:28])=[NH:27].[ClH:31]>CO.Cl.Cl.NNC(N)=N>[ClH:31].[ClH:31].[C:26]([NH:29][N:30]=[CH:19][C:18]1[CH:21]=[CH:22][C:23]([O:24][CH3:25])=[C:16]([O:1][CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=2[O:14][CH3:15])[CH:9]=[N:30][NH:29][C:26](=[NH:27])[NH2:28])[CH:17]=1)(=[NH:28])[NH2:27]
Reactant: N=C(N)NN
Reactant: COc1ccc(C=O)cc1OCCCOc1cc(C=O)ccc1OC
Agent: Cl
Solvent: CO
Product: COc1ccc(C=NNC(=N)N)cc1OCCCOc1cc(C=NNC(=N)N)ccc1OC
Yield: 86.5 %

Procedure:
3,3'-(trimethylenedioxy)di-p-anisaldehyde (1.032 g), aminoguanidine hydrochloride (0.829 g), and aminoguanidine dihydrochloride (0.02 g) were heated in 95% methanol (10.5 mL) for 16 hr. Cooling and filtration gave 1.372 g of 3,3'-(trimethylenedioxy)di-p-anisaldehyde bis(amidinohydrazone) dihydrochloride, mp 233-5° C.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15](Br)[N:14]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1)#[N:2].[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:1]([CH2:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:14]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1)#[N:2]
Reactant: OB(O)c1ccccc1
Reactant: N#CCc1cccc(NC(=O)c2cccc(Br)n2)c1
Product: N#CCc1cccc(NC(=O)c2cccc(-c3ccccc3)n2)c1

Procedure:
The pyridyl bromide (91) (150 mg, 0.47 mmol) was coupled to phenylboronic acid (64 mg, 0.52 mmol) using Method E. The crude residue was purified by column chromatography eluting with 20% EtOAc in heptane to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C@@H:4]([NH:18][C:19](=[O:28])[C:20]1[CH:25]=[C:24]([Br:26])[CH:23]=[CH:22][C:21]=1[OH:27])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH3:1][O:2][C:3](=[O:29])[C@@H:4]([NH:18][C:19](=[O:28])[C:20]1[CH:25]=[C:24]([Br:26])[CH:23]=[CH:22][C:21]=1[O:27][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][CH:11]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cc(Br)ccc1O
Reactant: BrCc1ccccc1
Product: COC(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cc(Br)ccc1OCc1ccccc1
Yield: 45.6 %

Procedure:
2-(S)-(2-Benzyloxy-5-bromo-benzoylamino)-3-biphenyl-4-yl-propionic acid methyl ester (82 mg) was prepared from 3-biphenyl-4-yl-2-(S)-(5-bromo-2-hydroxy-benzoylamino)-propionic acid methyl ester (150 mg, 0.33 mmol) and benzyl bromide (0.047 mL, 0.40 mmol) as described in general procedure G and purified over silica gel (7:3, DCM-hexanes).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][CH2:7][C:6](=O)[CH:5]([CH2:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=O)[CH2:4]1.[NH2:19][C:20]1[CH:28]=[C:24]([C:25]([OH:27])=[O:26])[C:23]([OH:29])=[CH:22][CH:21]=1>C(O)(=O)C>[C:25]([C:24]1[CH:28]=[C:20]([N:19]2[C:6]3[CH2:7][CH2:8][CH:3]([O:2][CH3:1])[CH2:4][C:5]=3[CH:10]=[C:11]2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:21]=[CH:22][C:23]=1[OH:29])([OH:27])=[O:26]
Reactant: Nc1ccc(O)c(C(=O)O)c1
Reactant: COC1CCC(=O)C(CC(=O)c2ccccc2)C1
Solvent: CC(=O)O
Product: COC1CCc2c(cc(-c3ccccc3)n2-c2ccc(O)c(C(=O)O)c2)C1

Procedure:
A mixture of 24.6 g. (0.1 mole) of 4-methoxy-2-phenacylcyclohexanone, 15.3 g. (0.1 mole) of 5-aminosalicylic acid, and 80 ml. of glacial acetic acid was heated under reflux for 1.5 hours, filtered, cooled and again filtered. The collected solid was washed with acetic acid and petroleum ether and recrystallized from acetonitrile to provide 22.5 g. (62%) of crystals, m.p. 207°-210°.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][S:10]2(=[O:15])=[O:14])[CH:5]=[CH:4][C:3]=1[C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][N:25]=2)[CH2:20][CH2:19]1)=[O:17].[CH3:32]B(O)O>>[CH3:30][C:29]1[C:24]([N:21]2[CH2:22][CH2:23][N:18]([C:16]([C:3]3[CH:4]=[CH:5][C:6]([CH2:8][N:9]4[CH2:13][CH2:12][CH2:11][S:10]4(=[O:15])=[O:14])=[CH:7][C:2]=3[CH3:32])=[O:17])[CH2:19][CH2:20]2)=[N:25][CH:26]=[C:27]([CH3:31])[CH:28]=1
Reactant: CB(O)O
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(CN4CCCS4(=O)=O)cc3Br)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(CN4CCCS4(=O)=O)cc3C)CC2)c(C)c1
Yield: 86 %

Procedure:
Using [2-bromo-4-(1,1-dioxo-1λ6-isothiazolidin-2-ylmethyl)phenyl][4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (120 mg) described in Example 461 and methylboronic acid (42 mg) and by the reaction and treatment in the same manner as in Example 115, the title compound (90 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH2:11](O)[CH2:12][OH:13]>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:7]2[O:13][CH2:12][CH2:11][O:8]2)[CH:9]=1
Reactant: OCCO
Reactant: O=Cc1cc(Cl)ccc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Oc1ccc(Cl)cc1C1OCCO1
Temperature: 25 °C
Yield: 95.8 %

Procedure:
A mixture of 5-chloro-2-hydroxybenzaldehyde (20.0 g, 0.128 mol), ethane-1,2-diol (40.0 g, 0.644 mol) and p-toluenesulfonic acid monohydrate (0.44 g, 2.56 mmol) dissolved in toluene (200 mL) was refluxed for 40 h with a dean-stark to remove water. After the reaction mixture was cooled to room temperature, EtOAc (200 mL) was added. Then the organic phase was washed with saturated NaHCO3 solution, dried over anhydrous Na2SO4 and concentrated to give the title compound as a light-yellow solid (24.6 g).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:14][O:13]1.C(Cl)Cl>CO>[CH3:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[C@@H:12]1[CH2:14][O:13]1
Reactant: Cc1c(C2CO2)ccc2c1COC2=O
Solvent: CO
Solvent: ClCCl
Product: Cc1c([C@@H]2CO2)ccc2c1COC2=O
Reaction time: 0.04 h

Procedure:
Racemic 4-methyl-5-oxiran-2-yl-2-benzofuran-1(3H)-one was resolved on a ChiralPak® AD-H column (5×25 cm) under SFC conditions on a Berger MGIII preparative SFC instrument. The racemate was diluted to 50 mg/ml in 1:1 DCM:MeOH. The separation was accomplished using 10% EtOH/CO2, flow rate 200 ml/min, 100 bar, 25° C. 500 ul Injections were spaced every 2.12 mins. The faster eluting (2R)-epoxide (I-15B) eluted at 5.2 min, and the slower eluting (2S)-epoxide (I-15A) eluted at 5.6 min.
Reaction SMILES: Cl.[CH3:2][C:3]1[O:4][C:5]2[C:14]3[CH:13]([CH2:15][CH2:16][NH2:17])[CH2:12][CH2:11][C:10]=3[CH:9]=[CH:8][C:6]=2[N:7]=1.C(N(CC)CC)C.[C:25]([O:28][CH:29]([CH3:33])[C:30](Cl)=[O:31])(=[O:27])[CH3:26]>O1CCCC1>[C:25]([O:28][CH:29]([CH3:33])[C:30]([NH:17][CH2:16][CH2:15][CH:13]1[C:14]2[C:5]3[O:4][C:3]([CH3:2])=[N:7][C:6]=3[CH:8]=[CH:9][C:10]=2[CH2:11][CH2:12]1)=[O:31])(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)C(=O)Cl
Reactant: Cc1nc2ccc3c(c2o1)C(CCN)CC3
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)OC(C)C(=O)NCCC1CCc2ccc3nc(C)oc3c21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40 %

Procedure:
2-(2-Methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethanamine hydrochloride (150 mg, 0.593 mmol) and triethylamine (166 μL, 1.19 mmol) were dissolved in tetrahydrofuran (5 mL), 2-chloro-1-methyl-2-oxoethyl acetate (108 mg, 0.712 mmol) was added, and the mixture was stirred at room temperature for 30 min. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=70/30→100/0) to give the title compound (78.4 mg, yield 40%).
Reaction SMILES: [C:1]([CH2:4][N:5]([C:10](=[O:44])[C:11]1[CH:16]=[C:15]([O:17]CC2C=CC=CC=2)[CH:14]=[C:13]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH:12]=1)[CH2:6][C:7]([OH:9])=[O:8])([OH:3])=[O:2].[H][H]>[Pd].C1COCC1>[C:7]([CH2:6][N:5]([C:10](=[O:44])[C:11]1[CH:12]=[C:13]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH:14]=[C:15]([OH:17])[CH:16]=1)[CH2:4][C:1]([OH:3])=[O:2])([OH:9])=[O:8]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(OCc2ccccc2)cc(C(=O)N(CC(=O)O)CC(=O)O)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCOc1cc(O)cc(C(=O)N(CC(=O)O)CC(=O)O)c1

Procedure:
A mixture of 0.30 g of N-(carboxymethyl)-N-[3-(octadecyloxy)-5-(phenylmethoxy)benzoyl]glycine and 0.1 g of 10% palladium on carbon in 25 ml of THF was stirred in a hydrogen atmosphere for 2 hours. The usual workup followed by recrystallization from ether-hexane gave N-(carboxymethyl)-N-[3-hydroxy-5-(octadecyloxy)benzoyl]glycine, mp 160°-164°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20]>O1CCCC1>[F:10][C:8]([F:9])([F:11])[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:19](=[O:20])[O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:7]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1cc(C(F)(F)F)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(Nc1cc(C(F)(F)F)ccn1)Oc1ccccc1

Procedure:
According to the procedure described in Example 113B, 2-amino-4-trifluoromethylpyridine (462 mg, 2.85 mmoles) was dissolved in 20 ml of tetrahydrofuran. To this solution was added potassium carbonate (511 mgs, 3.7 mmoles) followed by phenyl chloroformate (521 mgs, 3.33 mmoles). The mixture was concentrated and purified according to the procedure in Example 138 to afford phenyl 4-(trifluoromethyl)pyridin-2-ylcarbamate. 1H NMR (300 MHz, CDCl3) δ 9.53 (s, 1H), 8.56 (m, 1H), 8.38 (s, 1H), 7.6-7.4 (m, 2H), 7.3-7.2 (m, 2H), 6.8 (m, 1H).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:8]([OH:13])=[C:9]([O:11]C)[CH:10]=1)[C:6]#[N:7])=[O:2].B(Br)(Br)Br>ClCCl>[CH:1]([C:3]1[CH:4]=[C:5]([C:8]([OH:13])=[C:9]([OH:11])[CH:10]=1)[C:6]#[N:7])=[O:2]
Reactant: COc1cc(C=O)cc(C#N)c1O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: N#Cc1cc(C=O)cc(O)c1O
Temperature: 0 °C
Yield: 72.4 %

Procedure:
18 g of the product of Step A and 400 ml of dichloromethane were mixed together under nitrogen and the mixture was cooled to 0° C. 150 ml of a molar solution of boron tribromide in dichloromethane were added and the mixture stood for one night at ambient temperature. It was concentrated, cooled again to 0° C. and 250 ml of a normal solution of hydrochloric acid were added. The crystallized product was separated out, washed with water, dried then crystallized from an isopropanol-water mixture (1-2) to obtain 12 g of the expected product.
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[NH2:48][C@H:49]1[CH2:55][CH2:54][CH2:53][CH2:52][N:51]([C:56]2[CH:61]=[CH:60][CH:59]=[C:58]([O:62][CH3:63])[CH:57]=2)[C:50]1=[O:64]>>[CH2:34]([C@@H:14]([CH2:13][CH2:12][C@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]([NH:48][C@H:49]1[CH2:55][CH2:54][CH2:53][CH2:52][N:51]([C:56]2[CH:61]=[CH:60][CH:59]=[C:58]([O:62][CH3:63])[CH:57]=2)[C:50]1=[O:64])=[O:10])[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: COc1cccc(N2CCCC[C@H](N)C2=O)c1
Reactant: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)O)Cc3ccccc3)C(=O)N21
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)N[C@H]3CCCCN(c4cccc(OC)c4)C3=O)Cc3ccccc3)C(=O)N21

Procedure:
(4S,7S,10aS)-Methyl 4-((2R,5R)-2,5-dibenzyl-6-((S)-1-(3-methoxyphenyl)-2-oxoazepan-3-ylamino)-6-oxohexanamido)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate was synthesized as described in General Procedure H using Intermediate 23 (24 mg, 0.042 mmol) and Intermediate 65 (19 mg, 0.055 mmol) to give a white solid (21 mg, 62% yield). Anal. Calcd. for C44H54N4O7S m/z 782.7. found: 783.7 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.36-7.02 (m, 11H), 6.83 (dd, J=8.2, 2.1 Hz, 1H), 6.69 (dt, J=4.2, 1.6 Hz, 2H), 6.42 (s, 2H), 5.32 (t, J=4.6 Hz, 1H), 5.17-5.07 (m, 1H), 5.04-4.91 (m, 1H), 4.76 (dd, J=9.7, 6.9 Hz, 1H), 3.98 and 3.78 (2s, 3H), 3.93 (dd, J=15.4, 11.6 Hz, 1H), 3.68 (s, 3H), 3.63-3.54 (m, 1H), 3.16-3.06 (m, 1H), 2.90-2.67 (m, 5H), 2.53-2.32 (m, 3H), 2.07-1.79 (m, 5H), 1.79-1.43 (m, 11H), 1.40-1.23 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:11]2[CH2:16][CH2:15][CH2:14][CH:13]([C:17]3([CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=4)[C:25]4[C:20](=[CH:21][C:22]([Cl:26])=[CH:23][CH:24]=4)[NH:19][C:18]3=[O:27])[CH2:12]2)=[O:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:43](Cl)(=[O:45])[CH3:44]>O1CCCC1>[C:43]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([N:11]2[CH2:16][CH2:15][CH2:14][CH:13]([C:17]3([CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=4)[C:25]4[C:20](=[CH:21][C:22]([Cl:26])=[CH:23][CH:24]=4)[NH:19][C:18]3=[O:27])[CH2:12]2)=[O:10])=[CH:6][CH:7]=1)(=[O:45])[CH3:44]
Reactant: Nc1ccc(NC(=O)N2CCCC(C3(Cc4cccc(Cl)c4)C(=O)Nc4cc(Cl)ccc43)C2)cc1
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(NC(=O)N2CCCC(C3(Cc4cccc(Cl)c4)C(=O)Nc4cc(Cl)ccc43)C2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 49.5 %

Procedure:
To a solution of rac-3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carboxylic acid (4-amino-phenyl)-amide (55 mg, 0.11 mmol) (from Example 76b supra) in tetrahydrofuran (2 mL) was added triethylamine (16 mg, 0.16 mmol) (Aldrich), followed by the addition of acetyl chloride (10 mg, 0.13 mmol) (Aldrich). The mixture was stirred at room temperature for 20 minutes. The crude was quenched with water. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water, brine, dried over MgSO4 and concentrated. The residue was purified by chromatography to give rac-3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carboxylic acid (4-acetylamino-phenyl)-amide as a white solid (Yield 30 mg, 50%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:23]#[C:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:8][C:9]=1[N:10]1[C:15](=[O:16])[CH2:14][CH2:13][CH2:12][C@H:11]1[CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:4].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].CC1(C)[C@@]23C4(ON4S(=O)(=[O:47])C2)C[C@H]1CC3>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:23]#[C:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:8][C:9]=1[N:10]1[C@H:11]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:12][CH2:13][C@H:14]([OH:47])[C:15]1=[O:16])=[O:4]
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N1C(=O)CCC[C@H]1C1CCCCC1
Reactant: CC1(C)[C@@H]2CC[C@]13CS(=O)(=O)N1OC13C2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N1C(=O)[C@@H](O)CC[C@H]1C1CCCCC1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 45.1 %

Procedure:
To a solution of 3-((S)-2-cyclohexyl-6-oxo-piperidin-1-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester (3.2 g, 7.97 mmol, 1.0 equiv) in THF (15.0 ml) was added NaHMDS (1.0 M in THF) at −78° C. and the resulting solution was stirred at −78° C. for 1.5 hours. To this solution was then added a solution of (S)-(+)-(camphorsulfonyl)oxaziridine (3.65 g, 15.94 mmol, 2.0 equiv) in THF (10 ml) and the reaction mixture was stirred at −78° C. for 3 hours. The reaction was quenched by addition of sat. NH4Cl aq. solution. The mixture was extracted with EtOAc and the combined organic layer was dried over Na2SO4, and concentrate. The residue was purified by silica gel column chromatography, (Et2O/DCM 5%˜40%) to give 1.5 g of the desired product (yield 45%). MS: 418 [M+H+]
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[CH2:6][CH:7]([C:12]([O:14][CH3:15])=[O:13])[C:8]([O:10][CH3:11])=[O:9].[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]=[C:29]=[O:30]>>[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH:28][C:29]([O:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[CH2:6][CH:7]([C:8]([O:10][CH3:11])=[O:9])[C:12]([O:14][CH3:15])=[O:13])=[O:30]
Reactant: O=C=Nc1ccccc1Cl
Reactant: COC(=O)C(Cc1ccc(OC)c(CO)c1)C(=O)OC
Product: COC(=O)C(Cc1ccc(OC)c(COC(=O)Nc2ccccc2Cl)c1)C(=O)OC

Procedure:
Using dimethyl 2-[3-(hydroxymethyl)-4-methoxybenzyl]malonate and 2-chlorophenylisocyanate, the title compound was obtained in the same manner as described in Example 192b).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[F:11])[CH:6]=O)#[N:2].Cl.[O:13]([NH2:15])[CH3:14]>>[CH3:14][O:13][N:15]=[CH:6][C:5]1[CH:8]=[CH:9][C:10]([F:11])=[C:3]([C:1]#[N:2])[CH:4]=1
Reactant: N#Cc1cc(C=O)ccc1F
Reactant: CON
Agent: Cl
Product: CON=Cc1ccc(F)c(C#N)c1

Procedure:
Reaction of 3-cyano-4-fluorobenzaldehyde with methoxylamine hydrochloride as described in the preparation of compound 3-A gave the title oxime ether as a clear oil after chromatography on silica gel (elution hexane-ethyl acetate 8:2) (94% yield). 1HNMR indicated a 93:7 mixture of E- and Z-isomers. 1HNMR 400 MHz (CDCl3) δ (ppm): (E-isomer) 4.02 (3H, s, OCH3), 7.26 (1H, m, aromatic), 7.85 (2H, m, aromatics), 8.03 (1H, s, CH).
Reaction SMILES: [CH:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH2:5][CH2:4]1)=[O:2].C([O-])(=O)C.[Na+].[Br:22]Br.O>C(O)(=O)C>[CH:1]([N:3]1[CH2:4][CH2:5][N:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=2[Br:22])[CH2:7][CH2:8]1)=[O:2]
Reactant: COc1ccc(N2CCN(C=O)CC2)cc1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(N2CCN(C=O)CC2)c(Br)c1

Procedure:
Sodium acetate (VI, 9.702 g, 0.1182 mol) is added to a mixture of 1-formyl-4-(4-methoxyphenyl)piperazine (VI, 5.17 g, 23.5 mmol) and acetic acid (102 ml). When the sodium acetate had completely dissolved, a solution of bromine (7.912 g, 49.5 mmol) in acetic acid (9.5 ml) is added over 14 min. After 35 min the mixture is poured into water and extracted exhaustively with dichloromethane. The combined organic extracts are backwashed with water, followed by saturated sodium bicarbonate, dried over sodium sulfate and concentrated. The residue is chromatographed on silica gel eluting first with ethyl acetate/dichloromethane (10/90) and then ethyl acetate/dichloromethane (20/80). The appropriate fractions are pooled and concentrated to give 1-formyl-4-(2-bromo-4-methoxyphenyl)piperazine (VII), NMR (CDCl3) 2.94, 3.55, 3.74, 3.78, 6.83, 6.97, 7.16 and 8.10 δ.