Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13](=[O:51])[NH:14][CH:15]([CH2:43][C:44]1[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=1)[C:16]([N:18]1C[CH2:22][N:21]([CH:24]([C:36](=[O:39])[NH:37][CH3:38])[CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)[CH2:20][CH:19]1COC)=[O:17])=O)(C)(C)C.ClCCCl.FC(F)(F)C([O-])=O.O1[CH2:68][CH2:67][O:66][CH2:65]C1>Cl>[F:50][C:47]1[CH:48]=[CH:49][C:44]([CH2:43][CH:15]([NH:14][C:13]([CH:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)=[O:51])[C:16]([N:18]2[CH2:19][CH2:20][N:21]([CH:24]([C:36](=[O:39])[NH:37][CH3:38])[CH2:25][C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=3)[CH2:22][C:67]2([CH3:68])[O:66][CH3:65])=[O:17])=[CH:45][CH:46]=1
Reactant: CNC(=O)C(Cc1ccc2ccccc2c1)N1CCN(C(=O)C(Cc2ccc(F)cc2)NC(=O)C2CCCN2C(=O)OC(C)(C)C)C(COC)C1
Reactant: C1COCCO1
Agent: Cl
Agent: O=C([O-])C(F)(F)F
Solvent: ClCCCl
Product: CNC(=O)C(Cc1ccc2ccccc2c1)N1CCN(C(=O)C(Cc2ccc(F)cc2)NC(=O)C2CCCN2)C(C)(OC)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
Crude 2-{1-(4-fluorobenzyl)-2-[2-methoxymethyl-4-(1-methylcarbamoyl-2-naphthalen-2-yl-ethyl)-piperazin-1-yl]-2-oxo-ethylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester, 67, is dissolved in 4M hydrogen chloride in dioxane (10 mL) and stirred at room temperature for 1 hour. 1,2-dichloroethane (10 mL) is added. Removal of solvents in vacuo gives the crude hydrogen chloride salt of product which is then purified by preparative HPLC to afford 0.22 g (54% yield) of the desired product as the trifluoroacetate salt. A small amount of product is converted into free base by treating with NaHCO3 to obtain NMR spectra. 1H NMR (CDCl3, δ): 7.80–7.60 (m, 4H), 7.45–7.25 (m, 3H), 7.18–7.00 (m, 2H), 7.00–6.85 (m, 2H), 6.32–6.28 (m, 0.5H), 5.08–4.92 (m, 1H), 4.78–4.69 (,0.5H), 4.10 (d, J=13.0 Hz, 0.5H), 3.70–3.58 (m, 1H), 3.58–3.15 (m, 8H), 2.98–2.46 (m, 11H), 2.28–2.15 (m, 0.5H), 2.15–1.50 (m, 8H). HRFAB(positive) m/e 604.2399 calculated for C34H42FN5O4 (M+H)+, Found 604.3292.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[Cl:12][C:13]1([F:39])[O:36][C:17]2=[CH:18][C:19]3[N:23]=[C:22]([S:24][CH2:25][C:26]4[C:31]([CH3:32])=[C:30]([O:33][CH3:34])[CH:29]=[CH:28][N:27]=4)[NH:21][C:20]=3[CH:35]=[C:16]2[O:15][C:14]1([F:38])[F:37].CN(C)C>C(Cl)Cl>[Cl:12][C:13]1([F:39])[O:36][C:17]2=[CH:18][C:19]3[N:23]=[C:22]([S:24]([CH2:25][C:26]4[C:31]([CH3:32])=[C:30]([O:33][CH3:34])[CH:29]=[CH:28][N:27]=4)=[O:6])[NH:21][C:20]=3[CH:35]=[C:16]2[O:15][C:14]1([F:37])[F:38]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccnc(CSc2nc3cc4c(cc3[nH]2)OC(F)(F)C(F)(Cl)O4)c1C
Agent: CN(C)C
Solvent: ClCCl
Product: COc1ccnc(CS(=O)c2nc3cc4c(cc3[nH]2)OC(F)(F)C(F)(Cl)O4)c1C
Reaction time: 4 h
Yield: 64.3 %

Procedure:
A solution of 0.42 g of approximately 85% pure m-chloroperoxybenzoic acid in 90 ml of methylene chloride is added dropwise to a solution of 0.9 g of 6-chloro-6,7,7-trifluoro-6,7-dihydro-2-[(4-methoxy-3-methyl-2-pyridyl)methylthio]-1H-[1,4]-dioxino[2,3-f]benzimidazole in 180 ml of methylene chloride at -40° C., with stirring. Stirring is continued for 4 hours and the solution is allowed to come to -20° C. 0.29 ml of trimethyl amine are added, and the organic phase is washed with potassium bicarbonate solution and with water, dried with magnesium sulfate and concentrated in vacuo. The residue is stirred with ethyl acetate and subsequently with acetone. 0.6 g (64%) of the title compound of m.p. 198°-200° C. (decomposition) are obtained.
Reaction SMILES: CCN=C=NCCCN(C)C.[C:12]([O:16][C:17]([N:19]1[CH2:22][CH:21]([NH2:23])[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].[Cl:24][C:25]1[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][C:26]=1[C:27]([NH:29][CH2:30][C:31](O)=[O:32])=[O:28]>>[C:12]([O:16][C:17]([N:19]1[CH2:22][CH:21]([NH:23][C:31](=[O:32])[CH2:30][NH:29][C:27](=[O:28])[C:26]2[CH:34]=[C:35]([C:38]([F:41])([F:40])[F:39])[CH:36]=[CH:37][C:25]=2[Cl:24])[CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: O=C(O)CNC(=O)c1cc(C(F)(F)F)ccc1Cl
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Agent: CCN=C=NCCCN(C)C
Product: CC(C)(C)OC(=O)N1CC(NC(=O)CNC(=O)c2cc(C(F)(F)F)ccc2Cl)C1

Procedure:
The title compounds were prepared as white solids from EDCI coupling between 3-amino-azetidine-1-carboxylic acid tert-butyl ester and (2-chloro-5-trifluoromethyl-benzoylamino)-acetic acid (prepared by the method similar to Ingersoll, A. W. et. al., Organic Syntheses 1932, XII, 40-2) using the procedure described in Step C of Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][O:29][CH3:30])=S)=[CH:21][CH:20]=1.I([O-])(=O)(=O)=O.[Na+]>CN(C=O)C.O.O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:26](=[N:28][O:29][CH3:30])[NH:25][C:22]4[CH:21]=[CH:20][C:19]([F:18])=[CH:24][CH:23]=4)[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CONC(=S)Nc1ccc(F)cc1
Reactant: Clc1ccc2c(N3CCNCC3)ccnc2c1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: CON=C(Nc1ccc(F)cc1)N1CCN(c2ccnc3cc(Cl)ccc23)CC1

Procedure:
7-Chloro-4-(piperazin-1-yl)quinoline (297 mg, 1.2 mmol), N-(4-Fluorophenyl)-N′-methoxythiourea (240 mg, 1.2 mmol), and sodium periodate (278 mg, 1.3 mmol) in DMF-water 1:1 (40 mL) are heated at 85° C. for 1 h. The reaction mixture is diluted with water and extracted with ether. The organic phase is dried (MgSO4) and concentrated. The residue is purified by column chromatography with hexane-EtOAc yielding the title product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:11]=[O:12])[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.[CH3:13][C@H:14]([NH:23][CH3:24])[C@@H:15](O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:11]2[N:23]([CH3:24])[C@@H:14]([CH3:13])[C@H:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12]2)[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1
Reactant: CN[C@@H](C)[C@@H](O)c1ccccc1
Reactant: O=Cc1cc(Br)cc2c1OCC2
Solvent: c1ccccc1
Product: C[C@H]1[C@H](c2ccccc2)OC(c2cc(Br)cc3c2OCC3)N1C
Yield: 77.5 %

Procedure:
A sample of 20 (650 mg, 2.9 mmol) and (1S,2S) pseudoephedrine (500 mg, 3.0 mmol) in 40 mL of benzene was refluxed overnight using a Dean-Stark trap. Solvent removal yielded yellow crystals which were recrystallized from a minimum of hot hexanes to give white crystals of 21 (841 mg, 79%), mp=83.5-85.5° C.
Reaction SMILES: Cl[C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:23][C:24]2[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[CH:25]=2)=[C:16]([CH:22]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18]>CN1CCCC1=O.C(=O)([O-])O.[Na+]>[Cl:30][C:28]1[CH:29]=[C:24]([CH:25]=[C:26]([Cl:31])[CH:27]=1)[O:23][C:15]1[CH:14]=[CH:13][C:12]([NH:11][C:2]2[C:3]3[NH:10][CH:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)=[CH:22][C:16]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: Clc1ncnc2cc[nH]c12
Reactant: CCOC(=O)c1cc(N)ccc1Oc1cc(Cl)cc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1cc(Nc2ncnc3cc[nH]c23)ccc1Oc1cc(Cl)cc(Cl)c1
Temperature: 140 °C
Reaction time: 2.5 h
Yield: 84.6 %

Procedure:
To a solution of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (61 mg) in 1-methyl-2-pyrrolidone (0.8 mL), was added ethyl 5-amino-2-(3,5-dichlorophenoxy)benzoate (186 mg), and the mixture was heated to 140° C. and stirred for 2.5 hrs. The reaction mixture was allowed to cool to room temperature, diluted with 5% aqueous sodium hydrogen carbonate solution (20 mL), and extracted with a mixed solvent (25 mL×3) of ethyl acetate/tetrahydrofuran (1/1). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (basic silica gel, eluent:hexane/ethyl acetate=8/2→0/10). The object fraction was concentrated under reduced pressure. Ethyl acetate was added to the residue, and the resultant precipitate was collected by filtration and dried under reduced pressure to give the title compound (149 mg) as pale-yellow powder crystals.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]([O:20][CH2:21][CH2:22]Br)([C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:24]1(=[O:31])[NH:29][C:28](=[O:30])[CH2:27][CH2:26][CH2:25]1.[Na]>CN(C)C=O>[C:28]1(=[O:30])[N:29]([CH2:2][CH2:3][O:4][C:5]([O:20][CH2:21][CH2:22][N:29]2[C:24](=[O:31])[CH2:25][CH2:26][CH2:27][C:28]2=[O:30])([C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:24](=[O:31])[CH2:25][CH2:26][CH2:27]1
Reactant: O=C1CCCC(=O)N1
Reactant: O=C(c1ccccc1)C(OCCBr)(OCCBr)c1ccccc1
Agent: [Na]
Solvent: CN(C)C=O
Product: O=C1CCCC(=O)N1CCOC(OCCN1C(=O)CCCC1=O)(C(=O)c1ccccc1)c1ccccc1
Temperature: 0 °C
Yield: 89.5 %

Procedure:
Benzil-di-(β-bromoethyl)ketal (13.26 g) and 8.91 g of sodium glutarimide were dissolved in 50 ml of N,N-dimethylformamide, and reacted at 50° C. for 7 hours. When the reaction mixture was poured into 200 ml of ice water, white crystals formed. These crystals were washed with water, and dried to give 13.6 g of benzil-di-(β-glutarimidoethyl)ketal.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=2)[C:10]([C:18]#[CH:19])=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:20]([C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)=[N+:21]=[N-:22].Cl>CN(C=O)C.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[CH3:30][O:29][C:27]([C:26]1[CH:25]=[CH:24][C:23]([N:20]2[CH:19]=[C:18]([C:10]3[C:11]4[C:16](=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=4)[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[N:9]=3)[N:22]=[N:21]2)=[CH:32][CH:31]=1)=[O:28]
Reactant: C#Cc1nn(C(=O)OC(C)(C)C)c2ccc(C)cc12
Reactant: COC(=O)c1ccc(N=[N+]=[N-])cc1
Agent: [Cu+2]
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-n2cc(-c3nn(C(=O)OC(C)(C)C)c4ccc(C)cc34)nn2)cc1
Temperature: 80 °C

Procedure:
Copper sulfate pentahydrate (0.08 g; 0.33 mmol; 0.06 eq.) was added to a solution of tert-butyl-3-ethynyl-5-methyl-1H-indazole-1-carboxylate (1.55 g; 6.03 mmol; 1.0 eq.), methyl 4-azidobenzoate (prepared as described in JOC (2006), 71(15), 5822-5825; 1.20 g; 6.77 mmol; 1.1 eq.) and D-(−)-isoascorbic acid sodium salt (0.24 g; 1.22 mmol; 0.20 eq.) in DMF (15 mL) and water (0.50 mL). The reaction suspension was heated in MW at 80° C. for 45 min then poured into HCl (0.1 N solution) and extracted with EtOAc. Combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude was purified by flash chromatography on silica (n-heptane/EtOAc, gradient from 90:10 to 60:40) to give the title compound as a yellow solid. 1H NMR (300 MHz, DMSO) δ 9.66 (s, 1H), 8.35-8.25 (m, 3H), 8.20 (d, J=8.8 Hz, 2H), 8.05 (d, J=8.7 Hz, 1H), 7.54 (dd, J=1.5, 8.7 Hz, 1H), 3.91 (s, 3H), 2.53 (s, 3H), 1.69 (s, 9H). HPLC (Condition A): Rt 5.07 min (purity 96.8%). MS (ESI+): 434.4.
Reaction SMILES: [O:1]1CCO[CH:2]1[CH:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15]([CH2:16][C@@H:17]([O:36][C:37](=[O:39])[CH3:38])[CH2:18][C@@H:19]2[O:27][C:28](=[O:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:14][CH:13]=3)[CH2:10][CH2:9]1)[CH3:7].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1>[C:37]([O:36][C@H:17]1[CH2:18][C@H:19]([O:27][C:28](=[O:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C@@:20]2([CH3:21])[C:15](=[CH:14][CH:13]=[C:12]3[C@@H:22]2[CH2:23][CH2:24][C@@:25]2([CH3:26])[C@H:11]3[CH2:10][CH2:9][C@@H:8]2[CH:6]([CH:2]=[O:1])[CH3:7])[CH2:16]1)(=[O:39])[CH3:38]
Reactant: CC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C5OCCO5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)c2ccccc2)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C=O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)c2ccccc2)C1
Temperature: 50 °C
Reaction time: 3 h
Yield: 49 %

Procedure:
In 5 ml of tetrahydrofuran was dissolved 100 mg of 20-(1,3-dioxolan-2-yl)-3β-acetoxy-1α-benzoyloxypregna-5,7-diene, followed by addition of 1 ml of water and 10 mg of p-toluenesulfonic acid. The mixture was stirred in an atmosphere of argon gas at 50° C. for 3 hours. The reaction mixture was then worked up in the same manner as Example 156 to give 45 mg of 3β-acetoxy-1α-benzoyloxypregna-5,7-diene-20-carbaldehyde showing the following physical properties.
Reaction SMILES: Cl[O-].[Na+].[CH:4]1([C@H:7]([O:12][CH2:13][CH:14]=[N:15][OH:16])[CH2:8]/[CH:9]=[CH:10]/[CH3:11])[CH2:6][CH2:5]1.C(N(CC)CC)C>ClCCl>[CH:4]1([C@@H:7]2[O:12][CH2:13][C:14]3=[N:15][O:16][C@@H:10]([CH3:11])[C@@H:9]3[CH2:8]2)[CH2:6][CH2:5]1
Reactant: C/C=C/C[C@@H](OCC=NO)C1CC1
Agent: [Na+]
Agent: [O-]Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1ON=C2CO[C@@H](C3CC3)C[C@H]21
Reaction time: 1 h

Procedure:
An aqueous solution of sodium hypochlorite (6.15% solution, 0.7 mL, 0.6 mmol) was added drop-wise to a solution of 2-{[(1R,3E)-1-cyclopropylpent-3-en-1-yl]oxy}-N-hydroxyethanimine (C26) (200 mg, 1.09 mmol) in dichloromethane (10 mL), followed by addition of triethylamine (11 μL, 79 μmol). The reaction mixture was stirred for 1 hour, then treated with a drop of triethylamine and additional aqueous sodium hypochlorite solution (6.15%, 0.5 mL, 0.4 mmol). After 20 minutes, the reaction mixture was partitioned between water (10 mL) and dichloromethane (20 mL); the organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Purification via silica gel chromatography (Gradient: 0% to 100% ethyl acetate in heptane) provided the product as an oil. The indicated relative stereochemistry of compound C27 was assigned based on nuclear Overhauser enhancement studies, which revealed interactions of the methine proton on carbon 3a with both the protons of the methyl group on carbon 3 and the methine proton on carbon 5. Yield: 150 mg, 0.828 mmol, 76%. 1H NMR (400 MHz, CDCl3) δ 4.64 (d, J=13.5 Hz, 1H), 4.17-4.25 (m, 1H), 4.08 (dd, J=13.6, 1.3 Hz, 1H), 2.84-2.93 (m, 1H), 2.76 (ddd, J=11.0, 7.9, 1.9 Hz, 1H), 2.21 (dddd, J=12.9, 6.6, 1.9, 0.5 Hz, 1H), 1.57 (ddd, J=12.9, 11.4, 11.4 Hz, 1H), 1.45 (d, J=6.2 Hz, 3H), 0.86-0.96 (m, 1H), 0.48-0.61 (m, 2H), 0.35-0.42 (m, 1H), 0.19-0.26 (m, 1H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C@@H:8]([C@@H:17]2[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:44])[NH:24][C@H:25]([CH2:34][N:35]([CH3:43])[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C@H:26]([CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[OH:27])[CH2:18]2)[O:9][CH2:10][CH2:11][NH:12][C:13](=[O:16])[O:14][CH3:15])[CH:5]=[CH:6][CH:7]=1>CCO.[Pd]>[CH:28]1([C@H:26]([OH:27])[C@H:25]([NH:24][C:23]([N:19]2[CH2:20][CH2:21][CH2:22][C@@H:17]([C@H:8]([C:4]3[CH:3]=[CH:2][CH:7]=[CH:6][CH:5]=3)[O:9][CH2:10][CH2:11][NH:12][C:13](=[O:16])[O:14][CH3:15])[CH2:18]2)=[O:44])[CH2:34][N:35]([CH3:43])[C:36]([O:38][C:39]([CH3:40])([CH3:42])[CH3:41])=[O:37])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: COC(=O)NCCO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)N[C@H](CN(C)C(=O)OC(C)(C)C)[C@@H](O)C2CCCCC2)C1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)NCCO[C@@H](c1ccccc1)[C@@H]1CCCN(C(=O)N[C@H](CN(C)C(=O)OC(C)(C)C)[C@@H](O)C2CCCCC2)C1

Procedure:
A solution of methyl 2-((R)-(3-chlorophenyl)((R)-1-((1S,2R)-1-cyclohexyl-1-hydroxy-3-(N-methyl-N-(tert-butoxycarbonyl)amino)propan-2-ylcarbamoyl)piperidin-3-yl)methoxy)ethylcarbamate (5 mg, 0.008 mmol) in EtOH (2 mL) was stirred with 10% Pd/C (5 mg) under H2 overnight. The mixture was filtered thru Celite. After removal of solvent in vacuo, the residue was used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:28]([NH2:29])=[N:27][C:12]2[N:13]=[C:14]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[N:15]=[CH:16][C:11]=2[CH:10]=1.[H-].[Na+].[CH:32]1([N:38]=[C:39]=[O:40])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.CO.CC#N>CN(C=O)C>[CH:32]1([NH:38][C:39]([NH:29][C:28]2[C:9]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])=[CH:10][C:11]3[CH:16]=[N:15][C:14]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[N:13][C:12]=3[N:27]=2)=[O:40])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: O=C=NC1CCCCC1
Reactant: CCN(CC)CCCCNc1ncc2cc(-c3c(Cl)cccc3Cl)c(N)nc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: CC#N
Product: CCN(CC)CCCCNc1ncc2cc(-c3c(Cl)cccc3Cl)c(NC(=O)NC3CCCCC3)nc2n1
Yield: 71.9 %

Procedure:
6-(2, 6-Dichlorophenyl)-N2 -(4-diethylamino-butyl)-pyrido[2,3-d]pyrimidine-2,7-diamine (1.0 g) from Example 53 in DMF (15 mL) was reacted with 60% sodium hydride suspension (0.092 g) and cyclohexyl isocyanate (0.289 g) according to the general procedure of Example 54 to give 0.927 g of the title compound, ESMS (20/80 MeOH/CH3CN+0.1% AcOH): M+ +H=558, 433.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:20]([S:21](=[O:27])(=[O:26])[NH:22]C(=O)C)=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[CH2:28][CH:29]2[CH2:34][CH:33]3[CH2:35][CH:30]2[CH:31]=[CH:32]3)=[CH:7][CH:6]=1)(=O)C>[OH-].[Na+]>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:20]([S:21](=[O:27])(=[O:26])[NH2:22])=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[CH2:28][CH:29]2[CH2:34][CH:33]3[CH2:35][CH:30]2[CH:31]=[CH:32]3)=[CH:7][CH:6]=1
Reactant: CC(=O)Nc1ccc(Nc2c(CC3CC4C=CC3C4)cc(C(=O)O)cc2S(=O)(=O)NC(C)=O)cc1
Agent: [Na+]
Agent: [OH-]
Product: Nc1ccc(Nc2c(CC3CC4C=CC3C4)cc(C(=O)O)cc2S(N)(=O)=O)cc1

Procedure:
The mixture of 5.1 g of 4-(4-acetamidophenylamino)-3-(2-norborn-5-enylmethyl)-5-acetylsulfamoylbenzoic acid and 50 ml of 2N aqueous sodium hydroxide is refluxed for 2 hours under nitrogen. It is cooled, filtered, the filtrate acidified with glacial acetic acid to a pH of 4-5 and the precipitate formed filtered off. It is washed with water, dissolved in 40 ml of hot ethanol, the solution filtered and the filtrate diluted with water. After standing the precipitate formed is filtered off and again recrystallized from aqueous ethanol, to yield the 4-(4-aminophenylamino)-3-(2-norborn-5-enylmethyl)-5-sulfamoylbenzoic acid of the formula ##SPC10##
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.[NH2:14][C:15]1[C:24]2[C:19](=[C:20](Br)[C:21]([CH3:25])=[CH:22][CH:23]=2)[N:18]=[N:17][C:16]=1[C:27]([NH2:29])=[O:28]>>[NH2:14][C:15]1[C:24]2[C:19](=[C:20]([C:2]3[CH:10]=[C:9]4[C:5]([C:6]([CH:11]5[CH2:13][CH2:12]5)=[N:7][NH:8]4)=[CH:4][CH:3]=3)[C:21]([CH3:25])=[CH:22][CH:23]=2)[N:18]=[N:17][C:16]=1[C:27]([NH2:29])=[O:28]
Reactant: Cc1ccc2c(N)c(C(N)=O)nnc2c1Br
Reactant: Brc1ccc2c(C3CC3)n[nH]c2c1
Product: Cc1ccc2c(N)c(C(N)=O)nnc2c1-c1ccc2c(C3CC3)n[nH]c2c1

Procedure:
The title compound was prepared in a manner similar to EXAMPLE 96 using 6-bromo-3-cyclopropyl-1H-indazole and 4-amino-8-bromo-7-methylcinnoline-3-carboxamide. 1H NMR (500 MHz, CD3OD) δ ppm 1.09 (d, J=7.32 Hz, 4H), 2.31 (s, 3 H), 2.31-2.41 (m, 1H), 7.03 (d, J=8.30 Hz, 1 H), 7.37 (s, 1 H), 7.71 (d, J=8.79 Hz, 1 H), 7.90 (d, J=7.81 Hz, 1 H), 8.22 (d, J=8.79 Hz, 1 H); ESI-MS m/z [M+H]+ 359.3.
Reaction SMILES: S(Cl)([Cl:3])=O.[Na+].[CH3:6][C:7]1[O:11][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:9][C:8]=1[CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([O-:29])(=O)=[O:27])=[CH:22][CH:21]=1>CN(C)C=O>[CH3:6][C:7]1[O:11][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:9][C:8]=1[CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([Cl:3])(=[O:29])=[O:27])=[CH:22][CH:21]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(S(=O)(=O)[O-])cc1
Reactant: O=S(Cl)Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(S(=O)(=O)Cl)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of thionyl chloride (8.0 mL) and 2 drops of N,N-dimethylformamide stirring under nitrogen at 0° C. is added the title B compound, 4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonic acid sodium salt (1.42 g, 3.8 mmol) in one portion. The resulting suspension is stirred at 0° C. for 10 minutes. The ice bath is removed and the suspension is stirred at room temperature for 1.5 hours. Three more drops of N,N-dimethyl-formamide is added, after which a clear solution results upon stirring for an additional hour. The solution is concentrated under vacuo to a solid residue. The residue is partitioned between water (20 mL) and ethyl acetate (20 mL). The organic layer is separated and washed successively with water (3×20 mL), 0.1N aqueous sodium hydroxide (3×20 mL) and brine (20 mL). The organic layer is dried over anhydrous MgSO4, filtered and concentrated in vacuo to give an oil which slowly solidifies to give 0.48 g of 4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonyl chloride: [M+1]+=363.99.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:4][CH:3]1[NH:19][C:20](=[O:29])[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[H-].[Na+].[CH3:32]I.S([O-])(O)(=O)=O.[Na+]>CN(C=O)C.O>[CH3:32][N:8]1[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:4][CH:3]([NH:19][C:20](=[O:29])[O:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:2]1=[O:1]
Reactant: CI
Reactant: O=C(NC1N=C(c2ccccc2)c2ccccc2NC1=O)OCc1ccccc1
Agent: O=S(=O)([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1C(=O)C(NC(=O)OCc2ccccc2)N=C(c2ccccc2)c2ccccc21
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 91 %

Procedure:
To a solution of benzyl 2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-ylcarbamate (13) (Sherril R. G.; Sugg, E. E. Improved Synthesis and Resolution of 3-Amino-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-ones. J. Org. Chem. 1995, 60, 730-734) (1.00 g, 2.60 mmol) in anhydrous DMF (10 mL), kept at 0° C. under N2, NaH (60% dispersion in mineral oil, 0.10 g, 1 eq) was added in small portions. After 1.5 hr stirring at 0° C., methyl iodide (0.17 mL, 1.05 eq) was added at once; the mixture was stirred for additional 1.5 h at the same temperature, and then poured into a stirred solution of H2O (60 mL) containing aqueous sodium hydrogen sulphate (2 mL, 1 N). A solid precipitated, which was filtered, dried under vacuum, and then purified by flash chromatography (CH2Cl2/MeOH/NH3 99:1:0.1 as eluent) giving benzyl 1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-ylcarbamate in 91% yield. M.p. 78-80° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.C(N[C:27]1[CH:40]=[CH:39][CH:38]=[CH:37][C:28]=1[O:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1)(=O)C>>[C:8]([NH:12][C:39]1[CH:40]=[CH:27][C:28]([O:29][C:30]2[CH:31]=[CH:32][C:33]([NH:34][C:20]([C:17]3[CH:18]=[CH:19][C:14]([C:3]4[CH:4]=[C:5]([C:8]5[O:9][C:10]([CH3:13])=[N:11][N:12]=5)[CH:6]=[CH:7][C:2]=4[CH3:1])=[CH:15][CH:16]=3)=[O:21])=[CH:35][CH:36]=2)=[CH:37][CH:38]=1)(=[O:9])[CH3:5]
Reactant: CC(=O)Nc1ccccc1Oc1ccc(N)cc1
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Product: CC(=O)Nc1ccc(Oc2ccc(NC(=O)c3ccc(-c4cc(-c5nnc(C)o5)ccc4C)cc3)cc2)cc1

Procedure:
N-[4-(4-Acetylaminophenoxy)phenyl]-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid and 4-(acetylaminophenoxy)aniline using method I. LCMS; retention time 3.42 min, MH+ 519.