Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:24])=[C:4]([N:10]2[CH2:14][CH:13]3[C@@H:15](CS([O-])(=O)=O)[CH2:16][CH2:17][N:12]3[C:11]2=[O:23])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[N-:25]=[N+:26]=[N-:27].[Na+]>CN(C=O)C>[Cl:1][C:2]1[C:3]([CH3:24])=[C:4]([N:10]2[CH2:14][C@@H:13]3[C@H:15]([N:25]=[N+:26]=[N-:27])[CH2:16][CH2:17][N:12]3[C:11]2=[O:23])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1c(N2CC3[C@@H](CS(=O)(=O)[O-])CCN3C2=O)ccc(C#N)c1Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(N2C[C@@H]3[C@H](N=[N+]=[N-])CCN3C2=O)ccc(C#N)c1Cl
Temperature: 75 °C
Reaction time: 3 h
Yield: 90.8 %

Procedure:
A solution of compound 90A (400 mg, 1.18 mmol) and sodium azide (309 mg, 4.75 mmol) in anhydrous DMF (3.2 mL) was placed in a pre-heated bath (75° C.) and stirred at 75° C. for 3 h. The solution was cooled, quenched with H2O (6.0 mL) and extracted with EtOAc (2×80 mL). The organic phase was washed with H2O (6.0 mL), brine (6.0 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The syrup was chromatographed (silica gel; CH2Cl2/CH3OH gradient) to yield the title compound (339.3 mg, 90.8%) as a white solid foam from CH2Cl2/Hexane. HPLC: 97.7% at 2.22 min (retention time) (Conditions: YMC S-5 C-18 (4.6×50 mm), eluting with 0-100% B, 4 min gradient. (A=90% H2O—10% CH3CN—0.1% TFA and B=10% H2O—90% CH3CN—0.1% TFA); Flow rate at 4 mL/min. UV detection at 220 nm. MS (ES+): m/z 317 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:30]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[CH:29][C:5]2[NH:6][C:7]([C:9]3[C:13]([NH:14][C:15]([N:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)=[O:16])=[CH:12][N:11](C4CCCCO4)[N:10]=3)=[N:8][C:4]=2[CH:3]=1.Cl>O1CCOCC1.CO>[F:1][C:2]1[C:30]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[CH:29][C:5]2[NH:6][C:7]([C:9]3[C:13]([NH:14][C:15]([N:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)=[O:16])=[CH:12][NH:11][N:10]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: O=C(Nc1cn(C2CCCCO2)nc1-c1nc2cc(F)c(N3CCOCC3)cc2[nH]1)N1CCCCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=C(Nc1c[nH]nc1-c1nc2cc(F)c(N3CCOCC3)cc2[nH]1)N1CCCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.3 %

Procedure:
A solution of 4 g of piperidine-1-carboxylic acid [3-(5-fluoro-6-morpholin-4-yl-1H-benzimidazol-2-yl)-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-yl]amide in solution in 50 mL of a 4N solution of hydrochloric acid in dioxane is stirred at 22° C. for 4 hours. In order for the reaction to be complete, the reaction medium is concentrated and again dissolved in 50 mL of a 4N solution of hydrochloric acid in dioxane and left stirring at ambient temperature for 18 hours. The suspension is filtered over sintered glass and the solid is washed with dioxane. After spin-filter-drying, the solid is triturated in isopropyl ether. Since the solid obtained is hygroscopic, it is taken up in methanol and the solution is concentrated under vacuum. The oil obtained is purified by flash chromatography on an Intelliflash apparatus on an analogix RS-120 cartridge. The elution is carried out with dichloromethane then ethyl acetate at 100%, and then with a 95/5 mixture of dichloromethane/methanol. After concentration of the fractions containing the product, the latter is triturated in isopropyl ether and the solid obtained is filtered and dried under vacuum until the weight is constant. 3.2 g of piperidine-1-carboxylic acid [3-(5-fluoro-6-morpholin-4-yl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]amide are obtained in hydrochloride form. 1H NMR (300 MHz, (CD3)2SO, δ in ppm): 1.48-1.67 (m: 6H); 3.03 (m: 4H); 3.48 (m: 4H); 3.78 (m: 4H); 7.18 (d, J=8 Hz: 1H); 7.46 (d, J=12 Hz: 1H); 8.01 (s: 1H); 9.53 (broad s: 1H); 12.50 (very broad s: 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH2:6].[O-:7][C:8]#[N:9].[K+].C(CC(O)=O)#N.C(OC(=O)C)(=O)C>>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH:6][C:8]([NH2:9])=[O:7]
Reactant: COCCCN
Reactant: N#C[O-]
Agent: N#CCC(=O)O
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Product: COCCCNC(N)=O

Procedure:
3-Methoxypropyl urea was prepared from methoxypropylamine and potassium cyanate. Seventy-six grams of this product was mixed with 43 g. of cyanoacetic acid and 100 ml. of acetic anhydride. The mixture was stirred and heated on a steam bath. When the temperature of the mixture reached 85°C., heat of reaction evolved and external cooling was applied to keep the temperature under control. After stirring for 1 hour on the steam bath, the mixture was cooled. The cyanoacetyl urea was recovered by filtration, washing with ether and drying. Yield 77.5 g., mp 128.5-130.5°.
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH2:7][CH2:8][NH:9][CH2:10][C:5]2=[N:4][N:3]=1.[C:11]([O-])([O-])=O.[K+].[K+].S(OC)(OC)(=O)=O>C1COCC1>[Br:1][C:2]1[N:6]2[CH2:7][CH2:8][N:9]([CH3:11])[CH2:10][C:5]2=[N:4][N:3]=1
Reactant: Brc1nnc2n1CCNC2
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: C1CCOC1
Product: CN1CCn2c(Br)nnc2C1
Temperature: 80 °C
Reaction time: 1 h
Yield: 53.2 %

Procedure:
A suspension of 3-bromo-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (Preparation 154, 29 mg, 0.143 mmol), K2CO3 (23.7 mg, 0.171 mmol), dimethyl sulfate (14 uL, 0.143 mmol in THF (3 mL) was stirred at 80° C. under microwave irradiation for 60 minutes. The reaction mixture was filtered and purified by elution through an SCX-2 column using 2M NH3/MeOH to give the title compound as yellow oil (16.5 mg, 53%).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH3:10][NH:11][CH2:12][C:13]([OH:15])=[O:14].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O.O>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([N:11]([CH3:10])[CH2:12][C:13]([OH:15])=[O:14])=[CH:3][CH:4]=1)#[N:7]
Reactant: N#Cc1ccc(F)cc1
Reactant: CNCC(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CN(CC(=O)O)c1ccc(C#N)cc1
Temperature: 100 °C

Procedure:
In a 500-ml pear-shaped flask, 4-fluorobenzonitrile (10.44 g, 86.26 mmoles), N-methylglycine (8.45 g, 94.89 mmoles) and potassium carbonate (14.28 g, 103.48 mmoles) were placed, followed by addition of 200 ml of dimethylsulfoxide as a solvent. A water cooling pipe was attached to the flask, and the reaction was carried out with heating on an oil bath heated at 100° C. for 9 hours with stirring using a magnetic stirrer. After cooling naturally, the reaction mixture was dissolved in 1 liter of water and subjected to acidolysis with 1/10N HCl, followed by filtration of a precipitate. After washing with water well, the precipitate was washed with hexane/benzene (4/1 in volume ratio). The yield of the product after dried was 14.21 g (74.79 mmoles, 86.7%). The melting point was 64.5° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][C@@H:19]([CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]([O:22][CH3:23])=[O:21]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][C@@H:19]([CH2:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:20]([O:22][CH3:23])=[O:21])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: COC(=O)[C@@H](N)CCc1ccccc1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Product: COC(=O)[C@H](CCc1ccccc1)NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1

Procedure:
Following General Procedure A and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and methyl (S)-2-amino-4-phenylbutanoate (prepared from (+)-α-amino-4-phenylbutyric acid (Bachem) using General Procedure AG), the title compound was prepared as a solid (mp=147-149.5° C.). The reaction was monitored by tlc (Rf=0.32 in 50% EtOAc/hexanes) and the product was purified by flash chromotography using EtOAc/hexanes as the eluent.
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH2:30][NH:31][C:32](=[O:37])[C:33]([F:36])([F:35])[F:34])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:42]>CN(C=O)C>[C:1]([O:5][C:6](=[O:38])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH2:30][N:31]([CH3:42])[C:32](=[O:37])[C:33]([F:34])([F:35])[F:36])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CCC(=O)OC(C)(C)C)c(CNC(=O)C(F)(F)F)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CCC(=O)OC(C)(C)C)c(CN(C)C(=O)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 72.5 %

Procedure:
A solution of 3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-2-[(2,2,2-trifluoro-acetylamino)-methyl]-phenyl}-propionic acid tert-butyl ester (151 mg, 0.28 mmol) in dry DMF (10 mL) was cooled in an ice bath and treated with NaH (22 mg, 0.55 mmol, 60% oil dispersion). After the reaction mixture was stirred for 25 min, iodomethane (0.15 mL, 3.0 mmol) was added, and the reaction was allowed to warm to ambient temperature gradually. After 4 h, more iodomethane (0.10 mL, 2 mmol) was added. The mixture was stirred overnight and was partitioned between EtOAc and aqueous LiCl solution. The organic layer was washed with brine, dried (Na2SO4), and concentrated. The residue was purified by silica gel radial chromatography (CH2Cl2/EtOAc 100/0 to 95/5) to give the title compound (111 mg, 73%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13]([NH:18][C@H:19]3[CH2:24][CH2:23][C@H:22]([OH:25])[CH2:21][CH2:20]3)=[N:14][CH:15]=2)[NH:10][C:9]1=[O:26].[Si:27](Cl)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28].N1C=CN=C1.O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13]([NH:18][C@H:19]3[CH2:20][CH2:21][C@H:22]([O:25][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[CH2:23][CH2:24]3)=[N:14][CH:15]=2)[NH:10][C:9]1=[O:26]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1Nc2nc(N[C@H]3CC[C@H](O)CC3)ncc2CN1c1ccccc1Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](Nc2ncc3c(n2)NC(=O)N(c2ccccc2Cl)C3)CC1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A suspension of 3-(2-chlorophenyl)-7-(trans-4-hydroxycyclohexylamino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (1.86 g, 5 mmol) (prepared as described in Example 73) was combined with tert-butyldimethylsilyl chloride (1.05 g, 7 mmol) and imidazole (0.75 g, 11 mmol) in dimethylformamide (35 mL). The reaction mixture was heated at 50° C. for 24 hours, cooled to room temperature and added to water, stirred for 30 minutes, filtered and dried to give 1.88 g of 3-(2-chlorophenyl)-7-(trans-4-tert-butyl-dimethylsilyloxycyclohexylamino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one, m.p.289-294° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:13]=[C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:15]=1[OH:16])[CH:8]=[CH:9][C:10](O)=O)([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:22][O:23][C:24](=[O:29])[C@H:25]([CH2:27][OH:28])[NH2:26].Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>ClCCl>[CH3:22][O:23][C:24](=[O:29])[C@H:25]([CH2:27][OH:28])[NH:26][CH2:10][CH:9]=[CH:8][C:7]1[CH:6]=[C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])[C:15]([OH:16])=[C:14]([C:17]([CH3:18])([CH3:20])[CH3:19])[CH:13]=1
Reactant: COC(=O)[C@@H](N)CO
Reactant: CC(C)(C)c1cc(C=CC(=O)O)cc(C(C)(C)C)c1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CO)NCC=Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Yield: 35.5 %

Procedure:
First, 20 g of 3,5-di-t-butyl-4-hydroxycinnamic acid, 11.2 g of serine methyl ester hydrochloride, 13.6 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, and 10 ml of triethylamine were added to 300 ml of dichloromethane, and then the mixture was allowed to react for 2 hours at room temperature. After completion of the reaction, this mixture was washed by addition of water, and the dichloromethane was distilled off under reduced pressure. The residue so obtained was separated and purified by column chromatography on silica gel using chloroform as an eluent, thereby obtaining 9.3 g of N-(3,5-di-t-butyl-4-hydroxycinnamyl)serine methyl ester.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](C(Cl)(Cl)Cl)[N:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[N:3]=1.[CH2:16]([O-:18])[CH3:17].[Na+].O.Cl>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([O:18][CH2:16][CH3:17])[N:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[N:3]=1
Reactant: Nc1nc(C(F)(F)F)nc(C(Cl)(Cl)Cl)n1
Reactant: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOc1nc(N)nc(C(F)(F)F)n1
Temperature: 20 °C

Procedure:
20.0 g (71 mmol) of 2-amino-4-trichloromethyl-6-trifluoromethyl-1,3,5-triazine were added at 22° C. to a solution of 0.48 g (7.1 mmol) of sodium ethanolate in 100 ml of ethanol. The pale yellowish green solution was then refluxed for 30 minutes and, after cooling to 20° C., 20 ml of water were added and the mixture was neutralized with 2 normal hydrochloric acid. After this, most of the solvent was removed at 40° C. under reduced pressure, adding 100 ml of water a little at a time so that the solid did not agglomerate. The product was isolated in a similar manner to Example 2.
Reaction SMILES: COC1C=CC(C[N:8]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH:11]=[CH:10][S:9]2(=[O:19])=[O:18])=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH:8]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH:11]=[CH:10][S:9]1(=[O:18])=[O:19]
Reactant: COc1ccc(CN2c3ccccc3C=CS2(=O)=O)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S1(=O)C=Cc2ccccc2N1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
The title compound was synthesized according to the method described in WO 2008/073956 A2. To a solution of 1-(4-methoxybenzyl)-1H-benzo[c][1,2]thiazine 2,2-dioxide (0.9 g, 3 mmol) in anhydrous methylene chloride was added trifluoroacetic acid (18 mL). The mixture was stirred at room temperature for 5 hours and then concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (25-70% ethyl acetate in hexanes) to give a white solid. (0.6 g, 72%). 1H NMR (CDCl3, 300 MHz) δ 7.43-7.38 (m, 2H), 7.29 (m, 1H), 7.20-7.14 (dt, 1H, J=1.2, 7.5 Hz), 7.02-6.99 (d, 1H, J=7.8 Hz), 6.78-6.75 (dd, 1H, J=2.4, 10.5 Hz).
Reaction SMILES: [NH:1]1[C:5]2([CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]2)[CH2:4][CH2:3][C:2]1=[O:12].[C:13]([O:17][C:18]([NH:20][NH2:21])=[O:19])([CH3:16])([CH3:15])[CH3:14].C([BH3-])#N.[Na+]>CC(O)=O.O.[OH-].[Na+]>[C:13]([O:17][C:18]([NH:20][NH:21][CH:8]1[CH2:9][CH2:10][C:5]2([NH:1][C:2](=[O:12])[CH2:3][CH2:4]2)[CH2:6][CH2:7]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: O=C1CCC2(CC1)CCC(=O)N2
Reactant: CC(C)(C)OC(=O)NN
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)OC(=O)NNC1CCC2(CCC(=O)N2)CC1
Temperature: 25 °C
Yield: 150.8 %

Procedure:
A solution of 1-Aza-spiro[4.5]decane-2,8-dione (Chembridge corporation, 800 mg; 4.78 mmol; 1.0 eq.) and hydrazinecarboxylic acid tert-butyl ester (309 mg; 2.34 mmol; 1.1 eq.) in AcOH (5 mL) was stirred at RT for 5 min. Sodium cyanoborohydride (133 mg; 2.13 mmol; 1.0 eq.) was then added and the reaction mixture was stirred O/N at RT. It was then diluted with water and basified to pH 9 by addition of a 5N solution of NaOH. During the addition, the reaction mixture was maintained at 20° C. by addition of crushed ice. It was extracted with DCM and the combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated to give the title compound as a yellow oil (1.0 g, 98%) which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][C@H:6]1[CH2:10][N:9]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][C@H:7]1[OH:18].[CH3:22][I:23]>>[I-:23].[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][C@H:6]1[C@@H:7]([OH:18])[CH2:8][N+:9]([CH3:22])([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:10]1
Reactant: CI
Reactant: O[C@@H]1CN(Cc2ccccc2)C[C@@H]1Oc1cccc(Cl)c1
Product: C[N+]1(Cc2ccccc2)C[C@H](O)[C@H](Oc2cccc(Cl)c2)C1
Product: [I-]

Procedure:
A mixture of 15.2 g. (0.05 mole) of cis-4-(3-chlorophenoxy)-1-phenylmethyl-3-pyrrolidinol and 56 g. (0.4 mole) of methyl iodide was heated at reflux for 60 hr. Excess methyl iodide was removed under vacuum. The pasty residue was washed with ether-acetone, leaving 13 g. (59%) of granular tan powder, m.p. 118-25° C.
Reaction SMILES: [CH2:1]([N:4]([C@@H:21]([CH3:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C@@H:5]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C@H:6]([OH:14])[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH:2]=[CH2:3]>C1(C)C=CC=CC=1.[Rh]Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:10]([O:9][C:7]([C@H:6]1[O:14][C@@H:1]([CH2:2][CH3:3])[N:4]([C@@H:21]([CH3:28])[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C@H:5]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: C=CCN([C@@H](C)c1ccccc1)[C@@H](c1ccccc1)[C@H](O)C(=O)OC(C)(C)C
Agent: Cl[Rh]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC[C@@H]1O[C@H](C(=O)OC(C)(C)C)[C@H](c2ccccc2)N1[C@@H](C)c1ccccc1
Yield: 82.6 %

Procedure:
To a solution of compound (27) from Example 12 (1.039 g, 2.73 mmol) in anhydrous toluene (25 ml) was added tris(triphenylphosphine) rhodium(I) chloride (126 mg, 5 mol %). This solution was refluxed for 4 hours whereafter the toluene was removed under reduced pressure. The residue was treated with diethyl ether, precipitating the catalyst, and the solution was passed through alumina grade 5. After removal of the solvent under reduced pressure, the resulting oil was purified by flash chromatography on silica gel [ethyl acetate/petroleum ether (1:19)] affording the title compound (Rf 0.40) as a colourless oil (0.86 g, 83%). δH (300 MHz; CDCl3) 7.33-7.18 (10H, m, Ph), 4.48 (1H, t, NCHO), 4.38 (1H, d, J=8.0, PhCHCH), 4.21 (1H, d, J=8.0, PhCHCH), 4.01 (1H, q, J=6.9, PhCHCH3), 1.91 (2H, m, CHCH2CH3), 1.27 (3H, d, J=6.9, PhCHCH3), 1.15 (3H, t, J=7.5, CHCH2CH3), 0.99 (9H, s, (CH3)3C).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[C:13]([C:17]1[CH:22]=[CH:21][C:20]([CH2:23]Br)=[CH:19][C:18]=1[NH:25][C:26](=[O:44])[CH2:27][CH:28]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]2[O:40][CH2:41][CH2:42][O:43][C:35]=12)[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])([CH3:16])([CH3:15])[CH3:14]>CN(C)C=O.O>[C:13]([C:17]1[CH:22]=[CH:21][C:20]([CH2:23][N:5]2[C:1](=[O:11])[C:2]3=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]3[C:4]2=[O:6])=[CH:19][C:18]=1[NH:25][C:26](=[O:44])[CH2:27][CH:28]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]2[O:40][CH2:41][CH2:42][O:43][C:35]=12)[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])([CH3:14])([CH3:15])[CH3:16]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCCCCC(CC(=O)Nc1cc(CBr)ccc1C(C)(C)C)c1cccc2c1OCCO2
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCC(CC(=O)Nc1cc(CN2C(=O)c3ccccc3C2=O)ccc1C(C)(C)C)c1cccc2c1OCCO2
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.5 %

Procedure:
138 mg (0.745 mmol) of potassium phthalimide were added to a solution of 288 mg (0.573 mmol) of N-[2-t-butyl-5-bromomethyl-phenyl]-3-(2,3-ethylenedioxyphenyl)octanamide (prepared as described in Preparation 70E) in 5 ml of dimethylformamide, and the resulting mixture was stirred at room temperature for 4 hours. At the end of this time, the reaction mixture was diluted with water and then extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel using a 3:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 295 mg (yield 91%) of the title compound as a colorless foam-like substance.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH:9]=[C:8]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[S:21][CH3:22])[C:7]4[C:23](=[O:27])[NH:24][C:25](=[O:26])[C:6]=4[C:5]=3[C:4]=2[CH:3]=1.C1(S(N2C(C3C=CC=CC=3)O2)(=O)=[O:35])C=CC=CC=1>C1COCC1>[OH:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH:9]=[C:8]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[S:21]([CH3:22])=[O:35])[C:7]4[C:23](=[O:27])[NH:24][C:25](=[O:26])[C:6]=4[C:5]=3[C:4]=2[CH:3]=1
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Reactant: CSc1ccccc1-c1cc2[nH]c3ccc(O)cc3c2c2c1C(=O)NC2=O
Solvent: C1CCOC1
Product: CS(=O)c1ccccc1-c1cc2[nH]c3ccc(O)cc3c2c2c1C(=O)NC2=O
Temperature: 20 °C
Reaction time: 2.5 h
Yield: 86 %

Procedure:
A mixture of the 9-hydroxy-4-[2-(methylsulfanyl)phenyl]pyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione (508) (34.5 mg, 0.092 mmol), prepared according to example 25, and 2-phenylsulfonyl-3-phenyloxaziridine (Davis reagent) (26.5 mg, 0.102 mmol) in THF (10 mL) was stirred at 20° C. for 2.5 h, then adsorbed directly onto silica gel and chromatographed. Elution with 0–3% MeOH/CH2Cl2 then 3–4% MeOH/CH2Cl2 gave (after crystallisation from THF/CH2Cl2/pentane) the 9-Hydroxy-4-[2-(methylsulfinyl)phenyl]pyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione (510) (I; Ar=2-(methylsulfinyl)phenyl) in a 86% yield as a yellow solid; mp 321–323° C. 1H NMR [(CD3)2SO] δ 11.86, 11.85 (2br s, 1H), 11.09 (br s, 1H), 9.30 (br s, 1H), 8.32 (d, J=2.4 Hz, 1H), 8.04, 7.97 (2d, J=7.6 Hz, 1H), 7.74 (t, J=7.6 Hz, 1H), 7.65, 7.62 (2t, J=7.4 Hz, 1H), 7.62, 7.54 (2s, 1H), 7.47 (d, J=9.1 Hz, 1H), 7.44 (d, J=8.4 Hz, 1H), 7.09 (dd, J=8.7, 2.5 Hz, 1H), 2.43, 2.31 (2s, 3H). Found: C, 64.60; H, 3.88; N, 6.87. C21H14N2O4S requires C, 64.61; H, 3.61; N, 7.18.
Reaction SMILES: [H-].[Na+].[CH2:3]([NH:12][C:13]1[C:21]2[C:16](=[CH:17][C:18]([Cl:23])=[CH:19][C:20]=2[Cl:22])[N:15]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:14]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32])C(C1C=CC=CC=1)=O.[CH2:36](I)[CH3:37].Cl.CN(C)[CH:42]=[O:43]>C(OCC)(=O)C>[CH2:36]([CH2:37][CH2:3][NH:12][C:13]1[C:21]2[C:16](=[CH:17][C:18]([Cl:23])=[CH:19][C:20]=2[Cl:22])[N:15]([C:24]([O:26][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:25])[C:14]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:42]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:43]
Reactant: CCI
Reactant: CCOC(=O)c1c(NCC(=O)c2ccccc2)c2c(Cl)cc(Cl)cc2n1C(=O)OC(C)(C)C
Reactant: CN(C)C=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(NCCCC(=O)c2ccccc2)c2c(Cl)cc(Cl)cc2n1C(=O)OC(C)(C)C
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
Suspend sodium hydride (52 mg of a 60% dispersion, 1.73 mmol) in anhydrous dimethylformamide and cool to -10° C. Add, by dropwise addition, a solution of 3-[(phenacyl)amino]-2-carbethoxy-4,6-dichloro-1-tert-butyloxycarbonyl-indole (0.75 g, 1.57 mmol) in dimethylformamide. Stir under a nitrogen atmosphere for 30 minutes. Add ethyl iodide (0.27 g, 1.73 mmol) and stir at -10° C. for 5 hours. Pour into 1N hydrochloric acid (100 mL) andextract into ethyl acetate. Separate the organic phase and dry (MgSO4). Evaporate the solvent in vacuo and purify by flash chromatography (4:1 methylene chloride/ethyl acetate and recrystallize (ethyl acetate/hexane) to give the title compound; mp 110°-11° C.
Reaction SMILES: CO[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[F:11].Br[CH2:14][C:15]1[S:19][C:18]([C:20]#[N:21])=[CH:17][CH:16]=1.[CH3:22][C@@H:23]1[CH2:27][CH2:26][CH2:25][N:24]1[CH2:28][C@@H:29]1[CH2:33][CH2:32][CH2:31][NH:30]1>>[F:11][C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][C:4]=1[C:3]([N:30]1[CH2:31][CH2:32][CH2:33][C@H:29]1[CH2:28][N:24]1[CH2:25][CH2:26][CH2:27][C@H:23]1[CH3:22])=[O:12])[O:10][CH2:14][C:15]1[S:19][C:18]([C:20]#[N:21])=[CH:17][CH:16]=1
Reactant: N#Cc1ccc(CBr)s1
Reactant: C[C@@H]1CCCN1C[C@@H]1CCCN1
Reactant: COC(=O)c1ccc(O)cc1F
Product: C[C@@H]1CCCN1C[C@@H]1CCCN1C(=O)c1ccc(OCc2ccc(C#N)s2)cc1F

Procedure:
The title compound is prepared in a manner substantially analogous to Procedures D and E using 2-fluoro-4-hydroxy-benzoic acid methyl ester [CAS 197507-22-5], 5-bromomethyl-thiophene-2-carbonitrile [CAS 134135-41-4], and 2-(R)-methyl-1-(2-(S)-pyrrolidinylmethyl)pyrrolidine. MS (ES+) m/e 428.3