Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:8][C:9]1([CH3:28])[CH2:26][C:13]2=[C:14]([C:21]3[CH:25]=[CH:24][NH:23][N:22]=3)[S:15][C:16](S(C)(=O)=O)=[C:12]2[C:11](=[O:27])[CH2:10]1.[OH-].[Na+]>C1COCC1.CCOC(C)=O>[CH3:8][C:9]1([CH3:28])[CH2:26][C:13]2=[C:14]([C:21]3[CH:25]=[CH:24][NH:23][N:22]=3)[S:15][C:16]([O:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[C:12]2[C:11](=[O:27])[CH2:10]1
Reactant: CC1(C)CC(=O)c2c(S(C)(=O)=O)sc(-c3cc[nH]n3)c2C1
Reactant: Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(C)CC(=O)c2c(Oc3ccccc3)sc(-c3cc[nH]n3)c2C1
Temperature: 25 °C
Yield: 16.7 %

Procedure:
To a solution of phenol (116 mg, 1.1 mmol) in THF (10 mL) was added 6,6-dimethyl-3-methanesulphonyl-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one (0.2 g, 0.62 mmol) and NaOH (0.3 mL of a 4M solution, 1.1 mmol). The mixture was heated at reflux overnight. Phenol (50 mg, 0.62 mmol) and NaOH (0.15 mL of a 4M solution, 0.62 mmol) were then added and the mixture heated at reflux for an additional 8 h. The solution was cooled to room temperature, diluted with EtOAc (100 mL) and washed with NaOH (1M, 2×100 mL). The organic layer was separated, dried (Na2SO4) and evaporated. The residue was chromatographed on silica gel, eluting with hexane:EtOAc (2:1) to give the title compound (35 mg, 18%) as a yellow solid. mp 232-234° C. 1H NMR (360 MHz, CDCl3) δ 1.10 (6H, s), 2.42 (2H, s), 2.86 (2H, s), 6.43 (1H, d, J=2.3 Hz), 7.20-7.26 (3H, m), 7.37 (1H, d, J=7.3 Hz), 7.39 (1H, d, J=8.7 Hz), 7.59 (1H, d, J=2.3 Hz). MS (ES+) 339 (M+1).
Reaction SMILES: [NH:1]([C:8]1[N:9]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14](Cl)[N:13]=[C:12]([CH3:20])[CH:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][NH:28][CH3:29]>O1CCOCC1>[NH:1]([C:8]1[N:9]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14]([N:28]([CH3:29])[CH3:27])[N:13]=[C:12]([CH3:20])[CH:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNC
Reactant: Cc1cc2c(c(Cl)n1)c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Solvent: C1COCCO1
Product: Cc1cc2c(c(N(C)C)n1)c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Reaction time: 24 h
Yield: 90.8 %

Procedure:
A mixture of 2-anilino-5-chloro-7-methyl-1-phenyl-1,6-naphthyridin-4(1H)-one (80 mg, 0.22 mmol) and dimethylamine (3M in THF, 0.73 mL, 2.20 mmol) in dioxane (3 mL) was heated to 80  C. for 24 h. The reaction mixture was cooled, concentrated in vacuo, diluted with water and the resulting mixture was extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated in vacuo to give 2-anilino-5-(dimethylamino)-7-methyl-1-phenyl-1,6-naphthyridin-4(1H)-one (74 mg, 91%): LCMS RT: 1.86 min, MH+: 371.3
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[CH2:7]/[N:8]=[CH:9]/[C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[C:17]([F:33])=[C:18](/[CH:22]=[C:23](/[C:26]2[CH:31]=[CH:30]C(Cl)=[CH:28][CH:27]=2)\[C:24]#[N:25])[CH:19]=[CH:20][CH:21]=1.C(N(CC)CC)C.Cl[CH2:42][Cl:43]>>[C:1]([O:5][C:6]([C@H:7]1[C@H:22]([C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([Cl:15])[C:17]=2[F:33])[C@:23]([C:26]2[CH:27]=[CH:28][C:42]([Cl:43])=[CH:30][CH:31]=2)([C:24]#[N:25])[C@H:9]([C:10]([CH3:13])([CH3:12])[CH3:11])[NH:8]1)=[O:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: ClCCl
Reactant: CC(C)(C)/C=N/CC(=O)OC(C)(C)C
Reactant: N#C/C(=C\c1cccc(Cl)c1F)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)[C@@H]1N[C@@H](C(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2)[C@H]1c1cccc(Cl)c1F
Yield: 30 %

Procedure:
In a manner similar to the method described in Example 1c, [2,2-dimethyl-prop-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 51a (1 g, 5 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-phenyl)-acrylonitrile (0.8 g, 2.7 mmol) prepared in Example 26a, AgF (1.5 g, 12 mmol), and triethylamine (2 g, 20 mmol) in dichloromethane (50 mL) at room temperature for 24 h to give (2R,3S,4R,5S)-5-tert-Butyl-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (0.4 g, 30%).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].C[Mg+].[Br-].[Cl:9][C:10]1[C:11]([CH2:18][S:19][C:20]2[N:25]=C(O)C=C(C)[N:21]=2)=[C:12]([CH:15]=[CH:16][CH:17]=1)[C:13]#[N:14].[CH2:28]1[CH2:32][O:31][CH2:30][CH2:29]1>>[Cl:9][C:10]1[C:11]([CH2:18][S:19][C:20]2[N:21]=[C:30]([OH:31])[CH:29]=[C:28]([CH3:32])[N:25]=2)=[C:12]([C:13](=[NH:14])[N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[CH:15]=[CH:16][CH:17]=1
Reactant: C1CCOC1
Reactant: Cc1cc(O)nc(SCc2c(Cl)cccc2C#N)n1
Reactant: CCNCC
Agent: C[Mg+]
Agent: [Br-]
Product: CCN(CC)C(=N)c1cccc(Cl)c1CSc1nc(C)cc(O)n1
Temperature: 40 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
In a 100 mL round bottom flask, diethylamine (0.31 mL, 3.0 mmol) was added into the solution of MeMgBr (0.90 mL, 3 mmol) in THF (20 mL). The resulting mixture was stirred at 40° C. for 1 hour, followed by addition of 3-chloro-2-{[(4-hydroxy-6-methylpyrimidin-2-yl)sulfanyl]methyl}benzonitrile (292 mg, 1.0 mmol). After another 1.5 hours, the solvent was removed under vacuum. The crude product was purified by CombiFlash (0 to 20% MeOH in DCM) to provide the title compound as a grey-yellow solid (200 mg, 68% yield); 1H NMR (400 MHz, DMSO-d6): δ 1.17 (t, 6H), 2.28 (s, 3H), 3.31 (q, 4H), 4.60-4.80 (m, 2H), 6.03 (br, 1H), 7.57 (m, 2H), 7.88 (d, 1H); M+365.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH2:16][NH:17][C:18]3[C:19]([CH3:33])=[C:20]([CH:29]=[CH:30][C:31]=3[CH3:32])[O:21][CH2:22][C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])[CH:11]=[C:12]([O:14]C)[CH:13]=2)[CH:5]=[CH:6][CH:7]=1.C(S)C.[Al+3].[Cl-].[Cl-].[Cl-].O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH2:16][NH:17][C:18]3[C:19]([CH3:33])=[C:20]([CH:29]=[CH:30][C:31]=3[CH3:32])[O:21][CH2:22][C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])[CH:11]=[C:12]([OH:14])[CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(CNc2c(C)ccc(OCC(=O)OC(C)C)c2C)cc(-c2cccc(F)c2)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCS
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(OCC(=O)OC(C)C)c(C)c1NCc1cc(O)cc(-c2cccc(F)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50793.3 %

Procedure:
To a solution of isopropyl 2-[3-[[3-(3-fluorophenyl)-5-methoxy-phenyl]methylamino]-2,4-dimethyl-phenoxy]acetate (390 mg, 0.9 mmol, 1.0 eq) in CH2Cl2 (10 mL) at 0° C. was added dropwise ethyl mercaptan (321 mg, 5.2 mmol, 6.0 eq) and AlCl3 (690 mg, 5.2 mmol, 6.0 eq). The reaction mixture was stirred at room temperature for 1 h then poured into water and extracted with EtOAc. The organic extract was washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was purified by column chromatography (petroleum ether: EtOAc, 100:1 to 10:1) to give the title compound as a white solid (200 g, 53%).
Reaction SMILES: C[O-].[Na+].Cl.Cl[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[CH2:13]([N:17]1[C:26](=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=[C:18]1[SH:28])[CH:14]([CH3:16])[CH3:15].O>CO>[CH2:13]([N:17]1[C:26](=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=[C:18]1[S:28][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[CH:14]([CH3:16])[CH3:15]
Reactant: ClCc1ccccn1
Reactant: CC(C)Cn1c(S)nc2ccccc2c1=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)Cn1c(SCc2ccccn2)nc2ccccc2c1=O
Reaction time: 15 h
Yield: 46.1 %

Procedure:
5.4 ml of 28% methanolic solution of sodium methoxide and 2.3 g of 2-chloromethylpyridine hydrochloride were added, in turn, to a solution of 3.0 g 3-isobutyl-2-mercapto-4(3H-)quinazolinone in 50 ml of methanol, and the stirring was continued at room temperature for 15 hours. The reaction solution was poured into about 300 ml of water and extracted with chloroform. The extract was dried over sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica column chromatography eluted with 10% ethyl acetate in chloroform. The fraction obtained from the eluent was further purified by crystallization from a mixture of ethyl acetate and diisopropylether to give 1.92 g of the title compound.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([NH:14][CH2:15][C:16]2[CH:17]=[C:18]([O:22][CH2:23][CH2:24][CH2:25][C:26]([O:28]CC)=[O:27])[CH:19]=[CH:20][CH:21]=2)=[O:13])[NH:3]1.[OH-].[Na+].C1COCC1.CO>O>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([NH:14][CH2:15][C:16]2[CH:17]=[C:18]([O:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])[CH:19]=[CH:20][CH:21]=2)=[O:13])[NH:3]1
Reactant: CCOC(=O)CCCOc1cccc(CNC(=O)c2nc3ccccc3c(=O)[nH]2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)CCCOc1cccc(CNC(=O)c2nc3ccccc3c(=O)[nH]2)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 69 %

Procedure:
A mixture of ethyl 4-{[3-({[(4-oxo-3,4-dihydroquinazolin-2-yl)carbonyl]amino}methyl)phenyl]oxy}butanoate obtained in Reference Example 43 (525 mg, 1.28 mmol), 4N aqueous sodium hydroxide solution (1.6 mL), THF (10 mL), methanol (10 mL) and water (10 mL) was stirred at 100° C. for 2 hr. The mixture was allowed to cool to room temperature, and the solvent was evaporated under reduced pressure. Water and 1N hydrochloric acid (6.41 mL) were added to the residue, and the resulting precipitate was collected by filtration, washed with water, and dried. The obtained crude crystals were recrystallized from ethanol to give the title compound as a white powder (339 mg, 69%).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1[O:4][C:5]2[C:15]([N:16]=1)=[CH:14][C:8]1[CH2:9][CH2:10][NH:11][CH2:12][CH2:13][C:7]=1[CH:6]=2.[Cl:18][CH2:19][CH2:20][CH2:21][S:22][C:23]1[N:24]([CH3:39])[C:25]([C:28]2[CH:37]=[CH:36][CH:35]=[C:34]3[C:29]=2[CH:30]=[CH:31][C:32]([CH3:38])=[N:33]3)=[N:26][N:27]=1>>[ClH:18].[ClH:18].[CH3:1][N:2]([CH3:17])[C:3]1[O:4][C:5]2[C:15]([N:16]=1)=[CH:14][C:8]1[CH2:9][CH2:10][N:11]([CH2:19][CH2:20][CH2:21][S:22][C:23]3[N:24]([CH3:39])[C:25]([C:28]4[CH:37]=[CH:36][CH:35]=[C:34]5[C:29]=4[CH:30]=[CH:31][C:32]([CH3:38])=[N:33]5)=[N:26][N:27]=3)[CH2:12][CH2:13][C:7]=1[CH:6]=2
Reactant: CN(C)c1nc2cc3c(cc2o1)CCNCC3
Reactant: Cc1ccc2c(-c3nnc(SCCCCl)n3C)cccc2n1
Product: Cc1ccc2c(-c3nnc(SCCCN4CCc5cc6nc(N(C)C)oc6cc5CC4)n3C)cccc2n1
Product: Cl

Procedure:
The title compound was prepared in analogy to General Procedure 1 from N,N-dimethyl-6,7,8,9-tetrahydro-5H-[1,3]oxazolo[4,5-h][3]benzazepin-2-amine (0.18 mmol) and 5-{5-[(3-chloropropyl)thio]-4-methyl-4H-1,2,4-triazol-3-yl}-2-methylquinoline and was obtained as a white slightly hygroscopic solid (0.045 mmol).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]Cl)=[C:6]([C:12]([Cl:15])([Cl:14])[Cl:13])[CH:5]=1)([O-:3])=[O:2].[CH2:16]([SH:20])[CH2:17][CH2:18][CH3:19]>C(OCC)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][S:20][CH2:16][CH2:17][CH2:18][CH3:19])=[C:6]([C:12]([Cl:15])([Cl:14])[Cl:13])[CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(SCl)c(C(Cl)(Cl)Cl)c1
Reactant: CCCCS
Solvent: CCOCC
Product: CCCCSSc1ccc([N+](=O)[O-])cc1C(Cl)(Cl)Cl
Yield: 92.1 %

Procedure:
61 g of 4-nitro-2-trichloromethylbenzenesulfenyl chloride in 800 ml of diethyl ether is reacted in a stirred apparatus with 18 g of 1-butylmercaptan for 6 hours at 25° C. The completion of the reaction is determined by gas chromatography. After removal of the solvent, there is obtained 66 g (92% of theory) of (4-nitro-2-trichloromethylphenyl)-n-butyl disulfide as a yellow oil.
Reaction SMILES: Br[C:2]1[C:3]([O:23][CH3:24])=[C:4]([CH:10]([N:12]2[C:16]3=[N:17][CH:18]=[N:19][C:20]([NH2:21])=[C:15]3[C:14]([CH3:22])=[N:13]2)[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[C:33]1([CH3:39])[CH:38]=CC=C[CH:34]=1.[OH2:40]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:21][C:20]1[N:19]=[CH:18][N:17]=[C:16]2[N:12]([CH:10]([C:4]3[C:3]([O:23][CH3:24])=[C:2]([CH2:7][CH2:2][C:3]([O:23][C:33]([CH3:34])([CH3:38])[CH3:39])=[O:40])[C:7]([CH3:8])=[C:6]([Cl:9])[CH:5]=3)[CH3:11])[N:13]=[C:14]([CH3:22])[C:15]=12
Reactant: Cc1ccccc1
Reactant: O
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1CCC(=O)OC(C)(C)C
Temperature: 110 °C

Procedure:
To a microwave vial was added 1-[1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Peak 1 from Example 167, step 4 chiral separation, 35 mg, 0.085 mmol), potassium (3-tert-butoxy-3-oxopropyl)trifluoroborane (30.0 mg, 0.13 mmol, from Frontier Scientific, item # P10370), potassium phosphate (54 mg, 0.26 mmol) and tetrakis(triphenylphosphine)palladium(0) (9.8 mg, 0.0085 mmol) and toluene (0.7 mL)/water (0.2 mL). The vial was sealed and degassed with N2 three times. The reaction was heated at 110° C. for 20 h. The crude was filtered and the product (20 mg, 50%) was purified by chromatography eluting with CH2Cl2/MeOH (max. MeOH 6%). LCMS calculated for C23H31ClN5O3 (M+H)+: m/z=460.2; Found: 460.3.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].C[Al](C)C.[CH3:13][S:14]([C:17]1[CH:18]=[CH:19][C:20]([C:23](OC)=[O:24])=[N:21][CH:22]=1)(=[O:16])=[O:15].Cl>C1(C)C=CC=CC=1.ClCCl>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:23](=[O:24])[C:20]1[CH:19]=[CH:18][C:17]([S:14]([CH3:13])(=[O:16])=[O:15])=[CH:22][N:21]=1
Reactant: COC(=O)c1ccc(S(C)(=O)=O)cn1
Reactant: Nc1ccccc1Cl
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(=O)Nc2ccccc2Cl)nc1
Temperature: 85 °C
Reaction time: 0.5 h

Procedure:
To 2-Chloroaniline (1.20 g, 0.0093 mol) in toluene (20 mL) was added trimethylaluminum (2.0 M 4.6 mL) then methyl 5-(methylsulfonyl)picolinate 4 (1.0 g, 4.65 mol) was added and the mixture was heated to 80-90° C. for 2 h. The reaction was cooled down and 1N HCl solution (10 mL) was added to be acidic. Dichloromethane (100 mL) was then added and the organic phase was further washed with water (100 mL) and dried over sodium sulfate. The solvent was removed and the residue was mixed with ether (50 mL) and stirred for 0.5 h. The solid was filtered and dried to give N-(2-chlorophenyl)-5-(methylsulfonyl)picolinamide 5 as a light yellow solid. Yield: 1.26 g, 87.2%.
Reaction SMILES: [F:1][C:2]1[C:3]([N:14]=P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[C:4](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][CH:7]=1.[N:34]([C:37]1[CH:42]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:40]=[CH:39][C:38]=1[O:47][CH3:48])=[C:35]=O.[CH3:49][O:50][C:51]1[C:52]2[CH:53]=[C:54]3[CH2:63][NH:62][CH2:61][CH2:60][N:55]3[C:56]=2[CH:57]=[CH:58][CH:59]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[N:14]=[C:35]([N:62]1[CH2:61][CH2:60][N:55]3[C:56]4[CH:57]=[CH:58][CH:59]=[C:51]([O:50][CH3:49])[C:52]=4[CH:53]=[C:54]3[CH2:63]1)[N:34]([C:37]1[CH:42]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:40]=[CH:39][C:38]=1[O:47][CH3:48])[CH:8]2[CH2:9][C:10]([O:12][CH3:13])=[O:11]
Reactant: COc1ccc(C(F)(F)F)cc1N=C=O
Reactant: COC(=O)/C=C/c1cccc(F)c1N=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1cccc2c1cc1n2CCNC1
Product: COC(=O)CC1c2cccc(F)c2N=C(N2CCn3c(cc4c(OC)cccc43)C2)N1c1cc(C(F)(F)F)ccc1OC

Procedure:
Starting with 500 mg (1.1 mmol) of the iminophosphorane from Example 12A, 238 mg (1.1 mmol) of 2-isocyanato-1-methoxy-4-(trifluoromethyl)benzene and 222 mg (1.1 mmol) of 9-methoxy-1,2,3,4-tetrahydropyrazino[1,2-a]indole from Example 34A, the general procedure [M] gives 270 mg (38% of theory) of product.
Reaction SMILES: [S:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])(=[O:3])[NH2:2].[CH2:14](Cl)Cl.CO.[Si](C=[N+]=[N-])(C)(C)C>CCCCCC.[OH-].[Na+].C(Cl)Cl>[CH3:14][O:10][C:9](=[O:11])[C:8]1[CH:7]=[CH:6][C:5]([S:1](=[O:3])(=[O:4])[NH2:2])=[CH:13][CH:12]=1
Reactant: NS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: ClCCl
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CO
Product: COC(=O)c1ccc(S(N)(=O)=O)cc1
Reaction time: 2 h
Yield: 95 %

Procedure:
To a stirred suspension of 4-sulfamoyl-benzoic acid (25.0 g, 0.124 mol) in 4:1 CH2Cl2/MeOH at rt was added 1.0 M TMSCHN2 in hexane (175 mL), and the reaction mixture was allowed to stir for 2 h. The mixture was diluted with 1N NaOH (100 mL) and CH2Cl2 (150 mL), and the layers were separated. The organic layer was dried over Na2SO4, then filtered, and the solvent was removed under reduced pressure to afford the desired ester (25.2 g, 95%), which was used without further purification. 1H NMR (400 MHz, DMSO-d6): 8.14 (d, J=8.1 Hz, 2H), 7.96 (d, J=8.1 Hz, 2H), 7.58 (s, 2H), 3.90 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[C:17]#[C:18][Si](C)(C)C)[CH2:5][N:6]1[CH2:9][CH:8]([C:10]([O:12][CH3:13])=[O:11])[CH2:7]1.[F-].[Cs+].CN(C=O)C>CO>[C:17]([C:16]1[CH:15]=[CH:14][C:4]([CH2:5][N:6]2[CH2:9][CH:8]([C:10]([O:12][CH3:13])=[O:11])[CH2:7]2)=[CH:3][C:2]=1[F:1])#[CH:18]
Reactant: COC(=O)C1CN(Cc2ccc(C#C[Si](C)(C)C)c(F)c2)C1
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Solvent: CO
Product: C#Cc1ccc(CN2CC(C(=O)OC)C2)cc1F
Reaction time: 2 h

Procedure:
Methyl 1-(3-fluoro-4-(2-(trimethylsilyl)ethynyl)benzyl)azetidine-3-carboxylate (20.9 g, 65 mmol), and cesium fluoride (11 g, 72 mmol), was added to DMF (50 mL). MeOH (100 mL) was added. After 2 h, MeOH was removed and the mixture was extracted with DCM and water. The organic layer is washed with brine and dried over magnesium sulfate. The solvent was removed and the material purified using Biotage (75 L, 7-100% EtOAc/hexanes) affording methyl 1-(4-ethynyl-3-fluorobenzyl)azetidine-3-carboxylate as light yellow oil. MS (ESI) m/z: Calculated: 247.1; Observed: 248.0 (M++1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:40])[CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][C@@H:25]2[O:28][C:29](=[O:31])[CH3:30])[C@:21]2([CH3:22])[C@@H:16]([CH2:17][C@H:18]([O:32][C:33](=[O:35])[CH3:34])[CH2:19][CH2:20]2)[CH2:15][C@H:14]3[O:36][C:37](=[O:39])[CH3:38])[CH2:11][CH2:10]1)[CH3:8])[CH3:2].C([N-]C(C)C)(C)C.[Li+].C1C[O:52]CC1>>[CH2:1]([O:3][C:4](=[O:40])[CH:5]([OH:52])[CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][C@@H:25]2[O:28][C:29](=[O:31])[CH3:30])[C@:21]2([CH3:22])[C@@H:16]([CH2:17][C@H:18]([O:32][C:33](=[O:35])[CH3:34])[CH2:19][CH2:20]2)[CH2:15][C@H:14]3[O:36][C:37](=[O:39])[CH3:38])[CH2:11][CH2:10]1)[CH3:8])[CH3:2]
Reactant: C1CCOC1
Reactant: CCOC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](OC(C)=O)C[C@@H]4C[C@H](OC(C)=O)CC[C@]4(C)[C@H]3C[C@H](OC(C)=O)[C@]12C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: CCOC(=O)C(O)C[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](OC(C)=O)C[C@@H]4C[C@H](OC(C)=O)CC[C@]4(C)[C@H]3C[C@H](OC(C)=O)[C@]12C
Temperature: -60 °C
Reaction time: 0.25 h

Procedure:
A solution of 3α,7α,12α-triacetoxy-5β-cholanic acid-ethyl ester (5 mmol) in dry THF (100 ml) was cooled to -78° C. and lithium diisopropylamide (LDA, 5.98 g, 7.5 mmol) was added thereto. After 15 minutes, a solution of trans-2-(phenylsulfonyl)-3-phenyloxaziridine (Davis reagent, 2.06 g, 6.73 mmol) in THF (10 ml) was added. The mixture was stirred at -60° C. for 3 hours. Normal workup, followed by purification over silica gel gave two diastereomers of 3α,7α,12α-triacetoxy-23-hydroxy-5β-cholanic acid-ethyl ester. The absolute stereochemistry of the diastereomers was not determined.
Reaction SMILES: CB1N2CCC[C@H]2C(C2C=CC=CC=2)(C2C=CC=CC=2)O1.B.[CH3:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-:34])=[O:33])[CH:27]=1)=[O:25].CO>C(Cl)Cl>[N+:32]([C:28]1[CH:27]=[C:26]([C@H:24]([OH:25])[CH3:23])[CH:31]=[CH:30][CH:29]=1)([O-:34])=[O:33]
Reactant: CC(=O)c1cccc([N+](=O)[O-])c1
Agent: B
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@@H]2CCCN12
Solvent: CO
Solvent: ClCCl
Product: C[C@@H](O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 96.7 %

Procedure:
To a solution of (S)-tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo[1,2-c]- [1,3,2]-oxazaborole-borane (6.06 mmol) in CH2Cl2 (6 mL) at −20° C. was added a solution of 3-nitroacetophenone (6.06 mmol) in CH2Cl2 (6 mL) in a dropwise fashion over 30 min. The resulting mixture was stirred 45 min. longer then poured into cold methanol (−20° C.), and this mixture allowed to stir overnight while warming to room temperature. The mixture was then concentrated in vacuo then more methanol (100 mL) added and concentrated, and then added another 100 mL methanol and concentrated. The resulting crude was purified on silica gel in 60:40 hexanes:ethyl acetate to yield 0.98 g of the title compound. 1H NMR (500 MHz, CDCl3): δ 8.22 (m, 1H); 8.08 (m, 1H); 7.69 (d, J=7.8 Hz, 1H); 7.50 (t, J=7.8 Hz, 1H); 5.00 (m, 1H); 2.62 (s, 1H); 1.53 (d, J=7.1 Hz, 3H).
Reaction SMILES: [NH:1]([C:3]1[N:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:7](=[O:13])[NH:6][C:5](=[O:14])[CH:4]=1)[NH2:2].[S:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[C:17]([CH:24]=O)=[CH:16]1.[CH3:26][N:27]1[CH:31]=[CH:30][CH:29]=[C:28]1[CH:32]=O>>[S:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[C:17]([CH2:24][N:2]2[C:32]([C:28]3[N:27]([CH3:26])[CH:31]=[CH:30][CH:29]=3)=[C:4]3[C:3]([N:8]([CH2:9][CH:10]([CH3:11])[CH3:12])[C:7](=[O:13])[NH:6][C:5]3=[O:14])=[N:1]2)=[CH:16]1
Reactant: O=Cc1csc2ccccc12
Reactant: CC(C)Cn1c(NN)cc(=O)[nH]c1=O
Reactant: Cn1cccc1C=O
Product: CC(C)Cn1c(=O)[nH]c(=O)c2c(-c3cccn3C)n(Cc3csc4ccccc34)nc21

Procedure:
This compound was isolated as a byproduct from a two step preparation as described: A): 2-(1-benzothien-3-ylmethyl)-7-isobutyl-3-(1-methyl-1H-pyrrol-2-yl)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione was prepared starting from 6-hydrazino-1-isobutylpyrimidine-2,4(1H,3H)-dione and condensing first with 1-benzothiophene-3-carbaldehyde, followed by 1-methyl-1H-pyrrole-2-carbaldehyde.
Reaction SMILES: Cl.[CH2:2]([N:6]([S:16]([C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=1)(=[O:18])=[O:17])[C@H:7]([C:13]([OH:15])=[O:14])[CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])[CH:3]([CH3:5])[CH3:4].[CH3:28][C:29]1[CH:34]=[CH:33][C:32]([S:35]([NH:38][C@H:39]([C:50](O)=[O:51])[CH2:40][C:41]2[C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[NH:43][CH:42]=2)(=[O:37])=[O:36])=[CH:31][CH:30]=1>>[CH3:28][C:29]1[CH:30]=[CH:31][C:32]([S:35]([NH:38][C@H:39]([C:50]([NH:12][CH2:11][CH2:10][CH2:9][CH2:8][C@H:7]([N:6]([S:16]([C:19]2[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:2][CH:3]([CH3:5])[CH3:4])[C:13]([OH:15])=[O:14])=[O:51])[CH2:40][C:41]2[C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[NH:43][CH:42]=2)(=[O:37])=[O:36])=[CH:33][CH:34]=1
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](Cc2c[nH]c3ccccc23)C(=O)O)cc1
Reactant: CC(C)CN([C@@H](CCCCN)C(=O)O)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: Cc1ccc(S(=O)(=O)N[C@@H](Cc2c[nH]c3ccccc23)C(=O)NCCCC[C@@H](C(=O)O)N(CC(C)C)S(=O)(=O)c2ccc(N)cc2)cc1

Procedure:
The title compound was prepared from Nα-isobutyl-Nα-(4-nitrobenzenesulfonyl)-L-lysine hydrochloride (350 mg, 1.0 mmol, example 5, step C) as described in general procedure Bc using Nα-(4-methylbenzenesulfonyl)-L-tryptophan (335 mg, 1.1 mmol) which was prepared in step A of example 2. The final product was purified by preparative HPLC to yield 650 mg (90%) of Nα-(4-nitrobenzenesulfonyl)-Nα-isobutyl-Nε-[N′α-(4-methylbenzenesulfonyl)-L-tryptophanyl]-L-lysine The latter derivative (300 mg) was hydrogenolysed following the indications of general procedure E. Purification by HPLC gave the desired material (235 mg, 75%).