Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)O.[C:9]([NH2:12])(=[O:11])[CH3:10]>O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.P.[W].[W].[W].[W].[W].[W].[W].[W].[W].[W].[W].[W]>[C:9]([NH:12][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)(=[O:11])[CH3:10]
Reactant: Oc1ccc(O)cc1
Reactant: CC(N)=O
Agent: [W]
Agent: P
Solvent: O
Product: CC(=O)Nc1ccc(O)cc1
Reaction time: 1.5 h

Procedure:
An intimate mixture of hydroquinone (5.5 g), acetamide (3.5 g) and phosphotungstic acid (0.3 g) was placed in a well stoppered stainless steel tube from which air has been displaced with nitrogen. The tube was kept in a temperature controlled oven at 280°-300° C. for 1.5 hrs. The tube was then removed from the oven, cooled, opened, contents extracted with ethyl acetate, crystallized and products analyzed by gas chromatography. Pure standard substances were used for calibration. The products were also analyzed and identified by GC-mass spectroscopy techniques. The conversion of hydroquinone was 95% by wt. and selectivity to N-acetyl para aminophenol was 86%. Pure N-acetyl para aminophenol could be isolated from the products by column chromatography using alumina.
Reaction SMILES: [CH:1]1([C:7](=[NH:9])[NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[Cl:19][C:20]([SH:23])(Cl)Cl>C(Cl)Cl>[Cl:19][C:20]1[S:23][N:8]=[C:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[N:9]=1
Reactant: N=C(N)C1CCCCC1
Reactant: SC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Clc1nc(C2CCCCC2)ns1
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
Cyclohexanecarboximidamide (100 mg, 792 μmol) and DIPEA (512 mg, 3.96 mmol) in 10 mL DCM at 0-5° C. were treated with perchloromethyl mercaptan (147 mg, 792 μmol) in 5 mL DCM and stirred for 1 hr at 0-5° C. The mixture was concentrated in vacuo to give a brown solid which was used with out further purification in the subsequent step.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:17](=[O:18])[N:16]2[C@H:19]([C:22]([O:24]C(C)(C)C)=[O:23])[CH2:20][CH2:21][C:15]2=[N:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)Cl.C(O)(C(F)(F)F)=O>O>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:17](=[O:18])[N:16]2[C@H:19]([C:22]([OH:24])=[O:23])[CH2:20][CH2:21][C:15]2=[N:14][CH:13]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCc2ncc(NC(=O)OCc3ccccc3)c(=O)n21
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cnc2n(c1=O)[C@H](C(=O)O)CC2)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl ester 1h (11.13 g, 28.9 mmol) was dissloved in 1:1 CH2Cl2/TFA. 1 mL H2O was added and the mixture was stirred overnight at rt. The mixture was concentrated and the resultant residue was co-evaporated with CCl4 (3×). The residual oil was triturated with 1:1 Et2O/hexanes (100 mL) and the solid (9.0 g, 95%) was collected and dried, to provide 1i. 1H NMR (300 MHz, CDCl3) δ8.69 (br s, 1H), MS (ESI) 330.3 (M+H+); 328.3 (M−H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([C:16]([C:26]3[CH:31]=[CH:30][C:29]([CH2:32][CH3:33])=[CH:28][CH:27]=3)([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH3:25])=[CH:20][CH:19]=3)O)[CH2:12][CH2:11]2)=[CH:5][CH:4]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([CH:16]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH3:25])=[CH:20][CH:19]=3)[C:26]3[CH:31]=[CH:30][C:29]([CH2:32][CH3:33])=[CH:28][CH:27]=3)[CH2:12][CH2:11]2)=[CH:7][CH:8]=1
Reactant: CCc1ccc(C(O)(c2ccc(CC)cc2)C2CCN(Cc3ccc(OC)cc3)CC2)cc1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1ccc(C(c2ccc(CC)cc2)C2CCN(Cc3ccc(OC)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 58.5 %

Procedure:
To a stirred solution of 1.0 gram (0.002 mole) of N-(4-methoxyphenylmethyl)-4-[bis(4-ethylphenyl)hydroxymethyl]piperidine (prepared in the manner of Example 1) in 10 mL of methylene chloride was slowly added 1.1 mL (0.007 mole) of triethylsilane, followed by 1.0 mL (0.013 mole) of trifluoroacetic acid. The reaction mixture was then stirred at ambient temperature during a five hour period. After this time the reaction mixture was neutralized with solid sodium carbonate. The mixture was then partitioned between 100 mL of methylene chloride and 50 mL of water. The organic layer was separated and washed with two 50 mL portions of an aqueous solution saturated with sodium chloride. The organic layer was then dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue, which was purified by subjecting it to preparative thin layer chromatography, with 25% acetone in methylene chloride as the eluant, yielding about 0.5 gram of N-(4-methoxyphenylmethyl)-4-[bis(4-ethylphenyl)methyl]piperidine. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C([O:3][C:4](=[O:35])[CH2:5][CH2:6][N:7]1[CH2:11][C@@H:10]([CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C@@:9]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[F:26])([C:17]#[N:18])[C@H:8]1[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=1[F:34])C.[Li+].[OH-]>C1COCC1.O>[Cl:33][C:29]1[C:28]([F:34])=[C:27]([C@@H:8]2[C@:9]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=3[F:26])([C:17]#[N:18])[C@H:10]([CH2:12][C:13]([CH3:15])([CH3:16])[CH3:14])[CH2:11][N:7]2[CH2:6][CH2:5][C:4]([OH:35])=[O:3])[CH:32]=[CH:31][CH:30]=1
Reactant: CCOC(=O)CCN1C[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)C[C@@H]1CN(CCC(=O)O)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 22 h
Yield: 94.5 %

Procedure:
To a mixture of rac-3-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidin-1-yl]-propionic acid ethyl ester (12.3 mg, 0.0235 mmol) in THF (2 mL) was added a solution of LiOH (Aldrich, 6.7 mg, 0.16 mmol) in water (1 mL) and the reaction mixture was stirred at rt for 22 hrs. The reaction mixture was partly concentrated and quenched with 1 N HCl (pH 6-7), extracted with EtOAc, washed with water (2×), and saturated NaCl. The organic phase was separated, and dried over Na2SO4. The mixture was then concentrated to give rac-3-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidin-1-yl]-propionic acid (11 mg, 100%). HRMS (ES+) m/z Calcd for C25H26Cl2F2N2O2+H [(M+H)+]: 495.1412; Found: 495.1413.
Reaction SMILES: [C:1]([N:3]=[C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)OC)#[N:2].[CH3:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH2:19])=[CH:16][CH:15]=1>CO>[C:1]([NH:3][C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)=[N:19][CH2:18][C:17]1[CH:20]=[CH:21][C:14]([CH3:13])=[CH:15][CH:16]=1)#[N:2]
Reactant: Cc1ccc(CN)cc1
Reactant: COC(=NC#N)c1ccccn1
Solvent: CO
Product: Cc1ccc(CN=C(NC#N)c2ccccn2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.2 %

Procedure:
Methyl N-cyano-2-pyridinecarboximidate (0.30 g, 1.9 mmol) was dissolved in methanol (10 ml), p-methylbenzylamine (0.25 g, 2.1 mmol) was added, and the resulting mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue thus obtained was crystallized from diethyl ether to give the title compound (0.41 g, 1.6 mmol, yield: 91%) as colorless crystals.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:7][NH:6][N:5]=[CH:4]1)[CH3:2].C[S:9][C:10](SC)=[N:11][S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])(=[O:14])=[O:13].N1C=CC=C[CH:25]=1>>[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:12]([N:11]=[C:10]([CH3:25])[S:9][N:5]1[CH2:4][CH:3]([CH2:1][CH3:2])[CH:7]=[N:6]1)(=[O:14])=[O:13]
Reactant: CCC1C=NNC1
Reactant: c1ccncc1
Reactant: CSC(=NS(=O)(=O)c1ccccc1Cl)SC
Product: CCC1C=NN(SC(C)=NS(=O)(=O)c2ccccc2Cl)C1

Procedure:
500 mg 4-Ethyl-4,5-dihydro-1H-pyrazole was dissolved in 10 mL pyridine, 1.51 g N-(Bis-methylsulfanyl-methylene)-2-chloro-benzenesulfonamide was added and the mixture was refluxed overnight. The mixture was concentrated in vacuo and H2O was added, followed by extraction twice with DCM. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude product was purified with flash chromatography (gradient DCM:acetone=100:0 to 95:5) to yield 1.30 g of a yellow oil. 1H NMR (400 MHz, CDCl3) δ 1.02 (t, J=7.5 Hz, 3H), 1.55-1.77 (m, 2H), 2.28 (s, 3H), 3.27-3.39 (m, 1H), 4.13 (dd, J=11.5 and 6.5 Hz, 1H), 4.58 (t, J=11.5 Hz, 1H), 7.16 (d, J=2 Hz, 1H), 7.39 (dt, J=7.5 and 2 Hz, 1H), 7.46 (dt, J=7.5 and 2 Hz, 1H), 7.52 (dd, J=7.5 and 2 Hz, 1H), 8.17 (dd, J=7.5 and 2 Hz, 1H).
Reaction SMILES: O.Cl(O)(=O)(=O)=O.[Cl-].[CH3:8][O:9][C:10](=[O:31])[C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]2[CH:29]=[C:28]3[C:23]([CH:24]=[CH:25][CH:26]=[N:27]3)=[CH:22][CH:21]=2)=[O:19])=[CH:13][C:12]=1[Cl:30]>C(O)(C)C>[CH3:8][O:9][C:10](=[O:31])[C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]2[CH:29]=[C:28]3[C:23]([CH2:24][CH2:25][CH2:26][NH:27]3)=[CH:22][CH:21]=2)=[O:19])=[CH:13][C:12]=1[Cl:30]
Reactant: COC(=O)c1ccc(NC(=O)c2ccc3cccnc3c2)cc1Cl
Agent: [Cl-]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(C)O
Solvent: O
Product: COC(=O)c1ccc(NC(=O)c2ccc3c(c2)NCCC3)cc1Cl
Yield: 30 %

Procedure:
Water (1.5 ml), 60% aqueous perchloric acid (0.01 ml) and pentamethylcycloopentadienyliridium(III) chloride dimer) (116 mg, 0.145 mmol, 0.05 equiv.) were added to 2-chloro-4-[(quinoline-7-carbonyl)-amino]-benzoic acid methyl ester (1.42 g, 4.17 mmol) in degassed isopropanol (100 ml) under a nitrogen atmosphere and the mixture was refluxed for 48 hours. The mixture was evaporated to give a tan solid. The solid was purified by flash chromatography (SiO2, 1:9 tert-butyl-methyl ether:dichloromethane to 1:1:8 tert-butyl-methyl ether:methanol:dichloromethane). The fractions were combined to afford 2-chloro-4-[(1,2,3,4-tetrahydro-quinoline-7-carbonyl)-amino]-benzoic acid methyl ester, 0.434 g (30% yield) as a tan solid. LC @215 nm; Rt 1.15: 98%, m/z (ES+): 345 (M+H+.); δH (250 MHz; d6-DMSO) 10.39 (1H, br.s), 8.07 (1H, m), 7.91-7.80 (2H, m), 7.05-6.90 (3H, m), 5.95 (1H, br.s), 3.82 (3H, s), 3.19 (2H, m), 2.70 (2H, m), 1.79 (2H, m).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]4[C:26]=3[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C.Cl.O1CCOCC1>CO.C(Cl)Cl>[C:27]1([C:26]2[N:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]3=[N:19][C:18]=2[C:15]2[CH:14]=[CH:13][C:12]([C:8]3([NH2:7])[CH2:11][CH2:10][CH2:9]3)=[CH:17][CH:16]=2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccccn4c3-c3ccccc3)cc2)CCC1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: C1COCCO1
Product: NC1(c2ccc(-c3nc4ccccn4c3-c3ccccc3)cc2)CCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 48.2 %

Procedure:
To a solution of {1-[4-(3-phenyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (50 mg, 0.11 mmol) in MeOH (0.45 mL) and CH2Cl2 (0.75 mL) was added a 4 molar solution of HCl in dioxane (0.57 mL, 2.2 mmol, 20 5equiv). The resulting solution was stirred at room temperature for 12 h, then was concentrated under reduced pressure. The remaining material was purified using MPLC (Biotage Isolera; 10 g SNAP cartridge: 100% CH2Cl2 4.0 min., gradient to 95% CH2Cl2/5% MeOH 9.5 min., gradient to 90% CH2Cl2/10% MeOH 6.1 min.) to give 1-[4-(3-phenyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutylamine (18 mg, 47%):
Reaction SMILES: C([O:5][C:6]([C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:39])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][C:24]([N:26]2[CH2:30][CH2:29][CH2:28][C@@H:27]2[C:31]([O:33]C(C)(C)C)=[O:32])=[O:25])[C:17]=1[CH3:38])=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[C:31]([C@H:27]1[CH2:28][CH2:29][CH2:30][N:26]1[C:24](=[O:25])[CH2:23][O:22][C:18]1[C:17]([CH3:38])=[C:16]([CH:21]=[CH:20][CH:19]=1)[O:15][CH2:14][C:13]([N:9]1[CH2:10][CH2:11][CH2:12][C@@H:8]1[C:6]([OH:7])=[O:5])=[O:39])([OH:33])=[O:32]
Reactant: Cc1c(OCC(=O)N2CCC[C@@H]2C(=O)OC(C)(C)C)cccc1OCC(=O)N1CCC[C@@H]1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(OCC(=O)N2CCC[C@@H]2C(=O)O)cccc1OCC(=O)N1CCC[C@@H]1C(=O)O
Reaction time: 8 h
Yield: 94.6 %

Procedure:
A solution of 300 mg (0.55 mmol) (R)-1-[[3-[2-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethoxy]-2-methyl-phenoxy]-acetyl]-pyrrolidine-2-carboxylic acid tert butyl ester in 4 ml trifluoroacetic acid was stirred for 3 h at room temperature. The solvent was removed in vacuo and the residue suspended in 10 ml ether. The resulting suspension was stirred overnight. Filtration and drying gave 226 mg (95%) of the title compound as a white powder.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[N:15]=[C:14]([OH:16])[C:13]([N+:17]([O-])=O)=[CH:12][N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C1COCC1.O>[NH2:17][C:13]1[C:14]([OH:16])=[N:15][C:10]([CH2:9][O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:11][CH:12]=1
Reactant: O=[N+]([O-])c1cnc(COCc2ccccc2)nc1O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Nc1cnc(COCc2ccccc2)nc1O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of step B product, 3-d, (25 g, crude) in THF/H2O (1000 mL, VTHF/VH2O=1:1) was added with Na2S2O4 (33.3 g, 191.6 mmol) and stirred at room temperature for 4 h. The reaction mixture was extracted with EA (1000 mL), washed with brine (200 mL), and concentrated in vacuum. The residue was purified by column chromatography to afford the product, 3-e, (7.8 g) as a white solid. 1H NMR (300 MHz, CDCl3): δ 4.42 (s, 2H), 4.63 (s, 2H), 7.33-7.36 (m, 6H). LC-MS (M+H)+ 232.1
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:13]([CH2:15][NH2:16])[OH:14].[C:17]([NH:24][C@@H:25]([C:27](O)=[O:28])[CH3:26])([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>C1COCC1>[C:20]([O:19][C:17](=[O:18])[NH:24][C@@H:25]([C:27](=[O:28])[NH:16][CH2:15][CH2:13][OH:14])[CH3:26])([CH3:21])([CH3:22])[CH3:23]
Reactant: NCCO
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: C[C@@H](NC(=O)OC(C)(C)C)C(=O)NCCO
Temperature: 60 °C
Reaction time: 0.75 h
Yield: 90 %

Procedure:
In a round-bottomed flask, Boc-D-alanine (1.0 g, 5.29 mmol was dissolved in THF (40 ml) and 1,1′-carbonyldiimidazole (1.03 g, 6.34 mmol) was added. The reaction mixture was stirred at 60° C. for 45 min then cooled to room temperature and ethanolamine (3.2 ml, 52.9 mmol) was added. The reaction mixture was stirred at room temperature overnight then quenched with 1 M aqueous HCl (15 ml) and extracted with dichloromethane. The organic layer was washed with 1 M aqueous HCl, water and brine. The aqueous layers were back-extracted with dichloromethane (2×). The organic layers were combined, dried over sodium sulfate, filtered and concentrated to afford 1.11 g (90%) of [(R)-1-(2-hydroxy-ethylcarbamoyl)-ethyl]-carbamic acid tert-butyl ester as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH:17]([OH:19])[CH3:18])[CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=[CH:4][C:3]=1[C:20]([NH2:22])=[O:21].[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31](Cl)=O)=[CH:26][CH:25]=1>>[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]2[NH:22][C:20](=[O:21])[C:3]3[CH:4]=[N:5][N:6]([CH:7]([CH:17]([OH:19])[CH3:18])[CH2:8][CH2:9][CH2:10][C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:2]=3[N:1]=2)=[CH:26][CH:25]=1
Reactant: CC(O)C(CCCc1ccccc1)n1ncc(C(N)=O)c1N
Reactant: O=C(Cl)Cc1ccc(F)cc1
Product: CC(O)C(CCCc1ccccc1)n1ncc2c(=O)[nH]c(Cc3ccc(F)cc3)nc21

Procedure:
Starting from 400 mg (1.32 mmol) of 5-amino-1-[1-(1-hydroxy-ethyl)-4-phenyl-butyl]-1H-pyrazole-4-carboxamide and 570 mg (3.31 mmol) of 4-fluorophenylacetyl chloride, the title compounds are prepared analogously to the protocol of Example 13. This gives 143 mg (27%) of the diastereomer which elutes more rapidly, M.p. 103° C., and 111 mg (21%) of the diastereomer which elutes more slowly, M.p.: 107° C.
Reaction SMILES: [NH2:1][C@H:2]([C:13]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[NH:23]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[C@H:24]([C:40]([NH:42][C@H:43]([C:48](O)=[O:49])[CH2:44][C:45](=[O:47])[NH2:46])=[O:41])[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:28][CH:27]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl.CN(C=O)C>[NH:23]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[C@H:24]([C:40]([NH:42][C@H:43]([C:48]([NH:1][C@H:2]([C:13]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1)=[O:49])[CH2:44][C:45](=[O:47])[NH2:46])=[O:41])[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)N[C@@H](CC(N)=O)C(=O)O
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)NCc1ccccc1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)NCc1ccccc1
Yield: 47.7 %

Procedure:
compound A416. Same procedure as above with Trp-NHCH2Ph (63.03 mg, 0.215 mmol), N-Boc-Tyr(Bn)-Asn-OH (105.0 mg, 0.216 mmol), EDC (44 mg, 0.226 mmol) and HOBt (31 mg, 0.226 mmol) in CH2Cl2/DMF (1.5 mL/1.5 mL). After treatment, the crude residue was triturated with CH2Cl2/pentane to afford a white solid (78 mg, 48%). 1H NMR (300 MHz, DMSO-d6) δ 1H NMR (300 MHz, DMSO-d6) δ 1.29 (s, 9H, (CH3)3), 2.30-3.26 (m, 6H, CH2 Tyr, CH2 Trp, CH2 Asn), 4.08 (m, 1H, CHα), 4.24 (s, 2H, NCH2Ph), 4.49 (m, 1H, CHα), 4.56 (m, 1H, CHα), 5.03 (broad s, 2H, OCH2Ph), 6.88-7.56 (m, 17H), 8.17 (d, J=8 Hz, 1H, NH), 8.23 (d, J=8 Hz, 1H, NH), 8.51 (t, J=6 Hz, 1H, NH), 10.84 (s, 1H, NH). 13C NMR (75 MHz, CD3OD) δ 28.5 (CH2 Trp), 28.6 ((CH3)3), 37.3, 38.1 (CH2 Tyr, CH2 Asn), 44.1 (NCH2Ph), 51.7, 55.9, 57.6 (CHα Tyr, Asn, Trp), 71.0 (OCH2Ph), 80.9 (C Boc), 110.9 (C), 112.4, 115.9, 116.0, 119.4, 119.9, 122.5, 124.8, 128.0, 128.5, 128.6, 128.8, 129.4, 129.5, 130.6 (C), 131.4 (CH), 138.0, 138.8, 139.5 (aromatic C), 157.9, 159.1 (aromatic C and CO Boc), 172.7, 173.6, 174.4, 174.9 (CO amide).
Reaction SMILES: Cl.[CH:2]1([NH:5][C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]=[C:17]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]4[CH3:30])[C:18]4[CH2:23][NH:22][CH2:21][C:19]=4[N:20]=3)=[C:11]([F:31])[CH:10]=2)=[O:7])[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:39][C:40]([CH3:42])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C=O)C>[CH:2]1([NH:5][C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]=[C:17]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]4[CH3:30])[C:18]4[CH2:23][N:22]([CH:40]([CH3:42])[CH3:39])[CH2:21][C:19]=4[N:20]=3)=[C:11]([F:31])[CH:10]=2)=[O:7])[CH2:3][CH2:4]1
Reactant: CC(C)=O
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2F)nc2c1CNC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)N1Cc2nc(-c3ccc(NC(=O)NC4CC4)cc3F)nc(N3CCOC[C@@H]3C)c2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 13 %

Procedure:
To a stirred solution of (S)-1-cyclopropyl-3-(3-fluoro-4-(4-(3-methylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea (example 149) (115 mg, 0.279 mmol) in anhydrous DMF (2 ml) was added triethylamine (780, 0.558 mmol) and anhydrous acetone (100 μL). The reaction was stirred at RT for 30 minutes after which time sodium triacetoxyborohydride (118 mg, 0.558 mmol) was added and the reaction was stirred for a further 2 hours at RT. The reaction was then partitioned between H2O and DCM and the aqueous phase was extracted into DCM. The organic extracts were combined, dried over magnesium sulphate and concentrated in vacuo. The sample was then purified via preparative HPLC at high pH to yield the title compound (16 mg, 13%).
Reaction SMILES: C([O:3][C:4](=[O:18])[C:5]([CH3:17])([S:7]([CH2:10][CH2:11][CH2:12][C:13](F)(F)F)(=[O:9])=[O:8])[CH3:6])C.[CH3:19][Si](C)(C)[O-].[K+].Cl>C1COCC1>[CH3:17][C:5]([S:7]([CH2:10][CH2:11][CH:12]([CH3:13])[CH3:19])(=[O:8])=[O:9])([CH3:6])[C:4]([OH:3])=[O:18]
Reactant: CCOC(=O)C(C)(C)S(=O)(=O)CCCC(F)(F)F
Reactant: C[Si](C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)CCS(=O)(=O)C(C)(C)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 109 %

Procedure:
To a solution of 170 g (0.59 mol) of 2-methyl-2-(4,4,4-trifluoro-butane-1-sulfonyl)-propionic acid ethyl ester in THF (3.4 L) are added 225.4 g (1.76 mol) of potassium trimethylsilanolate in portions over 0.5 h. The reaction is stirred at room temperature for 18 h. The reaction mixture is acidified with 2M aqueous HCl solution (2 L) to pH 2 and extracted with DCM (2×2 L). The combined organic extracts are dried (Na2SO4) and filtered. The filtrate is concentrated under reduced pressure to afford 143 g of 2-methyl-2-(3-methyl-butane-1-sulfonyl)-propionic acid as yellow solids. Yield: 93%; ES-MS: m/z 261 [M−H]. 1H-NMR (500 MHz, CHLOROFORM-d) δ ppm 1.71 (6H, s), 2.18-2.28 (2H, m), 2.30-2.42 (2H, m), 3.38 (2H, t, J=7.48 Hz), 6.96 (1H, br. s.)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[CH2:4][C:5]#[N:6].[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[CH2:4][C:5]#[N:6]
Reactant: N#CCc1ccc(F)cc1Cl
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: N#CCc1cc([N+](=O)[O-])c(F)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
10 g of 2-chloro-4-fluorobenzyl cyanide are dissolved at a temperature of -10° C., with stirring, in 85 ml of concentrated sulfuric acid, in the process of which a fine light-brown suspension is formed. There are then slowly added dropwise at -20° C., with stirring, 5 ml of fuming nitric acid. After completion of the addition, stirring is continued for a further half hour, the temperature rising to 0° C. The reaction mixture is poured onto 500 g of ice, and the substance which precipitates is extracted with methylene chloride. The methylene chloride phase is dried over sodium sulfate, and concentrated by evaporation to leave 10.5 g of 2-chloro-4-fluoro-5nitrobenzyl cyanide in the form of white crystals having a melting point of 67°-68° C.
Reaction SMILES: [O:1]=[C:2]1[C:6]2[C:7]3[C:24]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[NH:18][C:8]=3[C:9]3[NH:10][C:11]4[C:16]([C:17]=3[C:5]=2[CH2:4][NH:3]1)=[CH:15][CH:14]=[CH:13][CH:12]=4.[CH3:25][CH2:26][CH2:27]CCCC=CCCC.C(#[N:38])C>>[C:27]([CH2:26][CH2:25][N:10]1[C:9]2[C:8]3[NH:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=4[C:7]=3[C:6]3[C:2](=[O:1])[NH:3][CH2:4][C:5]=3[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2)#[N:38]
Reactant: CC#N
Reactant: CCCC=CCCCCCC
Reactant: O=C1NCc2c1c1c3ccccc3[nH]c1c1[nH]c3ccccc3c21
Product: N#CCCn1c2ccccc2c2c3c(c4c5ccccc5[nH]c4c21)C(=O)NC3
Temperature: 20 °C
Reaction time: 72 h

Procedure:
300 mg (0.96 mmole) 6,7,12,13-tetrahydro-5-oxo-5H-indolo[2.3-a]pyrrolo [3,4-c]carbazole, suspended in 20 mL acetonitrile, are mixed with 0.3 mL (4.56 mole) acrylic acid nitrile and 2 drops of 1,8-diazabicyclo[5,4,0[undec-7-ene (DBU) and stirred for 3 days at 20° C. The mixture of starting materials and product is filtered off, again mixed with the same amounts of acrylic acid nitrile, DBU and acetonitrile and stirred for a further 3 days at 20° C. After again repeating this procedure and after a further 3 days at 20° C., the 12-(2-cyanoethyl)-6,7,12, 13-tetrahydro-5-oxo-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole is filtered off in the form of beige colored crystals which decompose above 275° C.