Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:4]=1[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:39][C:40]1[CH:46]=[CH:45][C:43]([NH2:44])=[CH:42][CH:41]=1>C1COCC1>[Br:39][C:40]1[CH:46]=[CH:45][C:43]([NH:44][C:5](=[O:7])[C:4]2[CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=[CH:11][C:3]=2[O:2][CH3:1])=[CH:42][CH:41]=1
Reactant: COc1ccc([N+](=O)[O-])cc1C(=O)O
Reactant: Nc1ccc(Br)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: COc1ccc([N+](=O)[O-])cc1C(=O)Nc1ccc(Br)cc1
Reaction time: 0.5 h

Procedure:
A mixture of 2-methoxy-5-nitro-benzoic acid (2.00 g, 10.1 mmol), HATU (3.86 g, 10.1 mmol), TEA (4.23 mL) and 100 mL THF was stirred for 30 min. Then 4-bromoaniline (1.75 g, 10.1 mmol) was added and the mixture was stirred for 3 days and concentrated. The crude material was dissolved in EtOAc and the organic phase was washed with satd. aq. NaHCO3. The precipitate was collected and again dissolved in EtOAc and washed with water and satd. NaHCO3. The organic phase was dried with Na2SO4, filtered and concentrated to furnish the subtitle compound. Yield: 930 mg (26%). MS [M+H]+=351 (Br-isotope pattern); TLC: Rf=0.94 (silica gel, DCM:EtOH 9:1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:29])([C@H:16]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:25]=[N:26][NH:27][CH:28]=2)=[CH:20][CH:19]=1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.[Cl:30]N1C(=O)CCC1=O>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:29])([C@H:16]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[NH:25][N:26]=[N:27][C:28]=2[Cl:30])=[CH:20][CH:19]=1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: O=C1CCC(=O)N1Cl
Reactant: C[C@@H](c1ccc(-c2c[nH]nn2)cc1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Solvent: ClCCl
Product: C[C@@H](c1ccc(-c2[nH]nnc2Cl)cc1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
A solution of (2R,3S)-2-(2,4-difluorophenyl)-3-(4-[1,2,3-triazol-4-yl]phenyl)-1-(1,2,4-triazol-1-yl)butan-2-ol (2.0 g, 5 mmol-a product of Example 66) in dichloromethane (100 ml) was treated with N-chlorosuccinimide (0.81 g, 6 mmol). The mixture was stirred and irradiated at room temperature for 3 days then evaporated to dryness under reduced pressure. The residue was partitioned between ethyl acetate(50 ml) and saturated sodium bicarbonate (20 ml). The organic layer was washed with brine (20 ml), dried (Na2SO4) and evaporated to dryness under reduced pressure.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].[NH2:14][C:15]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](O)=[O:18].O>N1C=CC=CC=1>[N+:24]([C:23]1[C:15]2[N:14]=[C:6]([C:5]3[CH:9]=[CH:10][CH:11]=[C:3]([C:2]([F:13])([F:12])[F:1])[CH:4]=3)[O:7][C:17](=[O:18])[C:16]=2[CH:20]=[CH:21][CH:22]=1)([O-:26])=[O:25]
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: Nc1c(C(=O)O)cccc1[N+](=O)[O-]
Solvent: O
Solvent: c1ccncc1
Product: O=c1oc(-c2cccc(C(F)(F)F)c2)nc2c([N+](=O)[O-])cccc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 54.1 %

Procedure:
3-(trifluoromethyl)benzoyl chloride 2 (4.5 mL, 30.2 mmol) was added to a suspension of 2-amino-3-nitrobenzoic acid 1 (5.0 g, 27.5 mmol) in pyridine (65 mL). The reaction mixture was stirred at room temperature for 12 h then poured into ice cooled H2O (300 mL). The resulting precipitate was collected by filtration, rinsed with H2O, and dried under vacuum to give 3 (5 g, 51% yield) as a yellow solid which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([O:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[C:4]([CH2:25][CH3:26])[N:3]=1.OS(O)(=O)=O.C(OCC)(OCC)O[CH2:34][CH3:35].C([O-])([O-])=O.[K+].[K+]>CCO>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([O:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][CH2:21][C:22]([O:24][CH2:34][CH3:35])=[O:23])=[C:4]([CH2:25][CH3:26])[N:3]=1
Reactant: CCOC(OCC)OCC
Reactant: CCc1nc(N)nc(N)c1OCCCOc1ccccc1CCC(=O)O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)CCc1ccccc1OCCCOc1c(N)nc(N)nc1CC
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To a solution of 2,4-diamino-6-ethyl-5-(3-(2-(2-carboxyethyl)phenoxy)propoxy)pyrimidine (0.3604 g, 1 mmol) and a catalytic amount of con. H2SO4 in EtOH (4 mL) was added triethyl orthoformate (2 mL) and the mixture was left stirring at 25° C. for 8 hours. The reaction mixture was neutralized with K2CO3 and evaporated to dryness. The crude product was diluted with water and extracted with CH2Cl2. Evaporation to dryness gave the desired ester as white solid (0.3496 g, 90%, mp. 124.5-1255.5° C.). 1H NMR (500 MHz, DMSO-d6): 1.24 (3H, t, J=7.3 Hz), 1.26 (3H, t, J=7.7 Hz), 2.26 (2H, m), 2.59 (2H, q, J=7.7 Hz), 2.62 (2H, t, J=7.7 Hz), 2.95 (2H, t, J=7.7 Hz), 3.98 (2H, t, J=6.0 Hz), 4.13 (2H, q, J=7.1 Hz), 4.27 (2H, t, J=5.7 Hz), 5.17 (2H, bs), 5.28 (2H, bs), 6.90 (1H, d, J=8.2 Hz), 6.93 (1H, t, J=7.5 Hz), 7.17 (1H, dd, J=7.4, 1.4 Hz), 7.22 (1H, dt, J=7.8, 1.5 Hz).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([CH2:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[N:16]=2)[CH2:11][C:12](O)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.C[Si](C)(C)[O:41][NH2:42].N1C=CN=C1>ClCCl.C(OCC)(=O)C.CO>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([CH2:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[N:16]=2)[CH2:11][C:12]([NH:42][OH:41])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)ON
Reactant: O=C(O)C[C@@H](CCCC1CCCCC1)c1nc(Cc2ccncc2)no1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(C[C@@H](CCCC1CCCCC1)c1nc(Cc2ccncc2)no1)NO
Reaction time: 1 h
Yield: 35.8 %

Procedure:
A solution of (3R)-6-cyclohexyl-3-[3-(4-pyridinylmethyl)-1,2,4-oxadiazol-5-yl]hexanoic acid (Preparation 106) (380 mg, 0.96 mmol) in dichloromethane (10 ml) was treated with 1,1′-carbonyldiimidazole (156 mg, 0.96 mmol) and stirred under a nitrogen atmosphere for 1 hour. O-(Trimethylsilyl)hydroxylamine (388 μl, 2.89 mmol) was added and the mixture was stirred for 3.5 hours. The mixture was then treated with methanol (5 ml) and stirred at room temperature for 2 hours. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed with water and brine, dried over anhydrous magnesium sulphate, filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 95:5 (dichloromethane:methanol) to afford a white solid. Analysis suggests that 10% imidazole remains. The solid was dissolved in ethyl acetate and washed with water, dried over anhydrous magnesium sulphate, filtered and the solvent was removed under reduced pressure to afford the title compound as a white solid (128 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>C(O)C>[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)[CH2:14][CH2:13]1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CN1CCNCC1
Solvent: CCO
Product: CN1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Temperature: 5 °C

Procedure:
A 500 ml. 3-neck, r.b. flask fitted with y-tube and condenser and thermometer, stirrer and addition funnel was charged with a mixture of 2-chloro-5-nitropyridine (15.8 g. 0.1 mole) in ethanol (300 ml.). To this was added N-methylpiperazine (20 g. 0.2 mole) dropwise while stirring. After the addition (ca. 5 min.), the mixture was heated at reflux for 3 hr. while stirring continued. The solution was chilled to 5°C and the crystals were collected by filtration and dried at 60°C to yield 12 g. yellow crystals, m.p. 94°-96°C.
Reaction SMILES: [C:1]([C:3]1[CH:36]=[CH:35][C:6]([C:7]([NH:9][C:10](=[O:34])[NH:11][C:12]2[CH:26]=[CH:25][C:15]([O:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[C:14]([O:27][CH2:28][O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH:13]=2)=[O:8])=[CH:5][CH:4]=1)#[N:2].N1C=CC=CC=1.[SH2:43]>C(N(CC)CC)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10](=[O:34])[NH:11][C:12]2[CH:26]=[CH:25][C:15]([O:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[C:14]([O:27][CH2:28][O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH:13]=2)=[O:8])=[CH:35][CH:36]=1)(=[S:43])[NH2:2]
Reactant: CC(C)(C)OCOc1cc(NC(=O)NC(=O)c2ccc(C#N)cc2)ccc1OCC(=O)OC(C)(C)C
Reactant: S
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OCOc1cc(NC(=O)NC(=O)c2ccc(C(N)=S)cc2)ccc1OCC(=O)OC(C)(C)C

Procedure:
In a similar manner to Example 1, starting material step (b), the product of step (c) (2.2 g), pyridine (186 ml), triethylamine (26 ml) and H2S gas were reacted to give t-butyl 4-[3-(4-thiocarbamoylbenzoyl)ureido]-2-(t-butoxymethoxy)phenoxyacetate (2.6 g) as a yellow solid: m.p. 198°-199° C.; NMR Spectrum (DMSO-d6) 1.43 (9H, s), 1.44 (9H, s), 4.61 (2H, s), 4.66 (2H, s), 6.89 (1H, d), 7.09 (1H, dd), 7.27 (1H, d), 7.98 (4H, m), 9.68 (1H, s), 10.02 (1H, s), 10.66 (1H, s), 11.07 (1H, s); Mass Spectrum m/Z 582 (M +Na)+.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[S:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[N:7][C:6]=2[CH2:5][CH2:4][CH2:3]1.[F:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][N:17]=1>>[F:15][C:16]1[N:17]=[CH:18][C:19]([C:20]([C:3]2[CH2:4][CH2:5][C:6]3[N:7]=[C:8]([NH:11][C:12](=[O:14])[CH3:13])[S:9][C:10]=3[C:2]=2[OH:1])=[O:21])=[CH:23][CH:24]=1
Reactant: CC(=O)Nc1nc2c(s1)C(=O)CCC2
Reactant: O=C(Cl)c1ccc(F)nc1
Product: CC(=O)Nc1nc2c(s1)C(O)=C(C(=O)c1ccc(F)nc1)CC2

Procedure:
The title compound is synthesized according to general procedure A1 starting form 21.0 g (100 mmol), N-(7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl)-acetamide and 20.2 g (120 mmol, 95% pure) 6-fluoro nicotinic acid chloride. Yield: 27.0 g.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([O:11][C:12]([NH:14][C@@H:15]1[CH2:20][CH2:19][C@H:18](OS(C)(=O)=O)[CH2:17][CH2:16]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].[SH:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[C:33]([NH:37][C:38](=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[N:32][CH:31]=[CH:30]2>CC(N(C)C)=O>[C:7]([O:11][C:12](=[O:13])[NH:14][C@H:15]1[CH2:16][CH2:17][C@H:18]([S:26][C:27]2[CH:28]=[C:29]3[C:34](=[CH:35][CH:36]=2)[C:33]([NH:37][C:38](=[O:45])[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[N:32][CH:31]=[CH:30]3)[CH2:19][CH2:20]1)([CH3:8])([CH3:9])[CH3:10]
Reactant: O=C(Nc1nccc2cc(S)ccc12)c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](OS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Sc2ccc3c(NC(=O)c4ccccc4)nccc3c2)CC1

Procedure:
Potassium carbonate (160 mg) and methanesulfonic acid cis-4-tert-butoxycarbonylaminocyclohexyl ester (140 mg, 0.47 mmol) were added to a solution of N-(6-mercaptoisoquinolin-1-yl)benzamide residue in DMA (4 ml). The mixture was irradiated in a microwave at 120° C. for 600 s then concentrated in vacuo to give a residue. The residue was purified by preparative HPLC to give trans-[4-(1-benzoylaminoisoquinolin-6-ylsulfanyl)cyclohexyl]carbamic acid tert-butyl ester. Glacial acetic acid (1 ml) and 6M hydrochloric acid (2 ml) were added to the trans-[4-(1-benzoylaminoisoquinolin-6-ylsulfanyl)cyclohexyl]carbamic acid tert-butyl ester and the mixture was refluxed for 24 h. The mixture was then concentrated in vacuo to give a residue. The residue was loaded onto a pre-acidified SCX column using methanol and then eluted with 2M ammonia in methanol to give cude trans-6-(4-aminocyclohexylsulfanyl)isoquinolin-1-ylamine, which was further purified using prep-HPLC (9 mg), EIMS: m/z=274.5 [M+H]+
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C@@H:9]([C:23]([OH:25])=O)[CH2:10][CH2:11][C@@H:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=1[F:22])[CH2:13][NH2:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:34][C:35]([CH3:38])([OH:37])[CH3:36].C(N(CC)C(C)C)(C)C.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.C([O-])(O)=O.[Na+]>CCO>[F:22][C:16]1[C:17]([F:21])=[CH:18][CH:19]=[CH:20][C:15]=1[C@H:12]1[CH2:13][N:14]([CH2:34][C:35]([OH:37])([CH3:38])[CH3:36])[C:23](=[O:25])[C@H:9]([N:8]([C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@H](CC[C@H](CN)c1cccc(F)c1F)C(=O)O
Reactant: CC(C)(O)CCl
Agent: O=C([O-])O
Agent: On1nnc2cccnc21
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(O)CN1C[C@H](c2cccc(F)c2F)CC[C@@H](N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C1=O
Temperature: 75 °C
Reaction time: 18 h

Procedure:
A mixture of (5S) —N2,N2-bis(tert-butoxycarbonyl)-5-(2,3-difluorophenyl)-D-lysine (0.569 g, 1.24 mmol, described in Intermediate 4), 1-chloro-2-methyl-2-propanol (0.202 g, 1.86 mmol) and N,N-diisopropylethylamine (0.713 mL, 4.10 mmol) in EtOH (5 mL) was heated at 75° C. for 18 h. The reaction mixture was concentrated to dryness under reduced pressure and the residue was dissolved in CH2Cl2 (20 mL), then EDC (0.358 g, 1.87 mmol), HOAT (0.252 g, 1.87 mmol) and N,N-diisopropylethylamine (0.650 mL, 3.73 mmol) were added. The resulting mixture was stirred at ambient temperature for 18 h, then aqueous NaHCO3 was added. The layers were separated and the aqueous phase was extracted with CH2Cl2. The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—90:10 to 65:35, to give the title compound. MS: m/z=513 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[N:30]([C:33]1[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=1)=[C:31]=[O:32].C(O)(=O)C>O1CCCC1.CO>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([C:31]([NH:30][C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=2)=[O:32])[CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(N=C=O)cc1
Reactant: CC(C)(C)c1ccccc1-c1c[nH]c2ccccc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)n2cc(-c3ccccc3C(C)(C)C)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
3-(2-tert-Butylphenyl)-1H-indole (24.1 mg, 0.0967 mmol) in 0.5 mL anhydrous tetrahydrofuran was treated with 1M NaN(TMS)2 in THF (0.2 mL) and stirred for 5 minutes at ambient temperature. 1-Isocyanato-4-methylbenzene (15 μL, 0.116 mmol) in 0.5 mL anhydrous tetrahydrofuran was added and stirred for 5 minutes at ambient temperature. 50 μL acetic acid and 200 μL methanol are added and the reaction mixture charged to a silica gel column and purified by eluting with a gradient of ethyl acetate and hexanes to give 3-(2-tert-butylphenyl)-N-p-tolyl-1H-indole-1-carboxamide which was further purified by reverse phase HPLC to give Example 49 (19.1 mg, 52%) as a colorless solid and 99.5% purity. LC/MS (ESI+) 383.4.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][C:9]#[N:10].Cl.[O:12]1[C:17]2[CH:18]=[CH:19][CH:20]=[C:21]([C:22]3[CH2:23][CH2:24][NH:25][CH2:26][CH:27]=3)[C:16]=2[O:15][CH2:14][CH2:13]1>CC(C)=O>[O:12]1[C:17]2[CH:18]=[CH:19][CH:20]=[C:21]([C:22]3[CH2:23][CH2:24][N:25]([CH2:8][C:9]#[N:10])[CH2:26][CH:27]=3)[C:16]=2[O:15][CH2:14][CH2:13]1
Reactant: N#CCBr
Reactant: C1=C(c2cccc3c2OCCO3)CCNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#CCN1CC=C(c2cccc3c2OCCO3)CC1

Procedure:
2.5 g of potassium carbonate and, dropwise, a solution of 1.08 g of bromoacetonitrile in 10 ml of acetone are added to a solution of 1.9 g of the amine hydrochloride obtained in Stage B in 40 ml of acetone.
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]2[NH:8][C:9]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:13][N:12]=3)=[N:10][C:6]=2[CH:5]=1)([O-])=O.[Sn](Cl)(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>CO.C(N(CC)CC)C>[NH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([C:9]2[NH:10][C:6]3[CH:5]=[C:4]([NH2:1])[CH:21]=[CH:20][C:7]=3[N:8]=2)=[N:12]1
Reactant: O=[N+]([O-])c1ccc2[nH]c(-c3n[nH]c4ccccc34)nc2c1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CO
Product: Nc1ccc2nc(-c3n[nH]c4ccccc34)[nH]c2c1
Temperature: 25 °C
Yield: 1019.1 %

Procedure:
A stirred solution of 3-(5-nitro-1H-benzoimidazol-2-yl)-1H-indazole [90.8 mg, Reference Example 233(as)] in methanol (1 ml) was treated with tin chloride (616 mg). The reaction was heated at reflux for 16 hours and then cooled to ambient temperature. The pH of the reaction mixture was adjusted to pH 8 by addition of aqueous sodium bicarbonate and then this mixture was extracted with ethyl acetate. The organic extracts were dried over magnesium sulfate and then evaporated to yield an oil. The crude product was subjected to flash column chromatography on silica eluting with ethyl acetate and 10% triethylamine to give 2-(1H-indazol-3-yl)-3H-benzoimidazol-5-amine (826 mg). MS: 250.31 (M+H)+, 248.31 (M−H)−. HPLC (Method B): RT=2.03 minutes.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:4]=1[CH:5]=[CH:6][C:7]1[C:13]2[CH:14]=[C:15]3[O:20][CH2:19][O:18][C:16]3=[CH:17][C:12]=2[CH2:11][C:10]([CH3:21])=[N:9][N:8]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:4]=1[CH:5]=[CH:6][C:7]1[C:13]2[CH:14]=[C:15]3[O:20][CH2:19][O:18][C:16]3=[CH:17][C:12]=2[CH2:11][CH:10]([CH3:21])[NH:9][N:8]=1
Reactant: COc1ccc(C=CC2=NN=C(C)Cc3cc4c(cc32)OCO4)c(OC)c1
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: COc1ccc(C=CC2=NNC(C)Cc3cc4c(cc32)OCO4)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.4 %

Procedure:
A suspension of 1,1 g (3.0 mmoles) of 1-(2,4-dimethoxystyryl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine in 15 ml of anhydrous tetrahydrofurane is cooled to a temperature between 0° C. and 5° C., and 0.114 g (3.0 mmoles) of lithium aluminium hydride is added to it. The reaction mixture is stirred at 25° C. for 2 hours, cooled again to a temperature between 0° C. and 5° C. and decomposed with 0.36 ml of 10% aqueous potassium sodium tartrate solution. Then it is stirred further for 1 hour at 25° C., the precipitate is filtered off, the filtrate is dried and evaporated under reduced pressure. The crude end-product is recrystallized from 10 ml of ethanol, filtered, washed three times with 1 ml each of ethanol and dried at a temperature between 80° C. and 100° C. Thus 0.84 g (76.0%) of the desired product is obtained.
Reaction SMILES: C(O)(=O)C.[NH:5]1[CH2:10][CH2:9][CH:8]([C@H:11]([OH:13])[CH3:12])[CH2:7][CH2:6]1.C([O-])(=O)C.[Na+].[N:19]#[C:20]Br>CO.C(Cl)Cl>[OH:13][C@@H:11]([CH:8]1[CH2:9][CH2:10][N:5]([C:20]#[N:19])[CH2:6][CH2:7]1)[CH3:12]
Reactant: C[C@@H](O)C1CCNCC1
Reactant: N#CBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CC(=O)O
Product: C[C@@H](O)C1CCN(C#N)CC1
Reaction time: 12 h
Yield: 103.8 %

Procedure:
(1R)-1-(4-Piperidinyl)ethanol acetic acid salt (Example 167, Step 1, 568 mg, 3 mmol, 94% ee) and sodium acetate (2.46 g, 30 mmol) in MeOH (30 mL) was stirred at room temperature for 15 min. A solution of cyanogen bromide (953 mg, 9 mmol) in CH2Cl2 (4 mL) was added at 0° C. The mixture was stirred from 0° C. to 25° C. for 12 h. The salt was removed by filtration and washed by CH2Cl2. After concentration, the crude product was purified by chromatography on a silica gel column using 70% EtOAc/CH2Cl2 to give 480 mg (99%) of 4-[(1R)-1-hydroxyethyl]-1-piperidinecarbonitrile as an oil. 1H NMR (400 MHz, CDCl3): δ 3.69 (s, 1H), 3.67-3.57 (m, 1H), 3.54-3.43 (m, 2H), 3.08-2.94 (m, 2H), 1.96-1.84 (m, 1H), 1.67-1.65 (m, 1H), 1.53-1.35 (m, 3H), 1.20 (d, 3H, J=6.3 Hz).
Reaction SMILES: [NH:1]([C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36])[C@H:2]([C:15]([NH:17][C@H:18]([C:31]([NH:33]N)=[O:32])[CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].Cl.N(OCCC(C)C)=O.N1[CH2:61][CH2:60][CH2:59][C@H:55]1[C:56]([NH2:58])=[O:57].C(N(CC)CC)C>O1CCOCC1.CN(C)C=O>[NH:1]([C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36])[C@H:2]([C:15]([NH:17][C@H:18]([C:31]([N:33]1[CH2:61][CH2:60][CH2:59][C@H:55]1[C:56]([NH2:58])=[O:57])=[O:32])[CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: NC(=O)[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)NN
Agent: CC(C)CCON=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(N)=O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of compound XIII (1.25 g, 2 mmoles) in dimethylformaide (8 ml) is chilled to -40° C to -50° C in a Dry-ice-acetone bath and 3.66M hydrogen chloride in dioxane (1.37 ml) is added. To this is then added dropwise isoamyl nitrite (0.29 ml, 2.2 mmoles) and the mixture is stirred at -10° C to -20° for 10 minutes. The mixture is again chilled to -40° C to -50° C and an ice-cold solution of XIV (0.30 g, 2 mmoles) and triethylamine (1.1 ml, 7.7 mmoles) in dimethylformamide (10 ml) is introduced. The temperature is allowed to rise to 0° C, at which the mixture is stirred for 3 hours. After the pH have been adjusted to about 8 with an additional quantity of triethylamine (0.27 ml, 2 mmoles) the reaction mixture is kept at 4° C for 2 days. The solvent is removed by evaporation in vacuo at a bath temperature of 40° C. The resulting residue is dissolved in ethyl acetate and the solution is washed with ice-cold M hydrochloric acid and M sodium bicarbonate, dried over magnesium sulfate and evaporated in vacuo. Repeated precipiration of the residue obtained above yields the desired tripeptide XV; yield 1.29 g (91%), mp. 85°-90° C, [α]D22 - 40.5°±0.4° (c 2.0, methanol).
Reaction SMILES: [Na+].[CH2:2]([S:6]([NH-:9])(=[O:8])=[O:7])[CH2:3][CH2:4][CH3:5].CC(C)=O.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[O:23])=[CH:17][CH:16]=1>O>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:9][S:6]([CH2:2][CH2:3][CH2:4][CH3:5])(=[O:8])=[O:7])=[O:23])=[CH:17][CH:16]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CCCCS([NH-])(=O)=O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CCCCS(=O)(=O)NC(=O)Nc1ccc(Cl)cc1
Reaction time: 1 h
Yield: 65.7 %

Procedure:
1-butanesulfonamide sodium salt (9.1 g, 57 mmole) was dissolved in water (40 ml) and acetone (40 ml) was added. To the resulting mixture was added dropwise 40 ml of acetone containing 4-chlorophenyl isocyanate (8.6 g). After two hours solid was removed from the reaction mixture by filtration. The solid was washed with water and the combined filtrate was treated with 1N HCl (57 ml). After about one hour, precipitate was collected from the filtrate and washed with water. After drying at 65° C. under vacuum, 10.7 g of product were obtained.