Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][CH2:7][CH:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1.CC(C)([O-])C.[Na+].[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>CS(C)=O>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([S:29]([C:26]3[CH:27]=[CH:28][C:23]([CH3:22])=[CH:24][CH:25]=3)(=[O:31])=[O:30])[CH2:7][CH:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1
Reactant: Clc1ncc2c(n1)N1CCOCC1CN2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1ccc(S(=O)(=O)N2CC3COCCN3c3nc(Cl)ncc32)cc1
Temperature: 50 °C
Reaction time: 18 h
Yield: 13.5 %

Procedure:
2-Chloro-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x2, 300 mg, 1.324 mmol) was dissolved in DMSO (20 mL). Sodium tert-butoxide (153 mg, 1.588 mmol) was added followed by 4-methylbenzene-1-sulfonyl chloride (278 mg, 1.456 mmol). The reaction mixture was heated to 50° C. and stirred for 18 hours. Additional 4-methylbenzene-1-sulfonyl chloride (0.5 eq) was added and the reaction mixture was stirred for 18 hours at 50° C. The reaction mixture was subsequently quenched with aqueous saturated NH4Cl, diluted with ethyl acetate, and washed with aqueous saturated NH4Cl (3×20 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated. The crude product was loaded onto an ISCO® silica gel cartridge (12 g) and eluted using an ethyl acetatehexane gradient. The product was collected and concentrated in vacuo to afford the title compound as a yellow solid (68 mg, 14%). ESI-MS m/z [M+H]+ calc'd for C16H17ClN4O3S, 381.07; found 381.3.
Reaction SMILES: C([O:3]C1C=CC(F)=C(F)C=1CCN)C.[CH2:15]([O:17][C:18]1[CH:36]=[CH:35][C:34]([F:37])=[C:33]([F:38])[C:19]=1[CH2:20][CH2:21][NH:22][C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][N:27]=1)=S)[CH3:16].C1C(=O)N(Br)C(=O)C1>>[CH2:15]([O:17][C:18]1[CH:36]=[CH:35][C:34]([F:37])=[C:33]([F:38])[C:19]=1[CH2:20][CH2:21][NH:22][C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][N:27]=1)=[O:3])[CH3:16]
Reactant: CCOc1ccc(F)c(F)c1CCNC(=S)Nc1ccc(Br)cn1
Reactant: CCOc1ccc(F)c(F)c1CCN
Agent: O=C1CCC(=O)N1Br
Product: CCOc1ccc(F)c(F)c1CCNC(=O)Nc1ccc(Br)cn1

Procedure:
The methods described in Example 151 of WO 93/03022 was then used to transform this compound to 2-ethoxy-5,6-difluoro-phenethylamine. The method described in Example 411 of WO 93/03022 was then used to prepare N-(2-ethoxy-5,6-difluorophenethyl)-N′-(5-bromopyrid-2-yl)-thiourea. This product was then oxidised with NBS as Example 4 to provide N-(2-ethoxy-5,6-difluorophenethyl)-N′-(5-bromopyrid-2-yl)-urea. 1H-NMR (250 MHz, CDCl3): 1.4 (t, 3H), 3.0 (q, 2H), 3.95 (q, 2H), 6.5 (m, 1H), 6.8 (d, 1H), 6.95 (dd, 1H), 7.68 (dd, 1H), 8.90 (d, 1H) 8.9 (s, 1H), 9.0 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1(Cl)[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:13].C([O-])(=O)C.[Na+].[H][H]>C(O)(=O)C.[Pd]>[Cl:1][CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:13]
Reactant: O=C1Nc2ccccc2CCC1(Cl)Cl
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1Nc2ccccc2CCC1Cl

Procedure:
A solution of 3,3-dichloro-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one (20 g, 0.174 mol) and anhydrous sodium acetate (15.4 g, 0.188 mol) in glacial acetic acid (920 ml) was hydrogenated at atmospheric pressure using 5% Pd-C (1.72 g) as catalyst until the uptake of hydrogen ceased. The catalyst was filtered off and the acetic acid evaporated under reduced pressure. The residue was equilibrated between 10% (NaHCO3 (900 ml) and dichloromethane (300 ml). The aqueous layer (pH 8) was further extracted with dichloromethane (3×300 ml) and the combined organic solutions were dried over anhydrous sodium sulfate and evaporated to give 3-chloro-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one, m.p. 163°-167°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([N:18]3[C:22]4[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:21]=4[N:20]=[C:19]3[CH3:28])[CH:14]([CH2:29][OH:30])[CH2:13]1)[CH2:5]2.C(N(C(C)C)CC)(C)C.[CH:40]1([C:43](Cl)=[O:44])[CH2:42][CH2:41]1>C(Cl)Cl>[CH3:28][C:19]1[N:18]([CH:15]2[CH2:16][CH2:17][N:12]([CH2:11][C@H:6]3[CH2:5][C:4]4[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:43](=[O:44])[CH:40]([CH3:42])[CH3:41])[CH:3]=4)[CH2:7]3)[CH2:13][CH:14]2[CH2:29][OH:30])[C:22]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:21]=2[N:20]=1
Reactant: O=C(Cl)C1CC1
Reactant: Cc1ccc2c(c1)nc(C)n2C1CCN(CC2Cc3ccc(N)cc3C2)CC1CO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc2c(c1)nc(C)n2C1CCN(C[C@@H]2Cc3ccc(NC(=O)C(C)C)cc3C2)CC1CO
Reaction time: 1 h

Procedure:
[1-(5-Amino-indan-2-ylmethyl)-4-(2,5-dimethyl-benzoimidazol-1-yl)-piperidin-3-yl]-methanol (65 mg; 0.165 mmol) was dissolved in CH2Cl2 (1 mL). Diisopropylethylamine (70 μL; 0.4 mmol) and cyclopropanecarbonyl chloride (18 μL; 0.2 mmol) were added and the reaction mixture was stirred for one hour. All volatiles were removed and N-{(R)-2-[4-(2,5-Dimethyl-benzoimidazol-1-yl)-3-hydroxymethyl-piperidin-1-ylmethyl]-indan-5-yl}-isobutyramide was isolated by flash chromatography (1-10% CH3OH in EtOAc) as a waxy oil (68 mg; 90%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[OH-].[Na+].C(OCC)(=O)C>Cl.O1CCOCC1>[CH2:17]([O:16][C:14]([N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)=[O:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)N1CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 159.6 %

Procedure:
Commercially available N-tert-butyloxycarbonyl-piperazine (0.5 g, 2.68 mmol) was dissolved in 5 mL of THF:water (1:1) and cooled in an ice bath. Triethylamine (0.748 mL, 5.4 mmol), followed by benzyloxycarbonyl chloride (0.575 mL, 3.21 mmol) in diethyl ether was slowly added to the reaction mixture. It was stirred at 0° C. for 1.5 hours. Solvents were removed and 50 mL of ethyl acetate was added to the residue. The ethyl acetate layer was washed with saturated NaHCO3 (20 mL×3), brine (20 mL×3), and dried over anhydrous sodium sulfate. N-tert-butyloxycarbonyl-N;benzyloxycarbonyl-piperazine (1.0 g) was obtained after evaporated to dryness in quantitative yield. MS: M+NH4 =338. M+H+ =321. N-tert-butyloxycarbonyl-N'-benzyloxycarbonyl-piperazine (1.8 g, 3.13 mmol) was dissolved in 10 mL of 4N-HCl/dioxane. It was stirred at room temperature for 30 minutes. The reaction mixture was cooled in an ice bath, 1N-NaOH solution was carefully added to the mixture to adjust pH above 10. Ethyl acetate (50 mL×3) was used to extract the compound. The combined ethyl acetate layers were washed with brine, dried over anhydrous sodium sulfate. After removal of the solvent, 1.1 g of N-benzyloxycarbonyl-piperazine was obtained in quantitative yield. Following the procedure of Example 6, but replacing 1-benzylpiperazine with N-benzyloxycarbonyl-piperazine, provided the desired compound. The product of Example 3 (1.1 g, 1.06 mmol), N-benzyloxycarbonyl-piperazine (700 mg, 3.18 mmol), and triethylamine (0.44 mL, 3.15 mmol) in 5 mL of methylene chloride were used. 339 mg of pure compound (C-32-N-benzyloxycarbonyl-piperazinyl-C-24-TBDMS-Ascomycin) was isolated in 29% yield. MS (FAB) m/z: M+H=1108. M+K-1146. The above obtained product (329 mg, 0.297 mmol) was treated with 48%-HF (0.55 mL) in 10 mL of acetonitrile in the procedure described in Example 5. 316 mg of semi pure compound (C-32-N-benzyloxycarbonyl-piperazinyl-Ascomycin) was isolated. This was directly used for the next reaction without further purification. The obtained product (317 mg, 0.32 mmol) was carefully hydrogenated in 40 mL of methanol in the presence of 10%-palladium on charcoal until theoretical ammount of hydrogen gas was consumed. 290 mg of crude product was purified by reverse phase-HPLC. 117 mg of the pure title compound was obtained in 47% yield. MS (FAB) m/z: M+H=860. M+K=898. mp=132° C. (dec).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH:10]([CH2:21][OH:22])[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=1)[OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([Si:27](Cl)([CH3:29])[CH3:28])([CH3:26])([CH3:25])[CH3:24].N1C=CN=C1>C1COCC1>[CH2:1]([NH:8][CH2:9][CH:10]([CH2:21][O:22][Si:27]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:29])[CH3:28])[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=1)[OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCC(CNCc1ccccc1)C(O)c1ccc(Cl)c(Cl)c1
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCC(CNCc1ccccc1)C(O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.3 %

Procedure:
To a solution of (1RS,2SR)-2-[(benzylamino)methyl]-1-(3,4-dichlorophenyl)propane-1,3-diol (11.6 g) in THF (100 mL) were added tert-butylchlorodimethylsilane (5.63 g) and imidazole (2.55 g) under ice-cooling, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate. The diluted solution was washed with distilled water, saturated aqueous sodium hydrogen carbonate and brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (10.9 g).
Reaction SMILES: [Na].[F:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.CS(O[CH2:15][C@H:16]1[CH2:20][O:19][C:18]([CH3:22])([CH3:21])[O:17]1)(=O)=O>COCCO>[F:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:15][C@H:16]2[CH2:20][O:19][C:18]([CH3:22])([CH3:21])[O:17]2)=[CH:5][CH:4]=1
Reactant: Oc1ccc(F)cc1
Reactant: CC1(C)OC[C@H](COS(C)(=O)=O)O1
Agent: [Na]
Solvent: COCCO
Product: CC1(C)OC[C@H](COc2ccc(F)cc2)O1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 97.3 %

Procedure:
To a stirred solution of 2.7 parts of sodium in 50 parts of 2-methoxyethanol were added 13.2 parts of 4-fluorophenol. The whole was stirred for 15 minutes. A solution of 24.8 parts of (-)-(R)-2,2-dimethyl-1,3-dioxolane-4-methanol methanesulfonate (ester) in 70 parts of 2-methoxyethanol was added dropwise quickly. Stirring was continued for 1.5 hours at reflux temperature. After cooling, the mixture was poured into ice water. The product was extracted with methylbenzene. The extract was dried, filtered and evaporated, yielding 26 parts (97.3%) of (S)-4-[(4-fluorophenoxy)methyl]-2,2-dimethyl-1,3-dioxolane as a residue (145).
Reaction SMILES: [SH2:1].[F:2][C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[CH:13]=[N:14][C:15]([C:16]#[N:17])=[C:11]3[CH2:10][N:9]([CH3:18])[C:8](=[O:19])[C:7]=2[CH:20]=1>N1C=CC=CC=1.C(N(CC)CC)C>[F:2][C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[CH:13]=[N:14][C:15]([C:16](=[S:1])[NH2:17])=[C:11]3[CH2:10][N:9]([CH3:18])[C:8](=[O:19])[C:7]=2[CH:20]=1
Reactant: CN1Cc2c(C#N)ncn2-c2ccc(F)cc2C1=O
Reactant: S
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CN1Cc2c(C(N)=S)ncn2-c2ccc(F)cc2C1=O
Reaction time: 64 h
Yield: 91 %

Procedure:
A stream of hydrogen sulphide was conducted for 1/2 hr. through a solution of 4.4 g (0.0172 mol) of 8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carbonitrile in 100 ml of pyridine and 1 ml of triethylamine. The dark green solution was left to stand for 64 hrs., then de-gassed with a stream of nitrogen and subsequently completely freed from the solvents. The residue was partitioned between dichloromethane/tetrahydrofuran and water, extracted, concentrated, stirred vigorously in ether and filtered off under suction. There were obtained 4.55 g (91%) of 8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-thiocarboxamide as yellow crystals.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:11][C:3]=12.[CH3:18][CH:19]1[CH2:23][CH2:22][CH2:21][NH:20]1.C([O-])([O-])=O.[K+].[K+]>O>[CH3:8][C:6]1[NH:5][C:4]2=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:11][C:3]2=[C:2]([N:20]2[CH2:21][CH2:22][CH2:23][CH:19]2[CH3:18])[N:7]=1
Reactant: Cc1nc(Cl)c2nc(-c3ccccc3)cc-2[nH]1
Reactant: CC1CCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1nc(N2CCCC2C)c2nc(-c3ccccc3)cc-2[nH]1
Temperature: 105 °C
Reaction time: 20 h
Yield: 91 %

Procedure:
A mixture of 4-chloro-2-methyl-6-phenylpyrrolo[3,2-d]pyrimidine (Example 1(e)) (230 mg, 0.94 mmol), 2-methylpyrrolidine (Alfa) (799 mg, 9.4 mmol), K2CO3 (650 mg, 4.7 mmol) in H2O (1.5 mL) was stirred at 105° C. for 20 h. Upon cooling to room temperature, the reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (3×15 mL). The organic phase was washed with H2O (20 mL), saturated NaCl (20 mL), dried over Na2SO4, and concentrated with a rotary evaporator. Chromatography on silica gel with a gradient eluant of MeOH (0-10%):CH2Cl2 (100-90%) afforded 250 mg (93%) of the title compound as an off-white solid. Mp: 219-221° C. 1H NMR (CDCl3; 400 MHz) δ 1.39 (d, 3, J=6.3), 1.79 (m, 1), 2.22-2.07 (m, 3), 2.58 (s, 3), 3.90 (m, 1), 4.04 (m, 1), 4.59 (m, 1), 6.74 (s, 1), 7.38 (t, 1, J=7.4), 7.46 (t, 2, J=7.4), 7.63 (d, 2, J=7.4), 8.31 (s, 1). MS m/z: 293 (M+1), 291 (M−1). HRMS: Calcd for M+H: 293.1766. Found: 293.1770.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH2:7][N:6]1[C:19](=S)[CH2:20][C:21](=O)[CH3:22])=[O:4].[Cl:25][C:26]1[CH:31]=[C:30]([NH:32][NH2:33])[CH:29]=[CH:28][N:27]=1>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH2:7][N:6]1[C:19]1[N:32]([C:30]2[CH:29]=[CH:28][N:27]=[C:26]([Cl:25])[CH:31]=2)[N:33]=[C:21]([CH3:22])[CH:20]=1)=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2)CN1C(=S)CC(C)=O
Reactant: NNc1ccnc(Cl)c1
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2)CN1c1cc(C)nn1-c1ccnc(Cl)c1

Procedure:
In analogy to the procedure described in example 192 h, (2S,4R)-4-benzenesulfonyl-1-(3-oxo-thiobutyryl)-pyrrolidine-2-carboxylic acid methyl ester (example 261d) was reacted with (2-chloro-pyridin-4-yl)-hydrazine (CAS Reg. No. 700811-29-6) to give the title compound as yellow solid. MS (ESI): m/z=461.3 [M+H]+.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:9]=1[NH:10][C:11]1[C:12]([CH3:20])=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[CH:14]2)[C:7]#[N:8].C([Sn](CCCC)(CCCC)[C:26]1[S:27][CH:28]=[CH:29][N:30]=1)CCC.C(N(CC)CC)C>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:20][C:12]1[C:11]([NH:10][C:9]2[C:6]([C:7]#[N:8])=[CH:5][N:4]=[CH:3][C:2]=2[C:26]2[S:27][CH:28]=[CH:29][N:30]=2)=[CH:19][CH:18]=[C:17]2[C:13]=1[CH:14]=[CH:15][NH:16]2
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reactant: Cc1c(Nc2c(I)cncc2C#N)ccc2[nH]ccc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cc1c(Nc2c(C#N)cncc2-c2nccs2)ccc2[nH]ccc12

Procedure:
A mixture of 5-iodo-4[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile (120 mg, 0.32 mmol), 2-(tributylstannyl)-1,3-thiazole (340 mg, 0.91 mmol), dichlorobis(triphenylphosphine)palladium(II) (28 mg, 0.04 mmol), and triethylamine (36 mg, 0.35 mmol) in dioxane (4 mL) was heated at reflux for 24 h. 4-[(4-Methyl-1H-indol-5-yl)amino]-5-(1,3-thiazol-2-yl)nicotinonitrile was obtained following the work-up and purification procedures as described for the preparation of 5-(2-formyl-1-methyl-1H-imidazol-5-yl)-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile 541. HPLC retention time: 10.1 min.(g); MS: 332.2 (M+H); melting range: 245-247° C.; and HRMS: 332.0964.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([NH:17][NH:18][C:19]([CH3:22])([CH3:21])[CH3:20])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C>CN(C)C=O.C(OCC)C>[C:19]([N:18]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[NH:17][C:9](=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)NNC(=O)c1ccccc1
Reactant: BrCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)N(Cc1ccccc1)NC(=O)c1ccccc1
Temperature: 25 °C

Procedure:
Benzyl bromide (0.9 g), 1-benzoyl-2-t-butyl hydrazine (1 g) and triethylamine (0.52 g) were warmed in dimethylformamide (50 ml) at 50° C. for 2 hours. The reaction mixture was cooled to room temperature, diluted with diethylether (100 ml) and washed three times with 25 ml of water. The organic layer was dried over magnesium sulfate, filtered, and the solvent removed in vacuo to afford the product as a white solid. The product was chromatographed on silica gel (G:70 to 230 mesh) using methylene chloride as eluent to afford a 75% yield of a white solid: m.p. 147-149.
Reaction SMILES: [C:1]1(=[O:11])[C@H:9]2[C@@H:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[C:3](=[O:10])O1.[CH3:12][N:13]([CH3:30])[CH2:14][CH2:15][O:16][C:17]1[C:25]2[NH:24][C:23]3[CH2:26][CH2:27][NH:28][CH2:29][C:22]=3[C:21]=2[CH:20]=[CH:19][CH:18]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=[N:55][C:50]2[CH:51]=[CH:52]C=[N:54][C:49]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.NC1(C#N)CC1>CN(C=O)C>[C:49]([C:50]1([NH:55][C:1]([C@@H:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]2[C:3]([N:28]2[CH2:27][CH2:26][C:23]3[NH:24][C:25]4[C:17]([O:16][CH2:15][CH2:14][N:13]([CH3:30])[CH3:12])=[CH:18][CH:19]=[CH:20][C:21]=4[C:22]=3[CH2:29]2)=[O:10])=[O:11])[CH2:52][CH2:51]1)#[N:54]
Reactant: O=C1OC(=O)[C@@H]2CCCC[C@@H]12
Reactant: CN(C)CCOc1cccc2c3c([nH]c12)CCNC3
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: N#CC1(N)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)CCOc1cccc2c3c([nH]c12)CCN(C(=O)[C@@H]1CCCC[C@H]1C(=O)NC1(C#N)CC1)C3
Temperature: 25 °C
Reaction time: 2 h
Yield: 23 %

Procedure:
(3aR,7aR)-hexahydroisobenzofuran-1,3-dione (125 mg, 0.81 mmol) was added to N,N-dimethyl-2-(2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-6-yloxy)ethanamine (210 mg, 0.81 mmol) in DMF (10 ml) at room temperature under air. The resulting solution was stirred at room temperature for 2 hours. N,N-Diisopropylethylamine (0.535 ml, 3.24 mmol), HATU (462 mg, 1.21 mmol) and 1-amino-1-cyclopropanecarbonitrile HCL (144 mg, 1.21 mmol) were then added to the mixture. The resulting solution was stirred at room temperature for 20 hours. The crude product was purified by preparative HPLC (0.1% NH3, CH3CN/H2O gradient) as eluents to afford as a brown gum (89 mg, 23%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[CH:9][CH:10]=1)=[O:4].[OH-].[Na+].Cl>O1CCCC1>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]2[N:7]=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:10][CH:9]=2)=[CH:12][CH:13]=1
Reactant: COC(=O)c1ccc(-c2ccc(F)cc2)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2ccc(F)cc2)nc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 37 %

Procedure:
Combine 6-bromopyridine-3-carboxylic acid methyl ester (1.03 g, 4.78 mmol), 4-fluorophenylboronic acid (1.88 g, 13.41 mmol), and cesium fluoride (2.55 g, 16.78 mmol) in dimethylformamide (25 mL) and water (4 mL) with stirring. Place the hetereogeneous reaction mixture, open to the air, in an oil bath maintained at 80° C. After 5 minutes of heating, add Pd(OAc)2 (150 mg, 0.67 mmol) in one portion. After 17 hours, cool the reaction to room temperature, dilute with ethyl acetate and filter through a short plug of celite with additional ethyl acetate. Wash the organics with water, dry over magnesium sulfate, filter and evaporate. Purification by flash column chromatography yields 6-(4-fluorophenyl)pyridine-3-carboxylic acid methyl ester as a yellow solid. Dissolve the purified ester in tetrahydrofuran (0.25M) and add an equal volume of 1M sodium hydroxide. Stir vigorously at room temperature for 15 hours. Upon completion, acidify the reaction with conc. HCl and collect the white precipitate by filtration. Drying under vacuum yields 385 mg (37%) of the title compound. MS (m/e): 218.1 (MH+)
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][C:21]1[C:22](=[O:37])[N:23]([C:27]2[CH:32]=[CH:31][C:30]([N+:33]([O-])=O)=[CH:29][C:28]=2[CH3:36])[CH:24]=[CH:25][CH:26]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])=O.[NH4+]>C(O)C.C(OCC)(=O)C.[Pd]>[NH2:33][C:30]1[CH:31]=[CH:32][C:27]([N:23]2[CH:24]=[CH:25][CH:26]=[C:21]([CH2:20][CH2:19][O:18][Si:1]([C:14]([CH3:15])([CH3:16])[CH3:17])([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:22]2=[O:37])=[C:28]([CH3:36])[CH:29]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1-n1cccc(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1=O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cc(N)ccc1-n1cccc(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1=O
Temperature: 80 °C
Reaction time: 0.75 h

Procedure:
62 g (121 mmol) of the compound from Example 15A are dissolved in 2 l of a 1:1 mixture of ethanol and ethyl acetate, and 46 g (726 mmol) of ammonium formate and 0.6 g of palladium on carbon are added. The mixture is heated at 80° C. After 45 min, the mixture is allowed to cool and filtered through silica gel. The filter cake is washed with ethyl acetate and the filtrate is evaporated to dryness under reduced pressure. This gives 36 g (61% of theory) of the desired product.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:8][C:9]=1[NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[Cl:19])=[O:4].[Li+].[OH-]>C1COCC1.CO.O>[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[CH2:11][NH:10][C:9]1[CH:8]=[C:7]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[S:6][C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1NCc1ccc(Cl)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1sc(-c2ccccc2)cc1NCc1ccc(Cl)cc1Cl
Temperature: 100 °C
Reaction time: 16 h
Yield: 63.2 %

Procedure:
3-(2,4-Dichloro-benzylamino)-5-phenyl-thiophene-2-carboxylic acid methyl ester (70 mg, 0.18 mmol) was dissolved in a mixture of THF-MeOH—H2O (3:2:1) (20 mL) and then 1080 ul of LiOH 1N was added to it. After 16 h of stirring at temperature of 100° C., solvents were removed and then partitioned between 10 ml of H2O, 2 ml of KHSO4 5% and 10 ml of EtOAc. The organic layer was separated and the aqueous phase was washed twice with ethyl acetate (2×10 mL). The combined ethyl acetate layer was dried (MgSO4) and concentrated to obtain 43 mg (63%) of 3-(2,4-Dichloro-benzylamino)-5-phenyl-thiophene-2-carboxylic acid 1H-NMR (DMSO, 400 MHz): δ 7.65 ppm (m, 3H, Haro); 7.43-7.32 ppm (m, 5H, Haro); 7.23 ppm (s, 1H, Haro); 4.61 ppm (d, 2H, N—CH2).
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH2:20][C@H:21]1[N:27]=[C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[F:34])[C:25]2[CH:35]=[CH:36][CH:37]=[CH:38][C:24]=2[N:23]([CH3:39])[C:22]1=[O:40].C1(N=C=NC2CCCCC2)CCCCC1>>[CH3:7][C:4]([O:3][C:1](=[O:2])[NH:8][CH:9]([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:17]([NH:20][CH:21]1[N:27]=[C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[F:34])[C:25]2[CH:35]=[CH:36][CH:37]=[CH:38][C:24]=2[N:23]([CH3:39])[C:22]1=[O:40])=[O:19])([CH3:5])[CH3:6]
Reactant: CN1C(=O)[C@@H](N)N=C(c2ccccc2F)c2ccccc21
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CN1C(=O)C(NC(=O)C(Cc2ccccc2)NC(=O)OC(C)(C)C)N=C(c2ccccc2F)c2ccccc21

Procedure:
The procedure of Example 77 was carried out in which Boc-D-phenylalanine was coupled to 3(S)-(-)-amino-1,3-dihydro-1-methyl-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one with dicyclohexylcarbodiimide. Following the identical work-up and purification procedure of Example 77 gave the analytical product.