Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:15]2[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:14]=2[O:13][C:7]2([CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[CH:6]=1)=[O:4].[CH3:23]I.[H-].[Na+]>CN(C)C=O>[CH3:1][N:2]([CH3:23])[C:3]([C:5]1[C:15]2[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:14]=2[O:13][C:7]2([CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[CH:6]=1)=[O:4]
Reactant: CI
Reactant: CNC(=O)C1=CC2(CCOCC2)Oc2ccc([N+](=O)[O-])cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)C(=O)C1=CC2(CCOCC2)Oc2ccc([N+](=O)[O-])cc21
Temperature: 0 °C
Yield: 97.1 %

Procedure:
To a mixture of 0.64 g of N-methyl-6-nitrospiro[2H-1-benzopyran-2,4'-tetrahydropyran]-4-carboxamide, 1.05 g of methyl iodide and 40 ml of dried N,N-dimethylformamide was added 0.13 g of sodium hydride (60%) with stirring under ice-cooling and the mixture was stirred at room temperature for 17 hours. Ice water was added therein and the resultant mixture was extracted with ether. An organic layer was washed with water and dried. The solvent was distilled to obtain 0.65 g of N,N-dimethyl-6-nitrospiro[2H-1-benzopyran-2,4'-tetrahydropyran]-4-carboxamide. Subsequently, 0.63 g of a Lawesson's reagent and 30 ml of benzene were added therein, and the mixture was refluxed with heating for 1.5 hours. After the reaction solution was vacuum-condensed, the residue was purified according to silica gel column chromatography (developing solution, MeOH:CH2Cl2 =1:99) to obtain 0.43 g of N,N-dimethyl-6-nitrospiro[2H-1-benzopyran-2,4'-tetrahydropyran]-4-carbothioamide. Subsequently, 1.80 g of methyl iodide, 0.28 g of cyanamide and 20 ml of tetrahydrofuran were added therein. 0.29 g of sodium hydride (60%) was added therein with stirring under ice-cooling and the mixture was stirred at room temperature for 17 hours. Ice water was added therein and the resultant mixture was extracted with methylene chloride. After an organic layer was washed with water and dried, the solvent was distilled. The resultant residue was purified according to silica gel column chromatography (developing solution, MeOH:CH2Cl2 =1:99) to obtain 0.28 g of N-cyano-N',N'-dimethyl-6-nitrospiro[2H-1-benzopyran-2,4'-tetrahydro-pyran]-4-amidine with a melting point of 202°-203° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH:5]([CH2:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[CH3:23][C:24]([C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=1)([CH3:26])[CH3:25].[H-].[Na+]>>[C:16]1([CH2:15][O:14][C:12](=[O:13])[CH2:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])([C:4]([O:3][CH2:1][CH3:2])=[O:22])[CH2:31][C:30]2[CH:33]=[CH:34][C:27]([C:24]([CH3:26])([CH3:25])[CH3:23])=[CH:28][CH:29]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)C(CC(=O)OCc1ccccc1)C(=O)OCC
Reactant: CC(C)(C)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C(CC(=O)OCc1ccccc1)(Cc1ccc(C(C)(C)C)cc1)C(=O)OCC
Yield: 53 %

Procedure:
Prepared analogously to Example A62 from diethyl[(phenylmethoxycarbonyl)methyl]-malonoate and 4-(1,1-dimethylethyl)benzylbromide in the presence of sodium hydride in a yield of 53% of theory.
Reaction SMILES: [N-:1]=[C:2]=[O:3].[K+].O.[F:6][C:7]1[CH:8]=[C:9]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH:28]3[NH:32][CH2:31][CH2:30][S:29]3)[CH2:15][CH2:14]2)[CH:10]=[CH:11][CH:12]=1.C(=O)(O)[O-].[Na+]>C(O)C.C(O)(=O)C>[F:6][C:7]1[CH:8]=[C:9]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH:28]3[N:32]([C:2]([NH2:1])=[O:3])[CH2:31][CH2:30][S:29]3)[CH2:15][CH2:14]2)[CH:10]=[CH:11][CH:12]=1
Reactant: Fc1cccc(N2CCN(CCOc3ccccc3C3NCCS3)CC2)c1
Reactant: [N-]=C=O
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: NC(=O)N1CCSC1c1ccccc1OCCN1CCN(c2cccc(F)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.3 %

Procedure:
A mixture of 1.12 g of potassium isocyanate, 10 ml of water and 2 ml of acetic acid is added to a solution of 2.68 g of 2-{2-[2-(4-(3-fluorophenyl)piperazin-1-yl)ethyloxy]phenyl}thiazolidine in 20 ml of ethanol, and the mixture is stirred at room temperature for 2 hours. A mixture of 0.56 g of potassium isocyanate and 0.5 ml of acetic acid is added to said mixture, and the mixture is stirred at the same temperature for 2 hours. The mixture is made alkaline with sodium bicarbonate and concentrated under reduced pressure to remove solvent. The residue is extracted with ethyl acetate. The extract is washed with a saturated sodium chloride solution, dried and then concentrated under reduced pressure to remove solvent. The residue is purified by silica gel chromatograph (solvent, ethyl acetate), and the resultant product is recrystallized from a mixture of ethyl acetate and ether. 2.6 g of 2-{2-[2-(4-(3-fluorophenyl)piperazin-1-yl)ethyloxy]phenyl}thiazolidine-3-carboxamide are obtained.
Reaction SMILES: [ClH:1].C(O[C:5](=[NH:14])[C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][C:7]=1[F:13])C.[NH3:15]>>[ClH:1].[Br:12][C:9]1[CH:10]=[CH:11][C:6]([C:5]([NH2:14])=[NH:15])=[C:7]([F:13])[CH:8]=1
Reactant: CCOC(=N)c1ccc(Br)cc1F
Reactant: N
Agent: Cl
Product: N=C(N)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
A mixture of 4-bromo-2-fluoro-benzimidic acid ethyl ester hydrochloride (20.3 g, 72 mmol) in IMS (250 mL) at 0-5° C. was saturated with NH3 (gas), and the flask sealed before allowing to warm to RT and stirring for 18 h. Solvent was removed in vacuo and the residue triturated in diethyl ether to give 4-Bromo-2-fluoro-benzamidine hydrochloride as a white solid (18.1 g, 100%). 1H NMR δ (ppm) (DMSO-d6): 9.26 (4H, s), 7.92-7.87 (1H, m), 7.71-7.62 (2H, m).
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9](Cl)(=[O:11])=[O:10].[C:14]([NH:21][OH:22])([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].C(N(CC)CC)C>C1COCC1>[C:17]([O:16][C:14]([NH:21][O:22][S:9]([C:2]1[C:3]([CH3:8])=[CH:4][C:5]([CH3:7])=[CH:6][C:1]=1[CH3:13])(=[O:11])=[O:10])=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)NO
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(S(=O)(=O)ONC(=O)OC(C)(C)C)c(C)c1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2-mesitylene sulphonyl chloride (2.0 g, 9.14 mmol) in dry THF (50 mL), was added N-Boc-hydroxylamine (1.21 g, 9.14 mmol) and cooled to 0° C. under N2 atmosphere. The reaction mixture was stirred for 5 minutes. To this mixture triethylamine (1.1 g, 11 mmol) was added slowly over 10 minutes. The reaction mixture was stirred for 1 hour at 0° C. and upon completion, the solvent removed in vacuo. The residue was redissolved in dichloromethane (50 mL) and washed with water (2×50 mL), 10% aqueous NaHCO3 (50 mL) and dried over MgSO4. It was then concentrated under reduced pressure at room temperature to get the product as an off white solid; (2.1 g, 73%). TLC: pet ether/ethyl acetate (8/2) Rf-0.4. 1H NMR (DMSO-d6; 400 MHz): δ 11.16 (s, 1H), 7.12 (s, 2H), 2.49 (s, 6H), 2.28 (s, 3H), 1.23 (s, 9H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[C:18]4[C:17]5[CH:19]=[C:20]([NH:23][C:24](=[O:33])[C:25]6[C:30]([Cl:31])=[CH:29][N:28]=[C:27](Cl)[CH:26]=6)[CH:21]=[CH:22][C:16]=5[CH2:15][CH2:14][C:13]=4[C:12]([C:34]([NH2:36])=[O:35])=[N:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[NH:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>CCO>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[C:18]4[C:17]5[CH:19]=[C:20]([NH:23][C:24](=[O:33])[C:25]6[C:30]([Cl:31])=[CH:29][N:28]=[C:27]([N:37]7[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]7)[CH:26]=6)[CH:21]=[CH:22][C:16]=5[CH2:15][CH2:14][C:13]=4[C:12]([C:34]([NH2:36])=[O:35])=[N:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: NC(=O)c1nn(-c2ccc3c(c2)OCO3)c2c1CCc1ccc(NC(=O)c3cc(Cl)ncc3Cl)cc1-2
Reactant: C1CNCCN1
Solvent: CCO
Product: NC(=O)c1nn(-c2ccc3c(c2)OCO3)c2c1CCc1ccc(NC(=O)c3cc(N4CCNCC4)ncc3Cl)cc1-2
Reaction time: 24 h
Yield: 55.6 %

Procedure:
The title compound was synthesized by the same procedure as in Example 214 starting with the title compound of Example 211 (1 g, 0.0018 mol) and piperazine (3 g, 0.036 mol) in EtOH (4 mL). The reaction was run at 95° C. for 24 h. After allowing the reaction mixture to cool down, the volatiles were removed under vacuum. The residue was triturated with H2O and finally with EtOH to yield 0.572 g of the title compound (yield: 55%). 1H NMR (300 MHz, d6-DMSO): δ 2.71 (s, broad, 4H), 2.86-3.30 (m, 4H), 3.39 (s, broad, 4H), 6.07 (s, 2H), 6.85 (s, 1H), 6.93-6.95 (dd, 1H, J=8.2 Hz, 1.9 Hz), 7.00 (d, 1H, J=8.2 Hz), 7.09 (d, 1H, J=1.9 Hz), 7.24-7.30 (m, 3H), 7.38-7.41 (dd, 1H, J=8.2 Hz, 1.74 Hz), 7.49 (s, 1H), 8.12 (s, 1H), 10.32 (s, 1H). M+1=573.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C@H:7]2[CH2:8][C@@H:3]1[CH2:4][CH2:5][C@H:6]2[CH2:9][CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15]Cl.[CH3:18][NH:19][CH2:20][CH2:21][C:22]1[CH:31]=[CH:30][C:27]([O:28][CH3:29])=[C:24]([O:25][CH3:26])[CH:23]=1.C(N(CC)CC)C.[I-].[K+]>C(#N)C.ClCCl>[CH3:1][C:2]1([CH3:17])[C@H:7]2[CH2:8][C@@H:3]1[CH2:4][CH2:5][C@H:6]2[CH2:9][CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15][N:19]([CH2:20][CH2:21][C:22]1[CH:31]=[CH:30][C:27]([O:28][CH3:29])=[C:24]([O:25][CH3:26])[CH:23]=1)[CH3:18]
Reactant: CC1(C)[C@H]2CC[C@@H](CCOCCCCCl)[C@@H]1C2
Reactant: CNCCc1ccc(OC)c(OC)c1
Agent: [I-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(CCN(C)CCCCOCC[C@@H]2CC[C@H]3C[C@@H]2C3(C)C)cc1OC
Yield: 42.5 %

Procedure:
7 g 4-[2-((1S,2S,5S)-6,6-dimethylbicyclo[3,1,1]hept-2-yl)-ethoxy]-butyl chloride, 5.8 g N-methyl-homoveratrylamine, 4 ml triethylamine and a catalytic quantity of potassium iodide were refluxed in 10 ml acetonitrile for 8 hours. Then the reaction was stopped and 150 ml dichloromethane were added to the reaction mixture after it had become cold. The resulting solution was washed with 70 ml aqueous 2N sodium hydroxide solution and then twice with water, dried over sodium sulfate, and the solvent was distilled off. The crude title compound which remained as a residue was purified by chromatography on silica gel using ethyl acetate/methanol (8:2) as eluent. 4.8 g N-(4-[2-((1S,2S,5S)-6,6-dimethylbicyclo[3,1,1]hept-2-yl)-ethoxy]butyl)-N-[2-(3,4-dimethoxyphenyl)ethyl]-N-methylamine were obtained. Rf value=0.2. In addition, it was possible to isolate 2.3 g of unreacted 4-[2-((1S,2S,5S)-6,6-dimethylbicyclo[ 3,1,1]hept-2-yl)ethoxy]-butyl chloride. Rf value=0.6.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[CH:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:3]([CH:2]([CH:10]([OH:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:1]([O:7][CH2:8][CH3:9])=[O:6])[CH2:4][CH3:5]
Reactant: O=Cc1ccccc1
Reactant: CCCCC(=O)OCC
Product: CCCC(C(=O)OCC)C(O)c1ccccc1

Procedure:
A 100 milligram sample of the prepared hydroxy-ester is pyrolyzed in a sealed tube at 240°-245° C. for 1 hour. Examination of the pyrolyzate by liquid chromatography indicates that it consists of 60% of unreacted hydroxy-ester and 40% of a 1:1 mixture of ethyl valerate and benzaldehyde.
Reaction SMILES: [C:1]1([S:7]([NH2:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl.[Cl:14][C:15]1[CH:33]=[CH:32][CH:31]=[CH:30][C:16]=1[CH2:17][N:18]1[C:22]2[CH:23]=[C:24]([CH2:27]Cl)[CH:25]=[CH:26][C:21]=2[N:20]=[C:19]1[CH3:29].O>CN(C)C=O>[C:1]1([S:7]([NH:10][CH2:27][C:24]2[CH:25]=[CH:26][C:21]3[N:20]=[C:19]([CH3:29])[N:18]([CH2:17][C:16]4[CH:30]=[CH:31][CH:32]=[CH:33][C:15]=4[Cl:14])[C:22]=3[CH:23]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1nc2ccc(CCl)cc2n1Cc1ccccc1Cl
Reactant: NS(=O)(=O)c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc2ccc(CNS(=O)(=O)c3ccccc3)cc2n1Cc1ccccc1Cl
Reaction time: 1 h
Yield: 29.7 %

Procedure:
To a solution of 0.667 g of benzenesulfonic acid amide in 5 ml of N,N-dimethylformamide were added 0.127 g of 60% sodium hydride at room temperature, and the mixture was stirred for 1 hour. Further, 0.648 g of 1-(2-chlorobenzyl)-6-chloromethyl-2-methylbenzimidazole hydrochloride were added thereto, and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction solution to stop the reaction, and the solvent was distilled off under reduced pressure. The residue was extracted with ethyl acetate and with water. The organic layer was concentrated, and was purified through silica-gel column chromatography (eluent: ethyl acetate) to give 0.240 g of 6-benzenesulfonylaminomethyl-1-(2-chlorobenzyl)-2-methyl-benzimidazole (264).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH2:12]1[O:14][CH2:13]1>[Cr].CC(CC(C)C)=O>[OH:14][CH2:13][CH2:12][N:5]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6]
Reactant: C1CO1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [Cr]
Solvent: CC(=O)CC(C)C
Product: O=C1c2ccccc2C(=O)N1CCO

Procedure:
N-2-Hydroxyethyl phthalimide was prepared by allowing 147.2g (1.0 mole) of phthalimide to react in an autoclave with 53.0g (1.20 moles) of ethylene oxide in the presence of 1.47g (1%) of active chromium III tri-2-ethylhexanoate (COT) and 400 ml of methylisobutyl ketone (MiBK) at 160° to 165°C for two hours. On cooling, the N-2-hydroxyethyl phthalimide crystallized and was collected by filtration. A 94.7% yield of the hydroxyethyl imide was obtained. Under identical experimental conditions but in the absence of COT, the starting material was recovered unchanged.
Reaction SMILES: [NH:1]1[C:5]2=[C:6]([O:10][C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][C:12]=3[F:18])[N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[C:19]1([CH2:25][C:26]([N:28]=[C:29]=[S:30])=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1>[NH:1]1[C:5]2=[C:6]([O:10][C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:29]([NH:28][C:26](=[O:27])[CH2:25][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)=[S:30])=[CH:13][C:12]=3[F:18])[N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: Nc1ccc(Oc2nccc3cc[nH]c23)c(F)c1
Reactant: O=C(Cc1ccccc1)N=C=S
Solvent: C1CCOC1
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2nccc3cc[nH]c23)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.6 %

Procedure:
A mixture of 261 (44 mg, 0.18 mmol) and 2-phenylacetyl isothiocyanate (36 □L, 0.19 mmol) in THF (2 mL) was stirred at room temperature for 2 hours, and concentrated. The residue was purified by flash column chromatography, eluent EtOAc/hexane (1:1), to afford the title compound 262a (30 mg, 40%) as an off-white solid. 1H NMR (DMSO-d6) δ (ppm): 12.41 (s, 1H), 12.07 (s, 1H), 11.77 (s, 1H), 7.84(dd, 1H, J1=10.95 Hz, J2=2.0 Hz), 7.58(t, 1H, J1=J2=2.7 Hz), 7.51(d, 1H, J=5.7 Hz), 7.43-7.39 (m, 2H), 7.37-7.33(m, 4H), 7.31-7.26 (m, 2H), 6.55(dd, 1H, J1=1.76 Hz, J2=2.9 Hz), 3.84 (s, 2H), MS (m/z): 421.1 (M+H) (found).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH2:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Br[CH2:15][CH2:16][OH:17].C(=O)([O-])[O-].[K+].[K+].[CH2:24]([OH:26])[CH3:25]>>[OH:17][CH2:16][CH2:15][N:13]([CH2:12][CH2:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH2:25][CH2:24][OH:26]
Reactant: OCCBr
Reactant: CCO
Reactant: COc1ccc(CCN)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(CCN(CCO)CCO)cc1OC
Yield: 88 %

Procedure:
2-(3,4-Dimethoxyphenyl)ethylamine (80.0g), 2-bromoethanol (182 g) and potassium carbonate (201 g) were added to ethanol (1 () and the mixture was refluxed for 16 hours. After cooling, the mixture was filtered and the filtrate was concentrated in vacuo. The oily residue was dissolved in chloroform. The solution was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated in vacuo to give 104.5 g(88% ) of N,N-bis(2-hydroxyethyl)-2-(3,4-dimethoxyphenyl)ethylamine in oily form.
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[CH:10]=[C:11]([NH2:14])[CH:12]=[CH:13][C:8]=2[CH2:7][N:6]([CH2:15][CH3:16])[CH2:5][CH2:4]1)[CH3:2].Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[CH:26]=[CH:27][C:28]3[S:34][CH2:33][CH2:32][N:31]([CH2:35][CH2:36][O:37][CH3:38])[CH2:30][C:29]=3[CH:39]=2)[C:21]([Cl:40])=[CH:20][N:19]=1>>[Cl:40][C:21]1[C:22]([NH:24][C:25]2[CH:26]=[CH:27][C:28]3[S:34][CH2:33][CH2:32][N:31]([CH2:35][CH2:36][O:37][CH3:38])[CH2:30][C:29]=3[CH:39]=2)=[N:23][C:18]([NH:14][C:11]2[CH:12]=[CH:13][C:8]3[CH2:7][N:6]([CH2:15][CH3:16])[CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[C:9]=3[CH:10]=2)=[N:19][CH:20]=1
Reactant: CCN1CCN(CC)c2cc(N)ccc2C1
Reactant: COCCN1CCSc2ccc(Nc3nc(Cl)ncc3Cl)cc2C1
Product: CCN1CCN(CC)c2cc(Nc3ncc(Cl)c(Nc4ccc5c(c4)CN(CCOC)CCS5)n3)ccc2C1

Procedure:
The title compound was prepared from 1,4-Diethyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamine and (2,5-Dichloro-pyrimidin-4-yl)-[8-(2-methoxy-ethyl)-6,7,8,9-tetrahydro-5-thia-8-aza-benzocyclohepten-2-yl]-amine in an analogous manner to example 730. Product was isolated as a tan solid (0.040 g, 42%). Mp 62-66° C. LCMS (m/e) 568 (M); 1H-NMR (DMSO, 400 MHz) δ 9.17 (s, 1H), 8.80 (s, 1H), 8.13 (s, 1H), 7.62-57 (m, 2H,), 7.41-39 (d, 1H, J=8.85 Hz), 7.13-08 (m, 2H), 6.95-89 (d, 1H, J=8.34 Hz), 3.99 (s, 2H), 3.65-55 (s, 2H), 3.48-3.40 (q, 1H, J=5.79 Hz), 3.38-32 (t, 2H, J=5.56 Hz), 3.28-20 (m, 2H), 2.95-85 (m, 6H), 2.82-62 (m, 6H), 2.49-43 (t, 2H, J=5.81 Hz), 2.43-35 (m, 2H), 1.10-0.98 (m, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[C:4]([F:12])[CH:3]=1.[F:13][C:14]([F:25])([F:24])[C:15]([C:18]1[O:22][N:21]=[C:20]([NH2:23])[CH:19]=1)([CH3:17])[CH3:16].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:23][C:20]2[CH:19]=[C:18]([C:15]([CH3:17])([CH3:16])[C:14]([F:24])([F:13])[F:25])[O:22][N:21]=2)=[O:11])=[C:4]([F:12])[CH:3]=1
Reactant: O=C(O)Cc1ccc(Br)cc1F
Reactant: CC(C)(c1cc(N)no1)C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(c1cc(NC(=O)Cc2ccc(Br)cc2F)no1)C(F)(F)F
Temperature: 25 °C
Reaction time: 12 h
Yield: 25.4 %

Procedure:
To a mixture of 2-(4-bromo-2-fluorophenyl)acetic acid (100 mg, 0.429 mmol) in DCM (50 mL) was added 5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-amine (92 mg, 0.472 mmol), HATU (245 mg, 0.644 mmol) and Et3N (0.179 mL, 1.287 mmol). Then the mixture was stirred at 25° C. for 12 h. The mixture was concentrated and the crude material was purified by preparative TLC (PE/EA=2:1, Rf=0.4) to yield a yellow oil of 2-(4-bromo-2-fluorophenyl)-N-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)acetamide (50 mg, 0.109 mmol, 25.4% yield): 1H NMR (400 MHz, CDCl3) δ: 8.12 (s., 1H) 7.35-7.27 (m, 2H) 7.23-7.18 (m, 1H) 6.95 (s, 1H) 3.72 (s, 2H) 1.55 (s, 6H); ES-LCMS m/z 411 (M+2).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][CH2:17][CH2:18][NH:19][CH:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]1)[C:13](O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.C(N(C(C)C)C(C)C)C>CN(C=O)C>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:17][CH2:18][N:19]([CH:20]2[CH2:21][CH2:22][N:23]([C:26]([O:28][C:29]([CH3:31])([CH3:32])[CH3:30])=[O:27])[CH2:24][CH2:25]2)[C:13]1=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(NCCC[C@H](NC(=O)OCc2ccccc2)C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(N2CCC[C@H](NC(=O)OCc3ccccc3)C2=O)CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
Crude (S)-2-(benzyloxycarbonylamino)-5-(1-(tert-butoxycarbonyl)piperidin-4-ylamino)pentanoic acid (84 g, 187 mmol) was dissolved in DMF (600 mL), and cooled to 0° C. N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (35.8 g, 187 mmol) and N-ethyl-N-isopropylpropan-2-amine (32.5 mL, 187 mmol) were added and the reaction stirred at ambient temperature overnight. The reaction was concentrated and dissolved in EtOAc (1000 mL), washed with 1N HCl, saturated aqueous NaHCO3 and brine, dried over Na2SO4, filtered and concentrated. The residue was purified over silica gel (50% EtOAc in hexanes) to afford (S)-tert-butyl 3-(benzyloxycarbonylamino)-2-oxo-1,4′-bipiperidine-1′-carboxylate (49 g, 114 mmol, 60.8% yield) as white solid.
Reaction SMILES: [NH2:1][C@H:2]([CH2:25][CH3:26])[C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]([O:12][C:13]2[C:18]3[C:19]([CH3:23])([CH3:22])[CH2:20][O:21][C:17]=3[C:16]([CH3:24])=[CH:15][CH:14]=2)=[CH:10][CH:11]=1)=[O:4].C(N(CC)CC)C.Cl[C:35](Cl)([O:37]C(=O)OC(Cl)(Cl)Cl)Cl.C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[CH2:25]([C@H:2]1[NH:1][C:35](=[O:37])[N:5]([C:6]2[CH:7]=[N:8][C:9]([O:12][C:13]3[C:18]4[C:19]([CH3:22])([CH3:23])[CH2:20][O:21][C:17]=4[C:16]([CH3:24])=[CH:15][CH:14]=3)=[CH:10][CH:11]=2)[C:3]1=[O:4])[CH3:26]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC[C@@H](N)C(=O)Nc1ccc(Oc2ccc(C)c3c2C(C)(C)CO3)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC[C@H]1NC(=O)N(c2ccc(Oc3ccc(C)c4c3C(C)(C)CO4)nc2)C1=O
Temperature: 0 °C
Yield: 128 %

Procedure:
(2R)-2-amino-N-{6-[(3,3,7-trimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-3-pyridinyl}butanamide (Intermediate 31, 300 mg, 0.84 mmol) was dissolved in ethyl acetate (6 mL). Triethylamine (0.47 ml, 3.36 mmol) was added and the reaction mixture was cooled to 0° C. A solution of triphosgene (100 mg, 0.34 mmol) in ethyl acetate (6 mL) was slowly added. At the end of addition the mixture was treated with an aqueous saturated solution of NaHCO3 and two phases were separated. The organic layer was washed with brine, dried over Na2SO4 and evaporated to dryness to obtain a waxy solid. The residue was purified purified by flash chromatography on silica gel using cyclohexane/ethyl acetate 70:30 to cyclohexane/ethyl acetate 50:50 as eluents affording the title compound (166 mg) as a white foam.
Reaction SMILES: [C:1]([C:3]1[C:4]2[C:12]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[N:11][N:10]([C:18]3[CH:19]=[C:20]([C:23]([O:25]C)=[O:24])[S:21][CH:22]=3)[C:5]=2[C:6](=[O:9])[NH:7][CH:8]=1)#[N:2].C1COCC1.[OH-].[Na+].Cl>O.CO>[C:1]([C:3]1[C:4]2[C:12]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[N:11][N:10]([C:18]3[CH:19]=[C:20]([C:23]([OH:25])=[O:24])[S:21][CH:22]=3)[C:5]=2[C:6](=[O:9])[NH:7][CH:8]=1)#[N:2]
Reactant: COC(=O)c1cc(-n2nc(C3CCCC3)c3c(C#N)c[nH]c(=O)c32)cs1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1c[nH]c(=O)c2c1c(C1CCCC1)nn2-c1csc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 98.2 %

Procedure:
To a solution of methyl 4-(4-cyano-3-cyclopentyl-7-oxo-6,7-dihydro-1H-pyrazolo[3,4-c]pyridin-1-yl)thiophene-2-carboxylate (18 mg) in a mixed solvent of THF (1 mL), methanol (1 mL) and water (1 mL) was added 1N aqueous sodium hydroxide solution (0.195 mL), and the mixture was stirred at room temperature for 15 hr. To the reaction mixture was added 1N hydrochloric acid (0.195 mL), and the reaction mixture was concentrated under reduced pressure. To the residue was added water, and the resulting solid was washed with water and hexane to give the title compound (17 mg).
Reaction SMILES: [CH3:1][C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[CH2:21][C:22]([OH:24])=[O:23].[OH-].[Na+].COC(=O)CC1C2C(=NC=CC=2)N(CC2C=CC([N+]([O-])=O)=CC=2)C=1C>C1COCC1.CO>[NH2:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][N:10]2[C:5]3=[N:6][CH:7]=[CH:8][CH:9]=[C:4]3[C:3]([CH2:21][C:22]([OH:24])=[O:23])=[C:2]2[CH3:1])=[CH:17][CH:16]=1
Reactant: Cc1c(CC(=O)O)c2cccnc2n1Cc1ccc([N+](=O)[O-])cc1
Agent: COC(=O)Cc1c(C)n(Cc2ccc([N+](=O)[O-])cc2)c2ncccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(CC(=O)O)c2cccnc2n1Cc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
[2-Methyl-1-(4-nitro-benzyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid: 1M Aqueous NaOH (1.18 ml) is added to a stirring suspension of [2-methyl-1-(4-nitro-benzyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid methyl ester (0.2 g, 0.54 mmol) in 4:1 THF/MeOH (5 ml). The reaction mixture is allowed to stir at room temperature for 4 hours and then the solvent is removed in vacuo. The crude residue is dissolved in 1:1 THF/water and acidified to pH 3-4 using 6M HCl. After stirring for 30 minutes the resulting suspension is filtered and dried in vacuo at 110° C. to yield the titled product as a yellow solid. (MH+326)