Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:14][C:13]2=[N:15][NH:16][C:17](=[O:18])[C:10]3[C:11]4[C:12]2=[C:4]([NH:5][C:6]=4[CH:7]=[CH:8][CH:9]=3)[CH2:3]1.Br[CH2:21][CH2:22][O:23]C1CCCCO1.C([O-])([O-])=O.[K+].[K+].CC1C=CC(S(O)(=O)=O)=CC=1>CN(C=O)C.O.CO>[OH:23][CH2:22][CH2:21][N:5]1[C:4]2[CH2:3][C:2]([CH3:19])([CH3:1])[CH2:14][C:13]3=[N:15][NH:16][C:17](=[O:18])[C:10]4[C:11]([C:12]=23)=[C:6]1[CH:7]=[CH:8][CH:9]=4
Reactant: BrCCOC1CCCCO1
Reactant: CC1(C)CC2=NNC(=O)c3cccc4[nH]c(c2c34)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: CC1(C)CC2=NNC(=O)c3cccc4c3c2c(n4CCO)C1
Temperature: 70 °C
Yield: 69 %

Procedure:
To a solution of 2,2-dimethyl-2,3,5,10-tetrahydro-[1,2]diazepino[3,4,5,6-def]carbazol-6(1H)-one (100 mg, 0.39 mmol) in dry DMF (8 mL) was added 2-(2-bromoethoxy)tetrahydro-2H-pyran (194 mg, 1.17 mmol). K2CO3 (215 mg, 1.6 mmol) was added and the mixture was heated at 70° C. for 11.5 hours. Then water (100 mL) was added to the mixture, which was then extracted with EA (50 mL×3). The organic layers were combined, washed with brine, dried over Na2SO4, and concentrated to provide crude yellow oil. Then MeOH (15 mL) was added to the residue, followed by the addition of p-TSA.H2O (100 mg, 0.52 mmol), and the mixture was stirred at room temperature for 1 hour. Water (100 mL) was added to the mixture, extracted with EA (50 mL×3). The organic layers were combined, washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4, and concentrated The residue was purified by chromatography column on silica gel (elution with hexane/ethyl acetate) to give 80 mg (69% yield) of 10-(2-hydroxyethyl)-2,2-dimethyl-2,3,5,10-tetrahydro-[1,2]diazepino[3,4,5,6-def]carbazol-6(1H)-one as yellow solid. 1H NMR (DMSO-d6) δ 9.89 (s, 1H), 7.58 (d, 1H, J=8.4 Hz), 7.47 (d, 1H, J=7.2 Hz), 7.15 (dd, 1H, J=7.2, 8.4 Hz), 4.88 (t, 1H, J=5.4 Hz), 4.21 (t, 2H, J=5.4 Hz), 3.65-3.68 (m, 1H), 2.76 (s, 2H), 2.25 (s, 2H), and 1.07 (s, 6H). MS (ESI) m/e [M+1]+ 298.1.
Reaction SMILES: [CH2:1]([C:3]1([CH2:7][OH:8])[CH2:6][O:5][CH2:4]1)[CH3:2].[S:9](Cl)([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10].CCN(CC)CC>CN(C1C=CN=CC=1)C>[CH3:16][C:15]1[CH:17]=[CH:18][C:12]([S:9]([O:8][CH2:7][C:3]2([CH2:1][CH3:2])[CH2:6][O:5][CH2:4]2)(=[O:11])=[O:10])=[CH:13][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCC1(CO)COC1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: CCC1(COS(=O)(=O)c2ccc(C)cc2)COC1
Yield: 91 %

Procedure:
This compound was synthesized as a colorless oil from (3-ethyloxetan-3-yl)methanol (122.4 mg, 1.05 mmol), TsCl (261.2 mg, 1.37 mmol), Et3N (159.4 mg, 1.58 mmol), and DMAP (128.8 mg, 1.05 mmol) in 91% yield by following general procedure 1.1: 1H NMR (400 MHz, CDCl3, δH) 7.80 (d, J=8.3 Hz, 2H), 7.36 (d, J=8.0 Hz, 2H), 4.35 (d, J=6.3 Hz, 2H), 4.29 (d, J=6.3 Hz, 2H), 4.15 (s, 2H), 2.45 (s, 3H), 1.73 (q, J=7.5 Hz, 2H), 0.79 (t, J=7.5 Hz, 3H); 13C NMR (100 MHz, CDCl3, OH) 145.35, 132.72, 130.21, 128.18, 71.97, 42.99, 26.26, 21.90, 8.05. ESI-MS: 271.1 (M+H+), 293.1 (M+Na+).
Reaction SMILES: Cl.[CH3:2][C@@H:3]1[CH2:8][O:7][CH2:6][CH2:5][NH:4]1.[Cl:9][CH2:10][C:11]1[N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)[N:14]=[N:13][N:12]=1.C(N(C(C)C)CC)(C)C>C(#N)C>[ClH:9].[CH3:2][C@@H:3]1[CH2:8][O:7][CH2:6][CH2:5][N:4]1[CH2:10][C:11]1[N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:24])([F:23])[F:25])[CH:17]=2)[N:14]=[N:13][N:12]=1
Reactant: C[C@@H]1COCCN1
Reactant: FC(F)(F)c1cccc(-n2nnnc2CCl)c1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1COCCN1Cc1nnnn1-c1cccc(C(F)(F)F)c1

Procedure:
A solution of (3R)-3-methylmorpholine hydrochloride (52.4 mg, 0.381 mmol), 5-(chloromethyl)-1-[3-(trifluoromethyl)phenyl]-1H-tetrazole (50 mg, 0.190 mmol, commercially available from Otava, Kiev, Ukraine) and di-isopropylethylamine (0.067 mL, 0.381 mmol) in acetonitrile (1.5 mL) was heated to 120° C. for 15 minutes in a microwave reactor. The reaction mixture was allowed to cool and the solvent removed under vacuum. The residue was purified by MDAP and fractions containing the desired product were combined and the solvent removed. The residue was dissolved in a minimum of diethyl ether before the dropwise addition of 1N HCl in diethyl ether (3 mL) leading to precipitation. The solvent was removed under a stream of argon and the residue triturated with diethyl ether then dried under vacuum to yield the title compound as a white solid (46 mg).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.Br[CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].C([O-])([O-])=O.[K+].[K+].CN(C=O)C>O>[CH2:12]([O:11][C:9](=[O:10])[CH2:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[O:1][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(Cc1cccc(O)c1)OCc1ccccc1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCOc1cccc(CC(=O)OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.2 %

Procedure:
A mixture of benzyl 2-(3-hydroxyphenyl)acetate (1.39 g, 5.74 mmol), ethyl 4-bromobutanoate (1.23 g, 6.3 mmol), anhydrous K2CO3 (1.98 g, 14.4 mmol) and anhydrous DMF (10 mL) was stirred at room temperature overnight. Water was added to the mixture and extracted with ethyl acetate. The organic layer was washed with water, brine, dried (Na2SO4) and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate in petroleum ether, 25% to 50% v/v) to yield ethyl 4-(3-(2-(benzyloxy)-2-oxoethyl)phenoxy)butanoate (2.05 g, 100%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 1.17 (t, J=7.2 Hz, 3H), 1.96 (m, 2H), 2.45 (t, J=7.2 Hz, 2H), δ 3.70 (s, 2H), 3.94 (t, J=6.4 Hz, 2H), 4.07 (q, J=7.2 Hz, 2H), 5.11 (s, 2H), 6.83 (m, 3H), 7.20 (t, 1H), 7.20 (m, 5H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12](=[O:41])[CH:13]([C:24]3[CH:29]=[CH:28][C:27]([O:30][Si](C(C)C)(C(C)C)C(C)C)=[CH:26][CH:25]=3)[CH2:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:30][C:27]1[CH:28]=[CH:29][C:24]([CH:13]([C:12]([NH:11][C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[CH:1]=[N:2][CH:3]=[CH:4]3)=[O:41])[CH2:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:25][CH:26]=1
Reactant: CC(C)[Si](Oc1ccc(C(CCNC(=O)OC(C)(C)C)C(=O)Nc2ccc3cnccc3c2)cc1)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCC(C(=O)Nc1ccc2cnccc2c1)c1ccc(O)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To tert-butyl 4-(isoquinolin-6-ylamino)-4-oxo-3-(4-(triisopropylsilyloxy)phenyl)butylcarbamate (E306) in THF at 0° C. was added TBAF and the solution was stirred at 0° C. for 30 min. The solution was poured into NH4Cl(sat) and extracted with EtOAc. The combined organics were dried (Na2SO4), filtered, and evaporated. Column chromatography (SiO2, 5-8% MeOH/CH2Cl2) gave pure tert-butyl 3-(4-hydroxyphenyl)-4-(isoquinolin-6-ylamino)-4-oxobutylcarbamate (E307).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:10]([CH3:19])[N:9]=2)=[CH:4][CH:3]=1.[Br:20]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:10]([CH2:19][Br:20])[N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1ccc(-c2ccc(F)cc2)nc1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1ccc(-c2ccc(F)cc2)nc1CBr
Temperature: 25 °C
Yield: 35.1 %

Procedure:
Ethyl 6-(4-fluorophenyl)-2-methylnicotinate (82 mg, 0.32 mmol), N-bromosuccinimide (67 mg, 0.38 mmol) and AIBN (5 mg, 0.032 mmol) in carbon tetrachloride (7 ml) were irradiated (150W lamp) for 6 h then cooled to room temperature. The solid was filtered off and the filtrate concentated and purified by SPE chromatography to give the title compound (38 mg) as a 5:1 mixture with the dibrominated product. 1H NMR (250 MHz, CDCl3) δ (ppm): 8.32 (d, 1H), 8.11 (dd, 2H), 7.68 (d, 1H), 7.15 (t, 2H), 5.09 (s, 2H), 4.45 (q, 2H), 1.45 (t, 3H).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][N:8]=[C:9]2[C:14]=1[CH2:13][CH2:12][N:11]([C:15]([C:17]1[CH:25]=[CH:24][C:20]3[NH:21][N:22]=[N:23][C:19]=3[CH:18]=1)=[O:16])[CH2:10]2)=[O:5])C.[OH-].[Na+].C(O)C.Cl>O>[NH:21]1[C:20]2[CH:24]=[CH:25][C:17]([C:15]([N:11]3[CH2:12][CH2:13][C:14]4=[C:6]([C:4]([OH:5])=[O:3])[NH:7][N:8]=[C:9]4[CH2:10]3)=[O:16])=[CH:18][C:19]=2[N:23]=[N:22]1
Reactant: CCOC(=O)c1[nH]nc2c1CCN(C(=O)c1ccc3[nH]nnc3c1)C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1[nH]nc2c1CCN(C(=O)c1ccc3[nH]nnc3c1)C2
Temperature: 25 °C
Yield: 68.8 %

Procedure:
Starting material 40 (2.6 g, 6.4 mmol) was mixed with 2 N NaOH (15 ml) and ethanol (15 ml) and stirred at ambient temperature. Additional 15 ml 2 N NaOH were added. After the reaction was completed, the mixture was reduced to dryness, the solid was dissolved in water, adjusted to pH 2 with 2N HCl and the resulting precipitate was filtered and dried. Thus the desired product 41 (1.4 g, 4.4 mmol, 57%) could be isolated as solid.
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([N:10]2[CH2:17][C:14]3([CH2:16][CH2:15]3)[N:13]([S:18]([NH2:21])(=[O:20])=[O:19])[CH2:12][CH2:11]2)=[N:3][CH:2]=1.C([O-])([O-])=O.[Cs+].[Cs+].[O:28](C(OC(C)(C)C)=O)[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=O.O>CN(C=O)C>[C:32]([O:31][C:29]([N:7]1[C:6]2[N:1]=[CH:2][N:3]=[C:4]([N:10]3[CH2:17][C:14]4([CH2:16][CH2:15]4)[N:13]([S:18](=[O:20])(=[O:19])[NH2:21])[CH2:12][CH2:11]3)[C:5]=2[CH:9]=[CH:8]1)=[O:28])([CH3:35])([CH3:34])[CH3:33]
Reactant: NS(=O)(=O)N1CCN(c2ncnc3[nH]ccc23)CC12CC2
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1ccc2c(N3CCN(S(N)(=O)=O)C4(CC4)C3)ncnc21
Temperature: 0 °C
Reaction time: 16 h

Procedure:
7-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-4,7-diaza-spiro[2.5]octane-4-sulfonic acid amide (intermediate 1) (1.5 g, 4.86 mmol) was dissolved in dry DMF (20 ml), added Cs2CO3 (1.59 g, 4.86 mmol) and cooled to 0° C. A solution of BOC2O (1.06 g, 4.86 mmol) in dry DMF (10 mL) was added and the reaction mixture was allowed to warm up to rt and stirred at rt for 16 h. The crude mixture was treated with water (150 mL) and extracted with EtOAc (3×100 mL). The combined organic phases were washed with H2O (2×50 mL), brine (2×50 mL), dried over Na2SO4, filtered and concentrated in vacuo. The product was purified by flash chromatography on silica using EtOAc in heptane as eluent.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[NH:15]1[CH:16]=[CH:17][C:13]([NH:12][C:4]2[N:3]=[C:2]([C:23]3[CH:24]=[CH:25][C:20]([C:19]([F:30])([F:29])[F:18])=[CH:21][CH:22]=3)[C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)=[N:14]1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Product: FC(F)(F)c1ccc(-c2nc(Nc3cc[nH]n3)cc3ccccc23)cc1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 4-trifluoromethyl-phenylboronic acid to give (1H-pyrazol-3-yl)-[1-(4-trifluoromethyl-phenyl)-isoquinolin-3-yl]-amine. LC-MS m/e 355(MH+).
Reaction SMILES: C[O:2][C:3](=[O:17])[CH:4]=[CH:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([CH:13]=[O:14])=[CH:8][C:7]=1[CH2:15][CH3:16]>CO.[OH-].[Na+]>[CH2:15]([C:7]1[CH:8]=[C:9]([CH:13]=[O:14])[CH:10]=[C:11]([CH3:12])[C:6]=1[CH:5]=[CH:4][C:3]([OH:17])=[O:2])[CH3:16]
Reactant: CCc1cc(C=O)cc(C)c1C=CC(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCc1cc(C=O)cc(C)c1C=CC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.4 %

Procedure:
A suspension of 3-(2-ethyl-4-formyl-6-methyl-phenyl)-acrylic acid methyl ester (5.93 g, 25.53 mmol) in methanol (140 mL) and 2 N aq. NaOH (45 mL) is stirred at rt for 1 h. The methanol is evaporated and the aq. solution is extracted twice with DCM. The aq. layer is acidified with 37% aq. HCl. The precipitate that forms is collected, washed with water and dried. The product is further purified by recrystallisation from EA (100 mL) to give 3-(2-ethyl-4-formyl-6-methyl-phenyl)-acrylic acid (4.2 g) as yellow crystals; LC-MS: tR=0.87 min.
Reaction SMILES: C(N(CC)CC)C.C(OC(Cl)=O)C(C)C.[NH:16]([C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])[C@H:17]([C:24]([OH:26])=O)[CH2:18][O:19][C:20]([CH3:23])([CH3:22])[CH3:21].[NH2:37][C@H:38]([C:43]([O:45][CH3:46])=[O:44])[CH2:39][CH:40]([CH3:42])[CH3:41].Cl>C(OCC)(=O)C>[NH:16]([C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])[C@H:17]([C:24]([NH:37][C@H:38]([C:43]([O:45][CH3:46])=[O:44])[CH2:39][CH:40]([CH3:42])[CH3:41])=[O:26])[CH2:18][O:19][C:20]([CH3:21])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](COC(C)(C)C)NC(=O)OCc1ccccc1
Reaction time: 0.17 h

Procedure:
2.75 ml of triethylamine and 2.63 ml of chloroformic acid isobutyl ester are added to 5.9 g of Z-Ser(But)-OH in 20 ml of ethyl acetate at -10°C. After 10 minutes, 4.0 g of H-Leu-OMe-HCl and 3.05 ml of triethylamine are added. After stirring for 11/2 hours in an ice bath, the mixture is extracted by shaking with phosphoric acid and sodium bicarbonate solution and after drying over sodium sulphate the ethyl acetate is evaporated completely. 8.2 g of a waxy mass are obtained. Melting point (after crystallisation from hexane): 56°-58°C.
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].Cl[CH2:6][CH2:7][CH2:8]/[C:9](/[C:25]1O[C:27]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)=[N:28][N:29]=1)=[CH:10]\[C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]2)=[C:13]([O:23][CH3:24])[CH:12]=1.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>CS(C)=O>[F:36][C:33]1[CH:34]=[CH:35][C:30]([C:27]2[N:1]3[CH2:6][CH2:7][CH2:8]/[C:9](=[CH:10]\[C:11]4[CH:16]=[CH:15][C:14]([N:17]5[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]5)=[C:13]([O:23][CH3:24])[CH:12]=4)/[C:25]3=[N:29][N:28]=2)=[CH:31][CH:32]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COc1cc(/C=C(\CCCCl)c2nnc(-c3ccc(F)cc3)o2)ccc1-n1cnc(C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COc1cc(/C=C2\CCCn3c2nnc3-c2ccc(F)cc2)ccc1-n1cnc(C)c1
Temperature: 70 °C
Reaction time: 6 h
Yield: 56 %

Procedure:
Sodium azide (0.15 g) was added to a solution of 2-{4-chloro-1-{1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-(E)-methylidene}butyl}-5-(4-fluorophenyl)[1,3,4]oxadiazole (366 mg) in DMSO (10 mL) at room temperature, and the reaction solution was stirred at 70° C. for six hours. The reaction solution was left to cool to room temperature. Then, ethyl acetate and a saturated sodium bicarbonate solution were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with a saturated sodium chloride solution, dried over magnesium sulfate and then concentrated under reduced pressure. Triphenylphosphine (0.33 g) was added to a mixed solution of the resulting residue in THF (10 mL) and water (0.5 mL) at room temperature, and the reaction solution was stirred at 60° C. for three hours. The reaction solution was left to cool to room temperature and concentrated under reduced pressure. THF and toluene were added to the residue, and the solution was again concentrated under reduced pressure. A solution of the resulting residue in acetic acid (5 mL) was stirred at 150° C. for 1.5 hours. The reaction solution was left to cool to room temperature and concentrated under reduced pressure. A saturated sodium bicarbonate solution was added to the resulting residue, followed by extraction with chloroform. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane-ethyl acetate system, then ethyl acetate-methanol system), solidified with ethyl acetate and hexane and separated by filtration to obtain 188 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[C:12]([OH:14])[C:11]([N+:15]([O-])=O)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.FC(F)(F)C(O)=O.C(N(CC)CC)C>C(O)C>[NH2:15][C:11]1[C:12]([OH:14])=[N:13][C:8]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[CH:9][CH:10]=1
Reactant: CN1CCN(c2ccc([N+](=O)[O-])c(O)n2)CC1
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CN1CCN(c2ccc(N)c(O)n2)CC1

Procedure:
To a suspension 6-(4-methylpiperazin-1-yl)-3-nitropyridin-2-ol.trifluoroacetic acid salt (0.17 g, 0.48 mmol) in ethanol (25 mL) is added triethylamine dropwise with agitation until all of the solid had dissolved. The mixture is then degassed with dry ice and treated with an aqueous slurry of Raney nickel (approx 1 mL). After shaking under 50 psi of hydrogen, the reaction mixture is filtered through a pad of diatomaceous earth and concentrated under reduced pressure to give 3-amino-6-(4-methyl-piperazin-1-yl)-pyridin-2-ol (0.15 g, contaminated with triethylammonium trifluoroacetate) as a blue solid.
Reaction SMILES: C(NC1SC(S(Cl)(=O)=O)=C(C)N=1)(=O)C.C[O:16][C:17](=[O:78])[C@@H:18]([NH:32][C:33]([CH:35]1[CH2:44][C:43]2[CH:42]=[C:41]3[O:45][CH2:46][C@H:47]([C:49]4[CH:54]=[CH:53][C:52]([O:55][CH2:56][C:57]5[CH:62]=[CH:61][C:60]([Cl:63])=[C:59]([Cl:64])[CH:58]=5)=[CH:51][CH:50]=4)[O:48][C:40]3=[CH:39][C:38]=2[CH2:37][N:36]1[S:65]([C:68]1[S:72][C:71]([NH:73]C(=O)C)=[N:70][C:69]=1[CH3:77])(=[O:67])=[O:66])=[O:34])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:22][CH:21]=1>>[NH2:73][C:71]1[S:72][C:68]([S:65]([N:36]2[CH:35]([C:33]([NH:32][C@@H:18]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:22][CH:21]=3)[C:17]([OH:78])=[O:16])=[O:34])[CH2:44][C:43]3[CH:42]=[C:41]4[O:45][CH2:46][C@H:47]([C:49]5[CH:54]=[CH:53][C:52]([O:55][CH2:56][C:57]6[CH:62]=[CH:61][C:60]([Cl:63])=[C:59]([Cl:64])[CH:58]=6)=[CH:51][CH:50]=5)[O:48][C:40]4=[CH:39][C:38]=3[CH2:37]2)(=[O:67])=[O:66])=[C:69]([CH3:77])[N:70]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1S(=O)(=O)c1sc(NC(C)=O)nc1C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Agent: CC(=O)Nc1nc(C)c(S(=O)(=O)Cl)s1
Product: Cc1nc(N)sc1S(=O)(=O)N1Cc2cc3c(cc2CC1C(=O)N[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)O)OC[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Yield: 46.5 %

Procedure:
The methyl ester hydrochloride salt (36 mg) was reacted with 2-acetylamino-4-methyl thiazole-5-sulfonyl chloride (26 mg) according to General Procedure E. The resulting (S)-2-({(S)-7-(2-acetylamino-4-methyl-thiazole-5-sulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-biphenyl-4-yl-propionic acid methyl ester (32 mg) was hydrolyzed according to General Procedures N and B to give the title compound (14 mg). LCMS: (m/z) 887.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](O)=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[C:29]([O:33][C:34](=[O:37])[CH2:35][NH2:36])([CH3:32])([CH3:31])[CH3:30].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[C:29]([O:33][C:34](=[O:37])[CH2:35][NH:36][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:28])([F:26])[F:27])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:12])([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)OC(=O)CN
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCC(=O)OC(C)(C)C)ccc21
Yield: 78.3 %

Procedure:
{[1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-acetic acid tert-butyl ester (41 mg) was prepared by following General Procedure F using 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylic acid (41 mg), glycine-tert-butyl ester (44 mg), HBTU (38 mg), and DIEA (0.1 ml). LC/MS: m/z 523. 1H NMR (DMSO-d6, 400 MHz): δ 8.76 (t, 1H), 8.20 (br, 1H), 8.12 (m, 1H), 8.05 (s, 1H), 7.88 (d, 1H), 7.73 (d, 1H), 7.46 (d, 1H), 7.31 (d, 1H), 3.90 (d, 2H), 3.65 (s, 3H), and 1.42 (s, 9H).
Reaction SMILES: [CH3:1][Mg]Br.[CH2:4]([O:11][C:12]([CH:14]1[CH2:19][CH2:18][CH:17]([CH2:20][CH:21]=[O:22])[CH2:16][CH2:15]1)=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O>C1COCC1>[CH2:4]([O:11][C:12]([CH:14]1[CH2:19][CH2:18][CH:17]([CH2:20][CH:21]([OH:22])[CH3:1])[CH2:16][CH2:15]1)=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=CCC1CCC(C(=O)OCc2ccccc2)CC1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: O
Product: CC(O)CC1CCC(C(=O)OCc2ccccc2)CC1
Reaction time: 0.5 h
Yield: 66.5 %

Procedure:
Methylmagnesium bromide (1 M solution in THF, 0.526 ml, 0.526 mmol) was added dropwise to 4-(2-oxo-ethyl)-cyclohexanecarboxylic acid benzyl ester (114 mg, 0.439 mmol) in THF (2.2 mL) at −78° C., and the mixture was stirred at the same temperature for 30 minutes. Water was added to the reaction mixture at the same temperature and extracted with ethyl acetate. The organic layer was sequentially washed with a saturated aqueous ammonium chloride solution, water and saturated brine and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 4-(2-hydroxy-propyl)-cyclohexanecarboxylic acid benzyl ester (80.7 mg, 67%).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](O)=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[NH2:29][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[N:32]1([CH2:31][CH2:30][NH:29][C:11]([C:9]2[CH:8]=[CH:7][C:6]3[N:2]([CH3:1])[C:3]([NH:14][C:15]4[S:16][C:17]5[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=5[N:19]=4)=[N:4][C:5]=3[CH:10]=2)=[O:12])[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1
Reactant: NCCN1CCOCC1
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCCN3CCOCC3)ccc21

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (2-morpholin-4-yl-ethyl)-amide (92 mg) was prepared by following General Procedure F starting from 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (100 mg), 4-(2-amino-ethyl)morpholine (36 uL), HBTU (112 mg), and DIEA (65 uL). LC/MS: m/z 521.9. 1H NMR (DMSO-d6, 400 MHz): δ 12.40 (bs, 1H), 8.11 (s, 1H), 7.95 (s, 1H), 7.92 (s, 1H), 7.79 (d, 1H), 7.73 (d, 1H), 7.52 (d, 1H), 7.36 (d, 1H), 3.85-3.48 (m, 7H), 2.89 (s, 2H), 2.73 (s, 2H), 2.51-2.48 (m, 4H).
Reaction SMILES: N[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].[Br:18]Br.N(OCCC(C)C)=O>C(Cl)(Cl)Cl>[Br:18][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: BrBr
Reactant: CCOC(=O)c1cnn(-c2ccccc2)c1N
Agent: CC(C)CCON=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cnn(-c2ccccc2)c1Br
Temperature: 25 °C
Reaction time: 24 h
Yield: 38 %

Procedure:
To a solution of 20.0 g of 5-amino-1-phenyl-1H-pyrazole-4-carboxylic acid, ethyl ester and 10 ml of bromine in 200 ml of chloroform was added 15.8 g of isoamyl nitrite dropwise. The reaction mixture was allowed to stir at room temperature for about 24 hours and the volatiles were removed under reduced pressure. The residue was recrystallized from ethanol/water to provide 10.0 g of 5-bromo-1-phenyl-1H-pyrazole-4-carboxylic acid, ethyl ester. Yield 38%. mp=86°-89° C.