Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]2[CH2:8][O:9][CH2:10][O:11][C:6]=2[C:5]([O:12][CH3:13])=[CH:4][CH:3]=1.CN(CCN(CCN(C)C)C)C.C([Li])CCC.[CH:31](N1CCOCC1)=[O:32].Cl>C1COCC1>[F:1][C:2]1[C:7]2[CH2:8][O:9][CH2:10][O:11][C:6]=2[C:5]([O:12][CH3:13])=[CH:4][C:3]=1[CH:31]=[O:32]
Reactant: COc1ccc(F)c2c1OCOC2
Reactant: O=CN1CCOCC1
Agent: CN(C)CCN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(C=O)c(F)c2c1OCOC2
Temperature: -74 °C
Reaction time: 1 h

Procedure:
To a solution of the 1.086 g of 5-fluoro-8-methoxy-4H-benzo[1,3]dioxine and 1.28 ml of N,N,N′,N′,N″-pentamethyldiethylenetriamine in 10 ml of THF there was added dropwise 2.4 ml of n-butyllithium (2.55 M, hexane solution) at −74° C. The mixture was stirred at −74° C. for 1 hour, and then 0.7 ml of N-formylmorpholine was added. After stirring at room temperature for 1 hour, 1N hydrochloric acid was added thereto while cooling on ice, and the mixture was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (153 mg) as an oil.
Reaction SMILES: [OH:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13]1SC=[CH:16][CH:17]=1.[O:18]=[C:19]1[C:27]2C(=CC=CC=2)[CH:21]([S:28][CH2:29][C:30]([NH:32]C2N=CC=CN=2)=O)[N:20]1CC1SC=CC=1>>[CH2:12]([N:3]1[C:4](=[O:11])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:2]1[O:1][CH2:27][C:19]([NH:20][C:21]1[S:28][CH:29]=[CH:30][N:32]=1)=[O:18])[CH2:13][CH2:17][CH3:16]
Reactant: O=C1c2ccccc2C(O)N1Cc1cccs1
Reactant: O=C(CSC1c2ccccc2C(=O)N1Cc1cccs1)Nc1ncccn1
Product: CCCCN1C(=O)c2ccccc2C1OCC(=O)Nc1nccs1

Procedure:
Compound 53 was prepared using the synthetic sequence in a manner analogous to the method described for the conversion of compound 12 to compound 16 and illustrated in Scheme 1b. 1H NMR (400 MHz, CDCl3): 611.56 (s, 1H), 7.76 (d, J=7 Hz, 1H), 7.60 (d, J=7 Hz, 1H), 7.44 (t, J=7 Hz, 1H), 7.36 (t, J=7 Hz, 1H), 7.07 (d, J=3 Hz, 1H), 6.93 (d, J=3 Hz, 1H), 5.63 (s, 1H), 3.93 (m, 1H), 3.37 (m, 1H), 2.97 (s, 2H), 1.60 (m, 2H), 1.36 (m, 2H), 0.93 (t, J=7 Hz, 3H). MS: m/z (MH+) 362.
Reaction SMILES: N([O-])=O.[Na+].[F:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2[CH:20]=[CH:19][C:18](N)=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:8][CH:7]=1.Cl.C(OC([S-])=[S:27])C.[K+]>O.C(OCC)(=O)C>[F:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([SH:27])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:8][CH:7]=1
Reactant: CCOC(=S)[S-]
Reactant: Nc1ccc(S(=O)(=O)c2ccc(F)cc2)cc1
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=S(=O)(c1ccc(F)cc1)c1ccc(S)cc1
Temperature: 45 °C
Reaction time: 0.08 h
Yield: 59.9 %

Procedure:
A solution of sodium nitrite (302 mg in 1 ml of water) is added to a suspension of 1 g (0.00398 mol) of 4-[(4-fluorophenyl)sulfonyl]benzeneamine in a solution of hydrochloric acid (1.68 ml of concentrated hydrochloric acid in 5 ml of water) at 5° C. After stirring for 5 minutes, this solution is added dropwise to a solution of 2.47 g of potassium ethylxanthate in 5 ml of water at 70° C. The reaction mixture is diluted with ethyl acetate. The organic phase is washed with a 1 N solution of sodium hydroxide and a saturated solution of sodium chloride and then dried over magnesium sulfate. After evaporation of the solvents, the residue is taken up in 15 ml of ethanol. 1.47 g of potassium hydroxide are added and the reaction mixture is heated at 45° C. for 10 minutes. It is then poured into iced water and partially purified by extraction with ethyl acetate. The aqueous phase, cooled with ice, is rendered acidic by the addition of concentrated hydrochloric acid and is then extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and the solvents are evaporated off to dryness. 640 mg (yield: 60%) of the expected product are thus obtained.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=1)=O)(C)(C)C.BrC1C=CC(CN2CCC[CH:27]2[CH2:31][O:32][CH2:33]C)=CC=1>>[CH2:31]([O:32][CH2:33][CH:6]1[CH2:10][CH2:11][CH2:12][N:8]1[CH2:9][C:13]1[CH:14]=[CH:15][C:16]([NH2:19])=[CH:17][CH:18]=1)[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ccc(N)cc1
Reactant: CCOCC1CCCN1Cc1ccc(Br)cc1
Product: CCOCC1CCCN1Cc1ccc(N)cc1
Yield: 47 %

Procedure:
Using the same procedure described for the preparation of 2-(4-Amino-phenyl)-pyrrolidine-1-carboxylic acid tert-butyl ester, the title compound is prepared from 1-(4-Bromo-benzyl)-2-ethoxymethyl-pyrrolidine (using the crude product obtained in the previous step) in 47% yield (two steps, based on crude residue, ˜85%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH3:35])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH3:36][C:37]1[C:38]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][CH2:53][S:54]([CH3:57])(=[O:56])=[O:55])[CH2:48][CH2:47]2)=[CH:39][C:40]([O:44][CH3:45])=[C:41]([CH:43]=1)[NH2:42].C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>C(Cl)Cl.CC(O)C>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:42][C:41]3[CH:43]=[C:37]([CH3:36])[C:38]([N:46]4[CH2:51][CH2:50][N:49]([CH2:52][CH2:53][S:54]([CH3:57])(=[O:56])=[O:55])[CH2:48][CH2:47]4)=[CH:39][C:40]=3[O:44][CH3:45])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH3:35]
Reactant: COc1cc(N2CCN(CCS(C)(=O)=O)CC2)c(C)cc1N
Reactant: COc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClCCl
Product: COc1cc(N2CCN(CCS(C)(=O)=O)CC2)c(C)cc1Nc1nccc(-c2c(-c3ccc(OC)c(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 120 °C
Yield: 47 %

Procedure:
5-[3-(2-Chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide (Intermediate Example 2) (100 mg, 0.203 mmol), 5-methyl-2-(methyloxy)-4-{4-[2-(methylsulfonyl)ethyl]-1-piperazinyl}aniline (Example 148, step D) (60 mg, 0.183 mmol), and p-toluenesulfonic acid (93 mg, 0.49 mmol) were weighed into a 20 mL vial. 10 mL of iPrOH was added and the mixture was heated to 120° C. for 48 h. The mixture was transferred to a 50 mL round bottom and neutralized with 2 mL of 0.5 N sodium methoxide. The solvent was rotovaped down. The residue was taken up in 10 mL of DCM. 1 g of silica gel was added. The solvent was rotovaped down and the pre-adsorbed solids were purified by flash chromatography to give the title compound (65 mg, 0.086 mmol, 49%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.77 (s, 1H), 9.35 (s, 1H), 8.45 (s, 1H), 8.22 (d, J=5.31 Hz, 1H), 8.09 (d, J=2.01 Hz, 1H), 7.76 (dd, J=8.61, 2.01 Hz, 1H), 7.68 (d, J=8.97 Hz, 1H), 7.49 (s, 1H), 7.40-7.45 (m, 1H), 7.33-7.40 (m, 1H), 7.27 (d, J=8.79 Hz, 1H), 7.17 (t, J=8.06 Hz, 2H), 6.94 (t, J=6.87 Hz, 1H), 6.75 (s, 1H), 6.55 (d, J=5.31 Hz, 1H), 3.97 (s, 3H), 3.79 (s, 3H), 3.31-3.35 (m, 2H), 3.05 (s, 3H), 2.82-2.90 (m, 4H), 2.76 (t, J=6.68 Hz, 2H), 2.53-2.65 (m, 4H), 2.13 (s, 3H). MS (ESI): 783 [M+H]+.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[C:6]([C:10]3[C:18]4[C:13](=[CH:14][C:15]([F:28])=[C:16]([C:19]5[O:23][C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[N:21][N:20]=5)[CH:17]=4)[N:12](S(C4C=CC(C)=CC=4)(=O)=O)[CH:11]=3)[N:5]=2)[CH2:3][CH2:2]1.O1CCOCC1.[OH-].[Na+]>[Cl-].[Na+].O>[CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[C:6]([C:10]3[C:18]4[C:13](=[CH:14][C:15]([F:28])=[C:16]([C:19]5[O:23][C:22]([NH:24][CH:25]([CH3:26])[CH3:27])=[N:21][N:20]=5)[CH:17]=4)[NH:12][CH:11]=3)[N:5]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nccc(C4CC4)n3)c3cc(-c4nnc(NC(C)C)o4)c(F)cc32)cc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)Nc1nnc(-c2cc3c(-c4nccc(C5CC5)n4)c[nH]c3cc2F)o1
Temperature: 100 °C
Yield: 29 %

Procedure:
A 5 mL glass microwave tube was charged with 5-(3-(4-cyclopropylpyrimidin-2-yl)-6-fluoro-1-tosyl-1H-indol-5-yl)-N-isopropyl-1,3,4-oxadiazol-2-amine (180 mg, 0.338 mmol) and treated with dioxane (2 mL) and 1 N NaOH (1 mL) and heated at 100° C. for 10 min in the microwave. The reaction mixture was treated with brine and extracted with EtOAc (2×20 mL), concentrated and purified by reverse phase using a Gilson automated platform (Silicycle Silichrome XT C18 column; 30×150 mm, 5 μm, 10-95% 0.1% TFA/CH3CN in 0.1% TFA/water by volume over 10 min), then dried in a Genevac Series II Evaporator affording the title compound (48.2 mg, 0.098 mmol, 29.0% yield) as a yellow amorphous solid. LC-MS (ESI, pos. ion) m/z: 379.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.93-12.03 (1H, m), 8.98 (1H, d, J=7.4 Hz), 8.59 (1H, d, J=5.1 Hz), 8.29 (1H, d, J=2.7 Hz), 7.85 (1H, d, J=7.4 Hz), 7.45 (1H, d, J=11.3 Hz), 7.21 (1H, d, J=5.3 Hz), 3.82 (1H, dq, J=13.2, 6.5 Hz), 2.13-2.22 (1H, m), 1.27 (6H, d, J=6.5 Hz), 1.20-1.25 (2H, m), 1.12-1.20 (2H, m). 19F NMR (377 MHz, DMSO-d6) δ ppm −74.90 (3F, s), −119.9 (1F, s).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]>CO.[C].[Pd]>[NH2:10][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([F:1])[CH:9]=1
Reactant: N#Cc1ccc([N+](=O)[O-])cc1F
Agent: [Pd]
Solvent: CO
Product: N#Cc1ccc(N)cc1F
Reaction time: 3 h
Yield: 69.5 %

Procedure:
To a solution of 2-fluoro-4-nitrobenzonitrile (2.51 g) in methanol (125 mL) was added 10% palladium carbon (50% containing water, 237 mg), and the mixture was stirred under a hydrogen atmosphere for 3 hr. The reaction mixture was filtrated, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=1:1) to give the title compound as a pale-yellow solid (yield 1.43 g, 70%).
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[CH2:6][N:7]([C@@H:14]1[C:20]2=[CH:21][C:22]3[CH2:23][O:24][CH2:25][C:26]=3[C:27](Br)=[C:19]2[NH:18][CH2:17][CH2:16][CH2:15]1)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.[F-].[Cs+].[CH3:40]B(O)O>O1CCOCC1.C(OCC)(=O)C.O>[F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[CH2:6][N:7]([C@@H:14]1[C:20]2=[CH:21][C:22]3[CH2:23][O:24][CH2:25][C:26]=3[C:27]([CH3:40])=[C:19]2[NH:18][CH2:17][CH2:16][CH2:15]1)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1
Reactant: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]2CCCNc3c2cc2c(c3Br)COC2)n1
Reactant: CB(O)O
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: Cc1c2c(cc3c1NCCC[C@@H]3N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1)COC2
Temperature: 95 °C

Procedure:
To a solution of (S)-(3,5-Bis-trifluoromethyl-benzyl)-(4-bromo-3,5,6,7,8,9-hexahydro-1H-2-oxa-5-aza-cyclohepta[f]inden-9-yl)-(2-methyl-2H-tetrazol-5-yl)-amine (2.16 mmol) in dioxane (150 mL), add bis(diphenylphosphinoferrocene)palladium(II) chloride (0.22 mmol) followed by cesium fluoride (9.32 mmol) and methylboronic acid (6.48 mmol). Heat the mixture under nitrogen to 95° C. After heating for 2 h, cool the reaction mixture to room temperature and dilute with ethyl acetate (50 mL) and water (50 mL). Separate the organics and wash the aqueous with ethyl acetate (2×20 mL). Dry the combined organics over sodium sulfate, filter, and remove the solvent under vacuum. Chromatograph the crude product over silica gel, eluting with ethyl acetate/hexane (10-45%) to obtain the title compound as an off white solid. MS (ES+): 527 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:10]2=[CH:11][C:12]3[NH:13][C:14]4[C:19]([C:20]=3[CH:21]=[C:9]2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4.Br[C:24]1[CH:25]=[C:26]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:27]=[C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:29]=1.CC([O-])(C)C.[Na+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>CC1C=CC(C)=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:1][C:2]1([CH3:22])[C:10]2=[CH:11][C:12]3[N:13]([C:24]4[CH:29]=[C:28]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[CH:27]=[C:26]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)[CH:25]=4)[C:14]4[C:19]([C:20]=3[CH:21]=[C:9]2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4
Reactant: CC1(C)c2ccccc2-c2cc3c(cc21)[nH]c1ccccc13
Reactant: Brc1cc(-c2ccccc2)cc(-c2ccccc2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccc(C)cc1
Product: CC1(C)c2ccccc2-c2cc3c4ccccc4n(-c4cc(-c5ccccc5)cc(-c5ccccc5)c4)c3cc21

Procedure:
30 g (106 mmol) of 12,12-dimethyl-10,12-dihydro-10-azaindeno[2,1-b]fluorene, 13.3 g (114 mmol) of 5′-bromo-[1,1′;3′,1″]terphenyl and 30.5 g of NaOtBu are suspended in 1.5 l of p-xylene. 0.5 g (2.11 mmol) of Pd(OAc)2 and 1.6 ml of a 1 M tri-tert-butylphosphine solution are added to this suspension. The reaction mixture is heated under reflux for 16 h. After cooling, the organic phase is separated off, washed three times with 200 ml of water and subsequently evaporated to dryness. The residue is extracted with hot toluene, recrystallised from toluene and finally sublimed in a high vacuum, the purity is 99.9%. The yield is 15.8 g (31 mmol, 72%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][N:3]=1.OS(O)(=O)=O.[N+:15]([O-])([OH:17])=[O:16].[OH-].[Na+]>>[NH2:1][C:2]1[C:7]([N+:15]([O-:17])=[O:16])=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])O
Reactant: Nc1cc(Cl)c(Cl)cn1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Nc1ncc(Cl)c(Cl)c1[N+](=O)[O-]
Temperature: 55 °C
Reaction time: 0.05 h
Yield: 26.2 %

Procedure:
To a 50 ml round-bottomed flask containing 2-amino-4,5-dichloropyridine (0.275 g, 1.65 mmol) and cooled into an ice-bath was added conc. H2SO4 (2.79 g). The reaction mixture was stirred for 3 min and then HNO3 (70%; 0.186 g) was dropwise added. The reaction mixture was stirred at 0° C. (ice-bath) for 7 min, then heated to 55° C. and stirred at this temperature for 1 h, allowed to cool to room temperature, diluted with ice-water (˜15 ml) and the pH was adjusted to ˜7.5 with 10% aqueous NaOH. The yellow precipitate was collected by filtration, washed with water and dried in vacuo over P2O5, then absorbed on silica gel and the free running powder was placed on a 10 g isolute silica column. Elution with 2% ethyl acetate in dichloromethane afforded the title compound as a yellow solid (0.090 g, 26%); 1H-NMR (250 Mz, DMSO-d6) 7.39 (s, 2H, NH2), 8.39 (s, 1H, 6-H); LC-MS (ESI, m/z) 6.54 min—208, 210, 212 [(M+H)+, Cl2 isotopic pattern].
Reaction SMILES: C(OC([NH:11][C@@H:12]1[C:18](=[O:19])[N:17]([CH2:20][C:21]([O:23]C(C)(C)C)=[O:22])[C:16]2[CH:28]=[C:29]([C:32]([F:35])([F:34])[F:33])[CH:30]=[CH:31][C:15]=2[S:14][CH2:13]1)=O)C1C=CC=CC=1.[BrH:36].C(O)(=O)C>C(O)(=O)C>[BrH:36].[NH2:11][C@@H:12]1[C:18](=[O:19])[N:17]([CH2:20][C:21]([OH:23])=[O:22])[C:16]2[CH:28]=[C:29]([C:32]([F:35])([F:34])[F:33])[CH:30]=[CH:31][C:15]=2[S:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)CN1C(=O)[C@@H](NC(=O)OCc2ccccc2)CSc2ccc(C(F)(F)F)cc21
Agent: Br
Solvent: CC(=O)O
Product: N[C@H]1CSc2ccc(C(F)(F)F)cc2N(CC(=O)O)C1=O
Reaction time: 4 h

Procedure:
In 5 ml of acetic acid is dissolved 1.4 g of tert-butyl 3(R)-benzyloxycarbonylamino-4-oxo-7-trifluoromethyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate, and 10 ml of 30% hydrogen bromide-acetic acid solution is added to the solution, followed by allowing the mixture to stand at room temperature for 4 hours. Petroleum ether (100 ml) is added to the reaction solution, and the mixture is thoroughly shaken, followed by decanting the supernatant. After petroleum ether is again added to repeat the same procedure, the residue is dissolved in a mixture of ethyl acetate and benzene, and the mixture is concentrated to dryness under reduced pressure. Petroleum ether is added to the residue to give 0.75 g of 3(R)-amino-4-oxo-7-trifluoromethyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid hydrobromide as crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:10][NH:11][C:12](=[O:39])[CH2:13][CH2:14][C:15]([NH:17][CH2:18][C:19]2[C:20]([NH:32][CH:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[C:21]3[CH:29]=[N:28][N:27]([CH2:30][CH3:31])[C:22]3=[N:23][C:24]=2[CH2:25][CH3:26])=[O:16])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH:40]([C:42]1[CH:43]=[C:44](B(O)O)[CH:45]=[CH:46][CH:47]=1)=[O:41].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.CCOC(C)=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:30]([N:27]1[C:22]2=[N:23][C:24]([CH2:25][CH3:26])=[C:19]([CH2:18][NH:17][C:15](=[O:16])[CH2:14][CH2:13][C:12]([NH:11][CH2:10][C:4]3[CH:3]=[C:2]([C:46]4[CH:45]=[CH:44][CH:43]=[C:42]([CH:40]=[O:41])[CH:47]=4)[C:7]([O:8][CH3:9])=[CH:6][CH:5]=3)=[O:39])[C:20]([NH:32][CH:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[C:21]2[CH:29]=[N:28]1)[CH3:31]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CCC(=O)NCc1ccc(OC)c(Br)c1
Reactant: O=Cc1cccc(B(O)O)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CCC(=O)NCc1ccc(OC)c(-c2cccc(C=O)c2)c1
Yield: 69.8 %

Procedure:
A mixture of N-{[3-bromo-4-(methyloxy)phenyl]methyl}-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}butanediamide (0.964 g, 1.603 mmol), (3-formylphenyl)boronic acid (0.300 g, 2.0 mmol), tetrakis (triphenylphosphine) palladium (0) (0.081 g, 0.07 mmol), and sodium carbonate (0.477 g, 4.5 mmol) in 1,4-dioxane (12 mL) and water (4 mL) under an N2 atmosphere was microwaved for 30 min at 140° C. The reaction mixture was diluted with EtOAc and water. The organic layers separated. The organic layer was washed with saturated NaCl, and then dried over Na2SO4. The organic layer was evaporated to viscous taffy. The viscous taffy was purified on a Chromatotron Plate Silica Gel (1000μ) eluting with CH2Cl2-MeOH (97:3) to afford N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-{[3′-formyl-6-(methyloxy)-3-biphenylyl]methyl}butanediamide (701 mg, 69.8%) as a viscous, nearly colorless, taffy. LC-MS m/z 627.5 (M+H)+, 0.81 min (ret time).
Reaction SMILES: O.[NH:2]1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]([C:10]([OH:12])=O)=[N:3]1.Cl.CN(C)CCCN=C=NCC.C1C=CC2N(O)N=NC=2C=1.Cl.[Cl:36][C:37]1[CH:38]=[C:39]([C:44]2[O:48][C:47]([CH2:49][CH2:50][NH2:51])=[CH:46][CH:45]=2)[CH:40]=[CH:41][C:42]=1[Cl:43]>CN(C=O)C.C(Cl)Cl.CCN(C(C)C)C(C)C.O>[Cl:36][C:37]1[CH:38]=[C:39]([C:44]2[O:48][C:47]([CH2:49][CH2:50][NH:51][C:10]([C:4]3[NH:3][N:2]=[C:6]([C:7]([OH:9])=[O:8])[CH:5]=3)=[O:12])=[CH:46][CH:45]=2)[CH:40]=[CH:41][C:42]=1[Cl:43]
Reactant: NCCc1ccc(-c2ccc(Cl)c(Cl)c2)o1
Reactant: O=C(O)c1cc(C(=O)O)[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(O)c1cc(C(=O)NCCc2ccc(-c3ccc(Cl)c(Cl)c3)o2)[nH]n1

Procedure:
3,5-Pyrazoledicarboxylic acid monohydrate (8.02 g, 46.1 mmol) was dissolved in the mixture of dry DMF (35 ml), dry DCM (35 ml) and DIPEA (7.9 ml). 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 3.37 g, 17.6 mmol), HOBt (2.28 g, 16.9 mmol), and DIPEA (3 ml, 2.23 g, 17.3 mmol) were added at RT. The solution was mixed for 10 min. Then, 2-[5-(3,4-dichlorophenyl)-furan-2-yl]ethylamine hydrochloride (3.46 g, 11.8 mmol) dissolved in the mixture of dry DCM (35 ml) and DIPEA (2.0 ml, 1.48 g, 11.5 mmol) was dropped to the solution at RT. After stirring overnight water was added. The product was extracted into ethyl acetate. The organic phase was washed with water, dried and evaporated. The crude product was purified by flash chromatography using DCM as an eluent. The product was triturated in hot methanol. 1H NMR (400 MHz, DMSO-d6): 2.95 (2H, t), 3.56 (2H, m), 6.33 (1H, d), 7.01 (1H, d), about 7.03 (1H, broad s), 7.61 (1H, distorted dd), 7.63 (1H, distorted d), 7.83 (1H, d), about 8.45 (1H, broad s), about 14.05 (1H, broad s).
Reaction SMILES: C([O:8][C:9]1[C:17]2[N:16]=[C:15]([CH3:18])[N:14]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:13]=2[CH:12]=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>CCO.C1COCC1.[Pd]>[OH:8][C:9]1[C:17]2[N:16]=[C:15]([CH3:18])[N:14]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: CCOC(=O)Cn1c(C)nc2c(OCc3ccccc3)cccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)Cn1c(C)nc2c(O)cccc21
Yield: 93.2 %

Procedure:
To a solution of ethyl [4-(benzyloxy)-2-methyl-1H-benzimidazol-1-yl]acetate (2.57 g) in a mixture of EtOH (25.7 mL) and THF (12.9 mL) was added 10% palladium on carbon (50% wet, 0.78 g) at ambient temperature, and the resultant mixture was hydrogenated under atmospheric pressure of hydrogen for 2 hours. The catalyst was removed by filtration and evaporated in vacuo to give crude solid. The crude solid was recrystallized from solvent (EtOAc:n-hexane) to give ethyl (4-hydroxy-2-methyl-1H-benzimidazol-1-yl)acetate (1.73 g) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13](C(OC(C)(C)C)=O)[CH3:14])=[CH:9][C:8]=1[O:22][CH3:23])[CH3:2].COC(=O)COC1C=CC(N(C(OC(C)(C)C)=O)C)=CC=1OC.C(O)(C(F)(F)F)=O>>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH3:14])=[CH:9][C:8]=1[O:22][CH3:23])[CH3:2]
Reactant: CCOC(=O)COc1ccc(N(C)C(=O)OC(C)(C)C)cc1OC
Agent: COC(=O)COc1ccc(N(C)C(=O)OC(C)(C)C)cc1OC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)COc1ccc(NC)cc1OC

Procedure:
Analogously, to example 1.4, crude [4-(tert-butoxycarbonyl-methyl-amino)-2-methoxy-phenoxy]-acetic acid ethyl ester containing [4-(tert-butoxycarbonyl-methyl-amino)-2-methoxy-phenoxy]-acetic acid methyl ester was deprotected with TFA to give (2-methoxy-4-methylamino-phenoxy)-acetic acid ethyl ester containing (2-methoxy-4-methylamino-phenoxy)-acetic acid methyl ester as a brown oil, MS: 240 (MH+) and 226 (MH+).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([S:17]([NH2:20])(=[O:19])=[O:18])=[CH:13][CH:12]=3)=[N:9][NH:10][C:6]=2[CH:5]=[CH:4][NH:3]1.[H-].[Na+].CC1C=CC(S(O[CH2:34][CH:35]2[CH2:39][CH2:38][O:37][CH2:36]2)(=O)=O)=CC=1>CN(C=O)C>[O:1]=[C:2]1[C:7]2[C:8]([C:11]3[CH:12]=[CH:13][C:14]([S:17]([NH2:20])(=[O:19])=[O:18])=[CH:15][CH:16]=3)=[N:9][N:10]([CH2:34][CH:35]3[CH2:39][CH2:38][O:37][CH2:36]3)[C:6]=2[CH:5]=[CH:4][NH:3]1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCOC2)cc1
Reactant: NS(=O)(=O)c1ccc(-c2n[nH]c3cc[nH]c(=O)c23)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1ccc(-c2nn(CC3CCOC3)c3cc[nH]c(=O)c23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.9 %

Procedure:
To a solution of 4-(4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)benzenesulfonamide (28.7 mg) obtained in Step B of Example 100 in DMF (2 mL) was added sodium hydride (60% dispersion in mineral oil, 4.35 mg), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added tetrahydrofuran-3-ylmethyl 4-methylbenzenesulfonate (27.8 mg), and the mixture was stirred overnight at room temperature. The reaction mixture was extracted with water and ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (basic silica gel, ethyl acetate/methanol) to give the title compound (11.8 mg).