Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[S:22](Cl)([C:25]1[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=1)(=[O:24])=[O:23].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][S:22]([C:25]2[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=2)(=[O:24])=[O:23])=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)[C@H](Cc1ccc(OS(=O)(=O)c2ccc(C)cc2)cc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 4 h
Yield: 93.4 %

Procedure:
N-Boc-L-tyrosine methyl ester 3 (103 g, 0.35 mol) and tosyl chloride (66.7 g, 0.35 mol) were dissolved in toluene (517 g) and then cooled to 0° C. To the mixture was added dropwise triethylamine (35.5 g, 0.35 mol) at 0° C. over 90 min. The mixture was further kept at 0° C. for 4 hrs. The reaction mass was washed with 5% hydrochloric acid (255 g) and 5% aqueous sodium bicarbonate (294 g) and then concentrated at 35° C. under reduced pressure until the weight of the toluene layer reached to 243 g. After cooling to −10° C., to the concentrate was added dropwise n-hexane (310 g) over 3 hrs. Deposited crystals was filtered and dried to give N-Boc-O-tosyl L-tyrosine methyl ester 4 (147 g, yield 92%) as white crystals.
Reaction SMILES: N1C=CC=CC=1.[CH2:7]([S:19](Cl)(=[O:21])=[O:20])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[NH2:23][C:24]1[CH:25]=[C:26]([CH:38]=[CH:39][C:40]=1[O:41][CH3:42])[C:27]([NH:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=1)=[O:28].Cl>O>[CH2:7]([S:19]([NH:23][C:24]1[CH:25]=[C:26]([CH:38]=[CH:39][C:40]=1[O:41][CH3:42])[C:27]([NH:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=1)=[O:28])(=[O:21])=[O:20])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCS(=O)(=O)Cl
Reactant: COc1ccc(C(=O)Nc2ccc(Cl)c(Cl)c2)cc1N
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CCCCCCCCCCCCS(=O)(=O)Nc1cc(C(=O)Nc2ccc(Cl)c(Cl)c2)ccc1OC
Temperature: 25 °C
Yield: 79.7 %

Procedure:
Pyridine (5 mL) was added to a mixture of 1-dodecane-sulfonyl chloride (Maybridge) (0.8 g, 3.0 mmol) and 3-amino-4-methoxy-N-(3,4-dichloro-phenyl)-benzamide from Example 4 (0.73 g, 3.0 mmol) and stirred at room temperature. After 5 days the mixture was heated on a steambath for 1.5 hours, allowed to cool, and added to water (150 mL), acidified with 4N HCl, and stirred for an hour. The precipitate was filtered off, rinsed with water then with ethanol and dried to afford the product (1.3 g); m.p. 15-152° C. after recrystallization from ethanol and chromatography on silica gel in CHCl3/EtOAc (9:1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:46])[CH:7]([NH:23][C:24](=[O:45])[CH:25]([NH:30]CC1C2C=CC=CC=2C2C1=CC=CC=2)[CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].N1CCCCC1>O1CCCC1>[C:1]([O:5][C:6](=[O:46])[CH:7]([NH:23][C:24](=[O:45])[CH:25]([NH2:30])[CH2:26][CH:27]([CH3:28])[CH3:29])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)CC(NCC1c2ccccc2-c2ccccc21)C(=O)NC(Cc1ccc(OCc2ccccc2)cc1)C(=O)OC(C)(C)C
Solvent: C1CCNCC1
Solvent: C1CCOC1
Product: CC(C)CC(N)C(=O)NC(Cc1ccc(OCc2ccccc2)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 76.8 %

Procedure:
A solution of the product from Example AH (3-(4-benzyloxy-phenyl)-2-{2-[(9H-fluoren-9-ylmethyl)-amino]-4-methyl-pentanoylamino}-propionic acid tert-butyl ester) (12.2 g, 20.0 mmol) in 500 mL of tetrahydrofuran was treated with piperidine (80 mL). The resulting solution was stirred at room temperature for 48 hours. The reaction mixture was concentrated and the residue purified by chromatography (silica gel, gradient elution EtOAc—15% EtOH/EtOAc). The resulting yellow solid was broken up in heptane to give the title compound as a white solid (6.77 g, 77%), mp=56-60° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[C:11]3[NH:12][NH:13][CH2:14][CH2:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.[CH2:23]([N:25]=[C:26]=[O:27])[CH3:24]>ClCCl>[CH2:23]([NH:25][C:26]([N:13]1[CH2:14][CH2:15][N:10]2[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[C:11]2[NH:12]1)=[O:27])[CH3:24]
Reactant: CCN=C=O
Reactant: Fc1ccc(-c2nn3c(c2-c2ccncc2)NNCC3)cc1
Solvent: ClCCl
Product: CCNC(=O)N1CCn2nc(-c3ccc(F)cc3)c(-c3ccncc3)c2N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
A mixture of 7-(4-fluorophenyl)-8-(pyridin-4-yl)-1,2,3,4-tetrahydropyrazolo[5,1-c][1,2,4]triazine (118 mg) and ethyl isocyanate (30 mg) in dichloromethane (2 ml) was stirred at ambient temperature for 1 hour. The mixture was concentrated in vacuo and the residue was crystallized from ethyl acetate to give 2-ethylcarbamoyl-7-(4-fluorophenyl)-8-(pyridin-4-yl)-1,2,3,4-tetrahydropyrazolo[5,1-c][1,2,4]triazine (120 mg).
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH:11]=[C:10]([N:12]3[CH:16]=[CH:15]C=N3)[N:9]=[CH:8]2)[CH:2]=1.[NH:23]1C=CN=[CH:24]1>>[C:1]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH:11]=[C:10]([N:12]3[CH:16]=[CH:15][N:23]=[CH:24]3)[N:9]=[CH:8]2)[CH:2]=1
Reactant: c1c[nH]cn1
Reactant: c1ccc(-c2cccc(-n3cnc(-n4cccn4)c3)c2)cc1
Product: c1ccc(-c2cccc(-n3cnc(-n4ccnc4)c3)c2)cc1
Yield: 60 %

Procedure:
The title compound was prepared by a method analogous to the synthesis of 1-(1-Biphenyl-3-yl-1H-imidazol-4-yl)-1H-pyrazole and using imidazole to give 60% yield. HRMS (ESI+): m/z=286.3366 [M+H]
Reaction SMILES: [CH2:1]([O:17][CH2:18][CH2:19][CH2:20][OH:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]=[CH2:16].CCN(CC)CC.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:1]([O:17][CH2:18][CH2:19][CH2:20][O:21][S:30]([CH3:29])(=[O:32])=[O:31])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]=[CH2:16]
Reactant: C=CCCCCCCCCCCCCCCOCCCO
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCCCCCCCCCCCCCCOCCCOS(C)(=O)=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To 7.1 g (23.7 mmol) of 31 was added 20 mL of DCM and 5.0 mL (36 mmol) of Et3N and the solution was cooled to 0° C. To this cooled solution was added dropwise 2.0 mL (26 mmol) of MsCl and a catalytic amount of DMAP. The reaction was stirred at room temperature overnight. The reaction mixture was then diluted with 50 mL of DCM and washed successively with saturated solution of aq. NaHCO3 (1×), water (1×) and brine (1×), dried over MgSO4 and the solvent was evaporated under reduced pressure. The crude product was then purified by combiflash using hexane/ethyl acetate as eluent to furnish 9 g of target product 32 in quantitative yield.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH:5]=O.[CH2:14]([N:16]([CH2:22][CH3:23])[C:17](=[O:21])[CH2:18][C:19]#[N:20])[CH3:15]>>[CH2:14]([N:16]([CH2:22][CH3:23])[C:17](=[O:21])[C:18]([C:19]#[N:20])=[CH:5][C:4]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]([OH:10])=[C:2]([OH:1])[CH:3]=1)[CH3:15]
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Reactant: CCN(CC)C(=O)CC#N
Product: CCN(CC)C(=O)C(C#N)=Cc1cc(O)c(O)c([N+](=O)[O-])c1

Procedure:
The procedure described in Example 99 was repeated using 1.83 g of 3,4-dihydroxy-5-nitrobenzaldehyde and 1.5 g of N,N-diethylcyanoacetamide. Yield 2.23 g (73%), m.p. 153°-156° C.
Reaction SMILES: [NH3:1].Cl.CO[N:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([O:14][CH3:15])[CH:8]=1>CO>[C:6]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([O:14][CH3:15])[CH:8]=1)(=[NH:5])[NH2:1]
Reactant: CON=Cc1ccc(O)c(OC)c1
Reactant: N
Agent: Cl
Solvent: CO
Product: COc1cc(C(=N)N)ccc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 100 ml of anhydrous methanol and about 50 ml of liquid ammonia, was added slowly 8.7 g of 4-methoxyiminomethyl-2-methoxyphenol hydrochloride. The mixture was stirred overnight at room temperature. The colorless crystals precipitated from the reaction mixture were collected by filtration, washed thoroughly with methanol, and dried to obtain 7.4 g of 4-amidino-2-methoxyphenol.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30](Br)[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[F:35][C:36]1[C:37]([O:45][CH3:46])=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1>Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:38]5[CH:39]=[CH:40][CH:41]=[C:36]([F:35])[C:37]=5[O:45][CH3:46])[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Br)n4)cc3)cc2)CC1
Reactant: COc1c(F)cccc1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(-c5cccc(F)c5OC)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using 1-{4′-[4-(6-bromo-pyridin-2-ylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 3-fluoro-2-methoxyphenylboronic acid. (1,1′-Bis(diphenylphosphino)ferrocene)-dichloropalladium(II) was used in place of tetrakis(triphenylphosphine)palladium(0).
Reaction SMILES: [C:1]([N:3]1[C:11]2[CH:10]=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=2[C:5]2[CH2:13][N:14]([CH3:17])[CH2:15][CH2:16][C:4]1=2)#[CH:2].Br[C:19]1[S:20][CH:21]=[CH:22][CH:23]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O.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>[CH3:17][N:14]1[CH2:15][CH2:16][C:4]2[N:3]([C:1]#[C:2][C:23]3[CH:22]=[CH:21][S:20][CH:19]=3)[C:11]3[CH:10]=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=3[C:5]=2[CH2:13]1
Reactant: C#Cn1c2c(c3cc(C)ccc31)CN(C)CC2
Reactant: Brc1cccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2C#Cc2ccsc2)CCN(C)C1
Temperature: 80 °C

Procedure:
5-Ethynyl-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (165 mg, 0.736 mm 2-bromothiophene (100 mg, 0.613 mmol), TBAF.3H2O (580 mg, 1.84 mmol), and dichlorobis (triphenylphosphine)palladium (II) (13 mg, 0.018 mmol) were placed in microwave vial and heated by microwave at 80° C. for 5 min. The reaction was monitored by TLC and LCMS. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3×50 mL). The combined organic layer was washed with water (2×50 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain product, which was subjected to preparative HPLC to yield 20 mg of 2,8-dimethyl-5-thiophen-3-ylethynyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (CDCl3, freebase) δ (ppm): 7.40 (d, 1H), 7.30-7.25 (m, 2H), 7.19 (s, 1H), 7.10-6.0 (m, 2H), 3.65 (s, 2H), 2.95 (t, 2H), 2.90 (t, 2H), 2.59 (s, 3H), 2.45 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.OS(O)(=O)=O.[CH2:17](O)[CH3:18]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:17][CH3:18])=[O:10])=[CH:6][CH:7]=1
Reactant: CCO
Reactant: O=C(O)Cc1ccc(Br)cc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1ccc(Br)cc1
Temperature: 25 °C

Procedure:
A solution of 43 g (200 mmol) of 4-bromophenylacetic acid and 0.2 g of conc. H2SO4 in 470 ml of ethanol was refluxed for 16 hours. The reaction mixture was cooled to ambient temperature, stirred with 6 g of solid KCO3 for 30 minutes and then filtered. The filtrate was concentrated in vacuo diluted with Et2O (200 ml), washed with 10% aqueous NaHCO3 (10 ml) and brine (10 ml), dried over MgSO4 and concentrated in vacuo to give the title compound as a colorless oil. PMR (CDCl3): δ1.25 (3H, t, J=7.0 Hz), 3.56 (2H, s), 4.15 (2H, q, J=7.0 Hz), 7.16 (2H, d, J=8.4 Hz), 7.45 (2H, d, J=8.4 Hz).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([CH3:7])[CH:6]=1.[CH3:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]3[N:27]=[CH:26][C:25]4=[CH:28][CH:29]=[C:30](B5OC(C)(C)C(C)(C)O5)[N:24]4[N:23]=3)=[CH:17][CH:16]=2)[CH2:11][CH2:10]1>>[CH3:7][N:5]1[CH:6]=[C:2]([C:30]2[N:24]3[C:25]([CH:26]=[N:27][C:22]([NH:21][C:18]4[CH:19]=[CH:20][C:15]([N:12]5[CH2:13][CH2:14][N:9]([CH3:8])[CH2:10][CH2:11]5)=[CH:16][CH:17]=4)=[N:23]3)=[CH:28][CH:29]=2)[N:3]=[CH:4]1
Reactant: CN1CCN(c2ccc(Nc3ncc4ccc(B5OC(C)(C)C(C)(C)O5)n4n3)cc2)CC1
Reactant: Cn1cnc(Br)c1
Product: CN1CCN(c2ccc(Nc3ncc4ccc(-c5cn(C)cn5)n4n3)cc2)CC1

Procedure:
[7-(1-Methyl-1H-imidazol-4-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine was prepared from 4-bromo-1-methyl-1H-imidazole and [4-(4-methyl-piperazin-1-yl)-phenyl]-[7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-amine in an analogous manner to Example 1042b. Product isolated as a yellow solid (16 mg, 17%). m.p.=200-202° C.; LCMS (m/e) 389 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.63 (s, 1H), 7.92 (d, 1H, J=1.3 Hz), 7.57-7.47 (m, 3H), 7.30-7.24 (m, 1H), 7.02-6.96 (m, 2H), 6.81 (d, 1H, J=4.8 Hz), 6.57 (bs, 1H), 3.74 (s, 3H), 3.24-3.18 (m, 4H), 2.66-2.57 (m, 4H), 2.38 (s, 3H).
Reaction SMILES: [CH2:1]([C@@H:3]1[CH2:7][CH2:6][CH2:5][NH:4]1)[CH3:2].[Cl:8][C:9]1[CH:14]=[C:13](Cl)[N:12]=[C:11]([NH2:16])[N:10]=1.CCN(CC)CC>CC#N>[Cl:8][C:9]1[CH:14]=[C:13]([N:4]2[CH2:5][CH2:6][CH2:7][C@H:3]2[CH2:1][CH3:2])[N:12]=[C:11]([NH2:16])[N:10]=1
Reactant: CC[C@@H]1CCCN1
Reactant: Nc1nc(Cl)cc(Cl)n1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC[C@@H]1CCCN1c1cc(Cl)nc(N)n1
Temperature: 80 °C
Reaction time: 8 h
Yield: 70.3 %

Procedure:
A mixture of (2R)-2-ethylpyrrolidine (80 mg, 0.59 mmol), 4,6-dichloro-2-pyrimidinamine (119 mg, 0.726 mmol) and Et3N (0.25 mL, 1.77 mmol) in CH3CN (6 mL) was stirred overnight at 80° C. The mixture was poured onto water (˜150 mL), sonicated and filtered to afford the title compound (94 mg, 70%) as a white solid. LC-MS (ES) m/z=227, 229 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:41])[CH2:26][C:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)[CH:29]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:35]1[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=1[C:30]1[CH:29]=[C:28]([C:27]2[CH2:26][C:25](=[O:41])[NH:24][C:9]3[CH:10]=[C:11]([C:20]([F:23])([F:21])[F:22])[C:12]([O:14][CH2:15][C:16]([F:19])([F:17])[F:18])=[CH:13][C:8]=3[N:7]=2)[CH:33]=[CH:32][CH:31]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2ccccn2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-c3ccccn3)c2)=Nc2cc(OCC(F)(F)F)c(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from [2-[3-oxo-3-(3-pyridin-2-yl-phenyl)-propionylamino]-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M40) (165 mg, 0.36 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (81 mg).
Reaction SMILES: [CH3:1][C:2]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[C:3]([O:5]CC1C=CC=CC=1)=[O:4]>C(OCC)(=O)C.[Pd]>[CH3:1][C:2]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[C:3]([OH:5])=[O:4]
Reactant: CC(C)=CCC(C)(C(=O)OCc1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)CCC(C)(C(=O)O)c1ccccc1
Reaction time: 72 h
Yield: 95.9 %

Procedure:
A solution of Example 28A (2.51 g, 8.14 mmol) in ethyl acetate (20 mL) was treated with 10% palladium on carbon (0.251 g, 10 weight percent) and stirred under a hydrogen balloon for 72 hours. The vessel was purged with nitrogen gas and the mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo to give the title compound (1.72 g, 96%). 1H NMR (300 MHz, CDCl3): δ 0.87 (m, 6 H) 1.09 (m, 2 H) 1.51 (m, 4 H) 1.98 (m, 2 H) 7.34 (m, 5 H). MS (DCI NH3+) m/z 238 (M+NH4)+.
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl.[CH3:11][O:12][C:13]1[CH:46]=[CH:45][C:16]([CH2:17][S:18][C@@H:19]2[CH2:23][N:22]([C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=3)=[O:25])[C@H:21]([C:37]([NH:39][C@H:40]3[CH2:44][CH2:43][NH:42][CH2:41]3)=[O:38])[CH2:20]2)=[CH:15][CH:14]=1.Cl[C:48]([O:50][CH2:51][C:52]1[CH:57]=[CH:56][C:55]([N+:58]([O-:60])=[O:59])=[CH:54][CH:53]=1)=[O:49]>CN(C)C1C=CN=CC=1.C(#N)C>[CH3:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:17][S:18][C@@H:19]2[CH2:23][N:22]([C:24]([O:26][CH2:27][C:28]3[CH:29]=[CH:30][C:31]([N+:34]([O-:36])=[O:35])=[CH:32][CH:33]=3)=[O:25])[C@H:21]([C:37]([NH:39][C@H:40]3[CH2:44][CH2:43][N:42]([C:48]([O:50][CH2:51][C:52]4[CH:53]=[CH:54][C:55]([N+:58]([O-:60])=[O:59])=[CH:56][CH:57]=4)=[O:49])[CH2:41]3)=[O:38])[CH2:20]2)=[CH:45][CH:46]=1
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N[C@H]3CCNC3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)N[C@H]3CCN(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 68.5 %

Procedure:
230 mg of diisopropylethylamine were added to a suspension of 1.0 g of (2S,4S)-4-(4-methoxybenzylthio)-2-[(3S)-pyrrolidin-3-ylaminocarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidine hydrochloride [prepared as described in step (ii) above] and 240 mg of 4-dimethylaminopyridine in 10 ml of dry acetonitrile, and the resulting mixture was cooled to 0° C. A solution of 430 mg of 4-nitrobenzyl chloroformate in 4 ml of dry acetonitrile was then added to the mixture. The mixture was then stirred at room temperature for 3 hours, after which a solution of 117 mg of 4-nitrobenzyl chloroformate in 2 ml of dry acetonitrile was added and the mixture was stirred at the same temperature for 1 hour. At the end of this time, the reaction mixture was freed from the solvent by distillation under reduced pressure, and the residue was diluted with 50 ml of methylene chloride. The diluted solution was washed with a saturated aqueous solution of sodium chloride. The aqueous washings were extracted with methylene chloride. The organic extract and the methylene chloride solution were combined and dried over anhydrous magnesium sulfate, and then the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 4:1 by volume mixture of methylene chloride and acetonitrile as the eluent, to give 862 mg of the title compound as a powder.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([NH2:15])(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4]1)[CH3:2].[Cl:16]N1C(=O)CCC1=O>>[Cl:16][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([S:12]([NH2:15])(=[O:13])=[O:14])[CH:7]=2)[N:3]([CH2:1][CH3:2])[CH:4]=1
Reactant: CCn1ccc2cc(S(N)(=O)=O)ccc21
Reactant: O=C1CCC(=O)N1Cl
Product: CCn1cc(Cl)c2cc(S(N)(=O)=O)ccc21
Yield: 36.9 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 77, 1-ethyl-1H-indole-5-sulfonamide (Intermediate 56, 50 mg, 0.22 mmol) and N-chlorosuccinimide (36 mg, 0.27 mmol) were converted to the title compound (21 mg, 35%). 1H NMR (DMSO-d6) δ 7.99 (d, J=1.3 Hz, 1H), 7.81 (s, 1H), 7.77-7.71 (m, 1H), 7.70-7.64 (m, 1H), 7.22 (s, 2H), 4.26 (q, J=7.3 Hz, 2H), 1.36 (t, J=7.2 Hz, 3H); MS (ESI+) m/z 259.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[C:21](N1C=CN=C1)([N:23]1C=CN=C1)=O.CN>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([NH:23][CH3:21])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1c(-c2ccc(Br)cc2)nc2cccnc21
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN
Solvent: C1CCOC1
Product: CNC(=O)Cn1c(-c2ccc(Br)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 2-(4-bromophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.5 g, 0.0166 mole) and 1,1'-carbonyldiimidazole (2.7 g, 0.0166 mole) in anhydrous tetrahydrofuran (100 ml) was stirred at room temperature with a stream of nitrogen bubbling through it for 21/2 hours. The nitrogen flow was stopped and a solution of monomethylamine (1M in tetrahydrofuran) (33 ml) was added. The solution was stoppered and stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo and the residue triturated in water (100 ml) and filtered. The filter cake (5.5 g, 96%) was recrystallized from tetrahydrofuran-ethanol to give 3.0 g of a white flocculent solid, mp 258°-259° C. after forming a polymorph from 250°-255° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:10][C:11]([CH:26]([CH3:28])[CH3:27])=[C:12]([CH2:14][CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([CH3:25])[CH:19]=2)=[O:17])[N:13]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38]>CC(C)=O>[C:37]([O:39][CH2:40][CH2:41][O:24][C:21]1[CH:22]=[CH:23][C:18]([C:16](=[O:17])[CH2:15][CH2:14][C:12]2[N:13]=[C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[OH:1])[O:10][C:11]=2[CH:26]([CH3:28])[CH3:27])=[CH:19][C:20]=1[CH3:25])(=[O:38])[CH3:36]
Reactant: CCOC(=O)CBr
Reactant: Cc1cc(C(=O)CCc2nc(-c3ccc(Cl)cc3O)oc2C(C)C)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)OCCOc1ccc(C(=O)CCc2nc(-c3ccc(Cl)cc3O)oc2C(C)C)cc1C
Reaction time: 20 h
Yield: 68.2 %

Procedure:
The obtained 3-[2-(2-hydroxy-4-chlorophenyl)-5-isopropyl-4-oxazolyl]-1-(3-methyl-4-hydroxyphenyl)propan-1-one (378 mg, 0.95 mmol) was dissolved in acetone (20 mL). To the solution, potassium carbonate (158 mg, 0.95 mmol) and ethyl bromoacetate (158 mg, 0.95 mmol) were added while cooling with ice. The mixture was allowed to room temperature, and stirred for 20 hours. After insoluble was filtered off, the mixture was washed with acetone to remove the solvent. The residue was purified by column chromatography on silica gel with hexane/ethyl acetate (4/1) to give the desired compound (315 mg) as white solid (yield 69%).
Reaction SMILES: C([N:8]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[CH2:9][C:10]([F:17])([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])C1C=CC=CC=1.C(O)(C(F)(F)F)=O>C(O)C.[OH-].[OH-].[Pd+2]>[CH:18]1([NH:8][CH2:9][C:10]([F:17])([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: CCOC(=O)C(C)(F)CN(Cc1ccccc1)C1CCCCC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: CCOC(=O)C(C)(F)CNC1CCCCC1
Yield: 95.1 %

Procedure:
A solution of ethyl 3-(benzyl(cyclohexyl)amino)-2-fluoro-2-methylpropanoate (1.6 g, 5 mmol) in ethanol (20 mL) was hydrogenated with Pd(OH)2 (20%, 176 mg, 0.25 mmol) in presence of TFA (5 mmol) at atmospheric pressure for 20 h. The reaction mixture was filtered through celite. The filtrate was concentrated and diluted to EtOAc/H2O, aqueous layer was basified to pH=11-12 by 1N NaOH. The organic layer was then dried and concentrated to give the product (1.1 g, 95%) as light yellow liquid. [M+H] calc'd for C12H22FNO2, 232; found 232.