Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]([Cl:12])([Cl:11])[Cl:10])[N:3]=1.C(N(CC)CC)C.[CH3:20][N:21]([CH3:25])[C:22](Cl)=[S:23]>CCOCC>[CH3:20][N:21]([CH3:25])[C:22](=[S:23])[O:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]([Cl:12])([Cl:10])[Cl:11])[N:3]=1
Reactant: Cc1cc(O)nc(C(Cl)(Cl)Cl)n1
Reactant: CN(C)C(=S)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: Cc1cc(OC(=S)N(C)C)nc(C(Cl)(Cl)Cl)n1
Yield: 54.7 %

Procedure:
A mixture of 5.7 g (0.025 mole) 4-hydroxy-6-methyl-2-trichloromethylpyrimidine, 2.6 g (0.025 mole) triethylamine, 3.2 g (0.025 mole) dimethylthiocarbamoyl chloride, and 100 ml ether was refluxed 16 hours. A trace of dark solid was filtered out and the solution was evaporated on a steam bath to give a solid residue. This residue was extracted with hot ligroin to yield 4.3 g (55% yield) of product (mp 81°-83° C.) on cooling. The structure was confirmed via infrared and elemental analysis.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[NH2:27][CH2:28][C:29]1[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[C:31]([F:39])[CH:30]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:14])([F:15])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:27][CH2:28][C:29]1[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[C:31]([F:39])[CH:30]=1
Reactant: COC(=O)c1ccc(CN)cc1F
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1F
Yield: 97.4 %

Procedure:
Use a method similar to the General Procedure 5-2 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (1.24 g, 2.91 mmol) with methyl 4-aminomethyl-2-fluoro-benzoate (1.065 g, 5.821 mmol) by using tris(dibenzylideneacetone)dipalladium(0) (0.533 g, 0.582 mmol), BINAP (0.725 g, 1.16 mmol) and cesium carbonate (3.32 g, 10.2 mmol) under nitrogen in anhydrous toluene (20 mL). Purify by chromatography on silica gel eluting with hexane/EtOAc (19:1 to 1:1 gradient over 71 min; 50 mL/min) to afford the desired intermediate as a yellow oil (1.3 g, 100%).
Reaction SMILES: F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)[N:10]1CCC[CH2:11]1.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([O:38][C:39]2[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][C:40]=2[C:41](O)=[O:42])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].CN>C(Cl)Cl>[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([O:38][C:39]2[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][C:40]=2[C:41](=[O:42])[NH:10][CH3:11])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)cc2C(=O)O)CC1
Reactant: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CNC(=O)c1cc(Cl)ccc1OC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.5 h
Yield: 81.3 %

Procedure:
Bromo-tris-pyrrolidinophosphonium hexafluorophosphate (1.57 g, 3.37 mmol) was added to a vigorously stirred mixture of 2-{[1-(tert-butoxycarbonyl)piperidin-4-yl]oxy}-5-chlorobenzoic acid (1.00 g, 2.8 mmol) and 40% aq methylamine (2 ml) in DCM (10 ml). Stirring was continued for 30 min. before partitioning between 1N hydrochloric acid (10 ml) and dichloromethane (10 ml). The organic layer was separated and washed with saturated sodium bicarbonate solution (20 ml) and water (20 ml), then dried over sodium sulfate and the solvent removed under reduced pressure. The residue was purified by flash column chromatography eluting with ethyl acetate:isohexane (1:1) to give the title compound as a colourless solid (0.84 g).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH3:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:11]=1.[C:26](=O)([O:29]C)[O:27][CH3:28]>C1COCC1>[F:24][C:22]([F:25])([F:23])[C:19]1[CH:18]=[CH:17][C:16]([C:12]2[CH:11]=[C:10]([CH2:9][C:26]([O:27][CH3:28])=[O:29])[CH:15]=[CH:14][N:13]=2)=[CH:21][CH:20]=1
Reactant: Cc1ccnc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: COC(=O)OC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)Cc1ccnc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 0 °C
Yield: 70.8 %

Procedure:
A solution of LDA (2M in THF/heptane/ethyl benzene, 44 ml, 88 mmol) was added dropwise to a stirred solution of 4-methyl-2-[4-(trifluoromethyl)phenyl]pyridine (10.5 g, 44 mmol) in dry THF (300 ml) under N2, such that the internal temperature remained <−70° C. After 1 hour at this temperature, dimethyl carbonate (8.9 ml, 106 mmol) was added. After 30 minutes the cooling bath was removed. When the internal temperature had reached −20° C. the reaction was transferred to a cold bath at −10° C., and then allowed to warm slowly to 0° C. After 1 hour at 0° C. the reaction was quenched with aqueous NH4Cl (half saturated, 100 ml). The reaction mixture was concentrated in vacuo. The residue was diluted with H2O (200 ml) and extracted with EtOAc (2×200 ml). The combined extracts were washed with brine (×1), then dried (MgSO4), filtered and evaporated. The residue was purified by chromatography on silica, eluting with 10-30% EtOAc/isohexane to give the ester (9.2 g, 71%) as a pale yellow liquid. 1H NMR (400 MHz, CDCl3) δ: 3.72 (2H, s), 3.75 (3H, s), 7.24 (1H, dd, J 1.4, 5.0), 7.72 (3H, t, J 8.4), 8.11 (2H, d, J 8.2), 8.68 (1H, d, J 5.0).
Reaction SMILES: C(NC1S[C:7]([S:11]([NH:14][CH2:15][C@@H:16]([C:42]([OH:44])=[O:43])[NH:17][C:18](=[O:41])[C:19]2[CH:24]=[CH:23][C:22]([C:25]([NH:27][C@@H:28]([C:30]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH:33]=[CH:32][CH:31]=3)[CH3:29])=[O:26])=[CH:21][C:20]=2[Cl:40])(=[O:13])=[O:12])=[C:8]([CH3:10])N=1)(=O)C.[CH3:45]C1C=C(C(N[C@@H](C2C3C(=CC=CC=3)C=CC=2)C)=O)C=C(C)C=1C(N[C@H](C(O)=O)CNC(C1SC=CC=1)=O)=O.BrC1C=C(C(N[C@@H](C2C3C(=CC=CC=3)C=CC=2)C)=O)C=CC=1C(N[C@H](C(O)=O)CNC(C1SC=CC=1)=O)=O.ClC1C=C(C(N[C@@H](C2C3C(=CC=CC=3)C=CC=2)C)=O)C=C(Cl)C=1C(N[C@H](C(O)=O)CNC(C1SC=CC=1)=O)=O>>[CH2:7]([S:11]([NH:14][CH2:15][C@@H:16]([C:42]([OH:44])=[O:43])[NH:17][C:18](=[O:41])[C:19]1[CH:24]=[CH:23][C:22]([C:25]([NH:27][C@@H:28]([C:30]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:33]=[CH:32][CH:31]=2)[CH3:29])=[O:26])=[CH:21][C:20]=1[Cl:40])(=[O:12])=[O:13])[CH2:8][CH2:10][CH3:45]
Reactant: CC(=O)Nc1nc(C)c(S(=O)(=O)NC[C@H](NC(=O)c2ccc(C(=O)N[C@H](C)c3cccc4ccccc34)cc2Cl)C(=O)O)s1
Reactant: Cc1cc(C(=O)N[C@H](C)c2cccc3ccccc23)cc(C)c1C(=O)N[C@@H](CNC(=O)c1cccs1)C(=O)O
Agent: C[C@@H](NC(=O)c1cc(Cl)c(C(=O)N[C@@H](CNC(=O)c2cccs2)C(=O)O)c(Cl)c1)c1cccc2ccccc12
Agent: C[C@@H](NC(=O)c1ccc(C(=O)N[C@@H](CNC(=O)c2cccs2)C(=O)O)c(Br)c1)c1cccc2ccccc12
Product: CCCCS(=O)(=O)NC[C@H](NC(=O)c1ccc(C(=O)N[C@H](C)c2cccc3ccccc23)cc1Cl)C(=O)O

Procedure:
3-[(2-acetamido-4-methylthiazol-5-yl)sulfonyl]amino-N-[2-chloro-4-[[[(1R)-1-(1-naphthalenyl)ethyl]amino]carbonyl]benzoyl]-L-alanine; N-[2,6-dimethyl-4-[[[(1R)-1-(1-naphthalenyl)ethyl]amino]carbonyl]benzoyl]-3-(thiophene-2-carbonyl)amino-L-alanine; N-[2-bromo-4-[[[(1R)-1-(1-naphthalenyl)ethyl]amino]carbonyl]benzoyl]-3-(thiophene-2-carbonyl)amino-L-alanine), and N-[2,6-dichloro-4-[[[(1R)-1-(1-naphthalenyl)ethyl]amino]carbonyl]benzoyl]-3-[(thiophene-2-carbonyl)amino]-L-alanine;
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:7]=[C:6]2[CH2:19][C:20]([NH2:22])=[O:21].B(Br)(Br)Br.C(Cl)Cl.Cl>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:7]=[C:6]2[CH2:19][C:20]([NH2:22])=[O:21]
Reactant: COc1ccc2c(c1)c(CC(N)=O)cn2Cc1ccccc1
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Product: NC(=O)Cc1cn(Cc2ccccc2)c2ccc(O)cc12
Yield: 89.9 %

Procedure:
A solution of 375 mg (1.23 mmol) of 5-methoxy-1-(phenylmethyl)-1H-indole-3-acetamide (Example 3) and 5 mL of 1M BBr3/methylene chloride in 75 mL of methylene chloride was stirred for 1.25 hours, and poured into 1N HCl. The methylene chloride layer was separated, washed with brine and dried (Na2SO4). The solvent was removed at reduced pressure to give as residue 310 mg (90% yield) of 5-hydroxy-1-(phenylmethyl)-1H-indole-3-acetamide, mp, 158-160° C.
Reaction SMILES: [CH3:1][N:2]([CH2:45][C:46](O)=[O:47])[C:3](=[O:44])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=[O:43])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:14][C:13]=2[C:24]2[CH:29]=[C:28]([C:30](=[O:42])[NH:31][C@@H:32]3[C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[CH2:35][CH2:34][CH2:33]3)[CH:27]=[CH:26][N:25]=2)[CH:5]=1.CCN=C=NCCCN(C)C.Cl.[N:61]1([CH2:67][CH2:68][O:69][CH2:70][CH2:71][OH:72])[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]1>ClCCl.CN(C)C1C=CN=CC=1>[OH:72][CH2:71][CH2:70][O:69][CH2:68][CH2:67][N:61]1[CH2:66][CH2:65][N:64]([C:46](=[O:47])[CH2:45][N:2]([CH3:1])[C:3](=[O:44])[C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)=[CH:14][C:13]=3[C:24]3[CH:29]=[C:28]([C:30](=[O:42])[NH:31][C@@H:32]4[C:41]5[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=5)[CH2:35][CH2:34][CH2:33]4)[CH:27]=[CH:26][N:25]=3)=[O:43])[CH:5]=2)[CH2:63][CH2:62]1
Reactant: CN(CC(=O)O)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Reactant: OCCOCCN1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CN(CC(=O)N1CCN(CCOCCO)CC1)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.2 %

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of (S)-2-(N-methyl-3-(4-(piperidin-1-yl)-2-(4-(1,2,3,4-tetrahydronaphthalen-1-ylcarbamoyl)pyridin-2-yl)phenylcarbamoyl)benzamido)acetic acid (200 mg, 0.31 mmol, 1.00 equiv) in dichloromethane (10 mL), EDC.HCl (113 mg, 0.59 mmol, 1.90 equiv), 4-dimethylaminopyridine (80 mg, 0.65 mmol, 2.11 equiv), 2-(2-(piperazin-1-yl)ethoxy)ethanol (103 mg, 0.59 mmol, 1.91 equiv). The resulting solution was stirred overnight at room temperature. The resulting solution was diluted with 30 mL of dichloromethane. The resulting mixture was washed with 2×30 mL of NH4Cl.aq. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product (200 mg) was purified by Prep-HPLC with the following conditions (1#-Waters 2767-3): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (23% CH3CN up to 34% in 6 min); Detector, Waters2545 UvDector 254&270 nm. 57.6 mg product was obtained. This resulted in 57.6 mg (23%) of (S)—N1-(2-(4-(2-(2-hydroxyethoxy)ethyl)piperazin-1-yl)-2-oxoethyl)-N1-methyl-N3-(4-(piperidin-1-yl)-2-(4-(1,2,3,4-tetrahydronaphthalen-1-ylcarbamoyl)pyridin-2-yl)phenyl)isophthalamide as a yellow solid. LC-MS (ES, m/z): 802 [M+H]+ H-NMR (300 MHz, DMSO, ppm): 12.38 (s, 1H), 9.94 (s, 1H), 9.21˜9.19 (d, J=8.4 Hz, 1H), 8.95˜8.90 (m, 1H), 8.00˜7.95 (m, 2H), 7.87˜7.84 (m, 3H), 7.67˜7.54 (m, 3H), 7.30˜7.13 (m, 5H), 5.27˜5.25 (m, 1H), 3.79˜3.69 (m, 3H), 3.57˜3.11 (m, 16H), 3.00˜2.92 (m, 4H), 2.78 (s, 2H), 2.00 (s, 2H), 1.85˜1.79 (m, 6H), 1.55 (s, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15]O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CS(Cl)(=O)=O.[F:29][C:30]1[CH:39]=[CH:38][C:33]2[N:34]=[C:35]([SH:37])[NH:36][C:32]=2[CH:31]=1.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>C1COCC1.CN(C)C1C=CN=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][S:37][C:35]2[NH:36][C:32]3[CH:31]=[C:30]([F:29])[CH:39]=[CH:38][C:33]=3[N:34]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Fc1ccc2nc(S)[nH]c2c1
Reactant: CC(C)(C)OC(=O)N1CCN(CCO)CC1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(CCSc2nc3ccc(F)cc3[nH]2)CC1
Temperature: 25 °C
Yield: 73.4 %

Procedure:
1-tert-Butoxycarbonyl-4-(2-hydroxyethyl)piperazine (6.00 g, 26.05 mmol) was dissolved in THF (36 mL), and triethylamine (3.43 g, 33.90 mmol) and 4-dimethylaminopyridine (159 mg, 1.30 mmol) were added thereto. Under cooling with ice, a solution of methanesulfonyl chloride (3.58 g, 31.25 mmol) in THF (9 mL) was added dropwise to the mixture. The resultant mixture was stirred for one hour and then filtrated, and the filtrate was concentrated under reduced pressure. The residue was dissolved in DMF (90 mL). While the solution was stirred at room temperature, 5-fluoro-2-mercaptobenzimidazole (4.82 g, 28.66 mmol), potassium carbonate (5.40 g, 39.07 mmol), and 18-crown-6 (688 mg, 2.60 mmol) were sequentially added to the solution, and the resultant mixture was stirred for two hours at 80° C. The reaction mixture was concentrated under reduced pressure, and water was added to the residue, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over sodium sulfate anhydrate, followed by concentration under reduced pressure. The residue was purified through silica gel column chromatography (silica gel 150 g, hexane:ethyl acetate=2:1 to 1:1 to 1:2), to thereby yield 1-tert-butoxycarbonyl-4-[2-(5-fluorobenzimidazol-2-ylthio)ethyl]piperazine (7.28 g, yield 73%).
Reaction SMILES: [NH:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:2]([C:4]([OH:6])=O)[CH3:3].ClC(OCC(C)C)=O.Cl.[NH2:23][C@H:24]([C:35]([OH:37])=[O:36])[CH2:25][CH2:26][CH2:27][NH:28][C:29](=[NH:34])[NH:30][N+:31]([O-:33])=[O:32]>CN(C=O)C>[NH:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:2]([C:4]([NH:23][C@H:24]([C:35]([OH:37])=[O:36])[CH2:25][CH2:26][CH2:27][NH:28][C:29](=[NH:34])[NH:30][N+:31]([O-:33])=[O:32])=[O:6])[CH3:3]
Reactant: N=C(NCCC[C@H](N)C(=O)O)N[N+](=O)[O-]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)O
Yield: 70.3 %

Procedure:
After 15.9 g (0.084 mole) of BOC-Ala-OH was dissolved in 84 ml of DMF, 10.9 ml (0.084 mole) of NEM was added to the solution. Then, 10.9 ml (0.084 mole) of isobutyl chloroformate was dropwise added to the solution at -20° C. The resulting mixture was reacted for 10 minutes. After completion of the reaction, 84 ml of a solution of 32.8 g (0.084 mole) of HCl.H-Arg(NO2)-CHA and 32.8 ml (0.252 mole) of NEM in DMF was dropwise added to the reaction solution at -15° to -10° C. After the dropwise addition, the mixture was reacted at the same temperature for 23 hours and further at room temperature (15° to 20° C.) for 18 hours. After the reaction, DMF was removed by distillation under reduced pressure and the residue was dissolved in 600 ml of AcOEt. After washing 3 times with 200 ml of cold 5% hydrochloric acid and twice with 200 ml of saturated sodium chloride aqueous solution, the solution was dried over anhydrous magnesium sulfate and decolored with activated charcoal. After drying, magnesium sulfate and activated charcoal were filtered off and the solvent was removed by distillation under reduced pressure. Recrystallization of the residue gave 31.0 g (70.3%) of BOC-Ala-Arg(NO2)-CHA.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]([O:18][CH3:19])=[CH:8][CH:9]=[C:10]([C:11]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[O:12])[C:5]=2[O:4][C:3]=1C(O)=O.N1C2C(=CC=CC=2)C=CC=1.Cl>[Cu].C(Cl)(Cl)Cl>[CH3:1][C:2]1[C:6]2[C:7]([O:18][CH3:19])=[CH:8][CH:9]=[C:10]([C:11]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[O:12])[C:5]=2[O:4][CH:3]=1
Reactant: COc1ccc(C(=O)c2cccs2)c2oc(C(=O)O)c(C)c12
Agent: [Cu]
Agent: Cl
Solvent: c1ccc2ncccc2c1
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(=O)c2cccs2)c2occ(C)c12
Temperature: 210 °C
Reaction time: 0.08 h

Procedure:
An intimate mixture of compound 2 (3.50 g, 11.0 mmol), quinoline (7 mL), and copper powder (0.70 g, 11.0 mol) was carefully heated to 210° C. and maintained at that temperature until gas evolution ceased (about 10 minutes). The resulting mixture was cooled to 80° C. and poured into 1N HCl (120 mL). Chloroform (50 mL) was added and the mixture stirred for 5 minutes and filtered through a pad of celite. The pad was washed with an additional portion of chloroform (25 mL). The organic layer was separated and the aqueous layer extracted with additional portions of chloroform (2×50 mL). The combined organic extracts were dried (Na2SO4) and concentrated. The crude product was purified by preparative HPLC using 15% ethyl acetate in hexane as eluant to afford 3-methyl-4-methoxy-7-(2-thienoyl)benzofuran. mp 131°-134° C.; 1H NMR d 2.40 (3H, d, J=1 Hz), 4.02 (3H, s), 6.71 (1H, d, J=8 Hz), 7.17 (1H, m), 7.38 (1H, d, J=1 Hz), 7.70 (3H, m).
Reaction SMILES: [F:1][C:2]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:3]=1[CH2:4][N:5]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:6](=[O:27])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][CH2:16][C:17]2[CH:26]=[CH:25][CH:24]=[CH:23][C:18]=2[C:19]([O:21]C)=[O:20])=[CH:11][CH:10]=1.[OH-].[K+].CCOC(C)=O>CCO>[F:1][C:2]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:3]=1[CH2:4][N:5]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:6](=[O:27])[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([S:15][CH2:16][C:17]2[CH:26]=[CH:25][CH:24]=[CH:23][C:18]=2[C:19]([OH:21])=[O:20])=[CH:13][CH:14]=1
Reactant: CCCCCCCN(Cc1ccc(F)cc1F)C(=O)CCc1ccc(SCc2ccccc2C(=O)OC)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCCCCCCN(Cc1ccc(F)cc1F)C(=O)CCc1ccc(SCc2ccccc2C(=O)O)cc1
Yield: 94.1 %

Procedure:
Methyl 2-{[(4-{3-[(2,4-difluorobenzyl)(heptyl)amino]-3-oxopropyl}phenyl)thio]methyl}benzoate (1.05 g, 1.89 mmol) was dissolved in EtOH (95%, 5 ml), potassium hydroxide (0.21 g, 3.77 mmol) was added. The reaction was performed in a single node microwave oven (7 min, 150° C.). Workup was by addition of EtOAc (5 ml) and washing with HCl (2×5 ml, 1M). The organic layer was dried (MgSO4) and the solvent was removed by evaporation to give 0.96 gram of 2-{[(4-{3-[(2,4-difluorobenzyl)(heptyl)amino]-3-oxopropyl}phenyl)thio]methyl}benzoic acid (yield 94.3%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH:11][C:12](=[O:20])OC2C=CC=CC=2)[N:2]=1.[CH3:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]2[C:33]([CH2:34][NH2:35])=[CH:32][CH:31]=[C:30]([C:36]([F:39])([F:38])[F:37])[N:29]=2)[CH2:24][CH2:23]1.C(N(CC)CC)C>CS(C)=O.O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH:11][C:12]([NH:35][CH2:34][C:33]2[C:28]([N:25]3[CH2:26][CH2:27][CH:22]([CH3:21])[CH2:23][CH2:24]3)=[N:29][C:30]([C:36]([F:39])([F:37])[F:38])=[CH:31][CH:32]=2)=[O:20])[N:2]=1
Reactant: O=C(Nc1cc2ccccc2cn1)Oc1ccccc1
Reactant: CC1CCN(c2nc(C(F)(F)F)ccc2CN)CC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC1CCN(c2nc(C(F)(F)F)ccc2CNC(=O)Nc2cc3ccccc3cn2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 77.1 %

Procedure:
Phenyl isoquinolin-3-ylcarbamate (100 mg, 0.38 mmol) and (2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methanamine (109 mg, 0.40 mmol) was dissolved in dimethyl sulfoxide. Then triethylamine (0.11 mL, 0.76 mmol) was added to it. The mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure. The crude was purified by column chromatography to give 1-(isoquinolin-3-yl)-3-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)urea (example compound 21) (130 mg, 77%).
Reaction SMILES: [CH3:1][CH2:2][C@:3]12[CH2:19][CH2:18][C@H:17]3[C@@H:8]([CH2:9][CH2:10][C:11]4[C@@H:16]3[CH2:15][CH2:14][CH2:13][CH:12]=4)[C@@H:7]1[C@@H:6]([O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1)[CH2:5][C@@H:4]2[OH:27].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.C([O-])(=O)C.[Na+]>C(Cl)Cl>[CH3:1][CH2:2][C@:3]12[CH2:19][CH2:18][C@H:17]3[C@@H:8]([CH2:9][CH2:10][C:11]4[C@@H:16]3[CH2:15][CH2:14][CH2:13][CH:12]=4)[C@@H:7]1[C@@H:6]([O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1)[CH2:5][C:4]2=[O:27]
Reactant: CC[C@]12CC[C@H]3[C@@H](CCC4=CCCC[C@@H]43)[C@@H]1[C@@H](OC1CCCCO1)C[C@@H]2O
Agent: O=[Cr](=O)([O-])Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC[C@]12CC[C@H]3[C@@H](CCC4=CCCC[C@@H]43)[C@@H]1[C@@H](OC1CCCCO1)CC2=O
Reaction time: 3.5 h
Yield: 61.9 %

Procedure:
At 0° C., 2.6 g of 18-methyl-15α-tetrahydropyran-2-yloxy-4-estren-17β-ol in 50 ml of methylene chloride is stirred with 3.6 g of pyridinium chlorochromate and 1.2 g of sodium acetate at 0° C. After 3.5 hours, the mixture is diluted with methylene chloride, washed with water, and dried. Chromatography of the crude product on silica gel with 3-3.5% acetone/hexane yields 1.6 g of 18-methyl-15α-tetrahydropyran-2-yloxy-4-estren-17-one as an oil. [α]D20 =+87.4°.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:10]([CH3:18])=[N:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH3:19][N:20]([CH3:24])[C:21]([NH2:23])=[O:22].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:19][N:20]([CH3:24])[C:21]([NH:23][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:10]([CH3:18])=[N:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1)=[O:22]
Reactant: Cc1nc([N+](=O)[O-])ccc1Oc1ccnc(Cl)c1
Reactant: CN(C)C(N)=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1nc([N+](=O)[O-])ccc1Oc1ccnc(NC(=O)N(C)C)c1
Temperature: 100 °C

Procedure:
A solution of Example A3 (8.0 g, 30 mmol) in dioxane (150 mL) was sparged with Ar under sonication for 20 min, treated with N,N-dimethylurea (10.6 g, 120 mmol), XANTPHOS (3.48 g, 6.02 mmol), and Cs2CO3 (1.226 g, 3.76 mmol), sparged with Ar under sonication for 30 min, treated with Pd2(dba)3 (2.76 g, 3.01 mmol), sparged again with Ar under sonication for 30 min and heated at 100° C. overnight. The mixture was cooled to RT and diluted with EtOAc. The solids were removed via filtration through diatomaceous earth and washed with EtOAc. The filtrates were concentrated to dryness. The residue was partitioned into EtOAc and water. The aqueous layer was back-extracted with EtOAc (3×) and the combined organics were dried (Na2SO4) and concentrated. MeCN was added and the mixture was sonicated. The solids were collected by filtration to provide 1,1-dimethyl-3-(4-((2-methyl-6-nitropyridin-3-yl)oxy)pyridin-2-yl)urea, crop 1. The filtrate was concentrated to dryness. Fresh MeCN was added and the mixture was again sonicated. The solids were collected by filtration to provide 1,1-dimethyl-3-(4-((2-methyl-6-nitropyridin-3-yl)oxy)pyridin-2-yl)urea, crop 2. The filtrate was concentrated in vacuo and purified via silica gel chromatography (MeOH/EtOAc) to afford 1,1-dimethyl-3-(4-((2-methyl-6-nitropyridin-3-yl)oxy)pyridin-2-yl)urea, crop 3. Crops 1-3 of 1,1-dimethyl-3-(4-((2-methyl-6-nitropyridin-3-yl)oxy)pyridin-2-yl)urea were combined (5.2 g, 54%). MS (ESI) m/z: 288.1 (M+H+).
Reaction SMILES: Br[CH:2]([F:21])[C:3]([NH:5][C:6]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=O)=[O:4].[NH2:22]C1C=CC(Cl)=CC=1C(C1C=CC=CC=1)=O.BrC(F)C(Br)=O.N>CCOCC>[F:21][CH:2]1[N:22]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]2[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:6]=2[NH:5][C:3]1=[O:4]
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1NC(=O)C(F)Br
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Agent: N
Agent: O=C(Br)C(F)Br
Solvent: CCOCC
Product: O=C1Nc2ccc(Cl)cc2C(c2ccccc2)=NC1F
Reaction time: 18 h

Procedure:
A solution of 3.71 g. of 2-(α-bromo-α-fluoro-acetamido)-5-chlorobenzophenone, obtainable from 2-amino-5-chlorobenzophenone and α-bromo-α-fluoroacetyl bromide, in 100 ml. of ether and 60 ml. of 13% methanolic NH3 is allowed to stand for 18 hours at 20° and is evaporated. Working up in the customary manner, using water/methylene chloride, gives 3-fluoro-5-phenyl-7-chloro-2,3-dihydro-1H-1,4-benzodiazepin-2-one.