Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([CH3:12])[CH:10]=2)[CH:5]=[C:4]([C:13]2[CH:14]=[C:15]([CH:21]=[CH:22][C:23]=2[CH3:24])[C:16]([N:18]=[C:19]=[O:20])=[O:17])[C:3]1=[O:25].[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)Cl>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([CH3:12])[CH:10]=2)[CH:5]=[C:4]([C:13]2[CH:14]=[C:15]([CH:21]=[CH:22][C:23]=2[CH3:24])[C:16]([NH:18][C:19](=[O:20])[NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:17])[C:3]1=[O:25]
Reactant: Nc1ccccc1
Reactant: Cc1cc2c(cn1)cc(-c1cc(C(=O)N=C=O)ccc1C)c(=O)n2C
Solvent: ClCCl
Product: Cc1cc2c(cn1)cc(-c1cc(C(=O)NC(=O)Nc3ccccc3)ccc1C)c(=O)n2C

Procedure:
3-(1,7-Dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-methylbenzoyl isocyanate 31 (10 mg, 0.03 mmol) is suspended in DCM at rt with aniline (3 mg, 0.3 mmol) for 1 h. Solvent is removed and the residue is purified by preparative LC/MS to give the desired product N1. 1H NMR (400 MHz, DMSO-d6) δ 11 (s, 1H), 10.8 (s, 1H), 8.99 (s, 1H), 8.1 (s, 1H), 8.01 (d, J=8 Hz, 1H), 7.95 (s, 1H), 7.69 (s, 1H), 7.59 (s, 1H), 7.57 (s, 1H), 7.48 (d, J=7.9 Hz, 1H), 7.36 (m, 2H), 7.12 (t, J=7 Hz, 1H), 2.7 (s, 3H), 2.51 (s, 3H), 2.25 (s, 3H); LC/MS (M+1, m/z): 427.2.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:27][CH2:28][C:29]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:30]=1[C:31](=[O:48])[N:32]([CH:40]1[CH2:45][CH2:44][C:43](=[O:46])[NH:42][C:41]1=[O:47])[C:33]([CH3:39])=[N:34]2>CN(C=O)C>[O:47]=[C:41]1[CH:40]([N:32]2[C:31](=[O:48])[C:30]3[C:35](=[CH:36][CH:37]=[CH:38][C:29]=3[CH2:28][NH:27][C:6](=[O:8])[C:5]3[CH:9]=[CH:10][CH:11]=[C:3]([C:2]([F:1])([F:13])[F:12])[CH:4]=3)[N:34]=[C:33]2[CH3:39])[CH2:45][CH2:44][C:43](=[O:46])[NH:42]1
Reactant: Cc1nc2cccc(CN)c2c(=O)n1C1CCC(=O)NC1=O
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: Cc1nc2cccc(CNC(=O)c3cccc(C(F)(F)F)c3)c2c(=O)n1C1CCC(=O)NC1=O
Reaction time: 1 h
Yield: 62.1 %

Procedure:
To a stirred solution of 3-trifluoromethyl-benzoic acid (0.28 g, 1.5 mmol) in DMF (8 mL) in a 40° C. oil bath, was added 1,1′carbonyldiimidazole (0.27 g, 1.6 mmol) and stirred for one hour. Then 3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.50 g, 1.5 mmol) was added and stirred for 15 minutes. The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-3-trifluoromethyl-benzamide as an off-white solid (440 mg, 62% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, grad. to 95/5 in 5 min, kept 5 min, 6.37 min (98.3%); mp, 233-235° C.; 1HNMR (DMSO-d6) 2.17-2.23 (m, 1H, CHH), 2.58-2.91 (m, 6H, CHCH2, CH3), 4.95-5.12 (m, 2H, CH2NH), 5.27 (dd, J=6, 11 Hz, 1H, CH), 7.36-8.27 (m, 7H, Ar), 9.23 (t, J=5 Hz, 1H, CH2NH), 11.05 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.79, 23.29, 30.60, 42.29, 56.52, 117.68, 123.85 (q, JC-F=3 Hz), 123.98 (d, JC-F3=273 Hz), 124.15, 125.53, 127.90 (d, JC-F=3 Hz), 129.19 (d, JC-F=32 Hz), 129.72, 131.37, 133.97, 135.05, 140.50, 148.50, 154.86, 161.07, 164.85, 169.54, 172.62. LCMS MH=473; Anal Calcd For C23H19N4O4F3: C, 58.48; H, 4.05; N, 11.86; F, 12.06. Found: C, 58.19; H, 3.84; N, 11.86; F, 12.00.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3=[CH:12][C:13]4[CH:14]=[CH:15][C:16]([C:19]([O:21]C)=[O:20])=[CH:17][C:18]=4[N:9]3[CH2:8][CH:7]=[CH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.N1(C(=O)C)CCNCC1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[CH:1]1[C:11]2[C:10]3=[CH:12][C:13]4[CH:14]=[CH:15][C:16]([C:19]([OH:21])=[O:20])=[CH:17][C:18]=4[N:9]3[CH2:8][CH:7]=[CH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH:1]1[C:11]2[C:10]3=[CH:12][C:13]4[CH:14]=[CH:15][C:16]([C:19]([OH:21])=[O:20])=[CH:17][C:18]=4[N:9]3[CH:8]=[CH:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc2cc3n(c2c1)CC=Cc1ccccc1-3
Agent: CC(=O)N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(O)c1ccc2cc3n(c2c1)C=CCc1ccccc1-3
Product: O=C(O)c1ccc2cc3n(c2c1)CC=Cc1ccccc1-3
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of methyl 7H-indolo[2,1-a][2]benzazepine-10-carboxylate, 13-cyclohexyl, 6-carboxylic acid (830 mg, 2.0 mmol), 1-(piperazin-1-yl)ethanone (310 mg, 2.4 mmol) and triethylamine (0.85 mL) in DMF (8 mL) was added HATU (910 mg, 2.4 mmol). The reaction mixture was stirred at rt for 2 h, diluted with H2O (˜15 mL) and the solids were collected by filtration washed with H2O and dried under vacuum overnight to yield 7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-6-[[4-(acetyl)-1-piperazinyl]carbonyl]-, methyl ester (1.19 g, 2.3 mmol, quant.) as a yellow solid. LCMS: m/e 526 (M+H)+, ret time 2.96 min, column B, 3 minute gradient.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:12](=[O:17])[CH2:13][C:14](=O)[CH3:15])[CH:9]=2)[NH:4][N:3]=1.[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1.[NH2:27][C:28]([NH2:30])=[O:29].[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>CC#N>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:12]([C:13]3[CH:23]([C:22]4[CH:25]=[CH:26][C:19]([F:18])=[CH:20][CH:21]=4)[NH:27][C:28](=[O:29])[NH:30][C:14]=3[CH3:15])=[O:17])[CH:9]=2)[NH:4][N:3]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: NC(N)=O
Reactant: CC(=O)CC(=O)Nc1ccc2[nH]nc(Br)c2c1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CC#N
Product: CC1=C(C(=O)Nc2ccc3[nH]nc(Br)c3c2)C(c2ccc(F)cc2)NC(=O)N1
Temperature: 100 °C
Yield: 8.1 %

Procedure:
The product of Step (c) (330 mg, 1.11 mmol, 1 equiv), 4-fluorobenzaldehyde (120 uL, 1.13 mmol, 1.00 equiv), urea (100 mg, 1.67 mmol, 1.67 equiv), and Ytterbium triflate (70 mg, 0.12 mmol, 0.10 equiv) were combined in CH3CN (6 mL). The reaction vessel was sealed and heated to 100° C. for 18 hours. The reaction was cooled to room temperature and the precipitate was collected by filtration. The solid was washed with Et2O/CH3CN several times, then purified by preparative LC-MS to afford 40 mg (8%) of a white solid. 1H NMR (400 MHz, d6-DMSO) 13.3 (s, 1H), 9.69 (s, 1H), 8.77 (s, 1H), 7.96 (s, 1H), 7.62 (m, 1H), 7.48 (s, 2H), 7.35 (m, 2H), 7.17 (m, 2H), 5.43 (m, 1H), 2.07 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[C:7](O)=O.[CH3:10][NH:11][C:12](=[S:15])[NH:13][NH2:14].CCN(C(C)C)C(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CN(C=O)C.CCOC(C)=O>[CH3:10][N:11]1[C:7]([C:6]2[O:5][CH:4]=[N:3][C:2]=2[CH3:1])=[N:14][NH:13][C:12]1=[S:15]
Reactant: CNC(=S)NN
Reactant: Cc1ncoc1C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ncoc1-c1n[nH]c(=S)n1C
Temperature: 20 °C
Reaction time: 6 h

Procedure:
4-Methyl-1,3-oxazole-5-carboxylic acid (commercially available) (12.9 g, 101.5 mmol) was dissolved in DMF (60 mL) and treated with 4-methyl-3-thiosemicarbazide (11.61 g, 1.10 eq). Then DIPEA (31.0 mL, 1.75 eq) was added at 20° C. Under ice bath cooling, T3P 50% w/w in EtOAc (90 mL) was added dropwise, maintaining the temperature below 15° C. over 20 minutes. The resulting mixture was then stirred at 20° C. for 6 hours.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[CH2:5]([C:7]1[CH2:12][CH2:11][C:10](=[O:13])[CH2:9][CH:8]=1)[CH3:6].O>CCOCC>[CH2:1]([C:10]1([OH:13])[CH2:11][CH2:12][C:7]([CH2:5][CH3:6])=[CH:8][CH2:9]1)[CH3:2]
Reactant: CC[Mg]Br
Reactant: CCC1=CCC(=O)CC1
Solvent: CCOCC
Solvent: O
Product: CCC1=CCC(O)(CC)CC1

Procedure:
To a stirred solution of 35 ml of 3.2M ethereal ethyl magnesium bromide (Aldrich) in 75 ml of dry ether was added dropwise at gentle reflux a solution of 10.0 g of 4-ethyl-3-cyclohexen-1-one in 25 ml of ether. After one hour longer at reflux, the mixture was cooled and treated dropwise with 80 ml of water. The aqueous layer was extracted with ether and the combined ether layers was dried, concentrated, and Claisen-distilled to give 7.3 g of the desired product, b.p. 82°-86° C. (5 mm.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[C:5]([N:7]([CH2:9][C@H:10]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[CH2:11][CH:12]=C)[CH3:8])=[O:6].C[N+]1([O-])CC[O:32]CC1.OS([O-])=O.[Na+]>CC(C)=O.O.O=[Os](=O)(=O)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[C:5]([N:7]([CH2:9][C@H:10]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[CH2:11][CH:12]=[O:32])[CH3:8])=[O:6]
Reactant: C=CC[C@H](CN(C)C(=O)c1cc(Br)cc(C(F)(F)F)c1)c1ccc(F)cc1
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CN(C[C@@H](CC=O)c1ccc(F)cc1)C(=O)c1cc(Br)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
To a solution of 3-bromo-N-[(2S)-2-(4-fluorophenyl)pent-4-en-1-yl]-N-methyl-5-(trifluoromethyl)benzamide (0.86 g, 1.9 mmol) in acetone (45 mL) were added OsO4 (2.5% in t-butyl alcohol, 0.49 mL, 0.039 mmol) and 4-methylmorpholine-4-oxide (0.41 g, 3.5 mmol). The solution was stirred under nitrogen at RT overnight and then an aqueous solution of NaHSO3 (39%, 45 mL) was added. The mixture was stirred for 2 h, diluted with water and then extracted twice with methylene chloride. The combined organic solutions were separated by means of a phase separator column and the solvent was removed by evaporation. The residue (1.08 g) was dissolved in THF (18 mL) and water (4.5 mL) and to the resultant solution was added NaIO4 (0.73 g, 3.4 mmol). The mixture was stirred under nitrogen overnight at RT. The mixture was partitioned between methylene chloride and water. The aqueous phase was extracted with methylene chloride and then the combined organic solutions were washed with brine and separated by means of a phase separator column. The solvent was removed by evaporation and there was obtained 0.78 g (90%) of the title compound. 1H NMR (500 MHz, CDCl3): 2.4-4.4 (cm, 8H), 6.8-7.8 (cm, 7H), 9.8 (s, 1H); LCMS: m/z 447 (M−1)+.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25](Cl)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:14])=[O:13])(C)(C)C.[NH:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]([CH2:40][CH2:41][NH2:42])=[CH:32]1>>[NH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:42][CH2:41][CH2:40][C:33]3[C:34]4[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=4)[NH:31][CH:32]=3)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:13])=[O:14]
Reactant: CC(C)(C)OC(=O)NCCCN(Cc1cccc(-c2ccnc(Cl)n2)c1)S(C)(=O)=O
Reactant: NCCc1c[nH]c2ccccc12
Product: CS(=O)(=O)N(CCCN)Cc1cccc(-c2ccnc(NCCc3c[nH]c4ccccc34)n2)c1

Procedure:
Intermediate 4 was coupled with 2-(1H-Indol-3-yl)-ethylamine following procedure F and the resulting product deprotected following procedure G. LC-MS showed the product had the expected M+H+ of 479. 1H NMR (Varian 300 MHz, CDCl3—CD3OD, shifts relative to the solvent peak at 7.24 ppm) 8.1 (m, 2H) 7.9 (m, 1H) 7.7 (d, 1H) 7.6 (m, 4H) 7.2 (m, 1H) 7.0 (m, 2H) 4.4 (d, 2H) 3.9 (m, 1H) 3.6 (m, 1H) 3.3 (m, 2H) 3.1 (m, 2H) 2.9 (m, 5H) 1.7 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:44]([NH2:45])=[CH:43][CH:42]=[CH:41][C:3]=1[C:4]([NH:6][C:7]1[CH:38]=[CH:37][C:10]([C:11]([N:13]([CH3:36])[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=2[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[O:28])=[O:12])=[CH:9][C:8]=1[O:39][CH3:40])=[O:5].[SH:46][CH2:47][C:48](O)=O>C(Cl)(Cl)Cl>[CH3:40][O:39][C:8]1[CH:9]=[C:10]([CH:37]=[CH:38][C:7]=1[NH:6][C:4]([C:3]1[C:2]2[N:1]=[C:48]([CH2:47][SH:46])[NH:45][C:44]=2[CH:43]=[CH:42][CH:41]=1)=[O:5])[C:11]([N:13]([CH3:36])[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=1[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([N:29]1[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]1)=[O:28])=[O:12]
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc(N)c1N
Reactant: O=C(O)CS
Solvent: ClC(Cl)Cl
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc2[nH]c(CS)nc12
Yield: 55 %

Procedure:
A solution of 4-(2,3-diaminobenzoyl)amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (100 mg) and mercaptoacetic acid (448 mg) was heated at 80° C. for 5 hours. The reaction mixture was diluted with chloroform and washed with aqueous sodium hydrogen carbonate. The extract was dried over sodium sulfate. After evaporation of the solvent, the residue was purified by silica gel column chromatography (10% methanol in chloroform) to give 3-methoxy-4-(2-mercaptomethyl-1H-benzimidazol-4-yl)carbonylamino-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (60 mg).
Reaction SMILES: [C:1]([C:3]1[C:8](OC)=[CH:7][C:6]([CH2:11][C:12]([OH:14])=[O:13])=[C:5](F)[CH:4]=1)#[N:2].C(OC(C)(C)C)(=O)CC(OC(C)(C)C)=O.[Br:31]C1C=C(C=CC=1F)C#N>>[Br:31][C:8]1[CH:7]=[C:6]([CH2:11][C:12]([OH:14])=[O:13])[CH:5]=[CH:4][C:3]=1[C:1]#[N:2]
Reactant: COc1cc(CC(=O)O)c(F)cc1C#N
Reactant: N#Cc1ccc(F)c(Br)c1
Agent: CC(C)(C)OC(=O)CC(=O)OC(C)(C)C
Product: N#Cc1ccc(CC(=O)O)cc1Br

Procedure:
(3-Bromo-4-cyanophenyl)acetic acid was prepared in a similar fashion to the previously described synthesis of (4-cyano-2-fluoro-5-methoxyphenyl)acetic acid starting from di-tert-butyl malonate and 3-bromo-4-fluorobenzonitrile. LC-MS (IE, m/z): 239, 241 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([F:23])[CH:20]=[C:21](Br)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([F:23])[CH:20]=[C:21]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[F:24])[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(F)cc(Br)c3O2)cc1
Reactant: OB(O)c1ccccc1F
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cc(F)cc(-c4ccccc4F)c3O2)cc1
Yield: 93.5 %

Procedure:
Treatment of (±)-(7-bromo-5-fluoro-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (2.00 g, 4.98 mmol) with 2-fluorophenyl boronic acid (1.05 g, 7.48 mmol), dichlorobis(tri-o-tolylphosphine)palladium(II) (0.196 g, 0.249 mmol), and potassium carbonate (1.72 g, 12.46 mmol) generally according to the procedure described for Intermediate 37 gave 1.94 g (94%) of (±)-[5-fluoro-7-(2-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a yellow oil. Rf=0.38 (silica, ethyl acetate:hexanes 3:17); Anal. calcd. for C22H18F2O4S: C, 63.45; H, 4.36. Found: C, 63.13; H, 4.19.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[C:10]#[C:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[NH2:21][NH2:22]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[NH:22][N:21]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: COc1ccc(C#CC(=O)c2cc(Cl)cc(Cl)c2)cc1
Reactant: NN
Solvent: CN(C)C=O
Product: COc1ccc(-c2cc(-c3cc(Cl)cc(Cl)c3)n[nH]2)cc1

Procedure:
To a solution of the intermediate from step A (1.13 g, 3.7 mmol) in DMF (20 mL) was added hydrazine (0.37 mL, 4.07 mmol, 35% aqueous solution). After 2 hours the reaction mixture was concentrated in vacuo. The residue was suspended in H2O (20 mL). A white precipitate crashed out. The aqueous layer was extracted with ethyl acetate (2×). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. An off-white solid was obtained. This material was used in the next step without any further purification. 1H NMR (CDCl3, 500 MHz): δ 7.7 (d, J=1.8 Hz, 2H), 7.66 (d, J=8.4 Hz, 2H), 7.35 (s, 1H), 7.03 (d, J=8.7 Hz, 2H), 6.8 (s, 1H), 3.91 (s, 3H). LC-MS: 2.92 min. (M+H)=319.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH2:13][C:14](=[O:16])[CH2:15][C:11]=2[C:10]([C:17]([OH:19])=[O:18])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[N:21]1[C:25](=[O:26])[CH2:24][CH2:23][C:22]1=[O:27].C(Cl)CCl>C(Cl)Cl>[O:27]=[C:22]1[CH2:23][CH2:24][C:25](=[O:26])[N:21]1[O:18][C:17]([C:10]1[C:11]2[CH2:15][C:14](=[O:16])[CH2:13][C:12]=2[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[N:9]=1)=[O:19]
Reactant: O=C1Cc2c(C(=O)O)nn(Cc3ccccc3)c2C1
Reactant: O=C1CCC(=O)N1O
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C1Cc2c(C(=O)ON3C(=O)CCC3=O)nn(Cc3ccccc3)c2C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of the intermediate from step C (1.34 g, 5.25 mmol) in CH2Cl2 (50 mL) was added N-hydroxy succinimide (1.21 g, 10.5 mmol) followed by EDC (2.01 g, 10.5 mmol). After stirring at room temperature for 18 hours, the reaction mixture was concentrated in vacuo. The residue was diluted with ethyl acetate (200 mL), washed with saturated NaHCO3, solution and brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. A yellow solid was obtained.
Reaction SMILES: C(C1NC=CN=1)(C1[NH:4]C=CN=1)=O.[C:13]([O:17][C:18]([N:20]([CH2:24][C:25]1[CH:34]=[C:33]2[C:28]([CH:29]=[CH:30][C:31]([Cl:39])=[C:32]2[CH2:35][C:36](O)=[O:37])=[CH:27][CH:26]=1)[CH2:21][CH2:22][F:23])=[O:19])([CH3:16])([CH3:15])[CH3:14].N>CN(C=O)C>[C:13]([O:17][C:18](=[O:19])[N:20]([CH2:24][C:25]1[CH:26]=[CH:27][C:28]2[C:33](=[C:32]([CH2:35][C:36](=[O:37])[NH2:4])[C:31]([Cl:39])=[CH:30][CH:29]=2)[CH:34]=1)[CH2:21][CH2:22][F:23])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)N(CCF)Cc1ccc2ccc(Cl)c(CC(=O)O)c2c1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Agent: N
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CCF)Cc1ccc2ccc(Cl)c(CC(N)=O)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Carbonyl diimidazole (95 mg, 0.58 mmol) was added at RT under an atmosphere of argon to a solution of (7-{[tert-butoxycarbonyl-(2-fluoro-ethyl)-amino]-methyl}-2-chloro-naphthalen-1-yl)-acetic acid (210 mg, 0.53 mmol) in DMF (2.0 ml). After 2 h at RT, concentrated aqueous ammonia (4.3 ml) is added, and the mixture is stirred for 15 minutes at RT. The emulsion is extracted with EtOAc. The organic layer is washed with brine and dried over Na2SO4. After concentration, the residue is purified by FCC (EtOAc) to yield the title compound. 1H NMR (d6-DMSO, 400 MHz): δ 1.38+1.46 (2x br s, 9H), 3.3-3.6 (br m, 2H), 4.08 (s, 2H), 4.40-4.65 (br m, 2H), 4.61 (s, 2H), 7.02 (br s, NH), 7.42 (br d, J=9 Hz, 1H), 7.48-7.58 (br m, 3H), 7.80-7.90 (br m, 2H), 7.95 (br d, J=9 Hz, 1H). ES+-MS: 412.3, 414.2 [M+H+H2O]+. ES−-MS: 393.3, 395.3 [M−H]−.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH:7]1[C:19]2[CH:18]([CH2:20][O:21][C:22]([N:24]3[CH2:28][CH2:27][CH2:26][C@H:25]3[C:29]([OH:31])=[O:30])=[O:23])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]=2[CH:10]=[CH:9][CH:8]=1.C(N(C(C)C)C(C)C)C.[C:41]([OH:46])(=[O:45])[C@H:42]([CH3:44])O>C(Cl)Cl.CN(C)C=O>[CH:16]1[C:17]2[CH:18]([CH2:20][O:21][C:22]([N:24]3[CH2:28][CH2:27][CH2:26][C@H:25]3[C:29]([O:31][C@@H:42]([CH3:44])[C:41]([OH:46])=[O:45])=[O:30])=[O:23])[C:19]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:12]=2[CH:13]=[CH:14][CH:15]=1
Reactant: C[C@H](O)C(=O)O
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@H](OC(=O)[C@@H]1CCCN1C(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Temperature: 0 °C
Yield: 71.3 %

Procedure:
Oxalyl chloride (2.34 mL, 26.7 mmol) was added dropwise to a solution of (S)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)pyrrolidine-2-carboxylic acid (Fmoc-Pro-OH) (6.00 g, 17.8 mmol) and N,N-dimethylformamide (69 μL, 0.889 mmol) in methylene chloride (71 mL) with stirring at 0° C. under a nitrogen atmosphere, and the reaction mixture was then stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, the resulting residue was mixed with methylene chloride (71 mL), N-ethyldiisopropylamine (DIPEA) (46.6 mL, 267 mmol) and L-(+)-lactic acid (24.0 g, 267 mmol) at 0° C., and the reaction mixture was stirred at room temperature for 2 hours. The reaction solution was washed with 1 N hydrochloric acid twice and a saturated aqueous sodium chloride solution twice, dried over sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by reverse-phase silica gel column chromatography (0.1% aqueous formic acid solution/0.1% formic acid-acetonitrile solution) to afford (S)-2-(((S)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)pyrrolidine-2-carbonyl)oxy)propanoic acid (Fmoc-Pro-Lac-OH) (Compound SP633) (5.2 g, 12.7 mmol, 71%).
Reaction SMILES: FC1C=CC(C2CC(O)C3C(=CC=C(O)C=3)O2)=CC=1.[OH:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[O:27][CH:26]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([OH:37])[CH:32]=1)[CH2:25][C:24]2=[O:38]>>[OH:37][C:33]1[CH:32]=[C:31]([CH:26]2[CH2:25][CH:24]([OH:38])[C:23]3[C:28](=[CH:29][CH:30]=[C:21]([OH:20])[CH:22]=3)[O:27]2)[CH:36]=[CH:35][CH:34]=1
Reactant: O=C1CC(c2cccc(O)c2)Oc2ccc(O)cc21
Agent: Oc1ccc2c(c1)C(O)CC(c1ccc(F)cc1)O2
Product: Oc1cccc(C2CC(O)c3cc(O)ccc3O2)c1

Procedure:
2-(3-Hydroxyphenyl)chroman-4,6-diol was prepared as described for 2-(4-fluorophenyl)chroman-4,6-diol in Example 2(b) but starting from 6-hydroxy-2-(3-hydroxyphenyl)chroman-4-one. 1H NMR (400 MHz, d6-DMSO) δ: 9.43 (bs, 1H), 8.88 (bs, 1H), 7.19-7.15 (m, 1H), 6.87 (d, 1H, J 2.7 Hz), 6.84-6.82 (m, 2H), 6.72-6.69 (m, 1H), 6.58 (d, 1H, J 8.7 Hz), 6.53 (dd, 1H, J 2.7, 8.7), 5.01 (d, 1H, J 11.3 Hz), 4.86 (dd, 1H, J 6.2, 10.8 Hz), 2.25-2.19 (m, 1H), 1.88-1.75 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][N:7]2[C:13](=[O:14])[C@H:12]3[CH2:15][CH2:16][CH2:17][C@H:11]3[N:10]([C:18](=[O:31])[CH2:19][N:20]3[C:24](=[O:25])[C:23]4=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]4[C:21]3=[O:30])[C:9]3[CH:32]=[CH:33][CH:34]=[CH:35][C:8]2=3)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:45](Cl)(=[O:48])[CH2:46][CH3:47]>ClCCl.O>[C:21]1(=[O:30])[N:20]([CH2:19][C:18]([N:10]2[C@@H:11]3[CH2:17][CH2:16][CH2:15][C@@H:12]3[C:13](=[O:14])[N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:45](=[O:48])[CH2:46][CH3:47])=[CH:37][CH:36]=3)[C:8]3[CH:35]=[CH:34][CH:33]=[CH:32][C:9]2=3)=[O:31])[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]12
Reactant: Nc1ccc(CN2C(=O)[C@H]3CCC[C@H]3N(C(=O)CN3C(=O)c4ccccc4C3=O)c3ccccc32)cc1
Reactant: CCC(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)Nc1ccc(CN2C(=O)[C@H]3CCC[C@H]3N(C(=O)CN3C(=O)c4ccccc4C3=O)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 79.3 %

Procedure:
To a suspension of (3aR*,10aS*)-9-(4-aminobenzyl)-4-(phthalimidoacetyl)-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta[e][l,4]diazepin-10(1H)-one (148 mg, 0.3 mmol) and triethylamine (50 μL, 0.36 mmol) in dichloromethane (3 mL) was added propionyl chloride (28 μL, 0.33 mmol) and the mixture was stirred at room temperature for 10 minutes. This reaction mixture was diluted with water and stirred. The aqueous layer was separated and the organic layer was dried over NaSO4 and concentrated under reduced pressure. The residue was crystallized from dichloromethane-ethanol-diethyl ether to provide 131 mg (yield 79%) of the title compound. m.p. 286.0°-286.5° C.