Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:13].BrC1C=CC(F)=C2C=1CC[C@@H]2O>CCCCCC.C(O)C>[Br:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C@@H:6]2[OH:13]
Reactant: N#Cc1ccc2c(c1Br)CCC2=O
Agent: O[C@H]1CCc2c(Br)ccc(F)c21
Solvent: CCO
Solvent: CCCCCC
Product: N#Cc1ccc2c(c1Br)CC[C@@H]2O

Procedure:
The compound is synthesized from 4-bromo-1-oxo-indan-5-carbonitrile (2.20 g, 5.1 mmol) in analogy to the preparation of intermediate 2 (Yield 1.30 g). GC (METHOD 1): tR=11.59 min; Mass spectrum (EI+): m/z=237 [M]+, e.e. 98% by chiral HPLC (Column: Daicel Chiralpak OJ-H, 4.6×250 mm, 5 μm Mobile phase: hexane:ethanol 95:5, 1 mL/min, 25° C.) tR=37.52 min.
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([Cl:11])=[CH:6][C:5]=1[NH:12][S:13]([C:16]1[C:21]2=[N:22][S:23][N:24]=[C:20]2[CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14].O[Li].O.Cl>C1COCC1.O>[N:24]1[S:23][N:22]=[C:21]2[C:16]([S:13]([NH:12][C:5]3[CH:6]=[C:7]([Cl:11])[C:8]([Cl:10])=[CH:9][C:4]=3[C:3]([OH:25])=[O:2])(=[O:15])=[O:14])=[CH:17][CH:18]=[CH:19][C:20]=12
Reactant: COC(=O)c1cc(Cl)c(Cl)cc1NS(=O)(=O)c1cccc2nsnc12
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(Cl)c(Cl)cc1NS(=O)(=O)c1cccc2nsnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To a solution of 2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4,5-dichloro-benzoic acid methyl ester (0.95 g, 2.3 mmol) in THF (21 mL) and water (7 mL) was added LiOH.H2O (0.38 g, 9.1 mmol). The biphasic mixture was stirred overnight at rt. The mixture was acidified with conc. HCl and extracted with DCM (3×). The combined organic layers were dried (MgSO4) and concentrated to provide 0.80 g (88%) of the pure acid as a white solid. 1H NMR (500 MHz, CDCl3): 11.07 (s, 1H), 8.41 (dd, J=7.0, 1.0, 1H), 8.27 (dd, J=8.8, 1.0, 1H), 8.01 (s, 1H), 7.94 (s, 1H), 7.75 (dd, J=8.8, 7.0, 1H).
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.[CH2:36]([C:40]1[O:41][C:42]2[CH:48]=[CH:47][C:46](Br)=[CH:45][C:43]=2[CH:44]=1)[CH2:37][CH2:38][CH3:39].C(OCC)(=O)C.CC1CCCCC1>C(OCC)(=O)C.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]>[CH2:36]([C:40]1[O:41][C:42]2[CH:48]=[CH:47][C:46]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:45][C:43]=2[CH:44]=1)[CH2:37][CH2:38][CH3:39]
Reactant: CCCCc1cc2cc(Br)ccc2o1
Reactant: CS(N)(=O)=O
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC1CCCCC1
Product: CCCCc1cc2cc(NS(C)(=O)=O)ccc2o1
Temperature: 100 °C

Procedure:
The following are placed in a 20 ml tube predried in an oven: 2 equivalents of base and 1.5 equivalents of methanesulfonamide, 2 mol % of Pd(dba)2 and 5 mol % of 2-(di-tert-butylphosphino)-2′,4′,6′-triisopropyl-1,1′-biphenyl (ligand L1). The tube is stoppered with a septum and placed under an inert atmosphere of argon, and 1 equivalent of 2-n-butyl-5-bromobenzofuran (compound IX or II) dissolved in 10 volumes of solvent is then added by syringe. The reaction medium is then stirred and heated to the reflux point of the solvent or at 100° C. for 24 hours, while monitoring the reaction progress by TLC (eluent: 20/80 ethyl acetate/methylcyclohexane) or by HPLC. At the end of the reaction, the reaction medium is diluted with ethyl acetate and then filtered while hot. The filtrate is then concentrated to give, when cold, crystallization of the desired compound I.
Reaction SMILES: C[N:2]1[CH2:7][CH2:6][CH:5]([CH:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[C:18]4[CH2:19][CH2:20][N:12]([C:13]=34)[C:11]3[CH:21]=[CH:22][CH:23]=[CH:24][C:10]=3[N:9]2[C:25]([O:27][CH2:28][C:29]([Cl:32])([Cl:31])[Cl:30])=[O:26])[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].Cl[C:40]([O:42][CH2:43][C:44]([Cl:47])([Cl:46])[Cl:45])=[O:41].ClC([O-])=O>ClCCl.CCCCCC.O.C1C=CC=CC=1>[Cl:45][C:44]([Cl:47])([Cl:46])[CH2:43][O:42][C:40]([N:2]1[CH2:7][CH2:6][CH:5]([CH:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[C:18]4[CH2:19][CH2:20][N:12]([C:13]=34)[C:11]3[CH:21]=[CH:22][CH:23]=[CH:24][C:10]=3[N:9]2[C:25]([O:27][CH2:28][C:29]([Cl:32])([Cl:31])[Cl:30])=[O:26])[CH2:4][CH2:3]1)=[O:41]
Reactant: CN1CCC(C2c3cccc4c3N(CC4)c3ccccc3N2C(=O)OCC(Cl)(Cl)Cl)CC1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: O=C([O-])Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCCCCC
Solvent: O
Product: O=C(OCC(Cl)(Cl)Cl)N1CCC(C2c3cccc4c3N(CC4)c3ccccc3N2C(=O)OCC(Cl)(Cl)Cl)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 3.43 g of 6-(1-methylpiperidin-4-yl)-1,2,6,7-tetrahydrobenzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepine-7-carboxylic acid, 2,2,2-trichloroethyl ester, 140 ml of benzene and 4.77 g of milled, anhydrous potassium carbonate was stirred under nitrogen and 1.2 ml of 2,2,2-trichloroethyl chloroformate was added. After an overnight reflux, another 1.2 ml of the chloroformate was added and reflux continued for 1 hour. After further addition of another 1.2 ml of chloroformate and another 1.5 hours of reflux, the mixture was allowed to cool to room temperature and 100 ml of distilled water was added. After short period of stirring, the mixture was poured into a separatory funnel and the phases were separated. The aqueous phase was basic to pH paper. It was extracted with 100 ml of ethyl acetate. The combined organic extracts were washed with 50 ml of 2N aqueous hydrochloric acid solution, 100 ml of saturated sodium bicarbonate solution, 100 ml of water and finally 100 ml of saturated sodium chloride solution and thereafter dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate in vacuo afforded a crude product contaminated with excess reagent. Flash chromatography on 280 g of silica gel using 1:1 dichloromethane/hexane as solvent afforded a gum, which was triturated to solid with 2:1 petroleum ether/ether solution. Filtration, washing and drying afforded 3.07 g of solid, m.p. 202°-205° C.
Reaction SMILES: CC(C)([O-])C.[Na+].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.Br[C:50]1[CH:51]=[C:52]2[C:58]([C:59]([F:71])([F:70])[C:60]3[CH:61]=[C:62]4[C:67](=[CH:68][CH:69]=3)[N:66]=[CH:65][CH:64]=[CH:63]4)=[N:57][O:56][C:53]2=[N:54][CH:55]=1.[CH:72]1([NH2:76])[CH2:75][CH2:74][CH2:73]1>C1(C)C=CC=CC=1.ClCCl.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]>[CH:72]1([NH:76][C:50]2[CH:51]=[C:52]3[C:58]([C:59]([F:71])([F:70])[C:60]4[CH:61]=[C:62]5[C:67](=[CH:68][CH:69]=4)[N:66]=[CH:65][CH:64]=[CH:63]5)=[N:57][O:56][C:53]3=[N:54][CH:55]=2)[CH2:75][CH2:74][CH2:73]1
Reactant: NC1CCC1
Reactant: FC(F)(c1ccc2ncccc2c1)c1noc2ncc(Br)cc12
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: FC(F)(c1ccc2ncccc2c1)c1noc2ncc(NC3CCC3)cc12
Temperature: 80 °C
Reaction time: 2 h
Yield: 5.2 %

Procedure:
To a pressure vial was added sodium tert-butoxide (38 mg, 0.40 mmol), xantphos (0.12 g, 0.20 mmol), Pd2(dba)3 (61 mg, 0.066 mmol), 6-((5-bromoisoxazolo[5,4-b]pyridin-3-yl)difluoromethyl)quinoline (0.10 g, 0.27 mmol), and cyclobutanamine (0.025 mL, 0.29 mmol) in toluene (3 mL). The mixture was stirred at 80° C. for two hours then was diluted with dichloromethane and filtered through celite. Purification of the filtrate by MPLC (eluted with a gradient of 10 to 50% ethyl acetate in hexanes) afforded the product as a yellow oil (5.1 mg, 5%). MS m/z=367.0 [M+1]+ Calc'd for C20H16F2N4O: 366.4
Reaction SMILES: [C:1]([C:3]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:4]=1[CH2:5][NH:6][C:7]([C:9]1[N:10]=[C:11]2[N:16]([C:17](=[O:27])[C:18]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:15][CH2:14][O:13][C:12]2([CH3:29])[CH3:28])=[O:8])#[CH:2].C(=O)(O)[O-].[K+].[Br:40][C:41](Br)=[N:42][OH:43]>C(OCC)(=O)C.O>[Br:40][C:41]1[CH:2]=[C:1]([C:3]2[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:4]=2[CH2:5][NH:6][C:7]([C:9]2[N:10]=[C:11]3[N:16]([C:17](=[O:27])[C:18]=2[O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:15][CH2:14][O:13][C:12]3([CH3:29])[CH3:28])=[O:8])[O:43][N:42]=1
Reactant: ON=C(Br)Br
Reactant: C#Cc1cc(F)ccc1CNC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCOC2(C)C
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1-c1cc(Br)no1)c(OCc1ccccc1)c2=O
Temperature: 22 °C
Reaction time: 1 h
Yield: 67.7 %

Procedure:
A solution of intermediate 179, N-(2-ethynyl-4-fluorobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide (0.350 g, 0.76 mmol) in a mixture of ethyl acetate (10 ml) and water (2 ml) was treated with potassium bicarbonate (0.230 g, 2.3 mmol) followed by dibromoformaldoxime (0.354 g, 1.75 mmol) (D. M. Vyas, Y. Chiang and T. W. Doyle, Tetrahedron Letters, 1984, 25, 487–490) and the resulting mixture stirred at 22° C. After 1 h, identical quantities of potassium bicarbonate and dibromoformaldoxime were added and the mixture stirred for another 1.5 h. The reaction mixture was then diluted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Crystallization of the residue from ether gave 0.300 g (68% yield) of the title material as a white solid. 1HNMR 400 MHz (CDCl3) δ ppm: 1.63 (6H, s, 2×CH3), 4.04 (4H, m, 2×CH2), 4.67 (2H, d, J=6.6 Hz, NCH2), 5.32 (2H, s, OCH2), 6.60 (1H, s, CH), 7.17 (1H, m, aromatic), 7.30–7.36 (4H, m, aromatics), 7.51–7.53 (2H, m, aromatics), 7.60 (1H,dd, J=5.5 Hz and J=8.6 Hz, aromatic), 8.01 (1H, broad t, NH). HRMS (ESI+) calculated for C27H25BrFN4O5 [M+H+]: 583.0992. found: 583.0986.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]2[CH3:18])[C:5]2[N:10]([CH3:11])[N:9]=[CH:8][C:6]=2[N:7]=1.Cl.[C@H]12C[C@H](NC1)CO2>>[Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][C@@H:16]3[CH2:18][C@H:13]2[CH2:14][O:15]3)[C:5]2[N:10]([CH3:11])[N:9]=[CH:8][C:6]=2[N:7]=1
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2cnn(C)c12
Agent: C1O[C@@H]2CN[C@H]1C2
Agent: Cl
Product: Cn1ncc2nc(Cl)nc(N3C[C@@H]4C[C@H]3CO4)c21

Procedure:
This compound was prepared in an analogous fashion to (S)-4-(5-chloro-1-methyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl)-3-methylmorpholine, using (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride salt as the starting material. 1H NMR (CDCl3, 500 MHz) δ ppm 7.96 (s, 1H), 5.15 (s, 1H), 4.76 (s, 1H), 4.20 (s, 3H), 4.13 (d, J=8.1 Hz, 1H), 3.97 (ddd, J=7.0 Hz, 4.7 Hz, 1.5 Hz, 2H), 3.69 (d, J=9.5 Hz, 1H), 2.09 to 1.94 (m, 2H); LC-MS m/z (method A)=266.1 [M+H]+, RT=1.37 min.
Reaction SMILES: C([O:4][CH2:5][C@H:6]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH:33]3[CH2:35][CH2:34]3)[C:14]=2[NH:18][C:19](=[O:32])[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[C:23]([F:31])[CH:22]=2)[C:9]1=[O:36])[CH3:7])(=O)C.C(=O)([O-])[O-].[K+].[K+].CO>O>[CH:33]1([C:13]2[C:14]([NH:18][C:19](=[O:32])[CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:30])[F:29])=[C:23]([F:31])[CH:22]=3)=[C:15]3[C:10](=[CH:11][CH:12]=2)[C:9](=[O:36])[N:8]([C@H:6]([CH3:7])[CH2:5][OH:4])[CH:17]=[CH:16]3)[CH2:35][CH2:34]1
Reactant: CC(=O)OC[C@@H](C)n1ccc2c(NC(=O)Cc3ccc(C(F)(F)F)c(F)c3)c(C3CC3)ccc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: C[C@H](CO)n1ccc2c(NC(=O)Cc3ccc(C(F)(F)F)c(F)c3)c(C3CC3)ccc2c1=O
Reaction time: 0.5 h

Procedure:
A round bottom flask was charged with (R)-2-(6-cyclopropyl-5-(2-(3-fluoro-4-(trifluoromethyl)phenyl)acetamido)-1-oxoisoquinolin-2(1H)-yl)propyl acetate (23 mg, 0.000046 mol), potassium carbonate (9.4 mg, 0.000068 mol) and methanol (2 mL, 0.05 mol) and 2 drops of water and the reaction was stirred for 30 minutes. The reaction mixture was then filtered over celite and the solvent removed under reduced pressure. The residue was then purified by preparative HPLC (reverse phase) to get the product as a sticky mass. MS m/z=463.5 (M+H). 1H NMR (400 MHz; Acetone-d) δ 9.02 (s, 1H), 8.03 (d, J=8.15 Hz, 1H), 7.61 (t, J=7.52 Hz, 1H), 7.42 (d, J=5.01 Hz, 1H), 7.39 (s, 1H), 7.24 (d, J=7.52 Hz, 1H), 6.91 (d, J=8.15 Hz, 1H), 6.36 (d, J=8.15 Hz, 1H), 4.99-4.97 (m, 1H), 3.93 (s, 2H), 3.68-3.64 (m, 2H), 2.04-1.94 (m, 1H), 1.24 (d, J=7.32 Hz, 3H), 0.81-0.77 (m, 2H), 0.60-0.56 (m, 2H).
Reaction SMILES: [CH:1]([C@:3]12[CH2:41][CH2:40][C@@H:39]([C:42]([CH3:44])=[CH2:43])[C@@H:4]1[C@@H:5]1[C@@:18]([CH3:21])([CH2:19][CH2:20]2)[C@@:17]2([CH3:22])[C@@H:8]([C@:9]3([CH3:38])[C@@H:14]([CH2:15][CH2:16]2)[C:13]([CH3:24])([CH3:23])[C:12]([C:25]2[CH:37]=[CH:36][C:28]([C:29]([O:31]C(C)(C)C)=[O:30])=[CH:27][CH:26]=2)=[CH:11][CH2:10]3)[CH2:7][CH2:6]1)=O.C(O)(=O)C.[N:49]1[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=1[CH2:55][CH2:56][NH2:57].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C([O-])(O)=O.[Na+]>[CH3:21][C@:18]12[C@@:17]3([CH3:22])[C@@H:8]([C@:9]4([CH3:38])[C@@H:14]([CH2:15][CH2:16]3)[C:13]([CH3:23])([CH3:24])[C:12]([C:25]3[CH:26]=[CH:27][C:28]([C:29]([OH:31])=[O:30])=[CH:36][CH:37]=3)=[CH:11][CH2:10]4)[CH2:7][CH2:6][C@@H:5]1[C@H:4]1[C@H:39]([C:42]([CH3:44])=[CH2:43])[CH2:40][CH2:41][C@:3]1([CH2:1][NH:57][CH2:56][CH2:55][C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][N:49]=1)[CH2:20][CH2:19]2
Reactant: NCCc1ccccn1
Reactant: C=C(C)[C@@H]1CC[C@]2(C=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: C=C(C)[C@@H]1CC[C@]2(CNCCc3ccccn3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of tert-butyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-formyl-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (0.1 g, 0.167 mmol) in DCE (2 ml) was added acetic acid (1M in DCM) (0.167 ml, 0.167 mmol) and 2-(2-pyridyl)ethylamine (0.024 ml, 0.200 mmol). The mixture was stirred for 15 minutes at rt and sodium triacetoxyborohydride (0.071 g, 0.334 mmol) was added. The mixture was stirred at rt for 1.5 h then an additional 0.1 g of sodium triacetoxyborohydride was added to the mixture and it was stirred for 23 h. To the mixture was added additional acetic acid (1M in DCM) (0.167 ml, 0.167 mmol), 2-(2-pyridyl)ethylamine (0.024 ml, 0.200 mmol), and sodium triacetoxyborohydride (0.071 g, 0.334 mmol). The mixture was stirred at rt for an additional 19 h, was diluted with 7 ml of sat. NaHCO3 and was extracted with dichloromethane (3×7 ml). The combined organic layers were dried with Na2SO4, the drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The mixture was purified by flash chromatography using a 0-10% MeOH in dichloromethane gradient. The fractions containing the expected product were combined and concentrated under reduced pressure to afford the title compound. LCMS: m/e 705.4 (M+H)+, 2.90 min (method 6).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][C@H:10]2[NH:23]C(OCC[Si](C)(C)C)=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.C(OCC)(=O)C>[NH2:23][C@H:10]1[C@H:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](NC(=O)OCC[Si](C)(C)C)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](N)C1
Temperature: 50 °C
Reaction time: 5 h
Yield: 0.1 %

Procedure:
To a solution of tert-butyl (6R,7S)-7-(3,4-dichlorophenyl)-6-({[2-(trimethylsilyl)ethoxy]carbonyl}amino)-1,4-oxazepane-4-carboxylate (0.67 g) in THF (5 mL) was added tetra-n-butylammonium fluoride (5.2 mL) at room temperature, and the mixture was stirred at 50° C. for 5 hr. The reaction mixture was diluted with ethyl acetate. The diluted solution was washed with distilled water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (0.4 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:12](=[O:18])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])=[C:6]([CH:11]=1)[N:7]([CH3:10])[CH:8]=O>C(O)CCCCCCC>[F:1][C:2]1[CH:11]=[C:6]2[C:5]([C:12](=[O:18])[C:13]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:8][N:7]2[CH3:10])=[CH:4][CH:3]=1
Reactant: CN(C=O)c1cc(F)ccc1C(=O)CS(C)(=O)=O
Solvent: CCCCCCCCO
Product: Cn1cc(S(C)(=O)=O)c(=O)c2ccc(F)cc21
Temperature: 25 °C

Procedure:
5'-Fluoro-N-methyl-2'-methylsulphonylacetylformanilide (0.20 g), prepared in a similar manner to that described in Example 11, was added to 1-octanol (25 ml) pre-heated to 160°. The mixture was heated at this temperature for 40 minutes and then allowed to cool to ambient temperature. The mixture was filtered, the solid washed with hexane (2×10 ml) and dried at 50° in vacuo to give 7-fluoro-1-methyl-3-methylsulphonyl-4-quinolone, m.p. 222.5°-224° (0.16 g). The product was heated at 90° with grinding to give 7-fluoro-1-methyl-3-methylsulphonyl-4-quinolone, m.p.234°-235° (0.16 g).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[C:12]2[CH:11]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:9]=[CH:8][C:7]=2[CH2:6][CH2:5][CH2:4]1.C(N(CC)CC)C.[C:24]([O:28][C:29](ON=C(C1C=CC=CC=1)C#N)=[O:30])([CH3:27])([CH3:26])[CH3:25].C(OCC)(=O)C>O1CCCC1>[C:29]([NH:1][CH2:2][CH:3]1[C:12]2[CH:11]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:9]=[CH:8][C:7]=2[CH2:6][CH2:5][CH2:4]1)([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:30]
Reactant: COC(=O)c1ccc2c(c1)C(CN)CCC2
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(c1)C(CNC(=O)OC(C)(C)C)CCC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 47.2 %

Procedure:
Part D--A solution of methyl 8-aminomethyl-5,6,7,8-tetrahydro-2-naphthoate (0.78 g, 0.0036 mol) and triethylamine (0.55 mL, 0.40 g, 0.004 mol) in aqueous tetrahydrofuran (50%, 75 mL) was added, portionwise as a solid, 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (0.99 g, 0.004 mol). All was stirred at ambient temperature over 3 hours. The solution was concentrated to half volume and extracted with diethylether. The aqueous layer was then acidified to a pH of 1.0 using hydrochloric acid (1N) and then extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure. The residue was purified by flash chromatography using hexane:ethyl acetate::8:2 to give methyl N-(BOC)-8-aminomethyl-5,6,7,8-tetrahydro-2-naphthoate (0.54 g, 0.0017 mol, 47%) as a white solid. mp=72°-80° C.; 1H NMR (DMSO) d 13.8 (s, 1H), 7.8-7.65 (m, 3H), 7.6-7.5 (m, 3H), 7.25-7.20 (m, 1H), 7.15-7.05 (m, 1H), 3.9-3.8 (m, 1H), 3.2-2.8 (m, 4H), 1.8-1.6 (m, 3H), 1.4 (s, 6H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([NH:13][C@H:14]([C:16]([OH:18])=O)[CH3:15])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl.[CH2:20]([O:22][C:23](=[O:28])[C@H:24]([CH2:26][OH:27])[NH2:25])[CH3:21]>CO.C(Cl)(Cl)Cl>[CH2:20]([O:22][C:23](=[O:28])[C@H:24]([CH2:26][OH:27])[NH:25][C:16](=[O:18])[C@H:14]([CH3:15])[NH:13][C:11](=[O:12])[CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[CH3:21]
Reactant: C[C@H](NC(=O)Cc1cccc([N+](=O)[O-])c1)C(=O)O
Reactant: CCOC(=O)[C@@H](N)CO
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCOC(=O)[C@H](CO)NC(=O)[C@H](C)NC(=O)Cc1cccc([N+](=O)[O-])c1

Procedure:
Following General Procedure C and using N-(3-nitrophenylacetyl)-L-alanine (prepared from 3-nitrophenylacetic acid (Aldrich) and L-alanine ethyl ester hydrochloride (Sigma) using General Procedure C, followed by hydrolysis using General Procedure AF) and L-serine ethyl ester hydrochloride (Sigma), the title compound was prepared as a solid (mp=179-181° C.). The reaction was monitored by tlc (Rf=0.2 in 5% MeOH/CHCl3) and the product was purified by silica gel chromatography using 5% MeOH/CHCl3 as the eluent.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:12]([C:20]1[CH:25]=[CH:24][C:23]([C:26](=O)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:22][CH:21]=1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[NH2:34][NH:35][C:36]([NH2:38])=[S:37]>CO>[C:12]([C:20]1[CH:25]=[CH:24][C:23]([C:26](=[N:34][NH:35][C:36]([NH2:38])=[S:37])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:22][CH:21]=1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NNC(N)=S
Reactant: O=C(c1ccccc1)c1ccc(C(=O)c2ccccc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: NC(=S)NN=C(c1ccccc1)c1ccc(C(=O)c2ccccc2)cc1
Reaction time: 12 h
Yield: 3.3 %

Procedure:
A catalytic amount of p-toluenesulfonic acid was added to a solution of 1,4 dibenzoylbenzene 1 (0.286 g, 1 mmol) in anhydrous methanol (10 mL). After stirring at reflux for 10 min, thiosemicarbazide (0.182 g, 2 mmol) was added to the reaction mixture and stirred for 12 h under an inert atmosphere of nitrogen gas. After 12 h, methanol was removed under reduced pressure and 10 mL of water was then added. The products were extracted with ethyl acetate (2×20 mL) and the combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Purification using flash chromatography (silica gel, hexanes:ethyl acetate, gradient 70:30) afforded 4-benzoyl benzophenone thiosemicarbazone 4 (0.012 g, 0.033 mmol) in a 3.3% yield. HRMS (ESI) calculated for C21H17N3OSH+ (M+H)+ 360.11651, found 360.11649.
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:42][C@H:43]1[CH2:49][CH2:48][CH2:47][CH2:46][N:45]([C:50]2[CH:55]=[CH:54][C:53]([Cl:56])=[CH:52][CH:51]=2)[C:44]1=[O:57]>>[CH2:34]([C@@H:14]([CH2:13][CH2:12][C@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]([NH:42][C@H:43]1[CH2:49][CH2:48][CH2:47][CH2:46][N:45]([C:50]2[CH:55]=[CH:54][C:53]([Cl:56])=[CH:52][CH:51]=2)[C:44]1=[O:57])=[O:10])[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: N[C@H]1CCCCN(c2ccc(Cl)cc2)C1=O
Reactant: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)O)Cc3ccccc3)C(=O)N21
Agent: Cl
Product: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)N[C@H]3CCCCN(c4ccc(Cl)cc4)C3=O)Cc3ccccc3)C(=O)N21

Procedure:
(4S,7S,10aS)-Methyl 4-((2R,5R)-2,5-dibenzyl-6-((S)-1-(4-chlorophenyl)-2-oxoazepan-3-ylamino)-6-oxohexanamido)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate was synthesized as described in General Procedure H using Intermediate 23 (7.0 mg, 0.012 mmol) and Intermediate 50 (3.4 mg, 0.012 mmol) to give a white solid (6.8 mg, 69% yield). Anal. Calcd. for C43H51ClN4O6S m/z 786.4. found: 787.4 (M+H)+; 1H NMR (500 MHz, CDCl3) δ ppm 7.33 (d, J=8.25 Hz, 2H), 7.22 (q, J=7.15 Hz, 4H), 7.19-7.10 (m, 6H), 7.11-7.04 (m, 2H), 6.89 (br. s., 1H), 6.85-6.73 (m, 1H), 5.31 (br. s., 1H), 5.14 (br. s., 1H), 4.98 (br. s., 1H), 4.78 (br. s., 1H), 3.92 (br. s., 1H), 3.68 (s, 3H), 3.61-3.52 (m, 1H), 3.24-3.08 (m, 1H), 2.92-2.75 (m, 3H), 2.76-2.65 (m, 2H), 2.46-2.26 (m, 3H), 2.09-1.43 (m, 17H).