Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1([O:26]CC)[C@@H:9]([CH3:10])[C@H:8]([NH:11][C:12](=[O:14])[CH3:13])[C:7]([C:15](=[O:24])[NH:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[C:6]([CH3:25])[O:5]1)[CH3:2]>O1CCCC1.Cl.O>[CH3:10][CH:9]([CH:8]([NH:11][C:12](=[O:14])[CH3:13])[CH:7]([C:15](=[O:24])[NH:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)[C:6](=[O:5])[CH3:25])[C:4]([O:3][CH2:1][CH3:2])=[O:26]
Reactant: CCOC1(OCC)OC(C)=C(C(=O)Nc2ccc(Cl)cc2)[C@@H](NC(C)=O)[C@@H]1C
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(C)C(NC(C)=O)C(C(C)=O)C(=O)Nc1ccc(Cl)cc1

Procedure:
Trans-2,2-diethoxy-3,6-dimethyl-4-acetylamino-5-(4'-chlorophenylcarbamoyl)-3,4-dihydro-2H-pyran (76.5 g) (Example 18) was stirred at room temperature in a mixture of tetrahydrofuran (200 ml) and 1N hydrochloric acid (10 ml) for 16 hours. The reaction mixture was diluted with water, extracted with ethyl acetate and the organic extract dried in anhydrous magnesium sulphate and evaporated to dryness. The residual solid was triturated with diethyl ether to give ethyl 2-methyl-3-acetylamino-4-(4'-chlorophenylcarbamoyl)-5-oxohexanoate, 66 g, m.p. 169°-73° C.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH3:5][O:6][C:7](=[O:15])[C:8]1[C:9](=[CH:11][CH:12]=[CH:13][CH:14]=1)[NH2:10]>C1(C)C=CC=CC=1>[CH3:5][O:6][C:7]([C:8]1[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=1[N:10]=[C:1]=[O:2])=[O:15]
Reactant: COC(=O)c1ccccc1N
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: COC(=O)c1ccccc1N=C=O
Yield: 100 %

Procedure:
Phosgene was bubbled through a solution of 10 g (66 mmol) of methylanthranilate in 15 ml of anhydrous toluene for 2 hours at reflux. Then the solvent was distilled off under reduced pressure to give 11.7 g (100%) of 2-methoxycarbonylphenyl-isocyanate; NMR (CDCl3) 3.89 (s, 3H, CH3); 7.0-7.63 (m, 3H, phenyl H-3, -4, -5); 8.0 (dd, 1H, phenyl H-6). This was converted to the title compound, in 34% overall yield, by condensation with an equimolar amount of 2-pyridylcarbinol followed by saponification of the resulting ester with 1 N sodium hydroxide and acidification of the reaction mixture to pH 4. The crude product was purified by crystallization from ethyl acetate; melting point=172-175° C.; NMR (DMSO-d6) 5.2 (s, 2H, methoxy CH2); 6.8-8.8 (m, 9H, aromatic, NH); 10.8 (broad s, 1H, OH).
Reaction SMILES: [C:1]([S:4][CH:5]1[N:8]([CH:9]([C:13]([CH3:15])=C)[C:10]([OH:12])=[O:11])[C:7](=[O:16])[CH:6]1[N:17]1[C:21](=[O:22])[C:20]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]2[C:18]1=[O:27])(=[O:3])[CH3:2].[O:28]=[O+][O-]>CO>[C:1]([S:4][CH:5]1[N:8]([CH:9]([C:13](=[O:28])[CH3:15])[C:10]([OH:12])=[O:11])[C:7](=[O:16])[CH:6]1[N:17]1[C:18](=[O:27])[C:19]2=[CH:26][CH:25]=[CH:24][CH:23]=[C:20]2[C:21]1=[O:22])(=[O:3])[CH3:2]
Reactant: C=C(C)C(C(=O)O)N1C(=O)C(N2C(=O)c3ccccc3C2=O)C1SC(C)=O
Reactant: O=[O+][O-]
Solvent: CO
Product: CC(=O)SC1C(N2C(=O)c3ccccc3C2=O)C(=O)N1C(C(C)=O)C(=O)O
Yield: 63 %

Procedure:
To a solution of α-[4-acetylthio-3-phthalimido-2-oxo-azetidin-1-yl]-α-isopropenyl acetic acid (100 mg) in methanol (10 ml) at 0° C. is introduced excess ozone. After the gas at the outlet makes a potassium iodide starch paper coloured, the reaction mixture is bubbled with sulfur dioxide gas. The reaction mixture is concentrated, and the obtained residue is dissolved in aqueous solution of sodium hydrogen carbonate, washed with ether, neutralized with hydrochloric acid, and extracted with methylene chloride. The extract solution is washed with water, dried, and evaporated to give α-[4-acetylthio-3-phthalimido-2-oxoazetidin-1-yl]-α-acetyl-acetic acid (64 mg). Yield: 63%. Foam.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][CH2:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:24][O:25][C:26]1[CH:33]=[C:32]([O:34][CH3:35])[C:31]([N:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)=[CH:30][C:27]=1[CH:28]=O.C[O-].[Li+]>CN(C=O)C.CO>[CH3:24][O:25][C:26]1[CH:33]=[C:32]([O:34][CH3:35])[C:31]([N:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)=[CH:30][C:27]=1/[CH:28]=[CH:2]/[C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][CH2:14][CH2:15][CH2:16][N:17]2[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]2)(=[O:11])=[O:12])=[CH:6][CH:5]=1)=[O:3]
Reactant: COc1cc(OC)c(N2CCCC2)cc1C=O
Reactant: CC(=O)c1ccc(S(=O)(=O)NCCCN2CCN(C)CC2)cc1
Agent: C[O-]
Agent: [Li+]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1cc(OC)c(N2CCCC2)cc1/C=C/C(=O)c1ccc(S(=O)(=O)NCCCN2CCN(C)CC2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 56.8 %

Procedure:
A solution 4-acetyl-N-[3-(4-methylpiperazin-1-yl)propyl]benzenesulfonamide (Ex-55A, 830 mg, 2.44 mmol) and 2,4-dimethoxy-5-pyrrolidin-1-ylbenzaldehyde (Ex-38B, 575 mg, 2.44 mmol) in DMF (10.8 mL) and MeOH (4.4 mL) was treated with lithium methoxide (278 mg, 7.32 mmol) and stirred for 20 h at room temperature under nitrogen atmosphere. The reaction mixture was quenched with water (75 mL) and extracted ethyl acetate (3×50 mL). The combined organic phase was brined, dried over sodium sulfate, and concentrated to a red solid. Column chromatography (5% MeOH in dichloromethane) gave 772 mg (57%) of the title compound as a brown solid, mp 64–68° C. 1H-NMR (300 MHz, DMSO-d6) 8.23 (d, 2H, J=8.7), 8.05 (d, 1H, J=15.3 Hz), 7.88 (d, 2H, J=7.5 Hz), 7.76 (t, 1H, J=4.8 Hz), 7.63 (d, 1H, J=15.3 Hz), 7.16 (s, 1H), 6.67 (s, 1H), 3.86 (s, 6H), 3.16 (br s, 4H), 2.76 (quartet, 2H, J=6.9 Hz), 2.15 (m, 10H), 2.06 (s, 3H), 1.80 (br s, 4H), 1.45 (quintet, 2H, J=6.9 Hz). HRMS (ESI) Calcd. for C29H40N4O5S: 557.2798 [(M+H)+]; Found: 557.2798.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12](O)=[O:13])[CH:10]=2)[NH:5][CH:4]([C:15]2[CH:16]=[N:17][CH:18]=[C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH:20]=2)[CH2:3]1.[CH:28]1([S:31]([NH2:34])(=[O:33])=[O:32])[CH2:30][CH2:29]1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:1][C:2]1([CH3:27])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([NH:34][S:31]([CH:28]3[CH2:30][CH2:29]3)(=[O:33])=[O:32])=[O:13])[CH:10]=2)[NH:5][CH:4]([C:15]2[CH:16]=[N:17][CH:18]=[C:19]([N:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)[CH:20]=2)[CH2:3]1
Reactant: NS(=O)(=O)C1CC1
Reactant: CC1(C)CC(c2cncc(N3CCOCC3)c2)Nc2ccc(C(=O)O)cc21
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC1(C)CC(c2cncc(N3CCOCC3)c2)Nc2ccc(C(=O)NS(=O)(=O)C3CC3)cc21
Yield: 15 %

Procedure:
A mixture of 4,4-dimethyl-2-(5-morpholin-4-yl-pyridin-3-yl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (200 mg, 0.54 mmol), 1-3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (160 mg, 0.82 mmol), 4-dimethylaminopyridine (100 mg, 0.82 mmol), cyclopropane sulfonic acid amide (196 mg, 1.62 mmol) in dichloromethane (10 mL) was refluxed for 12 h. Removal of the solvent to afford the oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded cyclopropanesulfonic acid [4,4-dimethyl-2-(5-morpholin-4-yl-pyridin-3-yl)-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-amide (38 mg, 15%) as a light yellow solid: MS (ESI) M+1=471.2.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH2:4].[C:5](C1CC(=O)N(O)C1=O)([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6]>C(Cl)(Cl)Cl.O>[NH2:1][CH2:2][CH2:3][NH:4][C:5](=[O:6])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(OCc1ccccc1)C1CC(=O)N(O)C1=O
Reactant: NCCN
Solvent: ClC(Cl)Cl
Solvent: O
Product: NCCNC(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 80 %

Procedure:
To a solution of 2-aminoethylamine LVIII (150 mL; 2.25 mol) in chloroform (1.5 L), cooled to 0° C. was added a solution of carbobenzoxy N-hydroxysuccinimide (112.14 g; 0.45 mol) in water (0.5 L) with vigorously stirring for one hour. The solid was filtered and the solution was washed with brine (3×), once with water and dried over anhydrous MgSO4. The solvent was evaporated under reduced pressure and the residue was purified on a silica gel column (100:1→30:1 DCM:MeOH) to yield benzyl 2-aminoethylcarbamate LIX as a colorless viscous oil (350 g; 1.80 mol; 80% yield). 1H NMR (CDCl3) 2.79-2.83 (m, 2H), 3.21-3.28 (m, 2H), 5.10 (s, 2H), 5.19 (brs, 1H), 7.29-7.34 (m, 1H), 7.35-7.38 (m, 4H); ESIMS found for C10H14N2O2 m/z 195.2 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:15])[CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:6][CH:5]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[C:48]([C:52]1[CH:57]=[CH:56][C:55]([C:58]2[CH:63]=[CH:62][C:61](O)=[CH:60][CH:59]=2)=[CH:54][CH:53]=1)([CH3:51])([CH3:50])[CH3:49]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([O:15][C:61]2[CH:62]=[CH:63][C:58]([C:55]3[CH:54]=[CH:53][C:52]([C:48]([CH3:51])([CH3:50])[CH3:49])=[CH:57][CH:56]=3)=[CH:59][CH:60]=2)[CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(C(O)CC(C)C)cc1
Reactant: CC(C)(C)c1ccc(-c2ccc(O)cc2)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C(CC(C)C)Oc2ccc(-c3ccc(C(C)(C)C)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of racemic 4-(1-hydroxy-3-methyl-butyl)-benzoic acid methyl ester (300 mg, 1.35 mmol) in toluene (14 mL) is added 1,1′-(azodicarbonyl)dipiperidine (ADDP, 512 mg, 2.03 mmol) at 0° C., followed by the addition of tributylphosphine (0.5 mL, 2.03 mmol) and 4′-tert butyl-biphenyl-4-ol (367 mg, 1.62 mmol). The reaction mixture is warmed up to room temperature and stirred overnight. The mixture is loaded on silica gel, eluted with hexanes with a gradient from 0% of ethyl acetate to 50% of ethyl acetate giving 4-[1-(4′-tertbutyl-biphenyl-4-yloxy)-3-methyl-butyl]-benzoic acid methyl ester. The ester product is taken into ethanol (5 mL), treated with sodium hydroxide (5N aqueous, 1 mL) for 3 h at room temperature. The mixture is concentrated, diluted with ethyl acetate, acidified with 5 N HCl (1 mL), extract with ethyl acetate. The organic layers are dried and concentrated giving 4-[1-(4′-tertbutyl-biphenyl-4-yloxy)-3-methyl-butyl]-benzoic acid (400 mg).
Reaction SMILES: [CH3:1][C:2](=[CH2:17])[CH2:3][C:4]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:9][C:8](=[O:10])[NH:7][CH2:6][CH2:5]1.ClCCl.ClC1C=CC=C(C(OO)=[O:29])C=1>C(OC)(C)(C)C>[CH3:17][C:2]1([CH2:3][C:4]2([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:9][C:8](=[O:10])[NH:7][CH2:6][CH2:5]2)[CH2:1][O:29]1
Reactant: C=C(C)CC1(c2ccccc2)CCNC(=O)O1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: COC(C)(C)C
Solvent: ClCCl
Product: CC1(CC2(c3ccccc3)CCNC(=O)O2)CO1
Temperature: 22.5 °C
Reaction time: 1 h

Procedure:
To a 1.0 L 2-neck RBF was charged (R)-3-(S)-1-(4-bromophenyl)ethyl)-6-(2-methylallyl)-6-phenyl-1,3-oxazinan-2-one (135.8 g, 59 wt %, 3.1:1 dr, 193 mmol, 1.00 equiv), dichloromethane (700 mL), and then 3-chloroperbenzoic acid (m-CPBA, 70%, 95.3 g, 386 mmol, 2.0 equiv). The resulting solution was agitated at rt (Tint=20-25° C.) for 1 h, which HPLC analysis indicates >99 A % (220 nm) conversion. The resulting solution was diluted with 700 mL of methyl tert-butyl ether (MTBE) and washed with 1×500 mL of 30 wt % solution of sodium thiosulfate and 1×500 mL of saturated aqueous solution of sodium bicarbonate. The wash sequence was repeated until the peak on an HPLC trace of the organic solution that corresponds to a HPLC sample peak of m-CPBA is <2.5 A % (220 nm), which in this example the wash sequence was repeated 3 times. The resulting organic layer was dried with anhydrous sodium sulfate, filtered and then concentrated to an oil via reduced pressure. The resulting material was diluted with 200 mL of anhydrous tetrahydrofuran and then concentrated to a thick oil via reduced pressure to provide (6S)-3-(S)-1-(4-bromophenyl)ethyl)-6-((2-methyloxiran-2-yl)methyl)-6-phenyl-1,3-oxazinan-2-one which was used directly in Step 5.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1[OH:10].C(=O)([O-])[O-].[K+].[K+].C([O:19][C:20](=[O:27])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]Br)C>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1[O:10][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][C:20]([OH:27])=[O:19]
Reactant: Oc1cc(Cl)c(Cl)cc1Cl
Reactant: CCOC(=O)CCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)CCCCCOc1cc(Cl)c(Cl)cc1Cl
Yield: 85 %

Procedure:
First, 987 mg (5 mmol) of 2,4,5-trichlorophenol (III) and 1.04 g (7.5 mmol) of anhydrous potassium carbonate were added to 8 ml of anhydrous dimethyl formamide and the mixture was stirred. Then, 1.67 g (7.5 mmol) of 6-bromohexanoic acid ethyl ester was added thereto, and the mixture was stirred at 60° C. for 16 hours. After the reaction was completed, the solvent was concentrated under reduced pressure. The residue was extracted with dichloromethane, washed with water, and was then concentrated under reduced pressure to dryness. The residue was dissolved in a mixed solution of 10 ml of dioxane and 12.5 ml of methanol, and 2.5 ml of 10 N sodium hydroxide was added thereto with stirring. The mixture was stirred at room temperature for 6 hours. After the reaction was completed, 5 ml of water was added to the mixture and neutralized with 6 N hydrochloric acid. The solvent was evaporated under reduced pressure to dryness, 1 N hydrochloric acid was added to the residue and the residue was extracted with chloroform. After washing with water, the residue was concentrated under reduced pressure to dryness and was powdered using a mixed solution of hexane and ether to obtain 6-(2,4,5-trichlorophenoxy) hexanoic acid (Ia) (hereinafter, referred to as “compound (Ia)”) in an amount of 1.32 g (yield: 85%).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([CH2:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[C:6]([CH3:9])[C:7]=1[CH3:8].[CH3:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1>C(Cl)Cl.CO>[CH3:17][C:18]1[CH:24]=[CH:23][C:21]([NH:22][C:2]2[N:3]=[N:4][C:5]([CH2:10][C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[C:6]([CH3:9])[C:7]=2[CH3:8])=[CH:20][CH:19]=1
Reactant: Cc1c(Cl)nnc(Cc2ccncc2)c1C
Reactant: Cc1ccc(N)cc1
Solvent: CO
Solvent: ClCCl
Product: Cc1ccc(Nc2nnc(Cc3ccncc3)c(C)c2C)cc1

Procedure:
The compound is prepared from 0.070 g 3-chloro-4,5-dimethyl-6-(pyridin-4-yl)methylpyridazine and 0.129 g para-methylaniline in the manner described in Example 82A. Title compound is obtained after FC in CH2Cl2/Methanol 19/1; m.p. 68-70° C. 1H-NMR (250 MHz,CDCl3): δ=8.45 (s, wide, 2H); 7.45 (d, 2H); 7.10 (“d”, wide, 4H); 6.10 (s, wide, 1H); 4.25 (s, 2H); 2.30 (s, 3H); 2.15 (s, 3H); 2.10 (s, 3H). ES-MS 305 (M+H).
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:40]([O:42]C(C)(C)C)=[O:41])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]4[O:25][CH:24]=[N:23][C:22]=4[C:26]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[O:27])=[CH:18][C:17]4[CH:34]=[C:35]([O:38][CH3:39])[CH:36]=[CH:37][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>ClCCCl>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:40]([OH:42])=[O:41])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]4[O:25][CH:24]=[N:23][C:22]=4[C:26]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[O:27])=[CH:18][C:17]4[CH:34]=[C:35]([O:38][CH3:39])[CH:36]=[CH:37][C:16]=4[C:15]=23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1ccc2c(c1)C=C(c1ocnc1C(=O)N1CCOCC1)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)OC(C)(C)C)cc21
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1)C=C(c1ocnc1C(=O)N1CCOCC1)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)O)cc21
Yield: 97 %

Procedure:
Dissolve tert-Butyl 13-cyclohexyl-3-methoxy-6-(4-(4-morpholinylcarbonyl)-1,3-oxazol-5-yl)-7H-indolo[2,1-a][2]benzazepine-10-carboxylate (203 mg, 0.325 mmol) in 1,2-dichloroethane (3 ml) add TFA (3 ml, 38.9 mmol), The reaction was capped under a nitrogen atmosphere at 25° C. for 2 hrs. Reaction volatiles were removed in vacuuo and the residue dissolved in 80 mL of ethyl acetate with heating. The solution was washed with 1N aqueous hydrochloric acid (2×40 mL), brine and dried over magnesium sulfate. The product solution was filtered, volatiles removed and the sample dried in vacuuo at room temperature overnight to give 179 mg (97%) of a yellow solid. 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 0.74-1.03 (m, 4 H) 1.06-1.31 (m, 6H) 1.32-1.50 (m, 3H) 1.56 (d, J=9.16 Hz, 2H) 1.77 (d, J=8.85 Hz, 2H) 1.86-2.18 (m, 5H) 2.83-2.91 (m, 1H) 3.60 (s, 3H) 3.64-3.89 (m, 4H) 3.88-3.93 (m, 4H) 3.95-4.08 (m, 1H) 4.43 (d, J=15.56 Hz, 1H) 5.64 (d, J=14.95 Hz, 1H) 6.99 (d, J=2.75 Hz, 1H) 7.07 (dd, J=8.70, 2.59 Hz, 1H) 7.48-7.56 (m, 2 H) 7.85-7.94 (m, 2H) 8.15 (s, 1H). LC-MS retention time 1.65 min; 568 m/z (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters Xterra MS 7u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].[C:18]([O:22][C:23]([NH:25][CH2:26][C:27]1[S:31][C:30](B(O)O)=[CH:29][CH:28]=1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>>[C:18]([O:22][C:23](=[O:24])[NH:25][CH2:26][C:27]1[S:31][C:30]([C:2]2[C:3]3[C:4]4[CH:17]=[CH:16][S:15][C:5]=4[C:6](=[O:14])[NH:7][C:8]=3[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])=[CH:29][CH:28]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Reactant: CC(C)(C)OC(=O)NCc1ccc(B(O)O)s1
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(CNC(=O)OC(C)(C)C)s1
Yield: 14.1 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (150 mg, 0.48 mmol) was reacted with 5-[(tert-butoxycarbonylamino)methyl]thiophen-2-ylboronic acid (130 mg, 0.53 mmol) to afford the desired product (30 mg, 18%) as a off-white solid: 1H NMR (500 MHz, CD3OD) δ 7.74 (d, J=5.4 Hz, 1H), 7.56 (d, J=9.1 Hz, 1H), 7.36 (d, J=9.1 Hz, 1H), 6.49 (d, J=3.1 Hz, 1H), 6.40 (br s, 1H), 6.01 (d, J=5.4 Hz, 1H), 4.27 (s, 2H), 3.82 (s, 3H), 1.39 (s, 9H).
Reaction SMILES: [F:1][C:2]1[C:3]([C:24]([O:26][CH3:27])=[O:25])=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][N:16]=2)=[N:11][CH:10]=1>C(O)(=O)C.C1COCC1.[Pt]>[NH2:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:12]2[S:13][C:9]([S:8][C:7]3[CH:6]=[CH:5][N:4]=[C:3]([C:24]([O:26][CH3:27])=[O:25])[C:2]=3[F:1])=[CH:10][N:11]=2)=[N:16][CH:17]=1
Reactant: COC(=O)c1nccc(Sc2cnc(Nc3ccc([N+](=O)[O-])cn3)s2)c1F
Agent: [Pt]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)c1nccc(Sc2cnc(Nc3ccc(N)cn3)s2)c1F
Reaction time: 8 h

Procedure:
A stirring solution of methyl 3-fluoro-4-(2-(5-nitropyridin-2-ylamino)thiazol-5-ylthio)picolinate (1.77 g, 4.34 mmol), 10% Pt/C (366 mg) in acetic acid (5 mL) and THF (20 mL) was purged 4× with H2, then pressurized to 140 psi in a steel bomb reactor and stirred overnight. The reaction was depressurized, and LCMS showed intermediate nitroso as predominant product. Pt/C (270 mg) was added and the reaction repressurized to 140 psi and stirred overnight. The reaction was depressurized, LCMS showed complete reaction. The reaction was filtered through Celite, washed with THF and DCM, the filtrate was concentrated. The residue was recrystallized from EtOAc and hexane, the solid was collected by filtration and washed with hexane. The product was obtained (828 mg, 51%) as a solid: 1H NMR (400 MHz, DMSO-d6) δ ppm: 11.43 (1H, s), 8.31 (1H, d, J=5.05 Hz), 7.72 (1H, s), 7.66 (1H, d, J=2.27 Hz), 7.11 (1H, t, J=5.31 Hz), 7.06 (1H, dd, J=8.59, 2.78 Hz), 6.87 (1H, d, J=8.59 Hz), 4.99 (2H, s), 3.89 (3H, s); LC/MS (M+H)+: 378. HPLC ret. time (Condition E): 1.45 min.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH:6]2[CH2:7][CH2:8][CH:3]1[C:4](=O)[C:5]2=O.COP(=O)OC.O.[NH2:19][NH2:20]>>[C:2]([C:3]1[CH:4]=[C:5]2[C:4]([CH:3]3[C:2]([CH3:11])([CH3:1])[CH:6]2[CH2:7][CH2:8]3)=[N:20][N:19]=1)([CH3:11])([CH3:6])[CH3:1]
Reactant: CC1(C)C2CCC1C(=O)C2=O
Reactant: NN
Agent: CO[PH](=O)OC
Solvent: O
Product: CC(C)(C)c1cc2c(nn1)C1CCC2C1(C)C

Procedure:
white solid MS (ESI): 231 (MH+). Prepared from 7,7-dimethyl-bicyclo[2.2.1]heptane-2,3-dione (Childs, Ronald F.; Rogerson, Carol V.; J. Am. Chem. Soc.; EN; 102; 12; 1980; 4159), 3,3-dimethyl-2-oxo-butyl)-phosphonic acid dimethyl ester, hydrazine monohydrate.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[F:10].Cl[C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][N:13]=1.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[F:10][C:3]1[CH:4]=[C:5]([CH:6]=[O:7])[CH:8]=[CH:9][C:2]=1[O:1][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][N:13]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: O=Cc1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: N#Cc1ccc(Oc2ccc(C=O)cc2F)nc1
Yield: 72.7 %

Procedure:
Using a method similar to Example 365, step 1, using 4-hydroxy-3-fluoro-benzaldehyde (3.00 g, 21.4 mmol), 6-chloro-nicotinonitrile (2.98 g, 21.5 mmol), and potassium carbonate (7.40 g, 53.5 mmol) in dimethylacetamide (100 mL) after 6 h at 100° C. provides 3.77 g (73%) of the title compound as a yellow solid (silica gel chromatography conditions: 19:1→1:4 hexanes:ethyl acetate): mass spectrum (electrospray): m/z=243.0 (M+1); 1H NMR (CDCl3): 10.00 (d, 1H, J=2.0 Hz), 8.42 (d, 1H, J=1.5 Hz), 8.01 (dd, 1H, J=2.0, 8.3 Hz), 7.80-7.72 (m, 2H), 7.43 (d, 1H, J=7.3 Hz), 7.19 (d, 1H, J=8.8 Hz).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:34]([OH:36])=[O:35])[CH2:20][C:21]3[CH:26]=[CH:25][C:24]([NH:27]C(OCC=C)=O)=[CH:23][CH:22]=3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(O)(=O)C.C([SnH](CCCC)CCCC)CCC>ClCCl.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>[NH2:27][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][C@@H:19]([C:34]([OH:36])=[O:35])[NH:18][C:16]([O:15][CH2:14][CH:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)=[O:17])=[CH:26][CH:25]=1
Reactant: C=CCOC(=O)Nc1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[SnH](CCCC)CCCC
Solvent: ClCCl
Solvent: CC(=O)O
Product: Nc1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Reaction time: 0.5 h

Procedure:
A 500 mL cylindrical glass vessel equipped with a coarse glass frit was charged with 10 g of N-[(9H-fluoren-9-ylmethoxy)carbonyl]-4-[[(2-propenyloxy)carbonyl]amino]-L-phenylalanine substituted Wang resin (10 g) obtained from Example 35 and a solution prepared from Pd(Ph3P)2Cl2 (1.6 g, 2.3 mmol) and acetic acid (5 mL, 83 mmol) in dry dichloromethane (150 mL). The resulting mixture was agitated for 30 minutes followed by the addition of tri-n-butyl tin hydride (20 mL, 74.3 mmol). The resulting mixture was agitated for 1 hour. To the mixture was added tri-n-butyl tin hydride (10 mL, 37 mmol). Agitation was continued for 1 hour and the mixture was filtered. To the resulting resin was added a solution prepared from Pd(Ph3P)2Cl2 (1.6 g, 2.3 mmol) and acetic acid (5 mL, 83 mmol) in dried dichloromethane (150 mL). The mixture was agitated for 30 minutes followed by the addition of tri-n-butyl tin hydride (20 mL, 74.3 mmol). The resulting mixture was agitated 1 hour. To the mixture was added additional tri-n-butyl tin hydride (10 mL, 37.15 mmol). Agitation continued for 1 hour. After the second deprotection cycle, the mixture was washed with dichloromethane (2×100 mL), methanol (2×100 mL) and dimethylformamide (2×100 mL) to give 4-amino-N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-phenylalanine on Wang resin suitable for use in subsequent steps.