Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][OH:12])[CH2:6][CH2:5]1.[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][N:23]([C:26](OC3C=CC([N+]([O-])=O)=CC=3)=[O:27])[CH2:22][CH2:21]2)=[CH:16][CH:15]=1>CCCCCCC.C1COCC1>[CH3:13][C:14]1[CH:15]=[CH:16][C:17]([N:20]2[CH2:21][CH2:22][N:23]([C:26]([O:12][CH2:11][CH2:10][CH:7]3[CH2:8][CH2:9][N:4]([CH3:3])[CH2:5][CH2:6]3)=[O:27])[CH2:24][CH2:25]2)=[CH:18][CH:19]=1
Reactant: Cc1ccc(N2CCN(C(=O)Oc3ccc([N+](=O)[O-])cc3)CC2)cc1
Reactant: CN1CCC(CCO)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: Cc1ccc(N2CCN(C(=O)OCCC3CCN(C)CC3)CC2)cc1
Temperature: 0 °C
Reaction time: 48 h
Yield: 8.6 %

Procedure:
NaH (60% dispersion in mineral-oil, 0.81 g, 42.2 mmol) was suspended in heptane (10 mL) under an argon atmosphere. The heptane was decanted off, and the flask was charged with THF (20 mL) and cooled to 0° C. A solution of 2-(1-methyl-piperidin-4-yl)-ethanol (1.01 g, 7.03 mmol) in THF (20 mL) was added drop-wise, followed by a solution of 4-nitrophenyl 4-(4-methylphenyl)piperazine-1-carboxylate (2.89 g, 8.46 mmol) in THF (20 mL). The reaction mixture was allowed to warm to room temperature and stirred for 48 hours. The reaction mixture was then cooled to 0° C. and quenched with the drop-wise addition of sat aq NaHCO3 solution and concentrated in vacuo. The residue was dissolved in EtOAc (200 mL), washed with a NaHCO3 solution (4×50 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by normal phase column chromatography (eluting with DCM, followed by a 90:10 mixture of DCM:MeOH) followed by reverse phase chromatography (gradient eluting with MeOH in water, with 1% formic acid in each solvent, 0-20%). The resulting residue was dissolved in DCM (50 mL) and stirred with solid K2CO3 for 20 minutes, filtered and concentrated in vacuo to give the title compound 2-(1-methylpiperidin-4-yl)ethyl 4-(4-methylphenyl)piperazine-1-carboxylate (0.21 g, 7%) as a cream solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([S:13](Cl)(=[O:15])=[O:14])=[CH:4][C:5]2[O:10][CH2:9][C:8](=O)[NH:7][C:6]=2[CH:12]=1.[CH3:17][O:18][C:19]1[CH:31]=[CH:30][C:22]([CH2:23][NH:24][C:25]2[S:26][CH:27]=[CH:28][N:29]=2)=[CH:21][CH:20]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].B.O1CCCC1>[Cl-].[NH4+].O.C1COCC1>[Cl:1][C:2]1[C:3]([S:13]([N:24]([CH2:23][C:22]2[CH:30]=[CH:31][C:19]([O:18][CH3:17])=[CH:20][CH:21]=2)[C:25]2[S:26][CH:27]=[CH:28][N:29]=2)(=[O:15])=[O:14])=[CH:4][C:5]2[O:10][CH2:9][CH2:8][NH:7][C:6]=2[CH:12]=1
Reactant: COc1ccc(CNc2nccs2)cc1
Reactant: O=C1COc2cc(S(=O)(=O)Cl)c(Cl)cc2N1
Agent: B
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2cc3c(cc2Cl)NCCO3)cc1
Reaction time: 0.08 h
Yield: 37.7 %

Procedure:
A 250-mL round-bottom flask was charged with 6-chloro-3-oxo-3,4-dihydro-2h-1-4-benzoxazine-7-sulfonyl chloride (Enamine, Kiev, Ukraine, 3.849 g, 13.64 mmol), N-(4-methoxybenzyl)thiazol-2-amine (3.61 g, 16.37 mmol), and THF (68.2 ml) to give a thick suspension. The flask was sonicated for 30 s, then cooled in a dry ice-acetone bath for 10 min. Lithium bis(trimethylsilyl)amide (1M in THF) (30.0 ml, 30.0 mmol) was added dropwise over 5 min. After another 5 min, the flask was transferred to an ice-bath. After 1 h of stirring, an additional portion of base solution (5 mL) was added. After 10 min, the mixture was diluted with saturated aq. ammonium chloride (150 mL) and water (50 mL). The mixture was extracted with EtOAc (3×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was concentrated from DCM (2×). The resulting solid was taken up in THF (100 mL) to give a thin suspension. The flask was cooled in an ice-bath for 5 min, then borane-tetrahydrofuran complex (1M in THF) (1.173 g, 13.64 mmol). Following the addition, the cooling bath was removed. After 2 h, borane-tetrahydrofuran complex (1M in THF) from another bottle (30 mL) was added. Some bubbling was observed, and the mixture lightened. After 16 h of stirring, the mixture was quenched by the careful addition of MeOH (20 mL). After 2 h, the mixture was concentrated, then concentrated from MeOH/DCM. The residual oil was treated with MeOH, and the resulting mixture was stirred for 5 h. The sides of the flask were scraped with a spatula, and the flask was cooled in an ice-bath for 10 min. The mixture was then filtered, and the collected solid was washed with ice-cold MeOH (2×), dried under a stream of N2 (g), then dried under vacuum to give 6-chloro-N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (2.3249 g, 5.14 mmol, 37.7% yield) as a white solid: 1H NMR (400 MHz, DMSO-d6) δ=7.41 (d, J=3.5 Hz, 1 H), 7.30-7.19 (m, 5 H), 6.85 (d, J=8.7 Hz, 2 H), 6.68 (s, 1 H), 5.15 (s, 2 H), 4.12 (t, J=4.3 Hz, 2 H), 3.71 (s, 3 H), 3.37 (d, J=2.2 Hz, 2 H); m/z (ESI) 452.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]([CH3:24])([CH3:23])[C:20]([NH2:22])=[O:21])[CH2:15][CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[N:3]=1.[CH:31]1([C:34]2[NH:35][C:36]3[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=3[N:38]=2)[CH2:33][CH2:32]1>>[CH:31]1([C:34]2[N:35]([C:2]3[N:10]=[C:9]4[C:5]([N:6]=[C:7]([CH2:12][N:13]5[CH2:18][CH2:17][N:16]([C:19]([CH3:24])([CH3:23])[C:20]([NH2:22])=[O:21])[CH2:15][CH2:14]5)[N:8]4[CH3:11])=[C:4]([N:25]4[CH2:26][CH2:27][O:28][CH2:29][CH2:30]4)[N:3]=3)[C:36]3[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=3[N:38]=2)[CH2:33][CH2:32]1
Reactant: c1ccc2[nH]c(C3CC3)nc2c1
Reactant: Cn1c(CN2CCN(C(C)(C)C(N)=O)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Product: Cn1c(CN2CCN(C(C)(C)C(N)=O)CC2)nc2c(N3CCOCC3)nc(-n3c(C4CC4)nc4ccccc43)nc21

Procedure:
2-(4-((2-Chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperazin-1-yl)-2-methylpropanamide (75 mg) was reacted with 2-cyclopropylbenzimidazole via General Procedure I for Buchwald coupling to give 38.7 mg 438 following reverse phase purification. MS (Q1) 559.1 (M)+
Reaction SMILES: [CH3:1][C:2]([CH3:60])([CH2:10][C:11]([O:13][C@H:14]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@@H:16]([CH2:17][CH2:18][C@:19]3([CH3:57])[C@@H:28]2[CH2:27][CH2:26][C@H:25]2[C@@:20]3([CH3:56])[CH2:21][CH2:22][C@@:23]3(/[CH:40]=[C:41](\[CH3:55])/[C:42]([NH:44][C:45]4([C:48]5[CH:53]=[CH:52][CH:51]=[C:50]([Cl:54])[CH:49]=5)[CH2:47][CH2:46]4)=[O:43])[CH2:35][C:34](=[O:36])[C:33]([CH:37]([CH3:39])[CH3:38])=[C:24]32)[C:15]1([CH3:59])[CH3:58])=[O:12])[C:3]([O:5]C(C)(C)C)=[O:4].C(O)(C(F)(F)F)=O.CC#N.O>C(Cl)Cl>[Cl:54][C:50]1[CH:49]=[C:48]([C:45]2([NH:44][C:42](=[O:43])/[C:41](/[CH3:55])=[CH:40]/[C@:23]34[CH2:35][C:34](=[O:36])[C:33]([CH:37]([CH3:38])[CH3:39])=[C:24]3[C@@H:25]3[C@@:20]([CH3:56])([CH2:21][CH2:22]4)[C@@:19]4([CH3:57])[C@@H:28]([C@:29]5([CH3:32])[C@@H:16]([CH2:17][CH2:18]4)[C:15]([CH3:58])([CH3:59])[C@@H:14]([O:13][C:11](=[O:12])[CH2:10][C:2]([CH3:1])([CH3:60])[C:3]([OH:5])=[O:4])[CH2:31][CH2:30]5)[CH2:27][CH2:26]3)[CH2:47][CH2:46]2)[CH:53]=[CH:52][CH:51]=1
Reactant: C/C(=C\[C@@]12CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)OC(C)(C)C)C(C)(C)[C@@H]5CC[C@]43C)C1=C(C(C)C)C(=O)C2)C(=O)NC1(c2cccc(Cl)c2)CC1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: C/C(=C\[C@@]12CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]5CC[C@]43C)C1=C(C(C)C)C(=O)C2)C(=O)NC1(c2cccc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.7 %

Procedure:
To a solution of 1-tert-butyl 4-((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((E)-3-((1-(3-chlorophenyl)cyclopropyl)amino)-2-methyl-3-oxoprop-1-en-1-yl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) 2,2-dimethylsuccinate (280 mg, 0.332 mmol) in DCM (6 mL) was added TFA (3 mL, 0.332 mmol). The reaction mixture was stirred at rt for 2 hr and evaporated in vacuo to afford crude product. This was diluted with DCM (30 mL), and washed with water, saturated NaHCO3, water, saturated NH4CI and then water. The organic layer was dried over Na2SO4, filtered and concentrated to obtain a residue, which was dissolved into MeCN— H2O (1:2, 9 mL) and freeze-dried to give the title compound (130 mg, 48%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ=12.16 (br. s., 1H), 8.62 (s, 1H), 7.34-7.17 (m, 2H), 7.14 (s, 1H), 7.05 (d, J=7.5 Hz, 1H), 6.57 (s, 1H), 4.40 (dd, J=4.4, 10.9 Hz, 1H), 3.23-3.08 (m, 1H), 2.83-0.62 (m, 57H); LC/MS: m/z calculated 787.5. Found 788.2 (M+1)+.
Reaction SMILES: O1[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl-].[NH4+]>O>[C:2]1([C:3]2[CH:2]=[CH:5][CH:4]=[CH:5][CH:4]=2)[CH:3]=[CH:2][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: c1ccc(-c2ccccc2)cc1
Temperature: 5 °C

Procedure:
Thoroughly dried 250 ml flask was equipped with thermometer, magnetic stirrer bar, condenser, addition funnel and two way valve was charged with 5 g of catalyst, 50 ml tetrahydrofuran freshly distilled over sodium benzophenone ketyl of blue color. Assembly was filled with nitrogen as described earlier. To this was added 5.09 g (0.025 mol of iodobenzene) 60 ml Grignard reagent as prepared previously was charged in addition vessel. Grignard reagent was slowly added to contents of the flask which was previously cooled to 5° C. Temperature of the flask was maintained at 5° C. for 24 h. Reaction mixture was cooled to room temperature to which was slowly added 20 ml water followed by saturated 20 ml ammonium chloride. Resulting suspension was fluttered to remove solids and subsequently washed thoroughly with tetrahydrofuran and water. Filtrates were extracted with dichloromethane to obtain biphenyl in 89% yield residue left after filtration was washed with water, tetrahydrofuran and ether and dried under vacuum.
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH3:11])=[O:9])=[C:4]([NH:14]S(C2C=CC=CC=2)(=O)=O)[CH:3]=1.[Cl:24][C:25]1[CH:34]=[CH:33][C:28]([C:29](=[O:32])[CH2:30]Br)=[CH:27][CH:26]=1>>[CH3:11][O:10][C:8](=[O:9])[CH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([CH3:1])=[CH:13][CH:12]=2)[NH:14][C:30]=1[C:29](=[O:32])[C:28]1[CH:33]=[CH:34][C:25]([Cl:24])=[CH:26][CH:27]=1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: COC(=O)/C=C/c1ccc(C)cc1NS(=O)(=O)c1ccccc1
Product: COC(=O)Cc1c(C(=O)c2ccc(Cl)cc2)[nH]c2cc(C)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-4-methyl-2-(phenylsulfonylamino)cinnamate (step 2 of Example 149) and 4-chlorophenacyl bromide.
Reaction SMILES: C[O:2][C:3](=[O:34])[C:4]1[CH:9]=[CH:8][C:7]([C@H:10]2[CH2:15][CH2:14][C@H:13]([O:16][CH2:17][C:18]3[C:19]([C:26]4[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:27]=4[Cl:33])=[N:20][O:21][C:22]=3[CH:23]3[CH2:25][CH2:24]3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.[OH-].[Na+]>O1CCCC1.CO>[CH:23]1([C:22]2[O:21][N:20]=[C:19]([C:26]3[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:33])[C:18]=2[CH2:17][O:16][C@H:13]2[CH2:14][CH2:15][C@H:10]([C:7]3[CH:6]=[CH:5][C:4]([C:3]([OH:34])=[O:2])=[CH:9][CH:8]=3)[CH2:11][CH2:12]2)[CH2:25][CH2:24]1
Reactant: COC(=O)c1ccc([C@H]2CC[C@H](OCc3c(-c4c(Cl)cccc4Cl)noc3C3CC3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc([C@H]2CC[C@H](OCc3c(-c4c(Cl)cccc4Cl)noc3C3CC3)CC2)cc1
Temperature: 52 °C

Procedure:
Trans-4-{4-[5-cyclopropyl-3-(2,6-dichloro-phenyl)-isoxazol-4-ylmethoxy]-cyclohexyl}-benzoic acid methyl ester (823.31 μmoles; 412.00 mg) is dissolved in tetrahydrofuran (8 mL) and methanol (10 mL). 2N aqueous NaOH (2.5 mL, 5 mmol) is added and the mixture is heated to 52° C. for 2 h. The reaction mixture is cooled and concentrated under reduced pressure. The residue is diluted with water (10 mL) and acidified with 5N HCl (1 mL). The solid is collected by filtration, washed with water, and dried in vacuo to give the title compound (313 mg, 78%) as a white solid. MS m/z 487.8 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[NH:23][N:24]=[C:25]([O:26][CH2:27][CH2:28][N:29]4C(=O)C5C(=CC=CC=5)C4=O)[C:18]=23)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.O.NN>C(O)C>[NH2:29][CH2:28][CH2:27][O:26][C:25]1[C:18]2[C:19](=[N:20][CH:21]=[N:22][C:17]=2[NH:16][C:4]2[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=3)=[C:2]([Cl:1])[CH:3]=2)[NH:23][N:24]=1
Reactant: O=C1c2ccccc2C(=O)N1CCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Yield: 68.7 %

Procedure:
A mixture of 2-{2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}-1H-pyrazolo[3,4-d]pyrimidin-3-yl)oxy]ethyl}-1H-isoindole-1,3(2H)-dione (prepared as described in Example 90/350 mg, 0.65 mmol) and hydrazine monohydrate (63111) in ethanol (2 ml) was refluxed overnight. After evaporation of the solvent, the crude material was purified by preparative HPLC (column beta-basic, Hypercil 5 μm, 21×100 mm) eluting with a mixture of water and acetonitrile containing 2g/l of ammonium carbonate (gradient) to give the title compound (184 mg, 69%); NMR Spectrum: 2.94 (t, 2H), 4.25 (t, 2H), 5.29 (s, 2H), 7.23 (d, 1H), 7.37 (t, 1H), 7.53-7.58 (m, 2H), 7.85-7.90 (m, 2H), 8.26 (s, 1H), 8.60 (br s, 2H). Mass Spectrum: 412 (MH+).
Reaction SMILES: [Br:1][C:2]1[C:14]([OH:15])=[CH:13][C:5]2[C:6]([CH3:12])([CH3:11])[O:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1.[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([S:23][CH2:24][CH2:25][CH2:26][CH2:27]Cl)=[CH:19][CH:18]=1>>[Br:1][C:2]1[C:14]([O:15][CH2:27][CH2:26][CH2:25][CH2:24][S:23][C:20]2[CH:19]=[CH:18][C:17]([CH3:16])=[CH:22][CH:21]=2)=[CH:13][C:5]2[C:6]([CH3:12])([CH3:11])[O:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1
Reactant: CC1(C)OC(=O)Nc2cc(Br)c(O)cc21
Reactant: Cc1ccc(SCCCCCl)cc1
Product: Cc1ccc(SCCCCOc2cc3c(cc2Br)NC(=O)OC3(C)C)cc1

Procedure:
Prepared analogously to Example 4 from 7-bromo-6-hydroxy-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 4-(4-methyl-phenylmercapto)-butylchloride.
Reaction SMILES: C[O:2][C:3](=[O:10])[CH:4]=[C:5]([CH2:8][CH3:9])[CH2:6][CH3:7].[OH-].[Na+].Cl>O1CCOCC1>[CH2:6]([C:5]([CH2:8][CH3:9])=[CH:4][C:3]([OH:10])=[O:2])[CH3:7]
Reactant: CCC(=CC(=O)OC)CC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCC(=CC(=O)O)CC
Reaction time: 8 h
Yield: 90.3 %

Procedure:
3-ethyl pent-2-enoic acid methyl ester (200 mg, 1.4 mmol) was dissolved in dioxane (1 ml). 1N NaOH (1 ml) was added, and the mixture was left overnight at 50° C.; 1N hydrochloric acid was added (2 ml), and the compound was extracted with ethyl acetate. The organic solution was dried over sodium sulfate, filtered and the solvent was removed under reduced pressure, obtaining 162 mg of 3-ethylpent-2-enoic acid as colourless oil. Yield 90%. 1H-NMR: (CDCl3, 500 MHz) chemical shift p.p.m. 1.06–1.11 (m, 6H, CH2CH3); 2.23 (q, 2H, CH3CH2); 2.64 (q, 2H, CH3CH2); 5.65 (s, 1H, CHC(O)).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[CH:9])[CH:5]=[C:4]([Cl:10])[CH:3]=1.C([Li])CCC.CON(C)[C:19]([C:21]1[CH:22]=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[C:26]([O:31][CH3:32])[CH:25]=2)=[O:20]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:19]([C:21]2[CH:22]=[N:23][C:24]3[C:29]([CH:30]=2)=[CH:28][CH:27]=[C:26]([O:31][CH3:32])[CH:25]=3)=[O:20])[CH:5]=[C:4]([Cl:10])[CH:3]=1
Reactant: C#Cc1cc(Cl)cc(Cl)c1
Reactant: COc1ccc2cc(C(=O)N(C)OC)cnc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc2cc(C(=O)C#Cc3cc(Cl)cc(Cl)c3)cnc2c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of the 1,3-dichloro-5-ethynylbenzene (185 mg, 1.08 mmol) in anhydrous THF cooled to −78° C. under a N2 atmosphere was added nButLi (750 μL, 1.18 mmol). After 5 minutes, a solution of the intermediate from step E (320 mg, 1.3 mmol) in THF (5 mL) was added. The reaction was gradually warmed to room temperature over 30 minutes and quenched with saturated NH4Cl solution. The resulting bi-phasic mixture was extracted with ethyl acetate, washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography using 20% ethyl acetate-hexanes to afford the product as a light yellow solid. 1H NMR (500 MHz, CDCl3): 9.54 (d, J=2.3 Hz, 1H), 8.85 (d, J=2.1 Hz, 1H), 7.92 (d, J=9.2 Hz, 1H), 7.62 (d, J=2.0 Hz, 2H), 7.5 (m, 2H), 7.34 (dd, J=2.5, 8.9 Hz, 1H), 4.04 (s, 3H). LC-MS: 3.92 min; (M+H)=356.0.
Reaction SMILES: FC1C=C(C=CC=1)C[O:6][C:7](=[O:24])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)=[C:10]([F:23])[CH:9]=1.FC1C=CC(COC(=O)C2C=CC(OCC3C=CC(F)=CC=3)=C(F)C=2)=CC=1>>[F:23][C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][C:11]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1)[C:7]([OH:24])=[O:6]
Reactant: O=C(OCc1cccc(F)c1)c1ccc(OCc2cccc(F)c2)c(F)c1
Agent: O=C(OCc1ccc(F)cc1)c1ccc(OCc2ccc(F)cc2)c(F)c1
Product: O=C(O)c1ccc(OCc2cccc(F)c2)c(F)c1
Yield: 89.5 %

Procedure:
As described for example 18b, 3-fluoro-4-(3-fluoro-benzyloxy)-benzoic acid 3-fluoro-benzyl ester (6.9 g, 18.6 mmol) [instead of 3-fluoro-4-(4-fluoro-benzyloxy)-benzoic acid 4-fluoro-benzyl ester] was converted to the title compound (4.4 g, 90%) which was obtained as a white solid. MS: m/e=263.0 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([SH:10])=[N:7][C:6]=2[CH:11]=1.Cl[CH2:13][C:14]#[N:15].C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10][CH2:13][C:14]#[N:15])=[N:7][C:6]=2[CH:11]=1
Reactant: N#CCCl
Reactant: Sc1nc2cc(Cl)ccc2s1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: N#CCSc1nc2cc(Cl)ccc2s1
Temperature: 25 °C

Procedure:
51.0 g (0.254 m), 5-chloro-2-mercaptobenzothiazole, 22.8 g (0.304 m) chloroacetonitrile and 30.7 g triethylamine are dissolved in 600 ml of toluene and the solution is heated to reflux for 3 hr, then allowed to cool to room temperature. The toluene solution is washed with water, dried over anhydrous magnesium sulfate and treated with Darco. After the solvent is removed, the residual solid is recrystallized from 300 ml. benzene. The recovered material is recrystallized from cyclohexane. A total yield of 52 g (86%) is obtained. The recrystallized sample has a melting point of 96°-7° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C@H:17]1([NH:27][C:28]([C@@H:30]2[CH2:39][C:38]3[C:33](=[CH:34][C:35]([C:40]([O:42][CH3:43])=[O:41])=[CH:36][CH:37]=3)[CH2:32][NH:31]2)=[O:29])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][CH2:18]1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10]([N:31]1[C@H:30]([C:28](=[O:29])[NH:27][C@H:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][CH2:19][CH2:18]2)[CH2:39][C:38]2[C:33](=[CH:34][C:35]([C:40]([O:42][CH3:43])=[O:41])=[CH:36][CH:37]=2)[CH2:32]1)=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1ccc2c(c1)CN[C@H](C(=O)N[C@@H]1CCCc3ccccc31)C2
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C(C)(C)C
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)c1ccc2c(c1)CN(C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)[C@H](C(=O)N[C@@H]1CCCc3ccccc31)C2
Temperature: 25 °C
Yield: 100.2 %

Procedure:
To a 0° C. solution of (S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoic acid (473 mg, 2.04 mmol) and (S)-methyl 3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-1,2,3,4-tetrahydroisoquinoline-7-carboxylate (745 mg, 2.04 mmol) in CH2Cl2 (12.4 mL) was added EDC (471 mg, 2.45 mmol), HOAt (334 mg, 2.45 mmol) and NMM (675 μL, 6.14 mmol). The resulting reaction mixture was allowed to warm to room temperature overnight and then quenched with EtOAc and sat. NaHCO3. The aqueous layer was extracted with EtOAc (3×). The combined organic extracts were washed with 1N HCl (2×), sat. aq. NaCl solution (1×), dried over MgSO4, filtered and concentrated in vacuo to give the title compound (1.18 g, 2.045 mmol, 100%) as a light yellow foam, which was used without further purification. MS (ESI+) m/z 578.2 (M+H)+.
Reaction SMILES: [C:1]([O:4][CH:5]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Br:15])[CH:10]=1)[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2].[C:16](OC(=N)C(Cl)(Cl)Cl)([CH3:19])([CH3:18])[CH3:17]>C1(C)C=CC=CC=1>[C:1]([O:4][CH:5]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Br:15])[CH:10]=1)[C:6]([O:8][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:7])(=[O:3])[CH3:2]
Reactant: CC(C)(C)OC(=N)C(Cl)(Cl)Cl
Reactant: CC(=O)OC(C(=O)O)c1cccc(Br)c1
Solvent: Cc1ccccc1
Product: CC(=O)OC(C(=O)OC(C)(C)C)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of compound 2 (500 mg, 1.83 mmol) in toluene (2.5 mL) was added t-butyl-trichloroacetimidate (0.33 mL). The reaction was stirred at room temperature for 5 hours. The solid precipitate was filtered off and washed with toluene. The filtrate was concentrated in vacuo to provide compound 3 which was used in the next reaction without further purification.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[CH:13]=[C:12]([C:15]([O:17]C)=[O:16])[CH:11]=[CH:10][C:9]=2[C:8]2[S:19][CH:20]=[CH:21][C:7]=2[C:6]1=[O:22].[Li+].[OH-].Cl>C1COCC1.CO.O>[OH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[CH:13]=[C:12]([C:15]([OH:17])=[O:16])[CH:11]=[CH:10][C:9]=2[C:8]2[S:19][CH:20]=[CH:21][C:7]=2[C:6]1=[O:22]
Reactant: COC(=O)c1ccc2c3sccc3c(=O)n(CCCO)c2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc2c3sccc3c(=O)n(CCCO)c2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 22 %

Procedure:
Methyl 5-(3-hydroxypropyl)-4-oxo-4,5-dihydrothieno[3,2-c]quinoline-7-carboxylate (1.0 eq, 19 mg, 0.060 mmol) was dissolved in a 1:1:1 mixture of THF, MeOH and water (0.5 ml). LiOH (40 mg) was added and the resulting mixture stirred at room temperature for 1.5 hours. Water, MeOH and HCl were added and the solution purified by preparative HPLC. Genevac evaporation afforded 5-(3-hydroxypropyl)-4-oxo-4,5-dihydrothieno[3,2-c]quinoline-7-carboxylic acid as a white solid (4 mg, 22% yield). LCMS (ES): 95% pure, m/z 304 [M+1]+. 1H NMR (CDCl3/CD3OD, 9:1, 400 MHz) δ 2.08 (qi, J=6.0, 2H), 3.61 (t, J=5.2, 2H), 4.62 (t, J=6.0, 2H), 7.53 (d, J=5.2, 1H), 7.77 (d, J=5.2, 1H), 7.93 (d, J=8.0, 1H), 7.99 (dd, J=1.2, J=8.4, 1H), 8.26 (d, J=0.8, 1H) ppm.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:9](=[O:11])[NH:8][C:7]([C:12]3[CH:13]=[C:14]([N:22](S(C)(=O)=O)[S:23]([CH3:26])(=[O:25])=[O:24])[CH:15]=[N:16][C:17]=3[O:18][CH2:19][CH2:20][CH3:21])=[N:6][C:5]=2[C:4]([CH2:31][CH2:32][CH3:33])=[N:3]1.[OH-].[K+]>C(O)CC>[CH3:1][N:2]1[C:10]2[C:9](=[O:11])[NH:8][C:7]([C:12]3[CH:13]=[C:14]([NH:22][S:23]([CH3:26])(=[O:24])=[O:25])[CH:15]=[N:16][C:17]=3[O:18][CH2:19][CH2:20][CH3:21])=[N:6][C:5]=2[C:4]([CH2:31][CH2:32][CH3:33])=[N:3]1
Reactant: CCCOc1ncc(N(S(C)(=O)=O)S(C)(=O)=O)cc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: CCCO
Product: CCCOc1ncc(NS(C)(=O)=O)cc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1
Yield: 60 %

Procedure:
The title compound of Example 76 (56 mg, 0.1 mmol) was dissolved in propanol (1.4 mL) and aq. KOH solution (1 M, 0.14 mL) and the mixture heated to 45° C. for 2.5 h. The reaction mixture was concentrated in vacuo and the residue diluted with water (2 mL) and acidified to pH 2-3 with conc. hydrochloric acid to afford a precipitate which was removed by filtration, washed with water and diethyl ether before drying to give the title compound as an off-white solid (26 mg, 0.06 mmol).