Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[F:13])[C:3]=1[C:14]([OH:16])=O.Cl.C(N=C=NCCCN(C)C)C.[F:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>ClCCl>[NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[F:13])[C:3]=1[C:14]([N:39]1[CH2:38][CH2:37][N:36]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[F:29])[CH2:41][CH2:40]1)=[O:16]
Reactant: Nc1onc(-c2ccccc2F)c1C(=O)O
Reactant: Fc1ccccc1N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Nc1onc(-c2ccccc2F)c1C(=O)N1CCN(c2ccccc2F)CC1
Yield: 75.5 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 5-amino-3-(2-fluorophenyl)isoxazol-4-carboxylic acid (409 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(2-fluorophenyl)piperazine (332 mg, 1.84 mmol), a white solid required compound (533 mg, 1.39 mmol, 75%) was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:23])[N:7]([CH:14]([CH2:18][CH2:19][C:20](=[O:22])[NH2:21])[C:15]([OH:17])=[O:16])[C:8]2=[O:13])([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:23])[N:7]([CH:14]([CH2:18][CH2:19][C:20](=[O:22])[NH2:21])[C:15]([OH:17])=[O:16])[C:8]2=[O:13]
Reactant: [H][H]
Reactant: NC(=O)CCC(C(=O)O)N1C(=O)c2cccc([N+](=O)[O-])c2C1=O
Agent: [Pd]
Solvent: CO
Product: NC(=O)CCC(C(=O)O)N1C(=O)c2cccc(N)c2C1=O
Reaction time: 0.5 h
Yield: 87.6 %

Procedure:
A mixture of 2-(4-nitro-1,3-dioxoisoindolin-2-yl)-4-carbamoylbutanoic acid (1.75 g, 5.45 mmol) and 10% Pd/C (0.2 g) in methanol (52 mL) is hydrogenated at 50 psi of hydrogen for 2 hours. The mixture is filtered through celite and the celite pad is washed with methanol (30 mL). The filtrate is concentrated in vacuo and the residue is slurried with ethyl acetate (20 mL) for 30 min. The resulting slurry is filtered and the solid is washed with ethyl acetate (10 mL) and dried (60° C., <1 mmHg) to give 2-(4-amino-1,3-dioxoisoindolin-2-yl)-4-carbamoylbutanoic acid (1.39 g, 88%) as a yellow solid; mp 165-167° C.; 1H NMR (DMSO-d6) δ13.08 (b, 1H), 7.46 (t, J=7.8 Hz, 1H), 7.22 (s, 1H), 7.02-6.97 (dd, J=4.1 and 5.5 Hz, 1H), 6.73 (s, 1H), 6.51 (s, 2H), 4.68-4.62 (dd, J=4.5 and 10.5 Hz, 1H), 2.50-1.99 (m, 4H); 13C NMR (DMSO-d6) δ173.07, 170.75, 168.88, 167.63, 146.66, 135.36, 132.03, 121.58. 110.87, 108.63, 50.74, 31.34, 24.03; Anal. Calcd. For C13H13N3O5: C, 53.60; H, 4.50; N, 14.43. Found: C, 53.71; H, 4.40; N, 14.31.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C>[OH:8][C:4]1[CH:3]=[C:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: OB(O)c1ccccc1
Reactant: Oc1cccc(I)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Oc1cccc(-c2ccccc2)c1
Temperature: 100 °C
Yield: 84.2 %

Procedure:
A stirred mixture of 660 mg (3 mmol) of 3-iodophenol, 439 mg (3.6 mmol) phenylboronic acid, and 173 mg (0.15 mmol) tetrakistriphenylphosphine in 10 mL of toluene, 5 mL ethanol, and 6 mL 2M sodium carbonate (aqueous) was heated at 100° C. in an inert atmosphere of nitrogen for 15 minutes. The cooled mixture was partitioned between EtOAc, ice, and brine and the organic phase was separated, washed with brine, dried over anhydrous Na2SO4, filtered and evaporated. The residue was purified by plate layer chromatography (PLC) using CH2Cl2 as the eluant to give 430 mg of the title product.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[NH:10][C:11]1[CH:16]=[CH:15][C:14](Br)=[C:13]([F:18])[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([O:24][CH2:25][CH3:26])(=[O:23])[CH:21]=[CH2:22].CCN(C(C)C)C(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:25]([O:24][C:20](=[O:23])[CH:21]=[CH:22][C:14]1[CH:15]=[CH:16][C:11]([NH:10][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:19])=[CH:12][C:13]=1[F:18])[CH3:26]
Reactant: O=C(Nc1ccc(Br)c(F)c1)OCc1ccccc1
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C=Cc1ccc(NC(=O)OCc2ccccc2)cc1F
Temperature: 130 °C
Reaction time: 48 h

Procedure:
A suspension of 9.72 g (4-bromo-3-fluoro-phenyl)-carbamic acid benzyl ester (30 mmol), 6 g ethyl acrylate (60 mmol), 10.2 ml DIPEA (60 mmol), 112 mg palladium acetate (, 3 mmol), and 1.57 g triphenylphosphine (6 mmol) in 10 ml DMF were stirred at 130° C. for 48 h. The reaction was monitored by TLC. The DMF was evaporated, the residue dissolved in dichloromethane, washed with water and brine, dried over Mg sulfate, filtered and the filtrate evaporated. The residue was purified by chromatography, using a 7/3 N-hexane/ethyl acetate mixture as eluent.
Reaction SMILES: [C:1]([NH:5][S:6]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([C:18]2[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH:19]=2)[CH:12]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[K+].[C:51]([C:53]1[N:54]=[C:55]([C:66]([O-])=[O:67])[N:56]([CH2:58][O:59][CH2:60][CH2:61][Si:62]([CH3:65])([CH3:64])[CH3:63])[CH:57]=1)#[N:52].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([NH:5][S:6]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:66]([C:55]2[N:56]([CH2:58][O:59][CH2:60][CH2:61][Si:62]([CH3:65])([CH3:64])[CH3:63])[CH:57]=[C:53]([C:51]#[N:52])[N:54]=2)=[O:67])=[C:13]([C:18]2[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH:19]=2)[CH:12]=1)(=[O:8])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)CC=C(c2cc(CCS(=O)(=O)NC(C)(C)C)ccc2N)CC1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CC=C(c2cc(CCS(=O)(=O)NC(C)(C)C)ccc2NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.2 %

Procedure:
A solution of 267 mg (0.732 mmol) of 2-[4-amino-3-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-ethanesulfonic acid tert-butyl amide (as prepared in the previous step) in CH2Cl2 (10 mL) was treated with 512 mg (1.10 mmol) of PyBroP, 246 mg (0.806 mmol) of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate potassium salt (as prepared in Example 11, step (d)) and 383 μL (2.20 mmol) of DIEA. The mixture was stirred at RT for 3 h, diluted with CH2Cl2 (20 mL), and washed with saturated aqueous NaHCO3 (1×15 mL). The organic layer was dried (MgSO4) and concentrated in vacuo. Silica gel chromatography of the residue on a 50-g Varian MegaBond Elut SPE column with 25% EtOAc-hexane afforded 311 mg (69%) of the title compound as a white solid: 1H-NMR (CDCl3; 400 MHz): δ 9.73 (br s, 1H), 8.32 (d, 1H, J=8.4 Hz), 7.76 (s, 1H), 7.13 (dd, 1H, J=8.4, 2.0 Hz), 7.02 (d, 1H, J=2.0 Hz), 5.94 (s, 2H), 5.77-5.72 (m, 1H), 4.07 (br s, 1H), 3.69-3.62 (m, 2H), 3.35-3.27 (m, 2H), 3.14-3.06 (m, 2H), 2.31-2.23 (m, 2H), 2.12-2.07 (m, 2H), 1.58 (t, 2H, J=6.4 Hz), 1.34 (s, 9H), 1.10 (s, 6H), 1.00-0.94 (m, 2H).
Reaction SMILES: [CH2:1]([O:4][CH3:5])[C:2]#[CH:3].I[C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1/[C:9](=[CH:17]/[C:18]1[NH:19][CH:20]=[CH:21][C:22]=1[O:23][CH3:24])/[C:10](=[O:16])[NH:11]2>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.CN(C=O)C.CCN(CC)CC>[CH3:5][O:4][CH2:1][C:2]#[C:3][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1/[C:9](=[CH:17]/[C:18]1[NH:19][CH:20]=[CH:21][C:22]=1[O:23][CH3:24])/[C:10](=[O:16])[NH:11]2
Reactant: C#CCOC
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(I)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCC#Cc1cccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2

Procedure:
Using Method C above, methyl propargyl ether (34 mg, 0.49 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (150 mg, 0.41 mmol) (Starting Material 2 supra) using (Ph3P)2PdCl2 (20 mg) and Cul (10 mg) as catalyst in DMF (2 mL) and Et3N (2 mL) as solvent at 70° C. for 18 h to yield (Z)-1,3-dihydro-4-(3-methoxy-1-propynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 69 mg, 55%).
Reaction SMILES: [N+:1]([C:4]1[C:13](Cl)=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2)([O-:3])=[O:2].[CH3:15][NH:16][CH3:17]>>[N+:1]([C:4]1[C:13]([N:16]([CH3:17])[CH3:15])=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2)([O-:3])=[O:2]
Reactant: CNC
Reactant: O=[N+]([O-])c1c(Cl)ccc2ncccc12
Product: CN(C)c1ccc2ncccc2c1[N+](=O)[O-]

Procedure:
5-Nitro-6-chloroquinoline, prepared as described by Manske & Kulka, Organic Reactions, Vol. VII, 59 (1953) and Campbell et al., J. Am. Chem. Soc., 68, 1559 (1946), was allowed to react with dimethylamine to yield 5-nitro-6-dimethylaminoquinoline. This material was converted to the title compound by the procedure described in Example 33.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[N:8]=[CH:7][C:6]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][NH:14][C:13](=[O:17])[CH:12]=2)=[CH:5][CH:4]=1.Br[C:21]1[CH:22]=[CH:23][C:24]2[C:25]3[CH2:34][N:33]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:32][CH2:31][C:26]=3[N:27]([CH3:30])[C:28]=2[CH:29]=1>>[CH3:30][N:27]1[C:28]2[CH:29]=[C:21]([N:14]3[CH:15]=[CH:16][C:11]([O:10][CH2:9][C:6]4[CH:7]=[N:8][C:3]([C:2]([F:1])([F:18])[F:19])=[CH:4][CH:5]=4)=[CH:12][C:13]3=[O:17])[CH:22]=[CH:23][C:24]=2[C:25]2[CH2:34][N:33]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:32][CH2:31][C:26]1=2
Reactant: Cn1c2c(c3ccc(Br)cc31)CN(C(=O)OC(C)(C)C)CC2
Reactant: O=c1cc(OCc2ccc(C(F)(F)F)nc2)cc[nH]1
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(C(F)(F)F)nc5)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CC2
Yield: 40.1 %

Procedure:
4-((6-(Trifluoromethyl)pyridin-3-yl)methoxy)pyridin-2(1H)-one (177 mg, 0.655 mmol) and tert-butyl 7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (200 mg, 0.54 mmol) were reacted following the procedure of Example 30 (step g) to provide the title compound (120 mg, 40%) as a yellow oil: 1H NMR (300 MHz, CDCl3) δ 8.80 (s, 1H), 7.95 (d, J=8.1 Hz, 1H), 7.76 (d, J=8.0 Hz, 1H), 7.51 (d, J=7.9 Hz, 1H), 7.35 (d, J=8.0 Hz, 1H), 7.28 (m, 1H), 7.01 (d, J=8.1 Hz, 1H), 6.06-6.04 (m, 2H), 5.16 (s, 2H), 4.65-4.60 (br m, 2H), 3.89-3.79 (br m, 2H), 3.63 (s, 3H), 2.87-2.78 (br m, 2H), 1.50 (s, 9H).
Reaction SMILES: [OH-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:10][O:11][C:12]([CH:14]1[CH2:19][CH2:18][CH2:17][N:16]2[C:20](=[O:40])[C:21]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)=[C:22]([C:23]3[CH:28]=[CH:27][N:26]=[C:25](S(C)(=O)=O)[N:24]=3)[N:15]12)=[O:13].O>C1COCC1>[CH3:10][O:11][C:12]([C@@H:14]1[CH2:19][CH2:18][CH2:17][N:16]2[C:20](=[O:40])[C:21]([C:33]3[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=3)=[C:22]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([O:9][C:3]4[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=4)[N:24]=3)[N:15]12)=[O:13]
Reactant: COC(=O)C1CCCn2c(=O)c(-c3ccc(F)cc3)c(-c3ccnc(S(C)(=O)=O)n3)n21
Reactant: Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)[C@@H]1CCCn2c(=O)c(-c3ccc(F)cc3)c(-c3ccnc(Oc4ccccc4)n3)n21
Yield: 54 %

Procedure:
NaOH (0.112 g, 2.8 mmol) is added to a solution of phenol (0.316 g, 3.36 mmol) in THF (100 mL). 2-(4-Fluorophenyl)-3-(2-methanesulfonylpyrimidin-4-yl)-1-oxo-5,6,7,8-tetrahydro-1H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid methyl ester, 32, (0.5 g) is dissolved in THF (50 mL) and added dropwise to the solution over 5 minutes. The resulting mixture is stirred at room temperature for 8 hours after which water (20 mL) is added. The solution is extracted with ethyl acetate (100 mL the organic layer washed with brine (50 mL) and concentrated in vacuo to afford 0.278 g (54% yield) of the desired product as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 1.75 (m, 2 H), 1.97 (m 1 H), 2.42 (d, J=12.8 Hz, 1 H), 3.27 (m, 1 H), 3.27 (m, 1 H), 3.6 (s, 3 H), 4.5 (br d, J=12.8 Hz, 1 H), 5.25 (m, 1 H), 6.87 (d, J=5.7 Hz, 1 H), 7.05 (m, 2H), 7.23 (m, 2 H), 7.35 (m, 3 H), 7.52 (m, 2 H), 8.42 (d, J=5.7 Hz, 1 H): exact mass calc. for C25H21FN4O4 460.46, MS-ESI (M+1) 461.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[CH2:13][CH2:14][CH2:15][C@@H:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][S:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=2)[CH2:18][C@@H:17]1[C:32]([O:34]C)=[O:33].[ClH:36]>CO.[OH-].[Na+].O>[ClH:36].[ClH:36].[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[CH2:13][CH2:14][CH2:15][C@@H:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][S:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=2)[CH2:18][C@@H:17]1[C:32]([OH:34])=[O:33]
Reactant: COC(=O)[C@H]1CN(CCSc2cccc(F)c2)CC[C@H]1CCCc1ccnc2ccc(OC)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc2nccc(CCC[C@@H]3CCN(CCSc4cccc(F)c4)C[C@@H]3C(=O)O)c2c1
Temperature: 60 °C
Reaction time: 20 h

Procedure:
A mixture of 0.54 g of methyl (3R,4R)-4-[3-(6-methoxyquinolin-4-yl)propyl]-1-[2-(3-fluorophenylthio)ethyl]piperidine-3-carboxylate in 4 cm3 of methanol and 0.8 cm3 of 5N aqueous sodium hydroxide was heated with stirring at 60° C. for 20 hours. After evaporating the solvents under reduced pressure (5 kPa) at a temperature in the region of 40° C. the residue obtained was taken up in 10 cm3 of water and then acidified with 0.4 cm3 of concentrated hydrochloric acid. The solution was evaporated under the same conditions and then the residue obtained was triturated in a dichloromethane/methanol (90/10 by volume) mixture. The insoluble material was filtered off and washed with 5 cm3 of dichloromethane. The filtrate was dried over sodium sulfate and then concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The residue was triturated in 10 cm3 of diisopropyl ether and then 1 cm3 of a 5N solution of hydrochloric acid in diisopropyl ether was added with stirring. The crystals were separated by filtration and then washed with 2 times 5 cm3 of diisopropyl ether. After drying in the air, 0.45 g of (3R,4R)-4-[3-(6-methoxyquinolin-4-yl)propyl]-1-[2-(3-fluorophenylthio) ethyl]piperidine-3-carboxylic acid dihydrochloride was obtained in the form of an amorphous solid with a pale yellow color which melts in the region of 140° C. with softening.
Reaction SMILES: Cl.[NH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH:6]=[CH:5][CH:4]=[CH:3]1.C(Cl)Cl.Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18]>Cl>[CH2:20]([O:19][C:17]([N:2]1[CH2:3][CH2:4][C:5]2[CH:6]=[CH:7][CH:12]=[CH:11][C:10]=2[CH2:9][CH2:8]1)=[O:18])[CH3:21]
Reactant: CCOC(=O)Cl
Reactant: C1=CNc2ccccc2C=C1
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)N1CCc2ccccc2CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
To a stirred solution of benzazepine hydrochloride (5.0 g, 27.2 mmol) in DCM (˜50 ml) diisopropyl ethylamine (10.4 ml, 59.8 mmol) was added at 0° C., followed by dropwise addition of ethyl chloroformate (2.86 ml, 29.9 mmol). The reaction was stirred at 0° C. for 1 hour and then allowed to warm to room temperature over 2 hours. LCMS indicated reaction was complete, and 1N HCl (˜100 ml) was added to the reaction. The layers were separated and the aqueous layer was extracted with additional DCM (2×). The combined DCM extracts were washed with brine and dried over Na2SO4. The solvent was evaporated in vacuo and the residue purified by silica-gel chromatography (gradient elution: 0 to 40% EtOAc in hexanes) to provide the sub-title product as an oil (5.5 g). 1HNMR (CDCl3) δ 7.14 (s, 4H), 4.18 (q, J=7.2 Hz, 2H), 3.61 (bs, 4H), 2.92 (bs, 4H), 1.29 (t, J=7.2 Hz, 3H); MS: ESI (positive): 220 (M+H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:2]=1.[F:13][C:14]([F:30])([F:29])[C:15]1[O:19][N:18]=[C:17]([C:20]2[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=2)[C:23](O)=[O:24])[N:16]=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH2:8][CH2:9][N:10]([C:23]([C:22]3[CH:26]=[CH:27][CH:28]=[C:20]([C:17]4[N:16]=[C:15]([C:14]([F:29])([F:13])[F:30])[O:19][N:18]=4)[CH:21]=3)=[O:24])[CH2:11][CH2:12]2)[CH:2]=1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: c1cncc(N2CCNCC2)c1
Product: O=C(c1cccc(-c2noc(C(F)(F)F)n2)c1)N1CCN(c2cccnc2)CC1
Yield: 47 %

Procedure:
This compound was synthesized from 1-(pyridin-3-yl)piperazine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described for example 37 step 3 (110 mg, yield 47%). 1H NMR (400 MHz, DMSO-d6) δ 8.32-8.31 (m, 1H), 8.18-8.15 (dt, J=6.7 Hz, 2.0 Hz, 1H), 8.08 (m, 1H), 8.03-8.02 (m, 1H), 7.76-7.71 (m, 2H), 7.36-7.33 (ddd, J=8.5 Hz, 3.0 Hz, 1.2 Hz, 1H), 7.25-7.22 (m, 1H), 3.81 (m, 2H), 3.50 (m, 2H), 3.21 (m, 4H). MS (ESI) m/z: Calculated for C19H16F3N6O2: 403.13. found: 404.2 (M+H)+
Reaction SMILES: [Br:1][CH:2]([CH2:6][O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([OH:5])=[O:4].S(Cl)(Cl)=O.[CH3:19]O>>[Br:1][CH:2]([CH2:6][O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([O:5][CH3:19])=[O:4]
Reactant: O=C(O)C(Br)COCc1ccccc1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)C(Br)COCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
A solution of 2-bromo-3-[(phenylmethyl)oxy]propanoic acid (6 g, 23.2 mmol) in methanol (40 ml) at rt under argon was treated with thionyl chloride (1.7 ml, 23.2 mmol) and the reaction was then stirred at rt for 3 h and then evaporated to give product as a yellow oil (6.3 g, 99%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:15]([CH3:18])=[C:11]([C:12]([OH:14])=O)[C:10]=1[C:19]([OH:21])=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OC(=O)C)(=O)C>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:15]([CH3:18])=[C:11]2[C:12]([O:21][C:19](=[O:20])[C:10]=12)=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(OCc2ccccc2)c(C(=O)O)c1C(=O)O
Solvent: CC(=O)OC(C)=O
Product: Cc1ccc(OCc2ccccc2)c2c1C(=O)OC2=O

Procedure:
The crude phthalic acid prepared above is heated in 150 ml acetic anhydride for two hours. The solvent is removed under reduced pressure and the crystalline residue collected and washed with ether. The anhydride may be recrystallized from nitromethane to give an analytical sample m.p. 200°-203°C.
Reaction SMILES: C([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([CH2:12][NH:13][C:14]([N:16]2[CH2:21][CH2:20][C:19]3([C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:23](=[O:30])[O:22]3)[CH2:18][CH2:17]2)=[O:15])[CH2:8][CH2:7]1)=[O:5])C.O.O[Li].O>C1COCC1>[C:4]([C@H:6]1[CH2:7][CH2:8][C@H:9]([CH2:12][NH:13][C:14]([N:16]2[CH2:17][CH2:18][C:19]3([C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:23](=[O:30])[O:22]3)[CH2:20][CH2:21]2)=[O:15])[CH2:10][CH2:11]1)([OH:5])=[O:3]
Reactant: CCOC(=O)[C@H]1CC[C@H](CNC(=O)N2CCC3(CC2)OC(=O)c2ccccc23)CC1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: O=C1OC2(CCN(C(=O)NC[C@H]3CC[C@H](C(=O)O)CC3)CC2)c2ccccc21

Procedure:
Dissolve. 1′-(trans-4-ethoxycarbonyl-cyclohexylmethyl)carbamoyl-spiro[isobenzofuran-1,4′piperidin]-3-one (21 mg, 0.05 mmol) in THF (2 mL) and add an equal volume of water. Add LiOH·H2O (11 mg, 0.26 mmol) to this mixture and heat at 60° C. for 3 hours with stirring. Evaporate the THF under reduced pressure, dilute the residue with water and acidify with 3N HCL. Extract the aqueous mixture with EtOAc, wash with brine, dry (Na2SO4) and concentrate under reduced pressure to obtain 1′-(trans-4-carboxy-cyclohexylmethyl)carbamoyl-spiro[isobenzofuran-1,4′piperidin]-3-one as a white solid.
Reaction SMILES: CS[C:3](=[O:14])[C:4]([C:6]1[N:7]=[C:8]([NH:11][CH:12]=[O:13])[S:9][CH:10]=1)=[O:5].[OH-:15].[Na+].Cl>O>[CH:12]([NH:11][C:8]1[S:9][CH:10]=[C:6]([C:4](=[O:5])[C:3]([OH:14])=[O:15])[N:7]=1)=[O:13]
Reactant: CSC(=O)C(=O)c1csc(NC=O)n1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=CNc1nc(C(=O)C(=O)O)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.6 %

Procedure:
In 200 ml of water is suspended 23 g of 2-(2-formylaminothiazol-4-yl)thioglyoxylic S-acid methyl ester, and 125 ml of a 2N aqueous sodium hydroxide solution was added thereto dropwise with water-cooling over a period of 30 minutes, after which the resulting mixture was stirred at room temperature for 1 hour. After completion of the reaction, the thus obtained reaction mixture was adjusted to pH 2.5 with 6N hydrochloric acid. The deposited crystals were collected by filtration, washed successively with water and acetone, and then dried to obtain 16.2 g (81.6% yield) of 2-(2-formylaminothiazol-4-yl)glyoxylic acid having a melting point of above 210° C.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=1)[OH:4].O=[C:13]([CH3:27])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:18][CH:17]=1.C1C=CC=CC=1.C([BH3-])#N.[Na+]>CO>[CH3:26][O:25][C:23]([CH2:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][CH2:14][CH:13]([NH:1][CH2:2][CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=2)[OH:4])[CH3:27])=[CH:21][CH:20]=1)=[O:24]
Reactant: NCC(O)c1cccc(F)c1
Reactant: COC(=O)Cc1ccc(OCC(C)=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)Cc1ccc(OCC(C)NCC(O)c2cccc(F)c2)cc1
Yield: 25.3 %

Procedure:
Following a procedure similar to that described in Example 6, but using 2 g of 2-amino-1-(3-fluorophenyl)ethanol (prepared as described in Preparation 13), 3.44 g of methyl 4-(2-oxopropoxy)phenylacetate (prepared as described in Preparation 3), 60 ml of benzene, 60 ml of absolute methanol and 3.6 g of sodium cyanoborohydride, 1.18 g of the title compound were obtained as crystals, melting at 52° C.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:13][C@H:12]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[NH:21][C:22]([C:24]4[C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[CH:27]=[CH:26][CH:25]=4)=[N:23][C:16]=23)[CH2:11][C@H:10]1[CH2:34][OH:35])(C(C)(C)C)(C)C.Cl[S:37]([NH2:40])(=[O:39])=[O:38].Cl.C([O-])([O-])=O.[Na+].[Na+]>CC(N(C)C)=O.O>[S:37](=[O:39])(=[O:38])([O:35][CH2:34][C@@H:10]1[CH2:11][C@@H:12]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[NH:21][C:22]([C:24]4[C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[CH:27]=[CH:26][CH:25]=4)=[N:23][C:16]=23)[CH2:13][C@@H:9]1[OH:8])[NH2:40]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1C[C@H](Oc2ccnc3[nH]c(-c4cccc5ccccc45)nc23)C[C@H]1CO
Reactant: NS(=O)(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: NS(=O)(=O)OC[C@@H]1C[C@@H](Oc2ccnc3[nH]c(-c4cccc5ccccc45)nc23)C[C@@H]1O
Reaction time: 0.02 h
Yield: 25.1 %

Procedure:
To a solution of ((1S,2S,4R)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-{[2-(1-naphthyl)-3H-imidazo[4,5-b]pyridin-7-yl]oxy}cyclopentyl)methanol (0.0624 g, 0.000127 mol) in DMA (2.00 mL) was added chlorosulfonamide (0.0736 g, 0.000637 mol) and the mixture was stirred for 1.0 min. To this was added 12 M of hydrochloric acid in water (2.00 mL) dropwise at 0° C. and the mixture was stirred for 10 min. The mixture was added dropwise to 50 mL of a 2N Na2CO3 solution, and was extracted by CH2Cl2 (3×30 ml). The combined organic layers were concentrated and the residue was purified by flash chromatography (0 to 10% MeOH/EtOAc) to provide the title compound (14.5 mg, 25%) as a white solid. 1H NMR (CD3OD, 400 MHz) δ: 8.49 (m, 1H,), 8.28 (m, 1H), 8.06 (d, 1H, J=8.3 Hz), 7.97 (m, 1H), 7.87 (dd, 1H, J=7.0 Hz, J=1.0 Hz) 7.63-7.54 (m, 3H), 6.89 (d, 1H, J=5.8 Hz) 5.40 (bs, 1H), 4.45 (dt, 1H, J=4.9 Hz, J=1.9 Hz), 4.35 (dd, 1H, J=7.2 Hz, J=2.5 Hz), 4.19 (dd, 1H, J=7.2 Hz, J=2.5 Hz), 2.62 (m, 1H), 2.44-2.39 (m, 1H), 2.31-2.25 (m, 1H), 2.18-2.14 (m, 2H). LC/MS: Rt=1.55 min, E+ 455 (AA standard).