Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH2:8][C:9](=[O:50])[CH:10]([C:12]1[CH:49]=[CH:48][CH:47]=[CH:46][C:13]=1[CH2:14][CH2:15][C:16]1[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][N:19]=[C:18]([NH:26][C:27]2[CH:28]=[CH:29][C:30]([CH:33]3[CH2:38][CH2:37][N:36](C(OC(C)(C)C)=O)[CH2:35][CH2:34]3)=[N:31][CH:32]=2)[N:17]=1)[CH3:11]>C(Cl)Cl>[NH:36]1[CH2:37][CH2:38][CH:33]([C:30]2[N:31]=[CH:32][C:27]([NH:26][C:18]3[N:17]=[C:16]([CH2:15][CH2:14][C:13]4[CH:46]=[CH:47][CH:48]=[CH:49][C:12]=4[CH:10]([CH3:11])[C:9]([NH2:8])=[O:50])[C:21]([C:22]([F:24])([F:23])[F:25])=[CH:20][N:19]=3)=[CH:28][CH:29]=2)[CH2:34][CH2:35]1
Reactant: CC(C(N)=O)c1ccccc1CCc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)nc2)ncc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C(N)=O)c1ccccc1CCc1nc(Nc2ccc(C3CCNCC3)nc2)ncc1C(F)(F)F
Reaction time: 2 h
Yield: 134 %

Procedure:
TFA (0.50 mL, 6.5 mmol) was added to tert-butyl 4-(5-((4-(2-(1-amino-1-oxopropan-2-yl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)pyridin-2-yl)piperidine-1-carboxylate A72 (0.060 g, 0.099 mmol) in DCM (5 mL) and the mixture was stirred for 2 hours. The mixture was concentrated under reduced pressure and quenched with 25% aq. NaOH (20 mL). The aqueous phase was extracted with EtOAc (3×20 mL) before the combined organics were dried (phase separation cartridge) and concentrated under reduced pressure. The suspension was sonicated with hexane and concentrated under reduced pressure to give the title compound (0.066 g, 134% residual solvent/water). LCMS-D: rt 3.025 min; m/z 499.3 [M+H]+.
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH2:9][CH2:10][NH:11][C:12](=[O:16])[C:13]([OH:15])=[O:14].[C:17](Cl)(=[O:21])[C:18]([CH3:20])=[CH2:19]>C1COCC1>[C:17]([O:8][CH2:9][CH2:10][NH:11][C:12](=[O:16])[C:13]([OH:15])=[O:14])(=[O:21])[C:18]([CH3:20])=[CH2:19]
Reactant: O=C(O)C(=O)NCCO
Reactant: C=C(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=C(C)C(=O)OCCNC(=O)C(=O)O
Reaction time: 6 h

Procedure:
To 730.7 g (5 moles) of diethyl oxalate was added dropwise at room temperature a solution of 61.1 g (1 mole) of ethanolamine in 500 ml of acetone and, after the addition finished, treatment of the mixture by distillation under reduced pressure to remove the formed ethanol and the acetone and an excess amount of diethyl oxalate yielded ethyl 2-hydroxyethyloxamate. A mixture of 80.5 g (0.5 moles) of this ethyl 2-hydroxyethyloxamate, 50.6 g (0.5 moles) of triethylamine (hereinafter, referred to as TEA), 20.0 g of water, and 1000 ml of dioxane was warmed under reflux for 8 hours and treated with solvent removal followed by dehydration yielded a triethylamine salt of 2-hydroxyethyloxamic acid. A mixture of 11.7 g (0.05 moles) of this triethylamine salt of 2-hydroxyethyloxamic acid and 5.1 g (0.05 moles) of TEA was treated with dehydration by molecular sieve and then, dissolved with warming into 300 ml of THF. To this THF solution was added dropwise under a refluxing condition during 0.5 hours a solution of 5.2 g (0.05 moles) of methacrylic acid chloride in 30 ml of THF and, after the addition finished, the mixture was further stirred under the condition for 6 hours and treated with fractional extraction to get methacryloyloxyet hyloxamic acid of the following structure: ##STR17## Besides, identification of the methacrylolyloxyethyloxamic acid 1 was carried out with 13C-NMR spectra analysis (ppm, in CDCL3) and the results were 17.93 for (2), 38.86 for (6); 62.35 for (5), 120.59 for (1), 138.86 for (3), 158.01 for (7), 160.56 for (8), and 167.06 for (4).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13](=[O:14])[N:12]3[CH:15]=[CH:16][S:17][C:11]3=[N:10][C:9]=2[CH3:18])=[CH:4][CH:3]=1.[CH2:19](Br)[CH3:20].[H-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[CH2:19]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13](=[O:14])[N:12]3[CH:15]=[CH:16][S:17][C:11]3=[N:10][C:9]=2[CH3:18])=[CH:6][CH:7]=1)[CH3:20]
Reactant: Cc1nc2sccn2c(=O)c1-c1ccc(O)cc1
Reactant: CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOc1ccc(-c2c(C)nc3sccn3c2=O)cc1
Temperature: 80 °C

Procedure:
To a solution of Step 1 intermediate (250 mg, 0.967 mmol) in DMF (4 ml) was added ethyl bromide (0.147 g, 1.355 mmol) and NaH (0.053 g, 1.355 mmol) and heated to 80° C. for 15.0 h. After completion of the reaction, the mixture was diluted with ethyl acetate, washed with water, brine, dried over anhydrous Na2SO4 to afford 300 mg of the desired compound as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.34 (t, J=6.6 Hz, 3H), 2.17 (s, 3H), 4.05 (q, J=6.6 Hz, 2H), 6.93-6.96 (m, 2H), 7.17-7.20 (m, 2H), 7.50 (d, J=4.5 Hz, 1H), 7.98 (d, J=4.8 Hz, 1H); ESI-MS (m/z) 311.28 (M+H)+.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C:13]2[S:14][C:15]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:16]([CH3:18])[N:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH:10]([CH3:12])[CH3:11].[F:24][B-](F)(F)F.O=[N+]=O>C(Cl)Cl>[F:24][C:2]1[CH:3]=[C:4]([C:13]2[S:14][C:15]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:16]([CH3:18])[N:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH:10]([CH3:12])[CH3:11]
Reactant: F[B-](F)(F)F
Reactant: CCOC(=O)c1sc(-c2ccc(OCC(C)C)c(N)c2)nc1C
Agent: O=[N+]=O
Solvent: ClCCl
Product: CCOC(=O)c1sc(-c2ccc(OCC(C)C)c(F)c2)nc1C
Reaction time: 4 h
Yield: 53 %

Procedure:
330 mg of Ethyl 2-(3-amino-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylate was dissolved in 15 ml of methylene chloride, 130 mg of nitronium tetrafluoroborate was added thereto with ice cooling, followed by stirring for 4 hours. The reaction mixture was concentrated, irradiated with a UV lamp at 300 nm for 20 hours and purified by silica gel chromatography to give 175 mg of ethyl 2-(3-fluoro-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylate. This product was hydrolyzed by a conventional process and recrystallized from acetone-water to give 108 mg of 2-(3-fluoro-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid (yield: 35%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:22][C:23]([O:25][CH3:26])=[O:24].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:15][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: COC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 135.6 %

Procedure:
A mixture of diphenylmethyl ester of N-tert-butoxycarbonyl-L-tyrosine (5.00 g), methyl chloroacetate (1.45 g) and potassium carbonate (1.85 g) in N,N-dimethylformamide (75 ml) was stirred for 20 hours at room temperature. The mixture was diluted with water (100 ml) and extracted with ethyl acetate. The extract was washed with diluted hydrochloric acid, aqueous sodium bicarbonate, and then brine. After dried over magnesium sulfate, the extract was evaporated to dryness to give diphenylmethyl ester of N-tert-butoxycarbonyl-O-methoxycarbonylmethyl-L-tyrosine (6.40 g), mp. 69°-73° C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[CH:23]=[C:22]([CH3:32])[C:10]=1[O:11][C:12]1[C:13]2[NH:21][N:20]=[N:19][C:14]=2[N:15]=[C:16](Cl)[N:17]=1.[NH2:33][C:34]1[CH:41]=[CH:40][C:37]([C:38]#[N:39])=[CH:36][CH:35]=1.FC(F)(F)CO>>[CH3:8][C:9]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[CH:23]=[C:22]([CH3:32])[C:10]=1[O:11][C:12]1[C:13]2[NH:21][N:20]=[N:19][C:14]=2[N:15]=[C:16]([NH:33][C:34]2[CH:41]=[CH:40][C:37]([C:38]#[N:39])=[CH:36][CH:35]=2)[N:17]=1
Reactant: Cc1cc(-c2ccncc2)cc(C)c1Oc1nc(Cl)nc2nn[nH]c12
Reactant: N#Cc1ccc(N)cc1
Solvent: OCC(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2ccncc2)cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)nc2nn[nH]c12
Temperature: 90 °C

Procedure:
Trifluoroacetic acid (8 eq) is added to a suspension of 7-(2,6-dimethyl-4-(pyridin-4-yl)phenoxy)-5-chloro-1H-[1,2,3]triazolo[4,5-d]pyrimidine (1 eq) and 4-aminobenzonitrile (4 eq) in 2,2,2-trifluoroethanol (1 ml/0.1 mmol) in a sealed tube. The resulting mixture is heated at 90° C. for 3 days. The reaction is cooled to room temperature, concentrated to dryness and purified by silica gel chromatography.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].[CH2:12]([CH:30]([CH2:34][C:35]([O-])=[O:36])[C:31]([O-])=[O:32])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>C(OCC)(=O)C.S(=O)(=O)(O)O>[CH2:12]([CH:30]1[CH2:34][C:35](=[O:36])[N:1]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[OH:11])[C:31]1=[O:32])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCCCCCCCCCCCCC(CC(=O)[O-])C(=O)[O-]
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCCCCCC1CC(=O)N(c2ccc([N+](=O)[O-])cc2O)C1=O
Temperature: 25 °C

Procedure:
In 3 liters of ethyl acetate and 50 ml of concentrated sulfuric acid were dissolved by heating 150 g of 2-amino-5-nitro-phenol and 350 g of octadecylsuccinate and the resulting solution was boiled under reflux for further 30 hours. Thereafter, the solution was cooled up to room temperature and washed twice with 2 liters of 10% hydrochloric acid and twice with 10% sodium carbonate solution. Then, ethyl acetated was distilled off and the residue was recrystallized from hexane to afford light yellow powdery crystal melting at 115°-120° C. in the yield of 153 g.
Reaction SMILES: [C:1]([C:4]1[C:23]([OH:24])=[CH:22][CH:21]=[CH:20][C:5]=1[O:6][CH2:7][CH:8]([OH:19])[CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)(=[O:3])[CH3:2].[C:25](OCC)(=O)[C:26]([O:28]CC)=[O:27]>CCOCC>[C:26]([C:25]1[O:24][C:23]2[C:4]([C:1](=[O:3])[CH:2]=1)=[C:5]([O:6][CH2:7][CH:8]([OH:19])[CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)[CH:20]=[CH:21][CH:22]=2)([OH:28])=[O:27]
Reactant: COc1ccc(OCC(O)COc2cccc(O)c2C(C)=O)cc1
Reactant: CCOC(=O)C(=O)OCC
Solvent: CCOCC
Product: COc1ccc(OCC(O)COc2cccc3oc(C(=O)O)cc(=O)c23)cc1

Procedure:
A mixture of 1-(2-acetyl-3-hydroxyphenoxy)-2-hydroxy-3-p-methoxyphenoxypropane (13.3 g) and diethyl oxalate (15 ml) was added to alcohol-free sodium ethoxide (prepared from sodium 3.0 g) in absolute ether (100 ml). The mixture was heated under reflux for 1.5 hours during which time a yellow solid separated. The residue was poured onto ice (100 g) and acidified with a solution of acetic acid (12 ml) in water (80 ml). The ether layer was separated and the aqueous solution was extracted with ether (3 × 25 ml). The combined ethereal layers were evaporated and the residue was dissolved in a mixture of acetic acid (80 ml) and hydrochloric acid (30 ml) and heated under reflux for 1 hour. On pouring into water (1 L) an off white solid was precipitated which was collected and recrystallized from acetic acid to give 1-(2-carboxychromon-5-yloxy)-2-hydroxy-3-p-methoxyphenoxypropane (12.0 g) as a white solid, m.p. 125°-126° C.
Reaction SMILES: [CH:1]1([NH:4][CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[N:16]=[CH:15][C:14]([CH3:17])=[CH:13][N:12]=3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[F:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[C:28]1[O:32][CH:31]=[N:30][CH:29]=1)[C:22](O)=[O:23]>>[CH:1]1([N:4]([CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[N:12]=[CH:13][C:14]([CH3:17])=[CH:15][N:16]=3)[CH2:7][CH2:6]2)[C:22](=[O:23])[C:21]2[CH:25]=[CH:26][C:27]([C:28]3[O:32][CH:31]=[N:30][CH:29]=3)=[C:19]([F:18])[CH:20]=2)[CH2:2][CH2:3]1
Reactant: Cc1cnc(N2CCC(NC3CC3)CC2)nc1
Reactant: O=C(O)c1ccc(-c2cnco2)c(F)c1
Product: Cc1cnc(N2CCC(N(C(=O)c3ccc(-c4cnco4)c(F)c3)C3CC3)CC2)nc1

Procedure:
The title compound is prepared from cyclopropyl-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl]-amine and 3-fluoro-4-oxazol-5-yl-benzoic acid following a procedure analogous to that described in Example 17. LC (method 1): tR=1.10 min; Mass spectrum (ESI+): m/z=422 [M+H]+.
Reaction SMILES: C([O:5][C:6](=[O:16])[C@@H:7]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[NH2:8])(C)(C)C.C(N(CC)CC)C.[Cl:24][C:25]1[C:26]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][C:27]=2[S:28][C:29]=1[C:30](Cl)=[O:31]>ClCCl>[Cl:24][C:25]1[C:26]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][C:27]=2[S:28][C:29]=1[C:30]([NH:8][C@H:7]([CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:6]([OH:5])=[O:16])=[O:31]
Reactant: CC(C)(C)OC(=O)[C@H](N)Cc1ccccc1
Reactant: O=C(Cl)c1sc2cc(C(F)(F)F)ccc2c1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(N[C@H](Cc1ccccc1)C(=O)O)c1sc2cc(C(F)(F)F)ccc2c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Following general method B, to a solution of A1 (55.33 mg, 0.25 mmol) in dry dichloromethane (2 mL) at 0° C. was added triethylamine (0.043 mL, 0.28 mmol) and 5 (74.78 mg, 0.25 mmol). The reaction mixture was stirred at room temperature overnight and concentrated under reduced pressure. Then dissolved the oil mixture in 2 mL CH2Cl2 and 2 mL TFA was add under argon. The reaction mixture was stirred at room temperature for 12 h (TLC monitor). The solvent was removed under reduce pressure and the crude compound was purified by flash chromatography on silica gel, using HOAc/ethyl acetate (1:100) as the eluent, gave 5a; (100.64 mg, 94.1%). [α]D25: −21.1 (c=0.30, CHCl3); 1H-NMR (300 MHz, CDCl3): δ 8.12 (s, 1H), 7.93 (d, J=8.7 Hz, 1H), 7.71-7.61 (m, 2H), 7.37-7.26 (m, 5H), 6.83 (s, 1H), 5.17-5.15 (m, 1H), 3.45-3.30 (m, 2H); 13C NMR (300 MHz, CDCl3): δ 175.31, 160.07, 139.09, 137.76, 135.24, 135.13, 129.90, 129.46, 128.84, 127.56, 125.63, 123.89, 122.16, 120.45, 120.40, 119.49, 54.09, 39.26, 29.70; HRMS (ESI): calcd for: C19H13ClF3NO3S [M−H]−=426.0184, obsd [M−H]−=426.0170.
Reaction SMILES: C(=O)(O)[O-].[Na+].[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH3:17])[C:12](=O)[CH2:11]2.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:20]>O1CCCC1>[CH3:17][N:13]1[C:14]2[C:10](=[CH:9][C:8]([O:7][CH3:6])=[CH:16][CH:15]=2)[CH2:11][C:12]1=[S:20]
Reactant: COc1ccc2c(c1)CC(=O)N2C
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CC(=S)N2C
Temperature: 50 °C

Procedure:
18.5 g (0.22 mol) of sodium bicarbonate are added to a solution of 19.5 g (0.11 mol) of 5-methoxy-1-methyl-2-indolinone prepared according to A. H. BECKETT, R. W. DAISLEY and J. WALKER (Tetrahedron 1968, 24 6093) and 16.5 g (0.037 mol) of phosphorus pentasulfide in 200 ml of tetrahydrofuran. The reaction medium is heated to a temperature of 50° C. for 1 h 30 min and then filtered and concentrated on a water bath under vacuum. The residue is taken up with ice-cold water and the mixture is extracted with methylene chloride. The organic phase is washed with saturated sodium chloride solution, dried and evaporated. The residue is used in the next stage without further treatment.
Reaction SMILES: [C:1](=O)(OC(Cl)(Cl)Cl)[O:2]C(Cl)(Cl)Cl.[NH2:13][C:14]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17].[OH-].[Na+].C1(C)C=CC=CC=1>O>[F:23][C:21]1[CH:20]=[CH:19][C:15]2[C:16](=[O:18])[O:17][C:1](=[O:2])[NH:13][C:14]=2[CH:22]=1
Reactant: Nc1cc(F)ccc1C(=O)O
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=c1[nH]c2cc(F)ccc2c(=O)o1
Reaction time: 0.25 h
Yield: 56.1 %

Procedure:
Bis(trichloromethyl) carbonate (3.73 g, 12.57 mmol) was added to a solution of 2-amino-4-fluorobenzoic acid (1.3 g, 8.38 mmol) in sodium hydroxide (2N in water) (8.80 mL, 17.60 mmol) and water (9 mL) at room temperature. The resulting suspension was stirred for 15 minutes then toluene (9.00 mL) was added. The mixture was stirred at room temperature for 18 hours. The resulting precipitate was collected by filtration, washed with water, followed by 20% acetronitrile in Et2O (10 mL) and dried under vacuum at 40° C. to afford 7-fluoro-1H-3,1-benzoxazine-2,4-dione (0.852 g, 56.1%) as a off-white solid.
Reaction SMILES: CC1C=CC(S([O:11][CH2:12][C:13]2([CH2:33][O:34][S:35]([C:38]3[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=3)(=[O:37])=[O:36])[CH2:18][CH2:17][C:16](O)(C3C=CC=C(OC4C=CC=CC=4)C=3)[CH2:15][CH2:14]2)(=O)=O)=CC=1.[OH-:45].[Na+]>C1COCC1.O>[CH3:44][C:41]1[CH:42]=[CH:43][C:38]([S:35]([O:34][CH2:33][C:13]23[CH2:18][CH2:17][C:16]([C:13]4[CH:18]=[CH:17][CH:16]=[C:15]([O:45][C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)[CH:14]=4)([CH2:15][CH2:14]2)[O:11][CH2:12]3)(=[O:37])=[O:36])=[CH:39][CH:40]=1
Reactant: [OH-]
Reactant: Cc1ccc(S(=O)(=O)OCC2(COS(=O)(=O)c3ccc(C)cc3)CCC(O)(c3cccc(Oc4ccccc4)c3)CC2)cc1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCC23CCC(c4cccc(Oc5ccccc5)c4)(CC2)OC3)cc1
Temperature: 25 °C
Yield: 171.6 %

Procedure:
A mixture of (4-hydroxy-4-(3-phenoxyphenyl)cyclohexane-1,1-diyl)bis(methylene) bis(4-methylbenzenesulfonate) (390 mg, 0.612 mmol) and powdered NaOH (320 mg, 8.00 mmol) in THF (5 mL) was refluxed for 24 h. The reaction was cooled to rt, diluted with water, and extracted with EtOAc. The organic layer was dried (MgSO4) and concentrated in vacuo. The crude oil was purified by flash chromatography on SiO2 (0 to 30% EtOAc:hexanes) to afford the title compound (244 mg, 86% yield) as a white solid. LCMS, [M+H]+=465.2. 1H NMR (500 MHz, CDCl3) δ 7.81 (d, J=8.3 Hz, 2H), 7.42-7.36 (m, 2H), 7.37-7.31 (m, 2H), 7.28 (dd, J=9.6, 6.3 Hz, 1H), 7.15-7.08 (m, 3H), 7.03-6.98 (m, 2H), 6.87 (ddd, J=8.1, 2.4, 0.9 Hz, 1H), 3.83 (d, J=1.3 Hz, 2H), 3.77 (s, 2H), 2.49 (s, 3H), 2.09-1.97 (m, 4H), 1.75 (tt, J=9.6, 2.8 Hz, 2H), 1.69-1.60 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6](C2CCCCO2)[N:5]=[CH:4][C:3]=1[O:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[C:18]#[N:19].Cl>CO.O>[Cl:1][C:2]1[C:7](=[O:8])[NH:6][N:5]=[CH:4][C:3]=1[O:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[C:18]#[N:19]
Reactant: N#Cc1ccccc1Oc1cnn(C2CCCCO2)c(=O)c1Cl
Agent: Cl
Solvent: CO
Solvent: O
Product: N#Cc1ccccc1Oc1cn[nH]c(=O)c1Cl
Temperature: 90 °C
Reaction time: 4 h
Yield: 91.6 %

Procedure:
A solution of 2-[5-chloro-6-oxo-1-(tetrahydro-pyran-2-yl)-1,6-dihydro-pyridazin-4-yloxy]-benzonitrile (61.8 g, 0.19 mol) in methanol (370 mL) was treated with a 6N aqueous hydrochloric acid solution (185 mL). The reaction was stirred at 90° C. for 4 h and then was allowed to cool to 25° C. The reaction was diluted with water. The resulting precipitate was collected by filtration, washed with water and dried in vacuo to afford 2-(5-chloro-6-oxo-1,6-dihydro-pyridazin-4-yloxy)-benzonitrile (43.1 g, 94%); ESI-MS 248 [M+H+]; HPLC: >99% (purity). 1H-NMR (300 MHz, DMSO-d6) δ 13.63 (s, 1H), 7.96-7.99 (m, 2H), 7.71-7.77 (m, 1H), 7.37-7.45 (m, 2H).
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1C(C2C=CC=CC=2)=CSC=1C(OC)=O.C(OCC)(OCC)OCC.[Cl:49]C1C=CC(N)=CC=1>C(O)(=O)C>[Cl:49][C:4]1[CH:5]=[CH:6][C:1]([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:10]=3[N:9]=[CH:8]2)=[CH:2][CH:3]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Agent: COC(=O)c1scc(-c2ccccc2)c1N
Solvent: CC(=O)O
Solvent: CCOC(OCC)OCC
Product: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccc(Cl)cc1
Yield: 36 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (60 mg, 0.26 mmol), triethyl orthoformate (0.5 ml), 4-chloroaniline (61 mg, 0.48 mmol), and acetic acid (0.06 ml) were used to give 31.6 mg (0.093 mmol, 36% yield) of the title compound.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)O.[BH4-].[Na+].O>CC(O)C>[N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[C:8]([CH2:6][C:2]2[NH:1][CH:5]=[CH:4][CH:3]=2)[CH:9]=1
Reactant: OC(c1cnc2ccccc2c1)c1ccc[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: c1c[nH]c(Cc2cnc3ccccc3c2)c1
Yield: 80.8 %

Procedure:
To a solution of (1H-pyrrol-2-yl)(3-quinolyl)methanol (40.0 mg) in 2-propanol (3 mL) was added sodium borohydride (33.9 mg), and the mixture was refluxed for one hour. To the mixture was added water, and the mixture was concentrated. The residue was separated using water and ethyl acetate, and the organic layer was dried, filtered, and concentrated. The residue was purified by silica gel column chromatography to give 2-(3-quinolylmethyl)-1H-pyrrole (30.0 mg, 75%).
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].[H-].[Na+].[CH:8]1([CH2:11][N:12]2[CH:17]=[C:16]([C:18]3[C:23]([O:24][C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=4[F:32])=[CH:22][N:21]=[C:20](S(C)(=O)=O)[N:19]=3)[CH:15]=[C:14]([CH3:37])[C:13]2=[O:38])[CH2:10][CH2:9]1>CN(C=O)C>[CH:8]1([CH2:11][N:12]2[C:13](=[O:38])[C:14]([CH3:37])=[CH:15][C:16]([C:18]3[C:23]([O:24][C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=4[F:32])=[CH:22][N:21]=[C:20]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])[N:19]=3)=[CH:17]2)[CH2:10][CH2:9]1
Reactant: Cc1cc(-c2nc(S(C)(=O)=O)ncc2Oc2ccc(F)cc2F)cn(CC2CC2)c1=O
Reactant: CS(N)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(-c2nc(NS(C)(=O)=O)ncc2Oc2ccc(F)cc2F)cn(CC2CC2)c1=O
Yield: 54.1 %

Procedure:
Methanesulfonamide (68 mg, 0.71 mmol), NaH (28 mg, 0.7 mmol, 60% in mineral oil) and the title compound from step 3 (80 mg, 0.18 mmol) in DMF (2 mL) were reacted in a similar manner as Example 152, step 6 to give the title compound (45.00 mg, yield: 54.4%) as an off-white solid. 1H NMR (CDCl3, 400 MHz) δ 8.81 (s, 1H), 8.60 (d, J=2.0 Hz, 1H), 8.14 (s, 1H), 8.12 (s, 1H), 7.05-6.98 (m, 2H), 6.91-6.89 (m, 1H), 3.87 (d, J=7.2 Hz, 2H), 3.45 (s, 3H), 2.23 (s, 3H), 1.25-1.22 (m, 1H), 0.64-0.59 (m, 2H), 0.40-0.37 (m, 2H). LCMS: 463.1 (M+H)+
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[N:9]([CH3:13])[CH:10]=[CH:11][N:12]=2)[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][CH:15]=1.[CH3:23][N:24]1[CH2:29][CH2:28][C:27]2([C:40]3[C:32](=[CH:33][C:34]4[CH2:35][CH2:36][NH:37][C:38]=4[CH:39]=3)[O:31][CH2:30]2)[CH2:26][CH2:25]1.C(N(CC)CC)C>S(Cl)(Cl)=O>[CH3:23][N:24]1[CH2:25][CH2:26][C:27]2([C:40]3[C:32](=[CH:33][C:34]4[CH2:35][CH2:36][N:37]([C:20]([C:17]5[CH:18]=[CH:19][C:14]([C:3]6[CH:4]=[CH:5][C:6]([C:8]7[N:9]([CH3:13])[CH:10]=[CH:11][N:12]=7)=[CH:7][C:2]=6[CH3:1])=[CH:15][CH:16]=5)=[O:22])[C:38]=4[CH:39]=3)[O:31][CH2:30]2)[CH2:28][CH2:29]1
Reactant: Cc1cc(-c2nccn2C)ccc1-c1ccc(C(=O)O)cc1
Reactant: CN1CCC2(CC1)COc1cc3c(cc12)NCC3
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1cc(-c2nccn2C)ccc1-c1ccc(C(=O)N2CCc3cc4c(cc32)C2(CCN(C)CC2)CO4)cc1
Reaction time: 72 h
Yield: 40.7 %

Procedure:
2'-Methyl-4'-(1-methylimidazol-2-yl)biphenyl-4-carboxylic acid (D90, 310 mg, 1.06 mmol) was heated at reflux in thionyl chloride (10 ml) for 30 minutes, cooled, evaporated in vacuo and the orange residue redissolved in dry THF (10 ml). 1'-Methyl-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (D8, 260 mg, 1.06 mmol) and triethylamine (0.15 ml, 1.06 mmol) were added and the mixture stirred for 72 hours. The mixture was evaporated in vacuo, the residue partitioned between H2O and CHCl3 (4 times) and the organics combined, dried over Na2SO4, filtered and evaporated in vacuo. The residue was purified by flash silica-gel chromatography with 2% MeOH/CHCl3 as eluant to yield the title compound as a pale yellow gum (224 mg, 41%) which was converted to the hydrochloride salt.