Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[N:21]=[CH:20][C:19]([CH2:22][O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:30][C:31]([O:33]C)=[O:32])=[CH:18][CH:17]=1.O1CCCC1.[OH-].[Na+].Cl>O.CO>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[N:21]=[CH:20][C:19]([CH2:22][O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:30][C:31]([OH:33])=[O:32])=[CH:18][CH:17]=1
Reactant: COC(=O)Cc1ccccc1OCc1ccc(OCCc2nc(-c3ccccc3)oc2C)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(COc2ccccc2CC(=O)O)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 86 %

Procedure:
To a mixture of methyl 2-[2-[[6-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]-3-pyridyl]methoxy]phenyl]acetate (0.60 g), tetrahydrofuran (3 mL) and methanol (3 mL) was added a 1N aqueous sodium hydroxide solution (3 mL), and the mixture was stirred at room temperature for 4 hrs. 1N Hydrochloric acid (3 mL) and water were added to the reaction mixture and the precipitated crystals were collected by filtration and dried with air to give crystals (0.50 g, 86%) of 2-[2-[[6-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]-3-pyridyl]methoxy]phenyl]acetic acid. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 159-160° C.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[OH:11])=[C:4]([O:12][CH3:13])[N:3]=1.[CH3:14][C:15]1([CH3:23])[O:20][CH:19](C)[CH:18](I)[CH2:17][O:16]1.[C:24](=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(Cl)(Cl)Cl>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[O:11][CH2:24][CH:18]2[CH2:17][O:16][C:15]([CH3:14])([CH3:23])[O:20][CH2:19]2)=[C:4]([O:12][CH3:13])[N:3]=1
Reactant: O=C([O-])[O-]
Reactant: CC1OC(C)(C)OCC1I
Reactant: COc1nc(N)nc2c1ncn2O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: COc1nc(N)nc2c1ncn2OCC1COC(C)(C)OC1
Temperature: 20 °C
Reaction time: 3 h
Yield: 69.8 %

Procedure:
A mixture of 2-amino-9-hydroxy-6-methoxypurine (50 mg, 0.276 mmol), 2,2-dimethyl-5-iodo-methyl-1,3-dioxan (70.6 mg, 0.276 mmol), potassium carbonate (40.1 mg, 0.290 mmol) and dimethylformamide (1 ml) was stirred at 20° C. for 3 hours. The suspension was diluted with chloroform (2 ml), filtered and the filtrate evaporated to dryness. The residue was chromatographed on silica gel (eluted with chloroform-ethanol, 100:1) yielding the title compound (59.6 mg, 70%). IR: νmax (KBr) 3396, 1640, 1581, 1480, 1390 cm-1 ; 1H NMR: δH [(CD3)2SO] 1.32 (3H, s, CH3), 1.35 (3H, s, CH3), 2.00 (1H, m, CH), 3.77 (2H, dd, J=11.8, 6.1 Hz, 2×H(ax)), 3.96 (3H, s, OCH3), 3.99 (2 H, dd, J=11.8, 4.1 Hz, 2×H(eq)), 4.36 (2H, d, J=6.8 Hz, CH2ON), 6.60 (2H, br.s, D2O exchangeable, NH2), 8.14 (1H, s, H-8). Found: C, 50.67; H, 6.31; N, 22.00%; m/e 309.1425. C13H19N5O4 +0.2 EtOH requires: C, 50.53; H, 6.41; N, 21.99%; m/e 309.1434.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:16]=[C:15]([Sn](CCCC)(CCCC)CCCC)[CH:14]=[C:6]([C:7]([N:9]([CH3:13])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=1.[CH3:31][C:32](=[CH2:36])[C:33](Cl)=[O:34].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C(Cl)(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:16]=[C:15]([C:33](=[O:34])[C:32]([CH3:36])=[CH2:31])[CH:14]=[C:6]([C:7]([N:9]([CH3:13])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=1
Reactant: C=C(C)C(=O)Cl
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(C(=O)OC)cc(C(=O)N(C)CCC)c1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClC(Cl)Cl
Product: C=C(C)C(=O)c1cc(C(=O)OC)cc(C(=O)N(C)CCC)c1
Temperature: 60 °C

Procedure:
Dissolve N-methyl-N-propyl-5-tributylstannanyl-isophthalamic acid methyl ester (885 mg, 168 mmol), 2-methyl-acryloyl chloride (172 mg, 1.64 mmol), tris(dibenzylideneacetone)dipalladium (46 mg, 0.05 mmol) and tricyclohexylphosphine (46 mg, 0.16 mmol)) in chloroform (15.5 mL) in a previously degassed vessel. Flush the mixture with nitrogen gas and heat the sealed mixture overnight at 60° C. Cool to room temperature and filter though a filtering agent. Concentrate the filtrate and purify (silica gel chromatography, eluting with 0:100 to 20:80 ethyl acetate:hexanes) to give the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[S:12][C:3]=12.[O:17]([C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(OCCO)C>[O:17]([C:24]1[CH:25]=[CH:26][C:27]([NH:28][C:2]2[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]3[C:10]4[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=4[S:12][C:3]=23)=[CH:29][CH:30]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: N#Cc1cnc2c(sc3ccccc32)c1Cl
Reactant: Nc1ccc(Oc2ccccc2)cc1
Solvent: CCOCCO
Product: N#Cc1cnc2c(sc3ccccc32)c1Nc1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 59.8 %

Procedure:
A mixture of 250 mg (1.02 mmol) of 4-chlorobenzo[4,5]thieno[3,2-b]pyridine-3-carbonitrile and 210 mg (1.12 mmol) of 4-phenoxyaniline in 5 mL of 2-ethoxyethanol is heated at reflux temperature for 4 hours then stirred at room temperature for 3 days. The reaction mixture is then heated at reflux temperature for an additional 6 hours, then cooled to room temperature and partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer is dried over sodium sulfate, filtered and concentrated in vacuo to provide 240 mg (60%) of a beige solid, mp 230-233° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([NH2:12])[CH2:8][CH:9]([CH3:11])[CH3:10].[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[O:23][CH2:24][CH2:25]Cl>CS(C)=O.O>[CH2:7]([NH:12][CH2:25][CH2:24][O:23][C:14]1[CH:15]=[CH:16][C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]=1)[CH2:8][CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)CCN
Reactant: ClCCOc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)CCNCCOc1ccc2ccccc2c1
Temperature: 140 °C

Procedure:
A mixture of anhydrous potassium carbonate (10 gm, in excess) and isoamylamine (0.24 ml, 0.003 mole) was taken in dry DMSO (40 ml). Now 2-(2-naphthyloxy)-1-chloroethane (0.5 gm, 0.002 mole) was added in it. Reaction mixture was refluxed at 140° C. for 6 hrs and the reaction was completed as checked by TLC. Reaction mixture was poured in distilled water (60 ml) and extracted with ethyl acetate thrice. The organic layer was separated and concentrated to get oily compound which was later crystallized by benzene hexane to get N-(isoamyl)-(2-(naphthalen-2-yloxy)-ethyl)amine, solid, m.p. 91° C., (yield 0.51 gm, 81%).
Reaction SMILES: IC.[OH:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][O:7][C:8]2=[O:13].[C:14](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:14][O:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][O:7][C:8]2=[O:13]
Reactant: O=C1OCc2c(O)cccc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cccc2c1COC2=O
Reaction time: 8 h
Yield: 93.2 %

Procedure:
Iodomethane (1.313 mL, 20.78 mmol) was added to 4-hydroxyisobenzofuran-1(3H)-one (3.12 g, 20.78 mmol) and potassium carbonate (5.74 g, 41.56 mmol) in DMF (50 mL) at 21° C. under air. The resulting solution was stirred overnight. The solvent was removed to give a yellow solid which was then quenched with potassium carbonate (70 ml). The mixture was extracted ethyl acetate (3×75 ml). The combined extracts were evaporated to give the desired material as a yellow solid (3.18 g, 93% yield), which was used without further purification; 1H NMR (400.132 MHz, CDCl3) δ 3.30 (2H, s), 5.37 (2H, s), 7.31-7.42 (2H, m), 7.51-7.61 (1H, m).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](Cl)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:11]([O-])(=O)[CH3:12].[K+].[C:16](=[O:19])([O-])[O-].[Na+].[Na+]>C(O)CCC>[CH:9]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=[C:7]([O:19][C:16]2[CH:12]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH:8]=1
Reactant: CC(=O)[O-]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCCCO
Product: O=[N+]([O-])c1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 200 °C

Procedure:
A 250 ml shaker bomb is charged with 79 g (0.50 mole) p-nitrochlorobenzene, 43 g n-butanol, 3 g (0.03 mole) potassium acetate, and 30 g (0.28 mole) sodium carbonate. The reactor is purged with nitrogen and heated to and maintained at 200° C. under autogenous pressure for 9 hours. No increase in pressure is observed and no 4,4'-dinitrodiphenyl ether is formed. This example illustrates that the reaction will not proceed using a protic solvent.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:13])[OH:12])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:16]([O:18][P:19]([CH2:24]OS(C1C=CC(Cl)=CC=1)(=O)=O)(=[O:23])[O:20][CH2:21][CH3:22])[CH3:17].O>CS(C)=O>[C:5]([O:13][C:11]([NH:10][CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:24][P:19](=[O:23])([O:18][CH2:16][CH3:17])[O:20][CH2:21][CH3:22])=[CH:7][CH:6]=1)=[O:12])([CH3:8])([CH3:6])[CH3:4]
Reactant: CCOP(=O)(COS(=O)(=O)c1ccc(Cl)cc1)OCC
Reactant: O=C(O)NCCc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOP(=O)(COc1ccc(CCNC(=O)OC(C)(C)C)cc1)OCC

Procedure:
A solution of 2-(4-hydroxyphenyl)ethylcarbamic acid, t-butyl ester1 (4.0 g, 16.9 mMol) in dry DMSO (37.5 ml) was cooled in an ice-bath and treated with sodium hydride (80% in mineral oil 0.557 g, 1.1 equiv) with stirring under argon according to the method described by Cornforth2. When effervescence ceased a solution of 4-chlorobenzenesulfonyloxymethylphosphonate diethyl ester (6.07 g, 1.05 equiv) in dry DMSO (110 ml) was added and the resulting pale yellow solution stirred at room temperature overnight. The mixture was then poured into water (550 ml) and extracted with diethyl ether/ethyl acetate (1:1, 3×150 ml) and finally ethyl acetate (3×100 ml). The combined extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated to dryness. The resulting oil was purified by chromatography on silica gel with a gradient of 3:2 pentane:ethyl acetate rising to 100% ethyl acetate to give the title compound as a colourless viscous oil.
Reaction SMILES: [OH:1][CH:2]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:21]=[C:20]([C:22]3[O:26][N:25]=[C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:23]=3[C:33]([F:36])([F:35])[F:34])[O:19][N:18]=2)=[CH:13][CH:12]=1)[C:3]([NH:5][CH2:6][CH2:7][C:8](O)=[O:9])=[O:4].C[N:38]1[CH2:43][CH2:42][O:41]C[CH2:39]1.[CH3:44]N(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:1][CH:2]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:21]=[C:20]([C:22]3[O:26][N:25]=[C:24]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:23]=3[C:33]([F:36])([F:34])[F:35])[O:19][N:18]=2)=[CH:13][CH:12]=1)[C:3]([NH:5][CH2:6][CH2:7][C:8]([N:38]1[CH2:43][C:42]([OH:41])([CH3:44])[CH2:39]1)=[O:9])=[O:4]
Reactant: O=C(O)CCNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CN1CCOCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC1(O)CN(C(=O)CCNC(=O)C(O)c2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)cc2)C1
Reaction time: 1 h
Yield: 28 %

Procedure:
(R/S)-3-(2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)propanoic acid (Int-V, 25 mg, 0.050 mmol), 4-methylmorpholine (20.13 mg, 0.199 mmol), 3-methylazetidin-3-ol, HCl (6.15 mg, 0.050 mmol), and HATU (24.60 mg, 0.065 mmol) were added to DMF (1 mL). This was stirred for 1 h before it was purified by prep HPLC (Sun Fire C18 5u19×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 10 min, 20 mL/min, 220 nM, product retention=11.3 min) to provide (R/S)-2-hydroxy-N-(3-(3-hydroxy-3-methylazetidin-1-yl)-3-oxopropyl)-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (9 mg, 0.014 mmol, 27.8% yield): LCMS=572.3 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.16-8.20 (2 H, m), 7.54-7.74 (7 H, m), 5.11 (1 H, s), 3.96-4.04 (2 H, m), 3.81-3.87 (2 H, m), 3.47-3.52 (2 H, m), 2.36-2.43 (2 H, m), 1.44 (3 H, d, J=6.60 Hz); HPLC peak RT=8.3 min (Method A).
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][C@H:8]3[C:7](=[O:16])[NH:6][C:5]=2[CH:4]=1.Cl.Cl.[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[C:22]([CH3:32])[CH:21]=1.[I-].C(C[P+](C)(C)C)#N.C(N(CC)C(C)C)(C)C>C(#N)CC>[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][N:29]([CH2:2][C:3]3[CH:12]=[N:11][C:10]4[N:9]5[CH2:13][CH2:14][CH2:15][C@H:8]5[C:7](=[O:16])[NH:6][C:5]=4[CH:4]=3)[CH2:28][CH2:27]2)=[C:22]([CH3:32])[CH:21]=1
Reactant: O=C1Nc2cc(CO)cnc2N2CCC[C@@H]12
Reactant: Cc1cc(F)ccc1N1CCNCC1
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: Cc1cc(F)ccc1N1CCN(Cc2cnc3c(c2)NC(=O)[C@@H]2CCCN32)CC1
Temperature: 105 °C
Yield: 56.8 %

Procedure:
(S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (100 mg, 0.456 mmol), 1-(4-fluoro-2-methylphenyl)piperazine dihydrochloride (122 mg, 0.456 mmol), (cyanomethyl)trimethylphosphonium iodide (166 mg, 0.684 mmol) and N,N-diisopropylethylamine (0.398 ml, 2.281 mmol) were suspended in propiononitrile (Volume: 1.370 ml) and heated in a closed vial at 90-120° C. for 4 h. The reaction mixture became a dark brown solution. It was cooled to room temperature, concentrated in vacuo, dissolved in DMSO (2 mL) and purified using HPLC (basic, 45-95% ACN in water, basic). The fractions were concentrated in vacuo and the resulting solid was recrystallized from water-MeOH (2:1, 6 mL) and dried in vacuum to afford (S)-3-((4-(4-fluoro-2-methylphenyl)piperazin-1-yl)methyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (102.3 mg, 0.259 mmol, 56.7% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.80-2.02 (m, 3H) 2.09-2.20 (m, 1H) 2.23 (s, 3H) 2.37-2.49 (m, 4H) 2.77 (br. s., 4H) 3.34-3.44 (m, 3H) 3.52-3.65 (m, 1H) 3.93-4.03 (m, 1H) 6.88-7.07 (m, 4H) 7.62 (s, 1H) 10.44 (s, 1H). [M+H] calc'd for C22H26FN5O, 396; found, 396.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([N:14]2[CH2:19][CH2:18][CH:17]([N:20]3[CH2:25][CH2:24][NH:23][C:22](=[O:26])[CH2:21]3)[CH2:16][CH2:15]2)[CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12].[F:27][CH2:28][CH2:29]I>CN(C=O)C.C1COCC1>[F:27][CH2:28][CH2:29][N:23]1[CH2:24][CH2:25][N:20]([CH:17]2[CH2:18][CH2:19][N:14]([C:7]3[CH:8]=[CH:9][C:10]([N+:11]([O-:13])=[O:12])=[C:5]([O:4][CH3:3])[CH:6]=3)[CH2:15][CH2:16]2)[CH2:21][C:22]1=[O:26]
Reactant: COc1cc(N2CCC(N3CCNC(=O)C3)CC2)ccc1[N+](=O)[O-]
Reactant: FCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cc(N2CCC(N3CCN(CCF)C(=O)C3)CC2)ccc1[N+](=O)[O-]
Reaction time: 0.75 h
Yield: 75.6 %

Procedure:
NaH (60% dispersion in mineral oil, 0.174 g, 4.35 mmol) was washed two times with hexanes. 10 mL of DMF and 5 mL of THF was added via syringe. 4-{1-[3-(Methyloxy)-4-nitrophenyl]-4-piperidinyl}-2-piperazinone (0.970 g, 2.90 mmol) in 20 mL of DMF and 10 mL of THF was added slowly via syringe. The reaction was stirred for 45 min, and 1-fluoro-2-iodoethane (0.28 mL, 3.4 mmol) was added via syringe. The reaction was stirred overnight and quenched by the addition of H2O. The mixture was poured into EtOAc and H2O, and the layers were separated. The organic layer was washed with brine, and the combined aqueous layers were extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography to afford 0.834 g (76%) of the title compound of step B. 1H NMR (400 MHz, DMSO-d6) δ 7.83 (d, J=9.0 Hz, 1H), 6.55 (dd, J=9.4, 2.5 Hz, 1H), 6.46 (d, J=2.4 Hz, 1H), 4.55 (t, J=4.9 Hz, 1H), 4.44 (t, J=4.9 Hz, 1H), 4.07-3.94 (m, 2H), 3.86 (s, 3H), 3.58 (t, J=4.9 Hz, 1H), 3.51 (t, J=5.1 Hz, 1H), 3.34-3.22 (m, 2H), 3.11 (s, 2H), 2.99-2.86 (m, 2H), 2.68 (t, J=5.2 Hz, 2H), 2.57-2.46 (m, 1H), 1.89-1.76 (m, 2H), 1.49-1.32 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Cl.Cl[CH2:13][C:14]1[N:15]([CH2:19][C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=2)[CH:16]=[CH:17][N:18]=1>CN(C=O)C>[Cl:27][C:22]1[CH:21]=[C:20]([CH:25]=[C:24]([Cl:26])[CH:23]=1)[CH2:19][N:15]1[CH:16]=[CH:17][N:18]=[C:14]1[CH2:13][O:8][C:4]1[CH:3]=[C:2]([NH2:1])[CH:7]=[CH:6][CH:5]=1
Reactant: ClCc1nccn1Cc1cc(Cl)cc(Cl)c1
Reactant: Nc1cccc(O)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1cccc(OCc2nccn2Cc2cc(Cl)cc(Cl)c2)c1
Reaction time: 0.17 h
Yield: 70 %

Procedure:
3-Aminophenol (87 mg, 0.8 mmol) was dissolved in DMF and NaH (33 mg, 0.83 mmol) was added. After 10 min, 2-(chloromethyl)-1-(3,5-dichlorobenzyl)-1H-imidazole hydrochloride (see Example 1) (100 mg, 0.32 mmol) was added in one portion. After 20 min, the reaction was partitioned between water (10 mL) and EtOAc (10 mL). The layers were separated and the aqueous layer was re-extracted with EtOAc (1×10 mL). The combined organic layers were washed with 1M NaOH (3×10 mL), water (10 mL) and brine, dried over MgSO4, filtered and concentrated to yield the title compound as a pale yellow oil (78 mg, 70%); MS m/z 348 [C17H15Cl2N3O+H]+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)=[CH:10][C:9]([CH:22]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:23]([O:25]CC)=[O:24])=[CH:8][C:7]=2[S:32][CH3:33])[CH2:3][CH2:2]1.CO.O.O[Li].O>C1COCC1>[CH:1]1([CH2:4][O:5][C:6]2[C:11]([C:12]3[CH:13]=[CH:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=3)=[CH:10][C:9]([CH:22]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:23]([OH:25])=[O:24])=[CH:8][C:7]=2[S:32][CH3:33])[CH2:3][CH2:2]1
Reactant: CCOC(=O)C(CC(C)C)c1cc(SC)c(OCC2CC2)c(-c2ccc(C(F)(F)F)cc2)c1
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CSc1cc(C(CC(C)C)C(=O)O)cc(-c2ccc(C(F)(F)F)cc2)c1OCC1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.6 %

Procedure:
To a stirred solution of ethyl 2-(6-(cyclopropylmethoxy)-5-(methylthio)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate (80 mg, 0.166 mmol) in a mixture of THF (10 mL), methanol (10 mL) and water (5 mL) was added LiOH.H2O (20 mg, 0.832 mmol) at room temperature and the mixture was stirred at RT for 2 h. After complete consumption of starting material as monitored by TLC, the reaction mixture was diluted with water (10 mL) and acidified using 1 N HCl at 0° C. The aqueous layer was extracted with EtOAc (2×20 mL); combined organic extracts were washed with water (10 mL), brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuo. The crude material was purified by column chromatography to afford 2-(6-(cyclopropylmethoxy)-5-(methylthio)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid (38 mg) as an off white solid. 1HNMR (500 MHz) (CDCl3): δ (ppm) 7.75 (d, 2H), 7.65 (d, 2H), 7.31 (s, 1H), 7.23 (s, 1H), 3.65 (t, 1H), 3.60 (d, 2H), 2.82 (s, 3H), 1.98 (m, 1H), 1.65 (m, 1H), 1.5 (m, 1H), 1.22 (m, 1H), 0.9 (d, 6H), 0.38 (d, 2H), 0.01 (d, 2H).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[CH:9][NH:10][CH:11]=[C:5]2[C:4]([CH2:12][CH:13]([CH3:15])[CH3:14])=[N:3]1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[CH2:21]Cl.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.Cl>[CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[CH:9][N:10]([CH2:21][C:20]3[CH:23]=[C:24]([O:28][CH3:29])[C:25]([O:26][CH3:27])=[C:18]([O:17][CH3:16])[CH:19]=3)[CH:11]=[C:5]2[C:4]([CH2:12][CH:13]([CH3:15])[CH3:14])=[N:3]1
Reactant: COc1cc(CCl)cc(OC)c1OC
Reactant: CC(C)Cc1nn(C)c(=O)c2c[nH]cc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cc(Cn2cc3c(CC(C)C)nn(C)c(=O)c3c2)cc(OC)c1OC
Reaction time: 16 h

Procedure:
A mixture of 2,6-dihydro-2-methyl-4(2-methylpropyl)-1H-pyrrolo[3,4-d]pyridazin-1-one (Example 18 step a, 0.031 g), 3,4,5-trimethoxybenzyl chloride (0.038 g), and cesium carbonate (0.090 g) in dry dimethyl formamide (0.8 ml) was stirred for 16 hours, and then diluted with dilute hydrochloric acid. The mixture was extracted with ethyl acetate, which was washed with brine, dried, and evaporated to a solid. The solid was purified by chromatography on silica (dichloromethane/ethanol 9:1) to give 2,6-dihydro-2-methyl-4-(2-methylpropyl)-6-[3,4,5-trimethoxyphenyl]methyl-1H-pyrrolo[3,4-d]pyridazin-1-one (0.033 g).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]1.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=O.II.[BH4-].[Na+]>CO.O1CCCC1.O>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12][N:1]1[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]1
Reactant: OC1CCNC1
Reactant: COc1cccc(C=O)c1
Agent: II
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1cccc(CN2CCC(O)C2)c1
Temperature: 0 °C
Reaction time: 5 h
Yield: 24.7 %

Procedure:
To pyrrolidin-3-ol (3.4 g, 39 mmol) in methanol (150 mL) was added 3-methoxybenzaldehyde (6.4 g, 47 mmol) and iodine (0.40 g, 32 mmol). After stirring for 5 h, the reaction mixture was cooled to 0° C. and sodium borohydride (2.9 g, 78 mmol) was added portionwise. The reaction mixture was warmed to ambient temperature and stirred overnight. Water (10 mL) was added and most of the tetrahydrofuran was removed in vacuo. Additional water (25 mL) was added and the aqueous layer was extracted with methylene chloride (50 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (methylene chloride to 90:9:1 methylene chloride/methanol/ammonium hydroxide) to provide 1-(3-methoxybenzyl)pyrrolidin-3-ol (2.0 g, 25%) as a yellow oil: 1H NMR (DMSO-d6, 300 MHz) δ 7.21 (dd, J=8.1, 8.1 Hz, 1H), 6.87-6.77 (m, 3H), 4.66 (d, J=4.5 Hz, 1H), 4.21-4.14 (m, 1H), 3.73 (s, 3H), 3.56-3.45 (m, 2H), 2.64 (dd, J=9.6, 6.3 Hz, 1H), 2.58-2.49 (m, 1H), 2.43-2.34 (m, 1H), 2.28 (dd, J=9.6, 7.5 Hz, 1H), 2.04-1.92 (m, 1H), 1.57-1.51 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[C:12]([F:15])([F:14])[F:13])[NH:8][C:7](C(O)=O)=[C:6]2[CH3:19].Cl>N1C2C(=CC=CC=2)C=CC=1.CCOC(C)=O.[Cu]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[C:12]([F:15])([F:13])[F:14])[NH:8][CH:7]=[C:6]2[CH3:19]
Reactant: COc1cc2c(C)c(C(=O)O)[nH]c2cc1C(F)(F)F
Agent: [Cu]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccc2ncccc2c1
Product: COc1cc2c(C)c[nH]c2cc1C(F)(F)F
Yield: 53 %

Procedure:
To a solution of 5-Methoxy-3-methyl-6-trifluoromethyl-1H-indole-2-carboxylic acid (2.0 g, 7 mmol) in 5 ml quinoline was added copper powder (50 mg), and the reaction mixture was heated to reflux for 1.5 hours. Copper powder (50 mg) was added, and the reaction mixture was refluxed for 1 hour. The reaction mixture was cooled, diluted with EtOAc, poured into 50 ml 6 N HCl, and extracted with EtOAc. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed (10% EtOAc/Hexanes) to give 5-Methoxy-3-methyl-6-trifluoromethyl-1H-indole (850 mg, 51%) as a solid.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:6]12[O:12][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11]2>O>[N:1]1([C@H:6]2[CH2:11][CH2:10][CH2:9][CH2:8][C@@H:7]2[OH:12])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: C1CCC2OC2C1
Solvent: O
Product: O[C@H]1CCCC[C@@H]1N1CCCC1
Yield: 87.4 %

Procedure:
Pyrrolidine (10.5 g, 148 mmol), cyclohexene oxide (15 mL, 148 mmol) and water (5 mL) were refluxed under nitrogen for 7 h. The cooled, orange mixture was partitioned between saturated sodium hydroxide aq (150 mL) and diethyl ether (150 mL). The aqueous layer was back-washed with diethyl ether (75 mL) and the combined diethyl ether layers were dried over sodium sulfate. The diethyl ether was removed in vacuo the residual oil was vacuum distilled (bp 51° C. at full vacuum) to give (1R,2R)/(1S,2S)-2-(Pyrrolidinyl)cyclohexan-1-ol (21.9 g, 87%). 13C NMR (50 MHz, APT, CDCl3) δ 70.47 (−), 64.82 (−), 47.44 (+), 33.15 (+), 25.11 (+), 24.23 (+), 24.00 (+), 21.12 (+).