Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:12][C:13]1[CH:14]=[C:15]2[C:19]3=[C:20]([CH2:22][O:23][CH2:24][CH2:25][N:18]3[C@H:17]3[CH2:26][CH2:27][NH:28][CH2:29][C@@H:16]23)[CH:21]=1.I[CH2:31][CH3:32].C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1>[CH2:31]([N:28]1[CH2:27][CH2:26][C@@H:17]2[N:18]3[CH2:25][CH2:24][O:23][CH2:22][C:20]4[CH:21]=[C:13]([NH:12][C:3]5[CH:4]=[CH:5][CH:6]=[C:7]([C:8]([F:10])([F:11])[F:9])[C:2]=5[F:1])[CH:14]=[C:15]([C:19]3=4)[C@@H:16]2[CH2:29]1)[CH3:32]
Reactant: Fc1c(Nc2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCOC3)cccc1C(F)(F)F
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN1CC[C@H]2[C@@H](C1)c1cc(Nc3cccc(C(F)(F)F)c3F)cc3c1N2CCOC3
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a solution of (7bR,11aS)-N-[2-fluoro-3-(trifluoromethyl)phenyl]-1,2,7b,8,9,10,11,11a-octahydro-4H-[1,4]oxazepino[6,5,4-hi]pyrido[4,3-b]indol-6-amine free base from EXAMPLE 95 (41 mg, 0.1 mmol) in 5 mL tetrahydrofuran was added iodoethane (0.020 mL, 0.22 mmol) and sodium carbonate (21 mg, 0.22 mmol). The reaction was stirred at 60° C. for 3 h and then was cooled, quenched with water, extracted with ethyl acetate, washed with brine, dried (MgSO4) and concentrated. The residue was purified by preparative HPLC (C18 reverse phase column, elution with a H2O/CH3CN gradient with 0.5% TFA) and the product containing fractions were concentrated, free-based with aq ammonium hydroxide, extracted with chloroform, washed with brine, dried (K2CO3) and concentrated to afford the title compound of EXAMPLE 144. 1H NMR(CDCl3) δ: 7.15 (t, 1H, J=7.3 Hz), 7.05-6.95 (m, 2H), 6.91 (d, 1H, J=1.9 Hz), 6.77 (d, 1H, J=1.8 Hz), 5.73 (d, 1H, J=2.9 Hz), 4.63 (ABq, 2H, JAB=14.3 Hz), 4.25 (app d, 1H, J=12.9 Hz), 3.75 (app t, 1H), 3.43-3.36 (m, 2H), 3.27 (dd, 1H, J=12.8, 2.9 Hz), 2.97-2.80 (m, 2H), 2.75 (app t, 1H), 2.55-2.45 (m, 2H), 2.40-2.30 (m, 1H), 2.15-2.00 (m, 2H), 1.88 (app t, 1H), 1.15 (t, 3H, J=7.2 Hz). LRMS (ES)+: 436.4 (M+H)+.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7](OB(O)O)=[CH:6][CH:5]=1)[CH2:2][CH3:3].[Br:14][C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][C:16]=1[F:22].C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[Br:14][C:15]1[CH:20]=[CH:19][C:18]([C:7]2[CH:8]=[CH:9][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][CH:6]=2)=[CH:17][C:16]=1[F:22]
Reactant: CCCc1ccc(OB(O)O)cc1
Reactant: Fc1cc(I)ccc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCO
Product: CCCc1ccc(-c2ccc(Br)c(F)c2)cc1
Temperature: 25 °C
Yield: 43.5 %

Procedure:
A solution of 16.5 g of 4-propylphenylboric acid as dissolved in 130 ml of ethanol was dropwise added to a mixture comprising 30 g of 1-bromo-2-fluoro-4-iodobenzene, 1.6 g of tetrakistriphenylphosphine palladium(O), 186 ml of benzene and 140 ml of 2M aqueous sodium carbonate solution, in nitrogen atmosphere at room temperature. The reaction solution was then refluxed for 5 hours, cooled to room temperature, extracted with chloroform and washed three times with water, and chloroform was removed by distillation. The residue formed was distilled under reduced pressure (b.p. 155° to 170° C./3 mmHg) to obtain 11.7 g of 4-bromo-3-fluoro-4'-propylbiphenyl.
Reaction SMILES: Br[C:2]1[N:6]([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])[N:5]=[C:4]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[N:3]=1.C(N(CC)CC)C.[C:36]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)#[CH:37]>O1CCCC1>[F:28][C:25]1[CH:26]=[CH:27][C:22]([C:4]2[N:3]=[C:2]([C:37]#[C:36][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[N:6]([CH2:7][C:8]([N:10]3[CH2:15][CH2:14][N:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=4)[CH2:12][CH2:11]3)=[O:9])[N:5]=2)=[CH:23][CH:24]=1
Reactant: O=C(Cn1nc(-c2ccc(F)cc2)nc1Br)N1CCN(c2ccccn2)CC1
Reactant: C#Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Cn1nc(-c2ccc(F)cc2)nc1C#Cc1ccccc1)N1CCN(c2ccccn2)CC1
Temperature: 70 °C
Reaction time: 2 h
Yield: 4.8 %

Procedure:
20 mg triphenylphosphinpalladium(II)chloride and 5 mg cupper(I)iodide were added to 100 mg 2-(5-bromo-3-(4-fluoro-phenyl)-(1,2,4)triazol-1-yl]-1-(4-pyridin-2-yl-piperazin-1-yl)-ethanone, 250 μl triethylamine and 45 mg ethynyl-benzene acid in 5 mL tetrahydrofuran. The reaction was stirred 2 h at 70° C. The reaction was filltered and evaporated. The residue was purified by HPLC to give 5 mg desired product. Rt: 1.24 min (method B), (M+H)+: 467
Reaction SMILES: [CH2:1]([N:3]1C=CC(=O)C(OCC2C=CC=CC=2)=C1COC)C.[CH2:21]([O:23][CH2:24][C:25]1O[C:27]([CH3:40])=[CH:28][C:29](=[O:39])[C:30]=1[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH3:22].CN>>[CH3:1][N:3]1[C:27]([CH3:40])=[CH:28][C:29](=[O:39])[C:30]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[C:25]1[CH2:24][O:23][CH2:21][CH3:22]
Reactant: CCn1ccc(=O)c(OCc2ccccc2)c1COC
Reactant: CCOCc1oc(C)cc(=O)c1OCc1ccccc1
Agent: CN
Product: CCOCc1c(OCc2ccccc2)c(=O)cc(C)n1C
Yield: 61.1 %

Procedure:
In an analogous procedure in the preparation of 1-ethyl-2-methoxymethyl-3-benzyloxy-pyridin-4(1H)-one using 2-(1-ethoxymethyl)-3-benzyloxy-6-methyl-pyran-4(1H)-one 5.76 g (20 mmol, 1 eq.) and 4.65 g (60 mmol, 3 eq.) of 40% aqueous methylamine yielded the title compound (3.68 g, 61.1%) after purification by column chromatography on silica gel (eluant: 15% CH3OH/85% CHCl3) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:9])=[CH:4][CH:3]=1.[Mn]([O-])(=O)(=O)=[O:18].[K+].C(=O)=O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:10]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:18])=[O:9])=[CH:6][CH:7]=1
Reactant: O=C(Cc1ccccc1)c1ccc(Cl)cc1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: O=C=O
Agent: [K+]
Solvent: c1ccncc1
Product: O=C(C(=O)c1ccc(Cl)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 25.1 %

Procedure:
A benzene solution containing 51.2 g 4-chlorophenylacetic acid and 39.3 g thionyl chloride is refluxed for 6 hours and the solvent removed. The crude reaction product is added dropwise to a slurry of 40 g aluminum chloride in 200 ml benzene maintaining the temperature below 50° C. After addition the reaction is refluxed for 1.5 hours. After cooling, the mixture is poured into ice and the resulting white solid is separated yielding 61.3 g of crude product. The product is taken up in methylene chloride and washed with 5% sodium hydroxide solution followed by water, dried over sodium sulfate and stripped yielding 49.3 g (71%) of >95% pure 4'-chlorodeoxybenzoin. 15 g of 4-chlorodeoxybenzoin is dissolved in 105 ml pyridine. An aqueous solution containing 15 g potassium permanganate is added and the reaction stirred for 6 hours at room temperature using dry ice to buffer the pH near 7. The mixture is extracted with methylene chloride, the extract washed with water, dried over Na2SO4 and stripped. The residue is recrystallized from ethanol yielding 6.1 g of white plate-like crystals which is identified as starting material. Concentration of the mother liquor yields 4 g of 4-chlorobenzil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:10]2[CH2:15][CH2:14][C:13]3([C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[NH:17][C:16]3=[O:24])[CH2:12][CH2:11]2)=[N:4][CH:5]=[N:6][C:7]=1[NH:8][CH3:9].[N:25]1[CH:30]=[C:29]([CH:31]=O)[CH:28]=[N:27][CH:26]=1.Cl>C(O)C>[CH3:9][N:8]1[C:31]([C:29]2[CH:30]=[N:25][CH:26]=[N:27][CH:28]=2)=[N:1][C:2]2[C:7]1=[N:6][CH:5]=[N:4][C:3]=2[N:10]1[CH2:11][CH2:12][C:13]2([C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][C:16]2=[O:24])[CH2:14][CH2:15]1
Reactant: CNc1ncnc(N2CCC3(CC2)C(=O)Nc2ccccc23)c1N
Reactant: O=Cc1cncnc1
Agent: Cl
Solvent: CCO
Product: Cn1c(-c2cncnc2)nc2c(N3CCC4(CC3)C(=O)Nc3ccccc34)ncnc21
Temperature: 80 °C
Yield: 28.3 %

Procedure:
To a solution of 1′-[5-amino-6-(methylamino)pyrimidin-4-yl]spiro[indole-3,4′-piperidin]-2(1H)-one (100 mg, 0.30 mmol) in anhydrous ethanol (12 mL) were added pyrimidine-5-carbaldehyde (38 mg, 0.35 mmol, Apollo Scientific Ltd.) and catalytic amount of hydrochloric acid (0.05 mL, 4N, Dioxane, Aldrich). The reaction mixture was heated to 80° C. for 18 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The product was purified by preparatory HPLC (reverse-phase, acetonitrile/water with 0.1% formic acid) to give 35.0 mg (28% yield) of the title compound.
Reaction SMILES: [C:1](Cl)(=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.N1C=CC=CC=1.[NH2:18][C:19]1[CH:40]=[CH:39][C:22]([CH2:23][O:24][C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][CH:34]=2)[CH2:31][CH:30]([CH2:35][N:36]([CH3:38])[CH3:37])[CH2:29][CH2:28]3)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[CH3:38][N:36]([CH2:35][CH:30]1[CH2:29][CH2:28][C:27]2[C:32](=[CH:33][CH:34]=[C:25]([O:24][CH2:23][C:22]3[CH:21]=[CH:20][C:19]([NH:18][C:1](=[O:10])[C:2]4[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=4)=[CH:40][CH:39]=3)[CH:26]=2)[CH2:31]1)[CH3:37]
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CN(C)CC1CCc2cc(OCc3ccc(N)cc3)ccc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)Nc2ccc(COc3ccc4c(c3)CCC(CN(C)C)C4)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
p-Anisoyl chloride (0.20 ml) was added dropwise to pyridine solution (6 ml) of 6-[(4-aminobenzyl)oxy]-2-[(N,N-dimethylamino)methyl]tetralin (300 mg) under ice-cooling, which was stirred at room temperature for 30 minutes. 10% aqueous potassium carbonate solution was added to the reaction mixture, and extraction was conducted using ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried, and then concentrated. The residue was purified using alumina column chromatography (development solvent: ethyl acetate), and recrystallized (THF-IPE) to give the titled compound (300 mg).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:6][CH2:5]1.[C:23]12[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=1)[NH:28]C(=O)[O:26][C:24]2=O.C([O-])(O)=O.[Na+]>CN(C)C1C=CN=CC=1.CN(C=O)C>[NH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:23]=1[C:24]([N:2]([CH3:1])[CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:6][CH2:5]1)=[O:26]
Reactant: CNCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(CC1CCN(C(c2ccccc2)c2ccccc2)CC1)C(=O)c1ccccc1N
Yield: 65.9 %

Procedure:
Step 3): A solution of 4-(N-methylamino)methyl-1-diphenylmethylpiperidine (1.8 g, 6.0 mmol), isatoic anhydride (0.9 g, 5.5 mmol) and 4-dimethylaminopyridine (0.74 g) in DMF (25 ml) was stirred at room temperature for 2 hours. The reaction mixture was poured into 1% NaHCO3 solution and extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate and hexane) to give 2-amino-N-methyl-N-[(1-diphenylmethylpiperidin-4-yl)methyl]benzamide (1.5 g, 67%).
Reaction SMILES: [N+:1]([C:4]1[CH:34]=[CH:33][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:27]=[CH:26][C:25]([N+:28]([O-])=O)=[CH:24][CH:23]=4)=[CH:17][C:16]=3[CH3:31])=[C:11]([CH3:32])[CH:10]=2)=[CH:6][CH:5]=1)([O-])=O.O.C>CN(C=O)C.[Pt]>[NH2:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][C:18]2[CH:19]=[CH:20][C:15]([C:12]3[CH:13]=[CH:14][C:9]([O:8][C:7]4[CH:33]=[CH:34][C:4]([NH2:1])=[CH:5][CH:6]=4)=[CH:10][C:11]=3[CH3:32])=[C:16]([CH3:31])[CH:17]=2)=[CH:23][CH:24]=1
Reactant: Cc1cc(Oc2ccc([N+](=O)[O-])cc2)ccc1-c1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1C
Agent: [Pt]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(Oc2ccc(N)cc2)ccc1-c1ccc(Oc2ccc(N)cc2)cc1C
Reaction time: 3 h
Yield: 85.2 %

Procedure:
4,4'-Bis(4-nitrophenoxy)-2,2'-dimethylbiphenyl (80 g) was dissolved in 350 ml of DMF and added carefully to a hydrogenation bottle containing 8 gm of 5% Pt/C. The solution was subjected to hydrogenation at 100° C. for 3 hours. Then 100 ml of water and 3 g of decolorizing charcoal were added and heated for 5 min. The solution was then filtered through a Celite pad and 1000 ml of water was added. The reaction mixture became a mixture of fluffy solid and a sticky resin and was stirred for 1 hour to give a tan colored solid. The solid was removed by filtration, crushed with a mortar and pestel and then stirred with 1000 ml of water for 1 hour. The solid was collected by filtration and dried to afford 59.2 g (85%) of the product mp=140° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[CH:20]=[N:19][N:18]=[C:17]2[CH2:21][N:22]2[C:26](=[O:27])[C:25]3=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]3[C:23]2=[O:32])=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].[Cl:33]N1C(=O)CCC1=O>C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[C:17]([CH2:21][N:22]3[C:26](=[O:27])[C:25]4=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]4[C:23]3=[O:32])=[N:18][N:19]=[C:20]2[Cl:33])=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8]
Reactant: O=C(c1ccccc1)c1cc(Br)ccc1-n1cnnc1CN1C(=O)c2ccccc2C1=O
Reactant: O=C1CCC(=O)N1Cl
Solvent: c1ccccc1
Product: O=C(c1ccccc1)c1cc(Br)ccc1-n1c(Cl)nnc1CN1C(=O)c2ccccc2C1=O

Procedure:
5-Bromo-2-[3-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]-benzophenone (0.01 mole) and N-chlorosuccinimide (0.013 mole) in benzene is stirred and refluxed under a nitrogen atmosphere for 7 hours to give 5-bromo-2-[3-chloro-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([CH:14]=[CH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[N:3]=1.[C:23]([O:27][C:28]([NH:30][C@H:31]1[CH2:36][CH2:35][CH2:34][CH2:33][C@H:32]1[NH2:37])=[O:29])([CH3:26])([CH3:25])[CH3:24].C(N(CC)CC)C>C1(C)C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:23]([O:27][C:28]([NH:30][C@@H:31]1[CH2:36][CH2:35][CH2:34][CH2:33][C@@H:32]1[NH:37][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([CH:14]=[CH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[N:3]=1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Reactant: COc1ccc2nc(C=Cc3ccc(Cl)cc3)nc(Cl)c2c1
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1ccc2nc(C=Cc3ccc(Cl)cc3)nc(N[C@H]3CCCC[C@H]3NC(=O)OC(C)(C)C)c2c1
Yield: 96.5 %

Procedure:
A solution of 391 mg of 4-chloro-2-(4-chlorostyryl)-6-methoxyquinazoline, 379 mg of cis-2-(tert-butoxycarbonyl)aminocyclohexylamine, and 358 mg of triethylamine in 20 mL of toluene was combined with a catalytic amount of 4-dimethylaminopyridine, and heated under reflux for 20 hours. After distilling the reaction solution off, the residue was combined with water, extracted with chloroform, dried over magnesium sulfate, and concentrated. The residue was purified by column chromatography on silica gel (chloroform:methanol=50:1) to obtain 580 mg of the desirable compound.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][NH:8]2)([O-:3])=[O:2].[H-].[Na+].I[CH3:16].O>CN(C)C=O>[CH3:16][N:8]1[C:9]2[C:5](=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[CH:11][CH:10]=2)[CH:6]=[N:7]1
Reactant: O=[N+]([O-])c1cccc2[nH]ncc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ncc2c([N+](=O)[O-])cccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 17.7 %

Procedure:
To a solution of 4-nitro indazole [WO-A-0135947] (5.0 g, 31 mmol) in dimethylformamide at 0° C. was added sodium hydride (1.34 g of a 60% dispersion in oil, 34 mmol). The mixture was stirred at room temperature for 10 minutes. Iodomethane (2.28 ml, 37 mmol) was added and the reaction stirred at room temperature for 90 minutes. Water (500 ml) was added and the reaction extracted into ethyl acetate (3×200 ml). The combined organic layers were washed with water (2×200 ml) then dried (Mg2SO4) and evaporated. Trituration overnight in dichloromethane/hexane gives 0.97 g of pure 1-methyl-4-nitro-1H-indazole. The remaining solution was condensed and purified by column chromatography on silica eluting with 40-20% hexane in dichloromethane to give additional 1-methyl-4-nitro-1H-indazole (1.30 g, total 2.27 g, 42%) as the less polar product 1H NMR (360 MHz, CDCl3) 4.18 (3H, s), 7.52 (1H, t, J 8.0), 7.77 (1H, d, J 8.4), 8.15 (1H, d, J 7.7), 8.61 (1H, s); and as the more polar, 2-methyl-4-nitro-2H-indazole (1.50 g, 28%). 1H NMR (400 MHz, CDCl3) 4.32 (3H, s), 7.40 (1H, t, J 8.0), 8.07 (1H, d, J 8.6), 8.18 (1H, d, J 7.6), 8.55 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[OH-].[K+].[F:14][C:15]([F:19])=[C:16]([F:18])[F:17]>CN(C)C=O.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:11][C:16]([F:18])([F:17])[CH:15]([F:19])[F:14]
Reactant: FC(F)=C(F)F
Reactant: O=[N+]([O-])c1ccc(O)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1ccc(OC(F)(F)C(F)F)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.83 h

Procedure:
20 Grams of 2-chloro-4-nitrophenol was dissolved in 200 ml of N,N-dimethylformamide, and 3.4 g of potassium hydroxide was added thereto. Tetrafluoroethylene was blown into the resulting solution at an inner temperature of 50° C., after which stirring was continued for 50 minutes at an inner temperature of 50° C. Thereafter, 3.5 g of potassium hydroxide was added to the stirred solution and the resulting solution was further stirred for 6 hours at an inner temperature of 100° C. The reaction solution was poured into ice water and extracted with ether. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated. The residue obtained wa subjected to column chromatography on silica gel with chloroform as an eluent to obtain 12.55 g of 3-chloro-4-(1',1',2',2'-tetrafluoroethoxy)nitrobenzene. 1H-NMR (CDCl3): δ(ppm) 8.37(1H, d, J=3 Hz), 8.20(1H, dd, J=9, 3 Hz), 7.57(1H, d, J=9 Hz), 6.07(1H, tt, J=53, 3 Hz)
Reaction SMILES: [OH:1][C@H:2]1[C:10]2[C:5](=[C:6]([C:11]3[N:15]=[C:14]([C:16]4[CH:17]=[CH:18][C:19]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([CH:23]=4)[C:21]#[N:22])[O:13][N:12]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.N1C=CC=CC=1.[C:34](Cl)(=[O:36])[CH3:35]>C(Cl)Cl>[C:34]([O:1][C@H:2]1[C:10]2[C:5](=[C:6]([C:11]3[N:15]=[C:14]([C:16]4[CH:17]=[CH:18][C:19]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([C:21]#[N:22])[CH:23]=4)[O:13][N:12]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1)(=[O:36])[CH3:35]
Reactant: CC(=O)Cl
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@H]4O)no2)cc1C#N
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)O[C@@H]1CCc2c(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)cccc21
Temperature: 25 °C
Reaction time: 96 h
Yield: 91.7 %

Procedure:
To a flask containing (R)-5-(3-(1-hydroxy-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile 5 (36 mg, 0.10 mmol) in DCM (1 mL) was added pyridine (24 μL, 0.3 mmol) and acetyl chloride (21 μL, 0.3 mmol). The reaction was stirred at room temperature for 4 days. The crude reaction mixture was washed with saturated sodium bicarbonate, dried over magnesium sulfate, and purified by chromatography (EA/hexane) to give 37 mg (92%) of (R)-4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl acetate 13 as a white solid. LCMS-ESI (m/z) calculated for C23H21N3O4: 403.2. found 426.1 [M+Na]+, tR=4.19 min. 1H NMR (400 MHz, CDCl3) δ 8.37 (d, J=2.1, 1H), 8.27 (dd, J=8.9, 2.2, 1H), 8.10 (dd, J=7.7, 0.9, 1H), 7.53 (d, J=7.4, 1H), 7.35 (t, J=7.7, 1H), 7.06 (d, J=9.0, 1H), 6.21 (dd, J=7.2, 3.7, 1H), 4.73 (hept, J=6.1, 1H), 3.44 (ddd, J=17.5, 8.3, 6.3, 1H), 3.26 (ddd, J=17.6, 8.7, 4.8, 1H), 2.52 (tdd, J=14.9, 7.9, 6.3, 1H), 2.21-2.06 (m, 1H), 2.02 (s, 3H), 1.41 (d, J=6.1, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH:12]=[O:13])=[N:9][C:8]([C@@H:14]([NH:16][C:17](=[O:33])[O:18][CH2:19][CH:20]1[C:32]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:26]3[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH3:15])=[CH:7]2.[OH:34]OS([O-])=O.[K+].O>CN(C=O)C>[CH:22]1[C:21]2[CH:20]([CH2:19][O:18][C:17]([NH:16][C@H:14]([C:8]3[N:9]=[C:10]([C:12]([OH:34])=[O:13])[C:11]4[C:6]([CH:7]=3)=[CH:5][CH:4]=[CH:3][C:2]=4[Cl:1])[CH3:15])=[O:33])[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]=2[CH:25]=[CH:24][CH:23]=1
Reactant: C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)c1cc2cccc(Cl)c2c(C=O)n1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)c1cc2cccc(Cl)c2c(C(=O)O)n1
Temperature: 25 °C

Procedure:
To a solution of (S)-(9H-fluoren-9-yl)methyl 1-(8-chloro-1-formylisoquinolin-3-yl)ethylcarbamate (348) (12.0 g, 26.3 mmol, 1.0 eq) in DMF (150 mL), OXONE (30 g, 48.78 mmol, 1.85 eq) was added and the resulting mixture was stirred at RT over night. The mixture was poured into water (600 mL) and then filtered. The solid was dissolved in ethyl acetate (100 mL), and then PE (300 mL) was added dropwise to this solution. The precipitate was collected by filtration to afford (S)-3-(1-(((9H-fluoren-9-yl)methoxy)carbonylamino)ethyl)-8-chloroisoquinoline-1-carboxylic acid (349).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH2:15])=[S:7])=[O:4].[Cl:16][CH2:17][C:18](Cl)=[O:19]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([NH:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:18](=[O:19])[CH2:17][Cl:16])=[S:7])=[O:4]
Reactant: O=C(Cl)CCl
Reactant: COC(=O)NC(=S)Nc1ccccc1N
Solvent: Cc1ccccc1
Product: COC(=O)NC(=S)Nc1ccccc1NC(=O)CCl
Temperature: 25 °C
Yield: 66.2 %

Procedure:
A suspension of 1-methoxycarbonyl-3-(2-aminophenyl)thiourea (9.00 g) in toluene (80 ml) was treated with chloroacetyl chloride (4.52 g) at room temperature and the mixture was heated to reflux for 1 hour with stirring. The mixture was then cooled to room temperature and the resultant white solid was filtered off and recrystallised from ethanol to give 1-methoxycarbonyl-3-(2-chloroacetamidophenyl)thiourea (7.98 g ), m.p. 156°-158° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)=[CH:10][C:9]([C@H:22]2[C@H:27]([O:28]CC3C=CC=CC=3)[C@@H:26]([O:36]CC3C=CC=CC=3)[C@H:25]([O:44]CC3C=CC=CC=3)[C@@H:24]([CH2:52][O:53]CC3C=CC=CC=3)[O:23]2)=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][O:7]2>C1COCC1.CO.[Pd]>[Cl:1][C:2]1[C:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)=[CH:10][C:9]([C@H:22]2[C@H:27]([OH:28])[C@@H:26]([OH:36])[C@H:25]([OH:44])[C@@H:24]([CH2:52][OH:53])[O:23]2)=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][O:7]2
Reactant: CCOc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c3c(c2Cl)CCCO3)cc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCOc1ccc(Cc2cc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c3c(c2Cl)CCCO3)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of compound 30 (255 mg, 0.309 mmol) in THF/MeOH (15 mL/15 mL) was added 10% Pd/C (71 mg) at rt. The reaction mixture was stirred at r.t. for 15 hours under hydrogen and filtered off. The filtrate was concentrated in vacuo and the residue was purified using reverse phase preparative HPLC to provide the title compound E012 (51 mg, 36%).