Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B.[C:2]([N:7]1[CH2:26][CH2:25][N:10]2[CH2:11][C@@H:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[C:18]([C@@H:9]2[CH2:8]1)=[CH:17][CH:16]=[CH:15][CH:14]=3)(=O)[CH2:3][CH2:4][CH3:5].[ClH:27]>O1CCCC1>[ClH:27].[ClH:27].[CH2:2]([N:7]1[CH2:26][CH2:25][N:10]2[CH2:11][C@@H:12]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:13]3[C:18]([C@@H:9]2[CH2:8]1)=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:3][CH2:4][CH3:5]
Reactant: CCCC(=O)N1CCN2C[C@@H](c3ccccc3)c3ccccc3[C@@H]2C1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: CCCCN1CCN2C[C@@H](c3ccccc3)c3ccccc3[C@@H]2C1

Procedure:
To a stirred solution of 1.0 M borane in tetrahydrofuran (100 ml) maintained under nitrogen at ambient temperature was added cis-1,3,4,6,7,11b-hexahydro-2-butyryl-7-phenyl-2H-pyrazino[2,1-a]isoquinoline (8.6 g, 0.021 m) and and the mixtdre heated to reflux for 3 hours, then cooled in an ice bath and carefully treated with 20% HCl (100 ml). This mixture was heated to reflux for 1 hour, then cooled, and the tetrahydrofuran removed on an aspirator. The remaining aqueous solution was basified to pH 11 with 50% NaOH and extracted with chloroform (3×50 ml). The extracts were dried over MgSO4 and evaporated to an oily residue. This was dissolved in methanol (50 ml) and isopropanol (50 ml) and acidified with HCl gas. The white solid, which precipitated immediately, was collected by filtration, recrystallized from methanol/ether, and vacuum dried at 90° for 24 hours to give 5.7 g of cis-1,3,4,6,7,11b-hexahydro- 2-butyl-7-phenyl-2H-pyrazino[2,1-a]isoquinoline dihydrochloride, m.p. 261°-262°.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][N:8]1[C@@H:11]([CH3:12])[C@@H:10]([CH2:13]/[CH:14]=[CH:15]/[Sn](CCCC)(CCCC)CCCC)[C:9]1=[O:29].Br[C:31]1[S:32][CH:33]=[CH:34][CH:35]=1.[OH-].[NH4+].[Cl-].[Na+]>CN(C)C=O.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][N:8]1[C@@H:11]([CH3:12])[C@@H:10]([CH2:13]/[CH:14]=[CH:15]/[C:31]2[S:32][CH:33]=[CH:34][CH:35]=2)[C:9]1=[O:29]
Reactant: Brc1cccs1
Reactant: CCCC[Sn](/C=C/C[C@H]1C(=O)N(OC2CCCCO2)[C@H]1C)(CCCC)CCCC
Agent: Cl[Pd]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: C[C@H]1[C@@H](C/C=C/c2cccs2)C(=O)N1OC1CCCCO1
Temperature: 80 °C
Yield: 54.2 %

Procedure:
To a solution of (3R,4S)-1-(2-tetrahydropyranyloxy)-3-((2E)-3-tributylstannyl-2-propene-1-yl)-4-methylazetidin-2-one (400 mg, 0.78 mmol) in 1 mL of dimethylformamide is added 2-bromothiophene (152 mg, 0.93 mmol) and triphenyphosphine palladium (II) dichloride (27 mg, 0.04 mmol). The resulting solution is heated at 80° C. for 2 h, then 0.5 mL ammonium hydroxide is added. The reaction mixture is poured into saturated sodium chloride solution (20 mL) and extracted with 1:1 ethyl acetate/hexane (50 mL). The combined organic layers were dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by silica gel chromatography (elution with 3:1 hexanes-ethyl acetate) to provide (3R,4S)-1-(2-tetrahydropyranyloxy)-3-((2E)-3-(thiophene-2-yl)-2-propene-1-yl)-4-methylazetidin-2-one as an oil (130 mg, 54% yield).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([OH:13])[C@H:9]1[CH2:14][N:15]1[C:23]2[CH:22]=[CH:21][C:20]([C:24]#[N:25])=[CH:19][C:18]=2[C:17]2[CH2:26][C@H:27]([NH:29][C:30]([O:32][CH:33]([CH3:35])[CH3:34])=[O:31])[CH2:28][C:16]1=2)=O)(C)(C)C.Cl>CO.O1CCOCC1>[CH:33]([O:32][C:30](=[O:31])[NH:29][C@@H:27]1[CH2:28][C:16]2[N:15]([CH2:14][C@@H:9]3[C@@H:10]([OH:13])[CH2:11][CH2:12][NH:8]3)[C:23]3[CH:22]=[CH:21][C:20]([C:24]#[N:25])=[CH:19][C:18]=3[C:17]=2[CH2:26]1)([CH3:35])[CH3:34]
Reactant: CC(C)OC(=O)N[C@H]1Cc2c(n(C[C@@H]3[C@@H](O)CCN3C(=O)OC(C)(C)C)c3ccc(C#N)cc23)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)OC(=O)N[C@H]1Cc2c(n(C[C@H]3NCC[C@@H]3O)c3ccc(C#N)cc23)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.5 %

Procedure:
A solution of (2R,3S)-2-((S)-7-cyano-2-isopropoxycarbonylamino-2,3-dihydro-1H-cyclopenta[b]indol-4-ylmethyl)-3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (0.50 g, 1.04 mmol) in methanol (20 mL) is treated with 4 N hydrogen chloride in 1,4-dioxane (20 mL), stirred at room temperature for 3 h and concentrated. The residue is suspended in ethyl acetate (200 mL) and treated with 2 N aqueous sodium hydroxide solution (20 mL). The organic layer is washed with brine, dried over sodium sulfate, and concentrated. The resulting residue is purified by medium pressure liquid chromatography, eluting with methanol:chloroform (5:95). Fractions containing pure product are combined and concentrated to afford 0.38 g (96%) of the title compound. LC-ES/MS/MS m/z 383.2 [M+H]+, TR=1.86 min.
Reaction SMILES: FC(F)(F)C(O)=O.COC1C=C(OC)C=CC=1C[N:13]1[C:18]([CH2:19][N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])=[C:17]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:16](=[O:36])[NH:15][C:14]1=[O:37]>>[O:29]=[C:28]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21](=[O:30])[N:20]1[CH2:19][C:18]1[NH:13][C:14](=[O:37])[NH:15][C:16](=[O:36])[C:17]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32]
Reactant: CCOC(=O)c1c(CN2C(=O)c3ccccc3C2=O)n(Cc2ccc(OC)cc2OC)c(=O)[nH]c1=O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1c(CN2C(=O)c3ccccc3C2=O)[nH]c(=O)[nH]c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 132.5 %

Procedure:
To trifluoroacetic acid (2 mL, 26.0 mmol) was added ethyl 1-(2,4-dimethoxybenzyl)-6-((1,3-dioxoisoindolin-2-yl)methyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (198.9 mg, 0.403 mmol) at 0° C. The mixture was stirred at 0° C. for 1 h, then at RT for 6 h. The mixture was concentrated under reduced pressure, and the residue was washed with IPE (5 mL) to give the title compound (183.3 mg). 1H NMR (400 MHz, CDCl3) δ ppm 1.42 (t, J=7.2 Hz, 3H), 4.45 (q, J=7.2 Hz, 2H), 4.98 (s, 2H), 7.78-7.81 (m, 2H), 7.91-7.93 (m, 2H), 8.19 (br s, 1H), 8.96 (br s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:4]=2[S:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:9]([C:19]([F:22])([F:21])[F:20])[CH:8]=1.C1C(=O)N([Br:35])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:35][CH2:27][C:25]1[CH:24]=[CH:23][C:4]2[S:5][C:6]([C:7]3[CH:12]=[CH:11][C:10]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)=[C:9]([C:19]([F:22])([F:21])[F:20])[CH:8]=3)=[C:2]([Cl:1])[C:3]=2[CH:26]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2sc(-c3ccc(-c4ccccc4)c(C(F)(F)F)c3)c(Cl)c2c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)(F)c1cc(-c2sc3ccc(CBr)cc3c2Cl)ccc1-c1ccccc1
Yield: 38 %

Procedure:
To a solution of 3-chloro-5-methyl-2-(2-trifluoromethyl-biphenyl-4-yl)-benzo[b]thiophene(110 mg, 0.273 mmol) in CCl4 (3 ml) is added NBS (49 mg, 1 eq.). The mixture is heated at reflux for 15 minutes before AIBN (4.5 mg, 0.1 eq.) is added. The reaction is further heated at reflux overnight. The mixture is filtered through Celite and washed with CCl4. The filtrate is concentrated and purified by column chromatography (EtOAc/Hexane, gradient) to give 50 mg of 5-bromomethyl-3-chloro-2-(2-trifluoromethyl-biphenyl-4-yl)-benzo[b]thiophene in 38% yield.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])/[CH:3]=[CH:4]/[C:5](O)=[O:6].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:43][NH:44][C:45]([C:47]1[C:48]([CH3:60])=[N:49][C:50]([CH3:59])=[CH:51][C:52]=1[N:53]1[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]1)=[O:46]>CN(C=O)C>[CH3:43][NH:44][C:45]([C:47]1[C:48]([CH3:60])=[N:49][C:50]([CH3:59])=[CH:51][C:52]=1[N:53]1[CH2:58][CH2:57][N:56]([C:5](=[O:6])/[CH:4]=[CH:3]/[C:2]([F:9])([F:8])[F:1])[CH2:55][CH2:54]1)=[O:46]
Reactant: O=C(O)/C=C/C(F)(F)F
Reactant: CNC(=O)c1c(N2CCNCC2)cc(C)nc1C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)c1c(N2CCN(C(=O)/C=C/C(F)(F)F)CC2)cc(C)nc1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 38.7 %

Procedure:
(E)-4,4,4-Trifluorobut-2-enoic acid (21 mg, 0.15 mmol) was dissolved in anhydrous DMF (1 ml), diisopropylethylamine (52 μl, 0.3 mmol) was added followed by HBTU (60 mg, 0.15 mmol) and the mixture was stirred at room temperature for 15 minutes. N,2,6-trimethyl-4-piperazin-1-yl-pyridine-3-carboxamide (37.2 mg, 0.15 mmol) was dissolved in a mixture of DMF (0.5 ml) and diisopropylethylamine (26 μl, 0.15 mmol) and the resulting solution was added to the solution of the activated carboxylic acid. The resulting mixture was stirred at room temperature for three hours, the solvent was removed under reduced pressure and the raw product was purified by preparative HPLC (gradient of water containing 0.1% ammonia and acetonitrile) to yield 21.4 mg of a solid (0.058 mmol, 38%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]=[C:19]=[O:20])=[CH:14][CH:13]=2)[CH:10]=1)=[O:5])[CH3:2].[CH:21]1([NH2:24])[CH2:23][CH2:22]1>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([NH:18][C:19]([NH:24][CH:21]3[CH2:23][CH2:22]3)=[O:20])=[CH:16][CH:17]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: NC1CC1
Reactant: CCOC(=O)c1cnn(Cc2ccc(N=C=O)cc2)c1
Solvent: C1CCOC1
Product: CCOC(=O)c1cnn(Cc2ccc(NC(=O)NC3CC3)cc2)c1
Temperature: 23 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(4-isocyanato-benzyl)-1H-pyrazole-4-carboxylic acid ethyl ester (99 mg, 0.365 mmol) in THF (2 ml) was added cyclopropylamine (41.7 mg, 0.730 mmol). The resulting solution was stirred for 30 min at 23° C. The solvent was evaporated, and the residual white solid was triturated in diethyl ether, filtered, washed with diethyl ether and ethanol, and dried under vacuum to afford the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([O:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28](=[O:42])[NH:29][C:30]3[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[C:32]([C:40]#[N:41])[CH:31]=3)[CH:23]=[CH:22]4)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)=O)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[C:40]([C:32]1[CH:31]=[C:30]([NH:29][C:28]([N:24]2[C:25]3[C:21](=[CH:20][C:19]([O:18][C:14]4[C:15]5[CH2:16][CH2:17][NH:8][CH2:9][C:10]=5[N:11]=[CH:12][N:13]=4)=[CH:27][CH:26]=3)[CH:22]=[CH:23]2)=[O:42])[CH:35]=[C:34]([C:36]([F:38])([F:39])[F:37])[CH:33]=1)#[N:41]
Reactant: CC(C)(C)OC(=O)N1CCc2c(ncnc2Oc2ccc3c(ccn3C(=O)Nc3cc(C#N)cc(C(F)(F)F)c3)c2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc(NC(=O)n2ccc3cc(Oc4ncnc5c4CCNC5)ccc32)cc(C(F)(F)F)c1

Procedure:
A solution of 4-[1-(3-cyano-5-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-7-carboxylic acid tert-butyl ester (132 mg, 0.28 mmol) in DCM (2 mL) and TFA (2 mL) is stirred at room temperature for 2 h. The reaction is concentrated in vacuo and purified via semi-prep HPLC (C18; 10-100% I/H2O with 0.1% NH4OH) to give the title compound. MS (ESI) m/z 479.0 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 8.38-8.42 (m, 2H), 8.35 (s, 1H), 8.28 (d, J=8.8 Hz, 1H), 8.07-8.12 (m, 2H), 7.47 (d, J=2.3 Hz, 1H), 7.14 (dd, J=8.8, 2.3 Hz, 1H), 6.83 (d, J=3.3 Hz, 1H), 3.85 (s, 2H), 3.06 (t, J=5.8 Hz, 2H), 2.74 (t, J=5.7 Hz, 2H).
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([C:22]2[CH:27]=[CH:26][C:25]([S:28][CH:29]3[CH2:31][CH2:30]3)=[CH:24][CH:23]=2)[C:8](N([C@H](C)[C@H](O)C2C=CC=CC=2)C)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.S(=O)(=O)(O)[OH:33]>O1CCOCC1.O>[CH:1]1([CH2:6][C@H:7]([C:22]2[CH:27]=[CH:26][C:25]([S:28][CH:29]3[CH2:31][CH2:30]3)=[CH:24][CH:23]=2)[C:8]([OH:9])=[O:33])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=S(=O)(O)O
Reactant: C[C@H]([C@H](O)c1ccccc1)N(C)C(=O)[C@H](CC1CCCC1)c1ccc(SC2CC2)cc1
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)[C@H](CC1CCCC1)c1ccc(SC2CC2)cc1
Temperature: 105 °C
Yield: 59 %

Procedure:
A solution of (R)-3-cyclopentyl-2-(4-cyclopropylsulfanyl-phenyl)-N-((1R,2R)-2-hydroxy-1-methyl-2-phenyl-ethyl)-N-methyl-propionamide (715 mg, 1.63 mmol) in dioxane (5 mL) was treated with a 9 N aqueous sulfuric acid solution (1.3 mL). The resulting solution was then heated at 105° C. for 16 h. The reaction was then cooled and diluted with water (13 mL) and extracted with a chloroform/methanol solution (3:2, 3×20 mL) and then combined the organic extracts dried over magnesium sulfate, filtered and concentrated. Purification on an AnaLogix Intelliflash system (12 g column, 10% ethyl acetate/hexanes to 80% ethyl acetate/hexanes) afforded (R)-3-cyclopentyl-2-(4-cyclopropylsulfanyl-phenyl)-propionic acid (278 mg, 59%) as a white solid: [α]25589=−52.6° (c=0.19, methanol); ES-HRMS m/e calcd for C17H22O2S (M−H)− 289.1268, observed 289.1268; 1H NMR (300 MHz, CDCl3) δ 1.61-2.05 (m, 4H, 2×CH2), 2.45 (s, 3 H, ArCH3), 3.76 (m, 2H, OCH2), 4.00 (m, 2H, SO3CH2), 4.08 (m, 1H, OCH), 7.35 (brd, 2H, Ar), 7.81 (brd, 2H, Ar).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:18])[NH:10][C:11]1[C:12](=[O:17])[NH:13][CH:14]=[CH:15][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C(=O)N([I:26])C(=O)C1>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:18])[NH:10][C:11]1[C:12](=[O:17])[NH:13][CH:14]=[C:15]([I:26])[CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: O=C(Nc1ccc[nH]c1=O)OCc1ccccc1
Solvent: ClCCl
Product: O=C(Nc1cc(I)c[nH]c1=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.1 %

Procedure:
(2-Oxo-1,2-dihydro-pyridin-3-yl)-carbamic acid benzyl ester (410 g, 1.68 mol, 1.0 Eq.) was charged to a flask followed by DCM (6.6 L) and NIS (378 g, 1.68 mol, 1.0 Eq.). The reaction was then allowed to stir at ambient temperature overnight. Tlc analysis showed starting material was still present, therefore a further amount of NIS (25 g, 0.11 mmol, 0.07 Eq.) was added and the reaction stirred for a further 3 hours. NMR analysis of the reaction showed 87% conversion, therefore the reaction mixture was filtered and the red solid washed with DCM (2 L) and Et2O (2 L). The solid was then slurried in dilute aqueous sodium thiosulfate solution (2 g in 2 L), filtered, and then slurried twice in water (2×1.5 L). The pale pink solid was dried on the filter and then in vacuo at 50° C. overnight to give the desired product as a pale pink solid (287 g, 775 mmol, 46%)
Reaction SMILES: [CH2:1]([N:8]1[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:15]2[C:10]([C:11]([C:23]([CH3:25])=[CH2:24])=[CH:12][CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.O=[Pt]=O>[CH2:1]([N:8]1[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:15]2[C:10]([C:11]([CH:23]([CH3:25])[CH3:24])=[CH:12][CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C(C)c1cccc2c(-c3ccccc3)n(Cc3ccccc3)nc12
Agent: O=[Pt]=O
Solvent: CCO
Product: CC(C)c1cccc2c(-c3ccccc3)n(Cc3ccccc3)nc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Thirty milligrams (30 mg; 0.092 mmol) of 2-benzyl-7-isopropenyl-3-phenyl-2H-indazole (Example 521) were dissolved in 2 ml of dry ethanol followed by the addition of 30 mg of PtO2. The reaction mixture was stirred under H2 atmosphere at room temperature for 2 hours, then filtered and the EtOH evaporated. Flash column chromatography (SiO2, dichloromethane/heptane, 1:1, as an eluant) afforded 2-benzyl-7-isopropyl-3-phenyl-2H-indazole in 80% yleld.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:21]=[C:22]([CH3:33])[C:23]=1[N:24]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[N:25]1)[O:5][CH:6]([C:10]1[CH:20]=[CH:19][C:13]([C:14]([O:16]CC)=[O:15])=[CH:12][CH:11]=1)[CH2:7][CH2:8][CH3:9].O.O1CCCC1.O.[OH-].[Li+]>CO>[CH3:1][C:2]1[CH:3]=[C:4]([CH:21]=[C:22]([CH3:33])[C:23]=1[N:24]1[CH:28]=[C:27]([C:29]([F:30])([F:32])[F:31])[CH:26]=[N:25]1)[O:5][CH:6]([C:10]1[CH:11]=[CH:12][C:13]([C:14]([OH:16])=[O:15])=[CH:19][CH:20]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CCCC(Oc1cc(C)c(-n2cc(C(F)(F)F)cn2)c(C)c1)c1ccc(C(=O)OCC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCCC(Oc1cc(C)c(-n2cc(C(F)(F)F)cn2)c(C)c1)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.7 %

Procedure:
To a vial containing ethyl 4-(1-(3,5-dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenoxy)butyl)benzoate (135 mg, 0.29 mmol) was added water (0.59 mL), tetrahydrofuran (0.591 mL), and methanol (0.59 mL). Lithium hydroxide monohydrate (615.0 mg, 14.6 mmol) was then added. The suspension was stirred at room temperature for 18 hours. The reaction was concentrated in vacuo. The residue was acidified to pH=3 with citric acid (5%). The mixture was extracted three times with ethyl acetate. The organics were dried over sodium sulfate, filtered and concentrated to give (+/−)-4-(1-(3,5-di methyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenoxy)butyl)benzoic acid (120 mg, 95%) as a white solid. 1H NMR (400 MHz, CDCl3, δ): 8.07 (d, J=8.4 Hz, 2H), 7.88 (s, 1H), 7.65 (s, 1H), 7.45 (d, J=8.2 Hz, 2H), 6.58 (s, 2H), 5.18 (dd, J=8.0, 4.9 Hz, 1H), 2.04-1.92 (m, 1H), 1.89 (s, 6H), 1.87-1.75 (m, 1H), 1.61-1.36 (m, 2H), 0.97 (t, J=7.4 Hz, 3H). MS (M+1): 433.
Reaction SMILES: C[O:2][C:3](=[O:29])[CH:4]([CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)=[CH:7][CH:6]=1.[OH-].[Na+]>CO>[CH:23]1([CH:4]([C:5]2[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)=[CH:7][CH:6]=2)[C:3]([OH:29])=[O:2])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: COC(=O)C(c1ccc(OCc2ccc3ccccc3n2)cc1)C1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(c1ccc(OCc2ccc3ccccc3n2)cc1)C1CCCCC1

Procedure:
A solution of the above ester and 1N sodium hydroxide (3 ml) in methanol (12 ml) was refluxed at 50° C. for 72 h and then concentrated in vacuo. To the residue was added water (5 ml) and 10% citric acid to pH 3, and the resulting solid was filtered crystallized from methanol to provide 500 mg of 2-cyclohexyl-2-[4-(quinolin-2-ylmethoxy)phenyl]acetic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:3]=1[C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([O:17]C)=[O:16])[CH:13]=2)[NH:8][C:7]=1[CH3:19])=[O:5].[OH-].[Na+]>C(O)C>[C:15]([C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:19])=[C:6]2[C:4](=[O:5])[C:3]1[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:2]=1[Cl:1])([OH:17])=[O:16]
Reactant: COC(=O)c1ccc2[nH]c(C)c(C(=O)c3ccc(Cl)cc3Cl)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1[nH]c2ccc(C(=O)O)cc2c1C(=O)c1ccc(Cl)cc1Cl
Yield: 97.1 %

Procedure:
3-(2,4-Dichlorobenzoyl)-5-(methoxycarbonyl)-2-methylindole (0.60 g) is suspended in ethanol (10 ml), to which is added an aqueous solution of 1.5 M sodium hydroxide (5 ml), and heated under reflux for 3 hours. The reaction mixture is concentrated under reduced pressure, and the residue is made acidic with water and 3 M HCl added thereto. The crystal formed is taken out through filtration, then suspended in ethanol-toluene, and concentrated under reduced pressure for azeotropic dehydration. Next, this is dried on calcium chloride in a vacuum desiccator to obtain a crystal of 5-carboxy-3-(2,4-dichlorobenzoyl)-2-methylindole (76) (0.56 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[CH2:12]3)[O:3]1.N1CCCCC1.[O:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[CH:31]=O>C(O)C>[O:26]1[CH:30]=[CH:29][CH:28]=[C:27]1/[CH:31]=[C:12]1/[C:13](=[O:18])[NH:14][C:15]2[C:11]/1=[CH:10][C:9]([B:4]1[O:3][C:2]([CH3:19])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]1)=[CH:17][CH:16]=2
Reactant: O=Cc1ccco1
Reactant: CC1(C)OB(c2ccc3c(c2)CC(=O)N3)OC1(C)C
Solvent: C1CCNCC1
Solvent: CCO
Product: CC1(C)OB(c2ccc3c(c2)/C(=C\c2ccco2)C(=O)N3)OC1(C)C
Temperature: 80 °C
Yield: 39.3 %

Procedure:
5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one (2.00 g, 7.7 mmol), ethyl alcohol (77 mL), piperidine (0.15 mL, 1.5 mmol), and 2-furaldehyde (0.77 mL, 9.3 mmol) were added to a 250 mL round-bottomed flask. The flask was sealed under a septum and heated to 80° C. for 5 hours. The mixture was cooled and filtered through a medium glass frit. The filtrate was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep® pre-packed silica gel column (120 g), eluting with a gradient of 0% to 70% EtOAc in hexane. The combined fractions were evaporated, and the product was crystallized out of EtOAc and hexanes at −20° C. to give (E)-3-(furan-2-ylmethylene)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one (1.02 g, 39%) as an orange solid. LCMS (M+H) 338.1 calc. for C19H21BNO4 338.1.
Reaction SMILES: [Br:1][C:2]1[C:10]([C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=2)=[CH:9][C:5]2[O:6][CH2:7][CH2:8][C:4]=2[CH:3]=1.[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+].C(Cl)Cl>C(Cl)Cl>[Br:1][C:2]1[C:10]([C:11]2[CH:12]=[CH:13][C:14]([NH:17][C:21]([C:20]3[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=3[F:18])=[O:22])=[N:15][CH:16]=2)=[CH:9][C:5]2[O:6][CH2:7][CH2:8][C:4]=2[CH:3]=1
Reactant: Nc1ccc(-c2cc3c(cc2Br)CCO3)cn1
Reactant: O=C(Cl)c1ccccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(-c2cc3c(cc2Br)CCO3)cn1)c1ccccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.5 %

Procedure:
To a solution of 5-(5-bromo-2,3-dihydrobenzo[3,4-b]furan-6-yl)-2-pyridylamine (139) (13 mg, 0.044 mmol) in 1 ml DCM was added 2-fluorobenzoyl chloride (11 μl, 0.088 mmol) followed by addition of DIEA (38 μl). The resulting solution was stirred at r.t. for overnight. The reaction mixture was worked up with aq. NaHCO3/DCM. DCM phase was washed with brine, concentrated to dryness. The residue was dissolved in 1 ml THF/MeOH/H2O (5:4:1) and stirred with 1N NaOH (100 μl) at r.t. for 2 h and before worked up with EA/aq. NaHCO3. Silica gel flash chromatography furnished N-[5-(5-bromo(2,3-dihydrobenzo[3,4-b]furan-6-yl))(2-pyridyl)](2-fluorophenyl)carboxamide (141) (11 mg, yield: 64.9%, purity>90%) as white solid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:51]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][CH:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1.[CH3:52][C:53]1[O:57][N:56]=[C:55]([C:58](Cl)=[O:59])[CH:54]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:51]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][CH:45]1[CH2:46][CH2:47][N:48]([C:58]([C:55]2[CH:54]=[C:53]([CH3:52])[O:57][N:56]=2)=[O:59])[CH2:49][CH2:50]1
Reactant: Clc1cnc2nc1Nc1ccc(NC3CCNCC3)c(c1)CCc1cncc(c1)N2
Reactant: Cc1cc(C(=O)Cl)no1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C(=O)N2CCC(Nc3ccc4cc3CCc3cncc(c3)Nc3ncc(Cl)c(n3)N4)CC2)no1
Yield: 52 %

Procedure:
The desired compound was prepared according to the procedure of Example D94 using 6-chloro-N-piperidin-4-yl-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine tris(trifluoroacetate) and 5-methylisoxazole-3-carbonyl chloride as the starting materials in 52% yield. LCMS for C27H28ClN8O2 (M+H)+: m/z=531.2.