Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1(O)[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][CH2:4][C:3]1([CH3:11])[CH3:10].C1(C)C=CC(S(O)(=O)=O)=CC=1.O.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC=CC=1>[CH3:1][C:2]1[C:3]([CH3:11])([CH3:10])[CH2:4][CH2:5][C:6]([CH3:9])([CH3:8])[CH:7]=1
Reactant: CC1(C)CCC(C)(C)C(C)(O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CC1=CC(C)(C)CCC1(C)C
Yield: 78.2 %

Procedure:
22.6 g of 1,2,2,5,5-pentamethylcyclohexanol are dissolved in 280 ml of benzene and, after the addition of 100 mg of p-toluenesulphonic acid, the mixture is boiled on a water separator for 7 hours. After cooling the solution, some solid sodium carbonate is added thereto, the mixture is filtered and the filtrate is evaporated at normal pressure. The residue is distilled in a water-jet vacuum. There are obtained 15.8 g of 1,3,3,6,6-pentamethylcyclohexen as a colorless liquid, b.p. 56°-57° C./17 mm.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[N:10]([CH:18]3[CH2:23][CH2:22][CH:21]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[CH2:20][CH2:19]3)[N:9]=2)=[CH:4][C:3]=1[Cl:31].[CH3:32][C:33]1[O:37][C:36]([CH:38]=O)=[CH:35][CH:34]=1.[C:40]([OH:43])(=[O:42])[CH3:41].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:40]([OH:43])(=[O:42])[CH3:41].[Cl:31][C:3]1[CH:4]=[C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[N:10]([C@H:18]3[CH2:23][CH2:22][C@H:21]([N:24]4[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]4)[CH2:20][CH2:19]3)[N:9]=2)[CH:6]=[CH:7][C:2]=1[NH:1][CH2:38][C:36]1[O:37][C:33]([CH3:32])=[CH:34][CH:35]=1
Reactant: Cc1ccc(C=O)o1
Reactant: CN1CCN(C2CCC(n3nc(-c4ccc(N)c(Cl)c4)c4c(N)ncnc43)CC2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Cc1ccc(CNc2ccc(-c3nn([C@H]4CC[C@H](N5CCN(C)CC5)CC4)c4ncnc(N)c34)cc2Cl)o1
Reaction time: 0.08 h

Procedure:
A mixture of 3-(4-amino-3-chlorophenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.200 g, 0.00045 mol) in 1,2-dichloroethane (20 mL) was reacted with 5-methyl-2-furfural (0.052 g, 0.00048 mol), acetic acid (0.095 g, 0.00159 mol) and sodium triacetoxyborohydride (0.336 g, 0.00159 mol) at ambient temperature. An additional two equivalents of sodium triacetoxyborohydride (0.672 g, 0.00318 mol) were added in two 24 hour intervals. The solvents were removed in vacuo and the residue was partitioned between chloroform (25 mL) and saturated aqueous sodium bicarbonate (50 mL). The phases were separated and the aqueous phase was extracted with chloroform (2×25 mL). The combined organic phases were dried over magnesium sulfate, and the solvent was removed in vacuo. The residue was purified by preparative RP-HPLC (Rainin C18, 8 μm, 300 A, 25 cm; 30% isocratic for five minutes, then 30%-60% acetonitrile—0.1M ammonium acetate over 15 min, 21 mL/min). The acetonitrile was removed in vacuo and the aqueous mixture was lyopholyzed to give trans 3-(3-chloro-4-{[(5-methyl-2-furyl)methyl]amino}phenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine acetate as a white solid (0.129 g, 0.00022 mol): 1H NMR (DMSO-d6, 400 MHz) δ 8.20 (s, 1H), 7.51 (d, 1H), 7.39 (dd, 1H), 6.93 (d, 1H), 6.20 (d, 1H), 6.14 (t, 1H), 5.98 (d, 1H), 4.55-4.66 (m, 1H), 4.38 (d, 2H), 2.23 (s, 3H), 2.18-2.61 (m, 10H), 2.14 (s, 3H), 1.91 (s, 3H), 1.87-2.09 (m, 5H), 1.37-1.53 (m, 2H); RP-HPLC (Delta Pak C18, 5 μm, 300A, 15 cm; 5%-95% acetonitrile—0.1M ammonium acetate over 20 min, 1 mL/min) Rt 14.48 min.; MS: MH+ 535.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[C:17]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[CH:16][CH:15]=[C:14]([CH3:24])[N:13]=1)=[O:11].Cl[C:26]1[N:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=1>>[Cl:32][C:29]1[CH:28]=[N:27][C:26]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[C:17]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)=[CH:16][CH:15]=[C:14]([CH3:24])[N:13]=2)=[O:11])=[N:31][CH:30]=1
Reactant: Cc1ccc(-c2cccnc2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)n1
Reactant: Clc1cnc(Cl)nc1
Product: Cc1ccc(-c2cccnc2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ncc(Cl)cn2)n1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(6-methyl-[3,3′-bipyridin]-2-yl)methanone and 2,5-dichloropyrimidine. ESI-MS (m/z): 437 [M+1]+.
Reaction SMILES: C(O[C:6](=[O:22])[NH:7][C:8]([C:14]1[CH:19]=[C:18]([Br:20])[CH:17]=[CH:16][C:15]=1[F:21])([CH2:12][OH:13])[CH:9]([F:11])[F:10])(C)(C)C.C([O-])([O-])=O.[Na+].[Na+].[Cl:29][CH:30](C)[C:31](Cl)=O>Cl.O1CCOCC1.ClCCl>[Br:20][C:18]1[CH:17]=[CH:16][C:15]([F:21])=[C:14]([C:8]([NH:7][C:6](=[O:22])[CH:30]([Cl:29])[CH3:31])([CH2:12][OH:13])[CH:9]([F:10])[F:11])[CH:19]=1
Reactant: CC(Cl)C(=O)Cl
Reactant: CC(C)(C)OC(=O)NC(CO)(c1cc(Br)ccc1F)C(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(Cl)C(=O)NC(CO)(c1cc(Br)ccc1F)C(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
[1-(5-Bromo-2-fluoro-phenyl)-2,2-difluoro-1-hydroxymethyl-ethyl]-carbamic acid tert-butyl ester [Example 42 step c)](2.21 g, 5.75 mmol) was dissolved in 20 mL HCl solution 4 mol/L in dioxane and stirred at room temperature for 60 minutes. The reaction mixture was evaporated to give a white solid which was directly taken up in 15 mL dichloromethane. 20 mL aqueous Na2CO3 solution (10% w/w) was added and the emulsion was cooled to 0-5° C. Racemic 2-chloro-propionyl chloride (787 mg, 6.20 mmol) was added dropwise and the reaction mixture was slowly warmed to room temperature. After 30 minutes, the layers were separated and washed with dichloromethane. The organic layers were combined, dried over Na2SO4 and evaporated. The crude product was purified on a silica gel column by eluting with heptanes/EtOAc 3/1->2/1 to give 632 mg of the first eluting and 619 mg of the second eluting diastereomer.
Reaction SMILES: C1(C)C=CC=CC=1.[OH-:8].[Na+].C1(NC2CCCCC2)CCCCC1.[F:23][C:24]1[N:29]=[C:28]([C:30]#[N:31])[C:27]([OH:32])=[N:26][CH:25]=1>O>[F:23][C:24]1[N:29]=[C:28]([C:30]([NH2:31])=[O:8])[C:27]([OH:32])=[N:26][CH:25]=1
Reactant: [OH-]
Reactant: N#Cc1nc(F)cnc1O
Agent: C1CCC(NC2CCCCC2)CC1
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: NC(=O)c1nc(F)cnc1O
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
300 ml of toluene was added to a 600 ml water solution of 37.5 g of sodium hydroxide. Then 150 g of dicyclohexylamine salt of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile was added at 15 to 25° C. and the solution was stirred at the same temperature for 30 minutes. The water layer was separated and washed with toluene, and then 150 ml of water was added, followed by dropwise addition of 106 g of a 30% hydrogen peroxide solution at 15 to 30° C. and one-hour stirring at 20 to 30° C. Then 39 ml of hydrochloric acid was added, the seed crystals were added at 40 to 50° C., and 39 ml of hydrochloric acid was further added dropwise at the same temperature. The solution was cooled to 10° C. the precipitate was filtered and collected to give 65.6 g of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide as a slightly yellowish white solid.
Reaction SMILES: [C:1]([C:3]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH2:18][CH3:19])(=[O:17])=[O:16])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)#[N:2].[CH3:20][C:21](C)([O-])[CH3:22].[K+].C(I)CC>>[C:1]([C:3]1[N:7]([CH2:20][CH2:21][CH3:22])[C:6]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][S:15]([CH2:18][CH3:19])(=[O:17])=[O:16])=[CH:12][CH:13]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CCS(=O)(=O)Nc1ccc(-c2ccc(C#N)[nH]2)cc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCCI
Product: CCCn1c(C#N)ccc1-c1ccc(NS(=O)(=O)CC)cc1
Yield: 6.2 %

Procedure:
N-[4-(5-cyano-1H-pyrrol-2-yl)phenyl]ethanesulfonamide (0.150 g, 0.54 mmol) was alkylated according to the procedure of Example 40 using potassium tert-butoxide (1.08 mL of a 1 M solution, 1.08 mmol) and propyl iodide (0.056 mL, 0.50 mmol) to afford the title compound (0.10 g, 6.2%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:18](=[O:19])[C:17]2[C:12](=[N:13][C:14](SC)=[N:15][CH:16]=2)[N:11]2[CH:22]=[CH:23][N:24]=[C:10]12.ClC1C=C(C=CC=1)C(OO)=O.[NH2:36][C:37]1[CH:38]=[N:39][C:40]2[CH2:41][CH2:42][N:43]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:44][C:45]=2[CH:46]=1>C(Cl)Cl.C(OCC)(=O)C>[C:50]([O:49][C:47]([N:43]1[CH2:42][CH2:41][C:40]2[N:39]=[CH:38][C:37]([NH:36][C:14]3[N:13]=[C:12]4[C:17]([C:18](=[O:19])[N:9]([C:3]5[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=5[Cl:1])[C:10]5[N:11]4[CH:22]=[CH:23][N:24]=5)=[CH:16][N:15]=3)=[CH:46][C:45]=2[CH2:44]1)=[O:48])([CH3:53])([CH3:51])[CH3:52]
Reactant: CSc1ncc2c(=O)n(-c3c(F)cccc3Cl)c3nccn3c2n1
Reactant: CC(C)(C)OC(=O)N1CCc2ncc(N)cc2C1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2ncc(Nc3ncc4c(=O)n(-c5c(F)cccc5Cl)c5nccn5c4n3)cc2C1
Reaction time: 5 h

Procedure:
A mixture of Example 95C (70.0 mg, 0.193 mmol) and m-chloroperoxybenzoic acid (52.0 mg, 0.232 mmol) in CH2Cl2 (2 ml) was stirred for 20 minutes. tert-Butyl 3-amino-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (57.9 mg, 0.232 mmol) was added to the reaction mixture. After 5 hours, the reaction mixture was diluted with ethyl acetate, washed with saturated aqueous NaHCO3, and brine. The organic layer was dried over MgSO4, filtered, concentrated, and purified on a 12 g column using the ISCO Companion flash system eluting with ethyl acetate to provide the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[CH3:9][C:10]1([CH3:13])[CH2:12][O:11]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[N:6]([CH2:9][C:10]([OH:11])([CH3:13])[CH3:12])[CH:7]=1
Reactant: O=c1ccc(Br)c[nH]1
Reactant: CC1(C)CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(O)Cn1cc(Br)ccc1=O
Temperature: 100 °C
Yield: 76 %

Procedure:
A mixture of 5-bromopyridin-2(1H)-one (600 mg, 3.5 mmol), 2,2-dimethyloxirane (750 mg, 10 mmol) and K2CO3 (960 mg, 6.9 mmol) in DMF (3 mL) was heated at 100° C. for 2 hours. The reaction mixture was allowed to cool to room temperature. The reaction mixture was diluted with ethyl acetate (80 mL), washed with water, brine, and dried over MgSO4. The organic layer was filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with 10 to 50% EtOAc/hexane) to give Compound B387a (650 mg, 76% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ 7.50 (d, J=2.6 Hz, 1H), 7.40 (dd, J=9.6, 2.8 Hz, 1H), 6.54 (d, J=9.7 Hz, 1H), 3.99 (s, 2H), 3.57-3.39 (s, 1H), 1.27 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[CH:9]=[C:8]([C:11]([OH:13])=O)[S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl.[CH3:15][NH:16][O:17][CH3:18].C1CCC(N=C=NC2CCCCC2)CC1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[C:10]2[CH:9]=[C:8]([C:11]([N:16]([O:17][CH3:18])[CH3:15])=[O:13])[S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc2c(Cl)cccc2s1
Reactant: CNOC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1cc2c(Cl)cccc2s1
Yield: 74.9 %

Procedure:
Stir a mixture of 4-chlorobenzo[b]thiophene-2-carboxylic acid (0.94 g, 4.44 mmol), N,O-dimethylhydroxylamine hydrochloride (0.86 g, 8.87 mmol), DCC (1.1 g, 5.32 mmol) and DIEA (1.43 g, 1.9 mL, 11.08 mmol) in DCM (8 mL) at ambient temperature for 2 hours. Filter the reaction mixture and the filtrate is washed with brine, dried over anhydrous Na2SO4 and concentrated under vacuum. Purify the residue by column chromatography on silica gel eluting with PE: EtOAc (5:1 to 3:1) to afford 4-chloro-N-methoxy-N-methylbenzo[b]thiophene-2-carboxamide as white solid (0.85 g, 75.2%). 1H NMR (400 MHz, CDCl3) δ 8.10-8.02 (m, 2H), 7.61-7.51 (m, 2H), 3.84-3.79 (s, 3H), 3.37-3.35 (s, 3H).
Reaction SMILES: C([O:3][C:4](=[O:19])[C@@H:5]([O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15]Br)=[CH:9][CH:8]=1)C.[O:20]([C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1(C2C=CC=CC=2)C=CC(OCCOC2C=CC(C[C@H](OC)C(O)=O)=CC=2)=CC=1>>[CH3:18][O:17][CH:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][O:33][C:30]2[CH:29]=[CH:28][C:27]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:32][CH:31]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:19]
Reactant: Oc1ccc(Oc2ccccc2)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCBr)cc1)OC
Agent: CO[C@@H](Cc1ccc(OCCOc2ccc(-c3ccccc3)cc2)cc1)C(=O)O
Product: COC(Cc1ccc(OCCOc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 283, Step 2) and 4-phenoxy-phenol via the same procedure used for the preparation of (2S)-3-{4-[2-(biphenyl-4-yloxy)-ethoxy]-phenyl}-2-methoxy-propionic acid (Example 283, Step 3) to produce a white solid.
Reaction SMILES: [CH:1]1[C:6]([CH:7]=[O:8])=[CH:5][C:4]2[O:9][CH2:10][O:11][C:3]=2[CH:2]=1.[CH3:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]2[O:21][CH2:22][O:23][C:17]=2[CH:16]=1)=O.[OH-].[Na+]>C(O)C>[CH2:22]1[O:21][C:18]2[CH:19]=[CH:20][C:15]([CH:13]=[CH:12][C:7]([C:6]3[CH:1]=[CH:2][C:3]4[O:11][CH2:10][O:9][C:4]=4[CH:5]=3)=[O:8])=[CH:16][C:17]=2[O:23]1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: CC(=O)c1ccc2c(c1)OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(C=Cc1ccc2c(c1)OCO2)c1ccc2c(c1)OCO2
Reaction time: 8 h

Procedure:
A mixture of piperonal (460 mg) and 3,4-methylenedioxyacetophenone (500 mg) in ethanol (20 ml) was treated with 1M NaOH solution (4 ml), then the mixture was stirred overnight. The pale yellow crystalline solid was filtered off, washed with water then cold aqueous ethanol and dried to give pure bis(3,4-methylenedioxy)chalcone DC-0006B (476 mg, 53%).
Reaction SMILES: CN.[CH3:3][O:4][C:5]1[CH:6]=[C:7]([C:15]2[S:16][C:17]([C:21]([O:23]CC)=O)=[C:18]([CH3:20])[N:19]=2)[CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12].COC1C=C(C=C(OC)C=1OC)[C:31]([NH2:33])=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=S.ClC(C(C)=O)C(OCC)=O>C(O)CCC.C(O)C>[CH3:20][C:18]1[N:19]=[C:15]([C:7]2[CH:6]=[C:5]([O:4][CH3:3])[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=2)[S:16][C:17]=1[C:21]([NH:33][CH3:31])=[O:23]
Reactant: COc1cc(C(N)=O)cc(OC)c1OC
Reactant: CCOC(=O)c1sc(-c2cc(OC)c(OC)c(OC)c2)nc1C
Agent: CCOC(=O)C(Cl)C(C)=O
Agent: CN
Agent: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: CCCCO
Solvent: CCO
Product: CNC(=O)c1sc(-c2cc(OC)c(OC)c(OC)c2)nc1C
Reaction time: 240 h
Yield: 60 %

Procedure:
Into a mixture of 80 ml of 40% solution of methylamine and 420 ml of ethanol, 16.9 g of ethyl 2-(3,4,5-trimethoxyphenyl)-4-methylthiazole-5-carboxylate which had been prepared by heating a mixture of 3,4,5-trimethoxybenzamide, phosphorus pentasulfide, ethyl α-chloroacetoacetate and n-butylalcohol under a reflux condenser for 5 hours was dissolved and the solution was left for 10 days at room temperature. Then the solution was condensed to solid under a reduced pressure. The thus obtained residue was recrystallized from an aqueous ethanolic solution to obtain the object as colourless minute aciculate melting at 177.5° to 179.5° C. in an amount of 10.5 g corresponding to the yield of 60%.
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH3:9])[CH2:3][C:4]([O:6][CH3:7])=[O:5].C(O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(OCC)(=O)C>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[O:1]=[C:2]([CH2:8][CH3:9])[CH2:3][C:4]([O:6][CH2:7][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:5]
Reactant: OCc1ccccc1
Reactant: CCC(=O)CC(=O)OC
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCC(=O)CC(=O)OCc1ccccc1

Procedure:
2.50 g (19.2 mmol) of methyl 3-oxovalerate, 6.23 g (57.6 mmol) of benzyl alcohol and 234 mg (1.92 mmol) of 4-dimethylaminopyridine were heated under reflux in 30 ml of toluene overnight. Ethyl acetate was added to the reaction solution. After washing with 1 N hydrochloric acid, the organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane/ethyl acetate=10/1) to obtain the title compound.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1)=[O:4].C(NC(C)C)(C)C.[N:23]1([C:29]2[N:36]=[CH:35][CH:34]=[CH:33][C:30]=2[C:31]#[N:32])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>C1(C)C=CC=CC=1>[C:31]([C:30]1[C:29]([N:23]2[CH2:24][CH2:25][N:26]([CH2:2][C:3]([NH:5][C:6]3[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=3)=[O:4])[CH2:27][CH2:28]2)=[N:36][CH:35]=[CH:34][CH:33]=1)#[N:32]
Reactant: O=C(CCl)Nc1ccc(C(F)(F)F)cc1
Reactant: N#Cc1cccnc1N1CCNCC1
Solvent: CC(C)NC(C)C
Solvent: Cc1ccccc1
Product: N#Cc1cccnc1N1CCN(CC(=O)Nc2ccc(C(F)(F)F)cc2)CC1
Temperature: 60 °C
Yield: 78.2 %

Procedure:
2-Chloro-N-(4-trifluoromethylphenyl)acetamide (820 mg, 3.45 mmol, Maybridge) and N,N-diisopropylamine (2.5 mL) in toluene (50 mL) were treated with 2-piperazin-1-ylnicotinonitrile (800 mg, 4.25 mmol, Chess) and heated to 60° C. for 18 hours. The mixture was allowed to cool to room temperature, transferred to a separatory funnel and washed with saturated aqueous sodium bicarbonate. The organic phase was dried (sodium sulfate), filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (gradient elution with 20% to 40% ethyl acetate:hexanes) to provide 1.05 g (78% yield) of the title compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 2.69 (m, 4H), 3.26 (s, 2H), 3.68 (m, 4H), 6.93 (dd, 1H, J=7.5, 4.7 Hz), 7.68 (AA′BB′, 2H, J=8.8 Hz), 7.88 (AA′BB′, 2H, J=8.5 Hz), 8.07 (dd, 1H, J=7.8, 2.0 Hz), 8.42 (dd, 1H, J=4.7, 2.0 Hz), 10.14 (br s, 1H); MS (DCI/NH3) m/e 390 (M+H)+;
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.Cl[C:9]1[C:28]([C:29]2[CH:30]=[N:31][CH:32]=[N:33][CH:34]=2)=[CH:27][C:12]([C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]([Cl:26])([F:25])[F:24])=[CH:18][CH:17]=2)=[O:14])=[CH:11][N:10]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[Cl:26][C:23]([F:24])([F:25])[O:22][C:19]1[CH:18]=[CH:17][C:16]([NH:15][C:13](=[O:14])[C:12]2[CH:27]=[C:28]([C:29]3[CH:34]=[N:33][CH:32]=[N:31][CH:30]=3)[C:9]([O:7][CH:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)=[N:10][CH:11]=2)=[CH:21][CH:20]=1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(-c2cncnc2)c1
Reactant: OC1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(OC2CCOCC2)c(-c2cncnc2)c1
Temperature: 120 °C
Reaction time: 26 h

Procedure:
Tetrahydro-2H-pyran-4-ol (0.105 mL, 1.095 mmol) was added to a stirred mixture of 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(pyrimidin-5-yl)nicotinamide (Example 76, 100 mg, 0.243 mmol) and K2CO3 (201.6 mg, 1.458 mmol) in MeCN (1 mL) and the RM was stirred at 110-130° C. for 26 h. The solvent was evaporated off under reduced pressure and the crude product was purified by SFC (Column 2-EP; gradient 9% to 19% in 6 min.) and lyophilized in water/MeCN (minimum volume) to give the title compound. UPLC-MS (Condition 2) tR=1.09 min, m/z=477.0/479.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.62-1.76 (m, 2H) 1.98-2.11 (m, 2H) 3.48-3.60 (m, 2H) 3.70-3.82 (m, 2H) 5.37-5.49 (m, 1H) 7.38 (d, J=9.16 Hz, 2H) 7.88 (d, J=9.00 Hz, 2H) 8.50 (d, J=2.38 Hz, 1H) 8.83 (d, J=2.51 Hz, 1H) 9.16 (s, 2H) 9.23 (s, 1H) 10.45 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C([Sn](CCCC)(CCCC)C1C=CC(C(F)(F)F)=CC=1[N+]([O-])=O)CCC.FC(F)(F)S(O[C:47]1[CH2:56][CH2:55][C:54]2[C:49](=[CH:50][CH:51]=[C:52]([O:57][CH3:58])[CH:53]=2)[CH:48]=1)(=O)=O>>[CH3:58][O:57][C:52]1[CH:53]=[C:54]2[C:49]([CH:48]=[C:47]([C:2]3[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=3[N+:12]([O-:14])=[O:13])[CH2:56][CH2:55]2)=[CH:50][CH:51]=1
Reactant: COc1ccc2c(c1)CCC(OS(=O)(=O)C(F)(F)F)=C2
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Br
Agent: CCCC[Sn](CCCC)(CCCC)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Product: COc1ccc2c(c1)CCC(c1ccc(C(F)(F)F)cc1[N+](=O)[O-])=C2

Procedure:
Synthesized from 1-bromo-2-nitro-4-trifluoromethylbenzene according to an analogous synthetic method to Preparation Example 76, tributyl(2-nitro-4-trifluoromethylphenyl)tin (7.4 and 6-methoxy-3,4-dihydronaphthalen-2-yl trifluoromethanesulfonate (2.2 g) were used according to an analogous synthetic method to Preparation Example 77 to provide 7-methoxy-3-(2-nitro-4-trifluoromethylphenyl)-1,2-dihydronaphthalene (1.5 g). The total amount of this compound was used according to an analogous synthetic method to Example 30 to provide the title compound (1.0 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4](I)[CH:3]=1.C([Mg]Cl)(C)C.[B:15](OC)([O:18]C)[O:16]C>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([B:15]([OH:18])[OH:16])[CH:3]=1
Reactant: COB(OC)OC
Reactant: Clc1ccc(Br)cc1I
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: OB(O)c1cc(Br)ccc1Cl
Temperature: -75 °C
Reaction time: 0.5 h
Yield: 79.3 %

Procedure:
4-Bromo-1-chloro-2-iodobenzene (10.35 g, 33 mmol) is dissolved in anhydrous tetrahydrofuran (60 ml) and the solution is cooled to −75° C. under an atmosphere of argon. Isopropylmagnesium chloride (17.1 ml, 34 mmol, 2M solution in tetrahydrofuran) is added dropwise over 30 minutes, maintaining the internal temperature below −70° C. by external cooling. Once the addition is complete, the reaction mixture is stirred at approximately −70° C. for 30 minutes and then allowed to warm to room temperature and stirred for 1 hour. The reaction mixture is then cooled to −78° C. and trimethyl borate (7.3 ml, 65 mmol) is added dropwise. The mixture is stirred at −78° C. for 30 minutes and then the cooling bath is removed and the mixture is stirred at room temperature for 1.5 hours. 2M Aqueous hydrochloric acid (30 ml) is added, and the crude product is extracted with ethyl acetate. The organic phase is washed with water and brine, dried over anhydrous magnesium sulfate, filtered and the filtrate evaporated in vacuo. Trituration with hexane gives 5-bromo-2-chlorophenylboronic acid (6.16 g) as an off-white solid.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:24]=[CH:23][C:14]([CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([NH2:22])[CH2:18][CH2:17]2)=[CH:13][C:12]=1[O:25][CH2:26][CH3:27]>CC(N(C)C)=O>[Cl:10][C:11]1[CH:24]=[CH:23][C:14]([CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([NH:22][C:2]3[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=3)[CH2:18][CH2:17]2)=[CH:13][C:12]=1[O:25][CH2:26][CH3:27]
Reactant: N#Cc1ccc(F)cc1
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1Cl
Solvent: CC(=O)N(C)C
Product: CCOc1cc(CN2CCC(Nc3ccc(C#N)cc3)CC2)ccc1Cl
Yield: 10 %

Procedure:
A solution of 4-fluoro-benzonitrile (36.3 mg, 0.30 mmol, 1.0 equiv; commercially available) and 1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-ylamine (96.8 mg, 0.36 mmol, 1.2 equiv; intermediate A2) in DMAc (2 mL) was heated by microwave irradiation to 210° C. for 3 h. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 10.9 mg (10%) of the title compound. MS (ISP): 370.1 [M+H]+.