Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1.Cl[CH2:18][C:19]1[CH:37]=[CH:36][C:22]([O:23][CH2:24][C:25]2[N:26]=[C:27]([C:31]3[O:32][CH:33]=[CH:34][CH:35]=3)[O:28][C:29]=2[CH3:30])=[C:21]([O:38][CH3:39])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[O:32]1[CH:33]=[CH:34][CH:35]=[C:31]1[C:27]1[O:28][C:29]([CH3:30])=[C:25]([CH2:24][O:23][C:22]2[CH:36]=[CH:37][C:19]([CH2:18][O:1][C:2]3[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:4]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[N:3]=3)=[CH:20][C:21]=2[O:38][CH3:39])[N:26]=1
Reactant: COC(=O)c1cc(O)nn1-c1ccccc1
Reactant: COc1cc(CCl)ccc1OCc1nc(-c2ccco2)oc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OCc2ccc(OCc3nc(-c4ccco4)oc3C)c(OC)c2)nn1-c1ccccc1
Temperature: 90 °C
Reaction time: 15 h
Yield: 93.7 %

Procedure:
A mixture of methyl 3-hydroxy-1-phenyl-1H-pyrazole-5-carboxylate (5.60 g), 4-(4-chloromethyl-2-methoxyphenoxymethyl)-2-(2-furyl)-5-methyloxazole (9.45 g), potassium carbonate (3.55 g) and N,N-dimethylformamide (200 ml) was stirred at 90° C. for 15 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to give methyl 3-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxybenzyloxy]-1-phenyl-1H-pyrazole-5-carboxylate (12.40 g, yield 94%). The crystals were recrystallized from ethyl acetate-hexane. melting point: 146–147° C.
Reaction SMILES: C(N(CC)CC)C.[OH:8][C:9]1[C:10]([CH3:23])=[C:11]([C:14]([O:19][CH2:20][CH2:21][OH:22])=[C:15]([CH3:18])[C:16]=1[CH3:17])[CH2:12]Cl.[CH3:24][NH:25][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[C:33]([CH3:35])[CH:32]=[CH:31][C:30]=1[CH:36]([CH3:38])[CH3:37]>CN(C)C=O>[OH:8][C:9]1[C:10]([CH3:23])=[C:11]([C:14]([O:19][CH2:20][CH2:21][OH:22])=[C:15]([CH3:18])[C:16]=1[CH3:17])[CH2:12][N:25]([CH2:26][CH2:27][O:28][C:29]1[CH:34]=[C:33]([CH3:35])[CH:32]=[CH:31][C:30]=1[CH:36]([CH3:38])[CH3:37])[CH3:24]
Reactant: Cc1c(C)c(OCCO)c(CCl)c(C)c1O
Reactant: CNCCOc1cc(C)ccc1C(C)C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(C(C)C)c(OCCN(C)Cc2c(C)c(O)c(C)c(C)c2OCCO)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 60.5 %

Procedure:
Triethylamine (2.1 ml) was added dropwise to a solution of 3-hydroxy-6-(2-hydroxyethoxy)-2,4,5-trimethylbenzyl chloride (2.45 g) and N-methyl-2-(2-isopropyl-5-methylphenoxy)ethylamine (2.07 g) in N,N-dimethylformamide (30 ml), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was poured on ice water and extracted with ethyl acetate. The obtained extract was purified by silica gel column chromatography (eluent; ethyl acetate/benzene=1/1) and recrystallized from methanol-water to give 2.51 g of the title compound (colorless needle crystals).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13](I)=[CH:12][CH:11]=1>>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([N:6]2[CH:7]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]2=[O:8])=[CH:12][CH:11]=1
Reactant: Clc1ccc(I)cc1
Reactant: Cc1ccc(=O)[nH]c1
Product: Cc1ccc(=O)n(-c2ccc(Cl)cc2)c1
Yield: 75 %

Procedure:
The reaction of 5-methyl-2-(1H)-pyridone and 1-chloro-4-iodobenzene (Aldrich Chemical Company) in the procedure of Example 1 yields 1-(4'-chlorophenyl)-5-methyl-2-(1H)-pyridone as a white crystalline solid in 75% yield.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([OH:9])([CH:6]([OH:8])[CH3:7])[CH3:5].[Cl:10][C:11]1[CH:16]=[C:15](Cl)[N:14]=[CH:13][N:12]=1.[Cl-].[NH4+]>O1CCCC1>[Cl:10][C:11]1[CH:16]=[C:15]([O:8][CH:6]([CH3:7])[C:4]([OH:9])([CH3:5])[CH3:3])[N:14]=[CH:13][N:12]=1
Reactant: CC(O)C(C)(C)O
Reactant: Clc1cc(Cl)ncn1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(Oc1cc(Cl)ncn1)C(C)(C)O
Reaction time: 0.17 h

Procedure:
In 8 ml of tetrahydrofuran was suspended 0.41 g of sodium hydride (60% in oil), to which 0.6 ml of a solution containing 0.49 g of 2-methylbutane-2,3-diol was added dropwise at 0° C., followed by stirring for 10 minutes. To this was added dropwise 0.6 ml of tetrahydrofuran containing 0.69 g of 4,6-dichloropyrimidine dissolved therein, followed by stirring at the same temperature for 4.5 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution, which was extracted three times with t-butyl methyl ether. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.74 g of 4-chloro-6-(2-hydroxy-1,2-dimethylpropyloxy)pyrimidine.
Reaction SMILES: [CH:1]([C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[N:6]=[C:5]([O:13][CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[CH:4]=1)=O.[CH2:27]([NH2:29])[CH3:28]>>[CH2:27]([NH:29][CH2:1][C:3]1[N:8]=[C:7]([C:9]([F:12])([F:10])[F:11])[N:6]=[C:5]([O:13][CH:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:18][CH2:19]2)[CH:4]=1)[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(C=O)nc(C(F)(F)F)n2)CC1
Reactant: CCN
Product: CCNCc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)nc(C(F)(F)F)n1

Procedure:
This compound was prepared according to the method of Example 41, Step 2 using tert-butyl 4-{[6-formyl-2-(trifluoromethyl)pyrimidin-4-yl]oxy}piperidine-1-carboxylate and ethylamine as starting materials. LCMS (M+H)+: 405.2.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6])#[N:2].Cl.N([O-])=O.[Na+].[N-:15]=[N+:16]=[N-].[Na+]>CCOCC.O.CCCCCC>[C:1]([C:3]1[CH:4]=[C:5]([N:6]=[N+:15]=[N-:16])[CH:7]=[CH:8][CH:9]=1)#[N:2]
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1cccc(N)c1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CCCCCC
Product: N#Cc1cccc(N=[N+]=[N-])c1

Procedure:
A suspension of 9.44g. (0.08 mole) of 3-cyanoaniline in 50 ml. of water at 0° C. was treated with 20 ml. of concentrated HCl, with slow addition, maintaining the reaction mixture temperature at or below 5° C. There was then added a solution of 6.07g. (0.088 mole) of NaNO2 in 20 ml. of water, and the reaction mixture was aged for 1/2 hour at 0°-5° C. Then to the clear reaction mixture solution was added 75 ml. of hexane, followed by a solution of 5.72g. (0.088 mole) of NaN3 in 20 ml. of water, which were added dropwise with stirring. A precipitate was observed to form, after which 100 ml. of ether was added. The organic and aqueous components of the reaction mixture was separated and the aqueous component was extracted with 100 ml. of ether. The organic component was dried over MgSO4 and concentrated to a volume of about 100 ml. An aliquot was blown down and the structure of the product confirmed for 3-cyanophenylazide.
Reaction SMILES: O[Li].O.[CH:4]1[C:9]([C:10]2[CH:11]=[CH:12][C:13]([F:17])=[CH:14][C:15]=2[F:16])=[CH:8][C:7]([C:18]([OH:20])=[O:19])=[C:6]([OH:21])[CH:5]=1.[CH2:22]1COCC1.Cl>CO.O>[F:16][C:15]1[CH:14]=[C:13]([F:17])[CH:12]=[CH:11][C:10]=1[C:9]1[CH:4]=[CH:5][C:6]([O:21][CH3:22])=[C:7]([C:18]([OH:20])=[O:19])[CH:8]=1
Reactant: C1CCOC1
Reactant: O=C(O)c1cc(-c2ccc(F)cc2F)ccc1O
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: CO
Product: COc1ccc(-c2ccc(F)cc2F)cc1C(=O)O
Yield: 93 %

Procedure:
LiOH.H2O (60 mg, 1.43 mmol) was added to a solution of fully methylated diflunisal (140 mg, 0.50 mmol) in MeOH:THF:H2O (4.5 mL 1:1:1), and stirred at rt for 4 h. Upon completion, the reaction was acidified with 30% HCl, extracted with ethyl acetate (3×5 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (2:1 ethyl acetate:hexane, 1% acetic acid) to afford 33 (122 mg, 93%) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 10.77 (br s, 1H), 8.31 (dd, 1H, J=2.5, 0.9 Hz), 7.75 (dt, 1H, J=8.6, 2.1 Hz), 7.41 (dt, 1H, J=8.9, 6.6 Hz), 7.15 (d, 1H, J=8.8 Hz), 6.94 (m, 1H), 4.13 (s, 3H). 13C NMR (CDCl3, 100 MHz) δ 177.7, 161.4, 158.2, 135.7, 133.9, 131.4, 129.0, 123.5, 118.1, 112.2, 112.0, 104.6, 56.9. HRESIMS calculated for C14H10F2O3 (M−H) 263.0520, found 263.0514. Normal phase HPLC retention time: 21.6 min. Reverse phase HPLC retention time: 11.9 min. >99% pure.
Reaction SMILES: CN1CCN(C2C=CC(NC3C4N(N=CN=4)C(C4C=C(C(N)=O)SC=4)=CN=3)=CC=2)CC1.Br[C:33]1[N:38]2[N:39]=[CH:40][N:41]=[C:37]2[C:36]([NH:42][C:43]2[CH:44]=[N:45][C:46]([N:49]3[CH2:54][CH2:53][N:52]([CH:55]([CH3:57])[CH3:56])[CH2:51][CH2:50]3)=[CH:47][CH:48]=2)=[N:35][CH:34]=1.CC1(C)C(C)(C)OB([C:66]2[CH:67]=[C:68]3[C:72](=[CH:73][CH:74]=2)[C:71](=[O:75])[NH:70][CH2:69]3)O1>C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:55]([N:52]1[CH2:53][CH2:54][N:49]([C:46]2[N:45]=[CH:44][C:43]([NH:42][C:36]3[C:37]4[N:38]([N:39]=[CH:40][N:41]=4)[C:33]([C:66]4[CH:67]=[C:68]5[C:72](=[CH:73][CH:74]=4)[C:71](=[O:75])[NH:70][CH2:69]5)=[CH:34][N:35]=3)=[CH:48][CH:47]=2)[CH2:50][CH2:51]1)([CH3:57])[CH3:56]
Reactant: CC(C)N1CCN(c2ccc(Nc3ncc(Br)n4ncnc34)cn2)CC1
Reactant: CC1(C)OB(c2ccc3c(c2)CNC3=O)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CN1CCN(c2ccc(Nc3ncc(-c4csc(C(N)=O)c4)n4ncnc34)cc2)CC1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(C)N1CCN(c2ccc(Nc3ncc(-c4ccc5c(c4)CNC5=O)n4ncnc34)cn2)CC1

Procedure:
This compound may be prepared using methods as described for Compound 6, step 4, using 5-bromo-N-(6-(4-isopropylpiperazin-1-yl)pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-amine (50 mg, 0.12 mmol), 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,3-dihydro-isoindol-1-one (56 mg, 0.216 mmol) and Pd(PPh3)4 (35 mg, 0.03 mmol) in 1.5M Na2CO3 (0.64 mL) and dioxane (2 mL). The crude product is purified by silica gel column chromatography eluting with 95:5 DCM:MeOH followed by 90:10 DCM:MeOH. The title compound is obtained after trituration with a 10:1 mixture n-hexane:DCM (19 mg, 34%). Conversion into the mesylate salt, using 0.1M methanesulfonic acid (0.35 mL), gives the title compound as a yellow solid (20 mg, 69%).
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:17]=[C:16]([C:18]([NH2:20])=[O:19])[O:15][N:14]=2)=[CH:9][CH:8]=1)(C)(C)C.C([O-])([O-])=O.[K+].[K+].C1OCCOCCOCCOCCOCCOC1.[F-].[K+].[Cl:49][C:50]1[CH:57]=[CH:56][CH:55]=[CH:54][C:51]=1[CH2:52]Cl>CN(C=O)C.O>[Cl:49][C:50]1[CH:57]=[CH:56][CH:55]=[CH:54][C:51]=1[CH2:52][O:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:17]=[C:16]([C:18]([NH2:20])=[O:19])[O:15][N:14]=2)=[CH:11][CH:12]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2cc(C(N)=O)on2)cc1
Reactant: ClCc1ccccc1Cl
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [F-]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1cc(-c2ccc(OCc3ccccc3Cl)cc2)no1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70.5 %

Procedure:
3-[4-(tert-Butyl-dimethyl-silanyloxy)-phenyl]-isoxazole-5-carboxylic acid amide (which may be prepared as described in Preparation of Intermediate 13; 40 mg, 0.126 mmol) was dissolved in DMF (1.5 mL). K2CO3 (19 mg, 0.14 mmol), 18-crown-6 (6 mg, 0.02 mmol), KF (8 mg, 0.14 mmol), and 2-chlorobenzyl chloride (20 μL, 0.158 mmol) were added. The reaction mixture was stirred at room temperature for 10 min and then at 40° C. for 12 h. H2O (2.5 mL) was added and the mixture was extracted with EtOAc. The organic layer was evaporated to give 3-[4-(2-chloro-benzyloxy)-phenyl]-isoxazole-5-carboxylic acid amide (29.2 mg, 71%) as a white powder. HRMS Calcd. for C17H13ClN2O3 (M+), 328.0615. Found: 328.0610.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[H-].[Na+].Br[C:9]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[N:12]=[C:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[N:10]=1.O>CN(C=O)C>[F:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH2:14][N:13]1[C:9]([N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)=[N:10][C:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)=[N:12]1
Reactant: Fc1ccccc1Cn1nc(-c2ccccn2)nc1Br
Reactant: c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccccc1Cn1nc(-c2ccccn2)nc1-n1cccn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of pyrazole (1.1 eq) in DMF is treated with sodium hydride (e.g., about 60% w/w in mineral oil, about 1.2 eq) and stirred for about 10 min at room temperature. 2-(5-Bromo-1-(2-fluorobenzyl)-1H-1,2,4-triazol-3-yl)pyridine (I-16, e.g., 1.0 eq) is then added. The resultant mixture is warmed to about 50° C. and stirred at that temperature for about 1 h. The reaction solution is cooled to room temperature, poured into water, and filtered to yield 2-(1-(2-fluorobenzyl)-5-(1H-pyrazol-1-yl)-1H-1,2,4-triazol-3-yl)pyridine (I-10) as a solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][S:25]2(=[O:31])=[O:30])[CH:3]=1.[O:32]1[CH2:36][CH2:35][NH:34][C:33]1=[O:37]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:34]4[CH2:35][CH2:36][O:32][C:33]4=[O:37])=[CH:3][C:4]=3[N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][S:25]3(=[O:31])=[O:30])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Cl)cc3N3CCCCS3(=O)=O)CC2)c(C)c1
Reactant: O=C1NCCO1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCOC4=O)cc3N3CCCCS3(=O)=O)CC2)c(C)c1
Yield: 19.8 %

Procedure:
By reaction and treatment in the same manner as in Example 201 and using [4-chloro-2-(1,1-dioxo-1,2-thiazinan-2-yl)phenyl][4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (161.5 mg) described in Preparation Example 128 and oxazolidin-2-one (30.4 mg), the title compound (35.4 mg) was obtained.
Reaction SMILES: [H-].[Na+].[C:3]([C:11]1[N:12]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH:13]=[CH:14][CH:15]=1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:21](OC)=[O:22].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[OH:22][CH:21]=[C:16]([N:12]1[CH:13]=[CH:14][CH:15]=[C:11]1[C:3](=[O:10])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC=O
Reactant: COC(=O)Cn1cccc1C(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(=CO)n1cccc1C(=O)c1ccccc1
Yield: 86.2 %

Procedure:
Sodium hydride (1.44 g, 55% in oil, 0.033 mol) was washed with petrol 60°-80° and suspended in DMF (15 ml). To this the methyl (2-benzoylpyrrol-1-yl)acetate (4.0 g, 0.0165 mol) in DMF (15 ml) and methyl formate (20.3 ml, 0.33 mol) was added dropwise at room temperature. After 4 hours it was poured into 200 ml of 10% potassium carbonate, washed with diethyl ether (2×100 mls), then the aqueous was neutralised with concentrated hydrochloric acid and extracted with diethyl ether (2×100 ml). These extracts were washed with brine, dried and evaporated to give methyl 3-hydroxy-2- (2-benzoylpyrrol-1-yl)acrylate (3.86 g, 86%) as a white crystalline solid melting at 112°-113°.
Reaction SMILES: [C:1]([O-])([O-])=[O:2].[K+].[K+].FC1C=C(F)C=C(F)C=1CBr.[CH3:18][O:19][C:20]1[C:25](C)=[CH:24][C:23]([N:27]2[C:32](=[O:33])[N:31]([CH2:34][C:35]3[C:40]([F:41])=[CH:39][C:38]([F:42])=[CH:37][C:36]=3[F:43])[C:30]3[CH:44]=[CH:45][CH:46]=[CH:47][C:29]=3[S:28]2(=[O:49])=[O:48])=[CH:22][C:21]=1C>CN(C=O)C>[CH3:1][O:2][C:21]1[CH:22]=[C:23]([N:27]2[C:32](=[O:33])[N:31]([CH2:34][C:35]3[C:36]([F:43])=[CH:37][C:38]([F:42])=[CH:39][C:40]=3[F:41])[C:30]3[CH:44]=[CH:45][CH:46]=[CH:47][C:29]=3[S:28]2(=[O:48])=[O:49])[CH:24]=[CH:25][C:20]=1[O:19][CH3:18]
Reactant: O=C([O-])[O-]
Reactant: COc1c(C)cc(N2C(=O)N(Cc3c(F)cc(F)cc3F)c3ccccc3S2(=O)=O)cc1C
Agent: Fc1cc(F)c(CBr)c(F)c1
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(N2C(=O)N(Cc3c(F)cc(F)cc3F)c3ccccc3S2(=O)=O)cc1OC

Procedure:
The title compound (29 mg, 0.06 mmol) was prepared from (IntA1) (84 mg, 0.25 mmol), K2CO3 (104 mg, 0.75 mmol) and 2,4,6-trifluorobenzyl bromide (68 uL, 0.30 mmol) in DMF (2 mL) using the methods of (115).
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)[N:4]=1.[CH3:15][C:16]1[S:17][C:18]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH:27]([OH:35])[CH2:28][N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[CH:21][C:19]=2[N:20]=1.C(N(C(C)C)CC)(C)C>CCO>[F:14][C:10]1[CH:9]=[C:8]([C:5]2[N:4]=[C:3]([CH2:2][N:32]3[CH2:33][CH2:34][N:29]([CH2:28][CH:27]([OH:35])[CH2:26][O:25][C:22]4[CH:23]=[CH:24][C:18]5[S:17][C:16]([CH3:15])=[N:20][C:19]=5[CH:21]=4)[CH2:30][CH2:31]3)[O:7][N:6]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Cc1nc2cc(OCC(O)CN3CCNCC3)ccc2s1
Reactant: Fc1cccc(-c2noc(CCl)n2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1nc2cc(OCC(O)CN3CCN(Cc4nc(-c5cccc(F)c5)no4)CC3)ccc2s1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To 5-(chloromethyl)-3-(3-fluorophenyl)-1,2,4-oxadiazole (300 mg, 1.41 mmol) and 1-(2-methylbenzothiazol-5-yloxy)-3-piperazine-1-yl-propan-2-ol, a compound of formula (6) (291 mg, 0.94 mmol) in EtOH (20 mL, anhydrous) was added diisopropylethylamine (0.329 m, 1.89 mmol), and the reaction was shaken on a J-Kem™ block overnight at 90° C. Upon cooling to room temperature, the solution was concentrated to an oil and purified on an Isco™ Combi Flash Si 10X, using Redi Sep columns (10 g), eluting with ethyl acetate, then gradient to 4:1 ethyl acetate/methanol, to yield 3-(4-{[3-(3-fluorophenyl)(1,2,4-oxadiazol-5-yl)]methyl}piperazinyl)-1-(2-methylbenzothiazol-5-yloxy)propan-2-ol, a compound of Formula I, (136 mg, 30%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][C:9]=2[NH2:15])=[O:5])[CH3:2].O1CCCC1.C(=O)([O-])[O-].[K+].[K+].Cl[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29]>O>[C:32]1([CH2:31][O:30][C:28]([NH:15][C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:8]=2[NH:7][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:14]3)=[O:29])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)c1cc2cccc(N)c2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cc2cccc(NC(=O)OCc3ccccc3)c2[nH]1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
0.8 g (3.925 mmol) of 7-amino-1H-indole-2-carboxylic acid ethyl ester are mixed with 16 ml of tetrahydrofurane and 1.08 g (7.83 mmol) of potassium carbonate. The reaction medium is cooled to 0° C. and 0.615 ml (4.30 mmol) of benzyl chloroformate are added. Agitation is performed for 1 hour 30 minutes at 0° C., and then the temperature of the mixture is allowed to rise again to ambient temperature over one hour. Then 30 ml of water are added and the product is extracted using ethyl acetate. The combined organic phases are dried on magnesium sulfate, filtered and concentrated under reduced pressure. The evaporation residue is purified by silica column chromatography eluting with the help of a methylcyclohexane/ethyl acetate mixture (90/1; v/v). The expected product is obtained in the form of white crystals with a yield of 61%.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[CH:11]=[CH:10][NH:9][C:5]=2[N:6]=[CH:7][N:8]=1.[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.[OH-].[Na+]>C1(C)C=CC=CC=1.O.S([O-])([O-])(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:1][O:2][C:3]1[C:4]2[CH:11]=[CH:10][N:9]([S:18]([C:15]3[CH:16]=[CH:17][C:12]([CH3:22])=[CH:13][CH:14]=3)(=[O:20])=[O:19])[C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: COc1ncnc2[nH]ccc12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ncnc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.4 %

Procedure:
A solution of 4-methoxy-7H-pyrrolo[2,3-d]pyrimidine [1.2 g, Reference Example 8] and para-toluene sulfonylchloride (1.77 g) in toluene (60 mL) was treated with a solution of sodium hydroxide (3.2 g) in water (30 mL), and tetrabutyl ammonium sulfate (27 mg). The solution was stirred vigorously at room temperature for 4 hours and partitioned between ethyl acetate and brine. The organic phase was separated, then dried over magnesium sulfate and then evaporated under reduced pressure. The residue was subjected to flash column chromatography on silica eluting with a gradient of ethyl acetate and cyclohexane (50:50 to 80:20, v/v) to give the title compound (2.23 g) as an amorphous solid. MS: 304 [MH]+. LCMS (Method B) RT=3.88 minutes.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Br)[C:5]([C:9]#[N:10])=[C:4]([S:11][CH3:12])[N:3]=1.[CH3:13][C:14]1[CH:15]=[N:16][NH:17][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1>[NH2:1][C:2]1[N:7]=[C:6]([N:16]2[CH:15]=[C:14]([CH3:13])[CH:18]=[N:17]2)[C:5]([C:9]#[N:10])=[C:4]([S:11][CH3:12])[N:3]=1
Reactant: Cc1cn[nH]c1
Reactant: CSc1nc(N)nc(Br)c1C#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CSc1nc(N)nc(-n2cc(C)cn2)c1C#N

Procedure:
From 2-amino-4-bromo-6-methylsulfanyl-pyrimidine-5-carbonitrile, 4-methyl-pyrazole and cesium carbonate in NMP. EI-MS m/e (%): 246 (M+, 85), 245 ([M—H]+, 100).
Reaction SMILES: [CH3:1][CH:2]([CH3:8])[CH2:3][CH2:4][C:5](Cl)=[O:6].[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]([OH:40])([C:36]([F:39])([F:38])[F:37])[C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=3)[CH2:20][CH2:19]2)=[O:17])=[CH:12][C:11]=1[F:41].C(N(CC)CC)C>ClCCl>[F:41][C:11]1[CH:12]=[C:13]([C:16]([N:18]2[CH2:19][CH2:20][N:21]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]([OH:40])([C:32]([F:33])([F:34])[F:35])[C:36]([F:38])([F:39])[F:37])=[CH:27][CH:26]=3)[CH2:22][CH2:23]2)=[O:17])[CH:14]=[CH:15][C:10]=1[NH:9][C:5](=[O:6])[CH2:4][CH2:3][CH:2]([CH3:8])[CH3:1]
Reactant: CC(C)CCC(=O)Cl
Reactant: Nc1ccc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CCC(=O)Nc1ccc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1F
Yield: 9 %

Procedure:
4-Methylvaleric acid (4.30 mmol, 0.543 mL, 0.5 g) was stirred in dichloromethane (5 mL) at 0° C. Oxalyl chloride (21.52 mmol, 1.848 mL, 2.73 g) was added. The reaction mixture allowed to warm to room temperature and stirred for 18 hours. The reaction mixture was concentrated under vacuum to give the intermediate 4-methylpentanoyl chloride. A mixture of 4-methylpentanoyl chloride (1.564 mmol, 0.211 g), (4-amino-3-fluorophenyl)(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazin-1-yl)methanone (1.043 mmol, 0.5 g) and triethylamine (2.086 mmol, 0.290 mL, 0.211 g) were stirred in dichloromethane at 0° C. for 1 hour. The reaction mixture was washed with water, dried over sodium sulfate, concentrated under vacuum and purified by silica chromatography (eluting with a solvent gradient from dichloromethane to 5% methanol/dichloromethane) to afford the title compound (54 mg).
Reaction SMILES: CS(O[CH2:6][C@@H:7]1[CH2:9][C@H:8]1[CH2:10][O:11][Si:12]([C:25]([CH3:28])([CH3:27])[CH3:26])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=O)=O.[C-]#N.[K+].[CH3:32][N:33](C=O)C>O>[Si:12]([O:11][CH2:10][C@@H:8]1[CH2:9][C@H:7]1[CH2:6][C:32]#[N:33])([C:25]([CH3:26])([CH3:27])[CH3:28])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CN(C)C=O
Reactant: CC(C)(C)[Si](OC[C@@H]1C[C@H]1COS(C)(=O)=O)(c1ccccc1)c1ccccc1
Agent: [C-]#N
Agent: [K+]
Solvent: O
Product: CC(C)(C)[Si](OC[C@@H]1C[C@H]1CC#N)(c1ccccc1)c1ccccc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
A mixture of trans-(2-(((tert-butyldiphenylsilyl)oxy)methyl)cyclopropyl)methyl methanesulfonate (1.23 g, 2.94 mmol), potassium cyanide (0.383 g, 5.88 mmol) and DMF (10 mL) was stirred overnight at 60° C. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 10→60% ethyl acetate/hexane) to give trans-2-(2-(((tert-butyldiphenylsilyl)oxy)methyl)cyclopropyl)acetonitrile (0.970 g, 2.78 mmol, 94%) as a colorless oil.