Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:3][C:4]([NH2:6])=[NH:5])#[N:2].[CH3:7][C:8](=O)[CH2:9][C:10](=O)[CH3:11].Cl>O>[C:1]([NH:3][C:4]1[N:6]=[C:10]([CH3:11])[CH:9]=[C:8]([CH3:7])[N:5]=1)#[N:2]
Reactant: N#CNC(=N)N
Reactant: CC(=O)CC(C)=O
Agent: Cl
Solvent: O
Product: Cc1cc(C)nc(NC#N)n1
Temperature: 120 °C
Yield: 69.9 %

Procedure:
A mixture of 42 g (0.5 mol) of cyanoguanidine ("dicyanodiamide") and 50 g (0.5 mol) of 2,4-pentanedione ("acetylacetone") is heated to 120° C. for 15 hours. The reaction mixture is then cooled, after which 500 ml of water are added and the solution is acidified with hydrochloric acid at 0° C. to 10° C. The product obtained in crystalline form during this procedure is isolated by filtering it off under suction. 51.8 g (70% of theory) of 2-cyanoamino-4,6-dimethyl-pyrimidine of melting point 205° C. are obtained.
Reaction SMILES: C(O[C:4](=[O:24])[C:5]([C:14]([C:16]1[CH:17]=[N:18][C:19]([CH3:23])=[C:20]([CH3:22])[CH:21]=1)=[O:15])=[CH:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)C>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH3:22][C:20]1[CH:21]=[C:16]([C:14]([C:5]2[C:4](=[O:24])[C:9]3[C:8](=[CH:13][CH:12]=[CH:11][CH:10]=3)[NH:7][CH:6]=2)=[O:15])[CH:17]=[N:18][C:19]=1[CH3:23]
Reactant: CCOC(=O)C(=CNc1ccccc1)C(=O)c1cnc(C)c(C)c1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cc1cc(C(=O)c2c[nH]c3ccccc3c2=O)cnc1C
Reaction time: 1 h
Yield: 58.7 %

Procedure:
Compound 3c was prepared following the procedure described in Step 2 of Example 1 using 400 mg (1.23 mmol) of 2-(5,6-dimethyl-pyridine-3-carbonyl)-3-phenylamino-acrylic acid ethyl ester 2d, and 50 mL of diphenyl ether. The reaction time was 1 h. Purification of the crude product by flash chromatography using 60-100% ethyl acetate in hexane followed by 0-25% methanol in ethyl acetate yielded 201 mg of the product 3c as off-white solid: LC-MSD, m/z for C17H14N2O2 [M+H]+=279.4, HPLC retention time: 0.25 min.
Reaction SMILES: [F:1][C:2]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[C:7]([F:13])[CH:6]=1)([F:4])[CH3:3].[CH3:14][C:15]([S@:18]([NH2:20])=[O:19])([CH3:17])[CH3:16]>ClCCCl.S([O-])([O-])(=O)=O.[Cu+2]>[F:1][C:2]([C:5]1[CH:12]=[CH:11][C:8](/[CH:9]=[N:20]/[S@@:18]([C:15]([CH3:17])([CH3:16])[CH3:14])=[O:19])=[C:7]([F:13])[CH:6]=1)([F:4])[CH3:3]
Reactant: CC(F)(F)c1ccc(C=O)c(F)c1
Reactant: CC(C)(C)[S@](N)=O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCCl
Product: CC(F)(F)c1ccc(/C=N/[S@](=O)C(C)(C)C)c(F)c1
Temperature: 55 °C
Yield: 46.3 %

Procedure:
To a mixture of 4-(1,1-difluoroethyl)-2-fluorobenzaldehyde (693 mg, from Step 4) and (R)-2-methylpropane-2-sulfinamide (513 mg, 4.24 mmol) in DCE (12.9 mL) was added copper(II) sulfate (882 mg, 5.52 mmol). The reaction mixture was placed in a pre-heated oil bath (55° C.) and heated for ˜2 d. The mixture was allowed to cool to room temperature, filtered through a pad of celite and rinsed with DCE. The combined filtrates were concentrated under reduced pressure. The residue was purified by column chromatography [SiO2, 24 g, heptane/ethyl acetate] providing (R,E)-N-(4-(1,1-difluoroethyl)-2-fluorobenzylidene)-2-methylpropane-2-sulfinamide (497 mg) as a yellow oil. LCMS m/z 292.1 (M+H)+, Rt 0.97 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([OH:7])=[CH:5][CH:4]=1.ClC1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=1.[OH-].[K+]>CS(C)=O>[OH:7][C:6]1[CH:8]=[CH:9][C:3]([O:2][C:1]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=2)=[CH:4][CH:5]=1
Reactant: COc1ccc(O)cc1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Temperature: 0 °C
Yield: 29.9 %

Procedure:
40 ml of dimethyl sulfoxide, 5.0 g of hydroquinone monomethyl ether, 5.0 g of 2-chloro-5-trifluoromethylpyridine and 2.3 g of potassium hydroxide were reacted at 150° C. for 3 hours with stirring. After cooling, the reaction product was added to a suitable amount of ice-water, and extracted with methylene chloride. The extract was washed with water and dried over anhydrous sodium sulfate, followed by distilling off the methylene chloride. The residue containing 2-(4-methoxyphenoxy)-5-trifluoromethylpyridine was mixed with 5.0 g of pyridine hydrochloride and heated at 140°-160° C. for 2 hours with stirring. After cooling the system, the reaction product was added to a suitable amount of ice-water and extracted with methylene chloride. This methylene chloride layer was back-extracted with a 5% sodium hydroxide aqueous solution, and the extract was acidified with 30% concentrated hydrochloric acid to obtain a solid material. This solid material was filtered out and dried to obtain 2.1 g of 2-(4-hydroxyphenoxy)-5-trifluoromethylpyridine.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH2:19][CH2:20]O)[CH:13]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([CH2:20][CH2:19][CH2:18][C:14]2[CH:13]=[N:12][CH:17]=[CH:16][CH:15]=2)[N:3]=1
Reactant: OCCCc1cccnc1
Reactant: Nc1ncnc2[nH]nc(I)c12
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Nc1ncnc2c1c(I)nn2CCCc1cccnc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 54 %

Procedure:
A suspension of 3-Iodo-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine, prepared as described in A. F. Burchat et al. Bioorg Med. Chem. Lett. 2002, 12, 1687-1690, (0.392 g, 1.5 mmol), 3-(pyridine-3-yl)propan-1-ol (0.388 ml, 3 mmol), and triphenylphosphine (0.983 g, 3.75 mmol) in THF (10 ml) under inert atmosphere was cooled in an ice bath and diisopropyl azodicarboxylate (0.581 ml, 3 mmol) was added dropwise and the reaction was then stirred for 72 hrs at ambient temperature. The reaction was concentrated and the residue was acidified with 1M HCl and washed with EtOAc. The aqueous layer was basified with solid Na2CO3 and extracted with EtOAc. The EtOAc was dried over Na2SO4, filtered and concentrated. The residue was purified on silica gel using an ISCO Companion chromatography system eluted with 0-20% MeOH/CH2Cl2 to give the title compound as an off-white solid (310 mg, 54%). MS (ESI(+)) m/e 381 (M+H)+, (ESI(−)) m/e 379 (M−H)−; 1H NMR (300 MHz, DMSO-d6) 8.39 (m, 2H), 8.20 (s, 1H), 7.61 (dd, 1H), 7.28 (m, 1H), 4.19 (t, 2H), 2.60 (m, 2H), 2.17 (m, 2H).
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].Cl.[CH:13]([N:16]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:18][CH2:19]Cl)([CH3:15])[CH3:14]>>[CH:13]([N:16]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:18][CH2:19][N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3])([CH3:15])[CH3:14]
Reactant: O=C1Nc2ccccc2C1=O
Reactant: CC(C)N(CCCCl)C(C)C
Agent: Cl
Product: CC(C)N(CCCN1C(=O)C(=O)c2ccccc21)C(C)C
Yield: 72.9 %

Procedure:
By using isatin and 3-diisopropylaminopropyl chloride hydrochloride, a method analogous to that described in Reference Example 1 was carried out, and the reaction product was purified with silica gel column chromatography (eluent: chloroform/methanol=50/1) and then recrystallized from hexane to obtain 1-(3-diisopropylaminopropyl)isatin having a melting point of 49°-50° C. (yield: 72.9%).
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4](B2OC(C)(C)C(C)(C)O2)[CH2:3][CH2:2]1.I[C:17]1[N:18]=[C:19]([CH:29]2[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]2)[N:20]([CH2:22][CH2:23][N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+].F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C>O.C(OC)(C)(C)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CS(C)=O>[O:1]1[CH2:6][CH:5]=[C:4]([C:17]2[N:18]=[C:19]([CH:29]3[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]3)[N:20]([CH2:22][CH2:23][N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[CH:21]=2)[CH2:3][CH2:2]1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(I)cn2CCN2CCCC2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Solvent: CS(C)=O
Solvent: O
Solvent: COC(C)(C)C
Product: CC(C)(C)OC(=O)N1CCC(c2nc(C3=CCOCC3)cn2CCN2CCCC2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 96.3 %

Procedure:
Combine 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (19.1 g, 1.6 eq), tert-butyl 4-[4-iodo-1-(2-pyrrolidin-1-ylethyl)imidazol-2-yl]piperidine-1-carboxylate (27 g, 56.9 mmol), sodium carbonate (120.6 g, 3.0 eq), and dimethyl sulfoxide (135 mL). Stir for five minutes. Add tri-tert-butylphosphonium tetrafluoroborate (1.7 g, 0.1 eq) and palladium(II) acetate (645.4 mg, 0.05 eq). Stir the resulting suspension at 75-80° C. under nitrogen for 45 minutes. Allow the mixture to cool to room temperature, then dilute with water (190 mL) and methyl tert-butyl ether (80 mL). Wash the aqueous layer with methyl tert-butyl ether (3×54 mL). Wash the organics with water (60 mL) and then with a 10% w/w aqueous solution of phosphoric acid (60 mL, 20 mL). Combine these aqueous layers and wash them with methyl tert-butyl ether (60 mL). Add sodium carbonate to the acidic aqueous layer to adjust the pH to 12. Wash the basic aqueous layer with methyl tert-butyl ether (120 mL, 30 mL). Wash the combined organics with aqueous saturated sodium chloride, dry over anhydrous magnesium sulfate, and concentrate in vacuo to give tert-butyl 4-[4-(3,6-dihydro-2H-pyran-4-yl)-1-(2-pyrrolidin-1-ylethyl)imidazol-2-yl]piperidine-1-carboxylate (23.6 g, 96%). MS (ES) m/z=431 [M]+.
Reaction SMILES: CC([O-])(C)C.[K+].[CH3:7][C:8](=[N:10][OH:11])[CH3:9].[CH3:12][O:13][C:14](=[O:34])[C:15]1[CH:20]=[C:19]([C:21](=[O:23])[CH3:22])[C:18](F)=[C:17]([F:25])[C:16]=1[NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[Cl:33]>C1COCC1>[CH3:12][O:13][C:14](=[O:34])[C:15]1[CH:20]=[C:19]([C:21](=[O:23])[CH3:22])[C:18]([O:11][N:10]=[C:8]([CH3:9])[CH3:7])=[C:17]([F:25])[C:16]=1[NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[Cl:33]
Reactant: CC(C)=NO
Reactant: COC(=O)c1cc(C(C)=O)c(F)c(F)c1Nc1ccccc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1cc(C(C)=O)c(ON=C(C)C)c(F)c1Nc1ccccc1Cl
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
t-BuOK (0.47 mL, 1.0 M in THF) was added to propan-2-one oxime (35 mg, 0.47 mmol). After stirring for 30 minutes, THF (0.5 mL) was added, and the reaction mixture was cooled to −78° C. A solution of 5-acetyl-2-(2-chlorophenylamino)-3,4-difluorobenzoic acid methyl ester (6) (50.0 mg, 0.147 mmol) in THF (1 mL) was added. The reaction mixture was slowly warmed to 0° C. and stirred for 2 hours. The reaction mixture was quenched with saturated aqueous NH4Cl, diluted with EtOAc and water. The aqueous layer was separated and extracted with EtOAc. The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo to give the 5-acetyl-2-(2-chloro-phenylamino)-3-fluoro-4-isopropylideneaminooxy-benzoic acid methyl ester. The recovered oxime was suspended in a 1:1 mixture of 5% aqueous HCl and MeOH (30 ml) and heated to reflux. After 1 hour, the reaction mixture was cooled to room temperature and diluted with EtOAc. The organic layer was washed with water, dried (MgSO4) and concentrated. Purification by flash column chromatography using the Biotage system (40% methylene chloride in hexanes) provided 17 mg (35% for two steps) of the desired product (7).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:20]([CH3:22])[CH3:21])[NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[CH:23](=[O:26])[C:24]#[CH:25]>C1COCC1.CC(C)=O>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[N:11]=[C:10]([CH:20]([CH3:22])[CH3:21])[N:9](/[CH:25]=[CH:24]/[CH:23]=[O:26])[C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[CH:14][CH:15]=1
Reactant: C#CC=O
Reactant: CC(C)c1nc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)[nH]1
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CC(C)c1nc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)n1/C=C/C=O

Procedure:
A solution of 4,5-bis(4-fluorophenyl)-2-(1-methylethyl)-1H-imidazole (200 mg) and propiolaldehyde (75% solution in toluene, 0.15 ml) in dry THF (15 ml) were heated under reflux, under nitrogen for 24 h. The residue was dissolved in acetone and absorbed onto silica gel before purifying by CC eluting with petroleum ether (b.p. 40°-60°)/ethyl acetate (2:1) to give the title compound (84 mg) as a pale yellow solid, δ(CDCl3), 1.49 (d,J=7 Hz, Me2CH), 3.25 (septet, J=7 Hz, Me2CH), 5.67 (dd,J=15 Hz, 7 Hz,CH=CH.CHO), 6.95 and 7.10-7.60 (t,J=9 Hz and m, CH=CH.CHO and aromatic protons), 9.40 (d, J=7 Hz, CH=CH.CHO).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C@@H:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([NH2:14])[CH:8]=1)[CH3:5].C[O:17][C:18](=O)[CH:19]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=1[Cl:32])[C:20](=O)[CH2:21][CH3:22]>>[CH3:1][O:2][C:3](=[O:15])[C@@H:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]2[C:8]=1[C:18](=[O:17])[C:19]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=1[Cl:32])=[C:20]([CH2:21][CH3:22])[NH:14]2)[CH3:5]
Reactant: CCC(=O)C(Cc1ccc(Cl)cc1Cl)C(=O)OC
Reactant: COC(=O)[C@H](C)Oc1ccc(F)c(N)c1
Product: CCc1[nH]c2c(F)ccc(O[C@@H](C)C(=O)OC)c2c(=O)c1Cc1ccc(Cl)cc1Cl

Procedure:
The title compounds were prepared by the method of Preparation 65c using (S)-2-(3-amino-4-fluorophenoxy)propionic acid methyl ester and 2-(2,4-dichlorobenzyl)-3-oxopentanoic acid methyl ester.
Reaction SMILES: Br[C:2]1[C:10]2[NH:9][C:8]3[CH:11]4[CH2:17][CH2:16][N:14]([CH2:15][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1)[CH2:13][CH2:12]4.[C:18]1([CH2:24][CH2:25][CH2:26][CH:27]=[CH:28]B2OC(C)(C)C(C)(C)O2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:18]1([CH2:24][CH2:25][CH2:26]/[CH:27]=[CH:28]/[C:2]2[C:10]3[NH:9][C:8]4[CH:11]5[CH2:17][CH2:16][N:14]([CH2:15][C:7]=4[C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH2:13][CH2:12]5)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Brc1cccc2c3c([nH]c12)C1CCN(CC1)C3
Reactant: CC1(C)OB(C=CCCCc2ccccc2)OC1(C)C
Product: C(=C/c1cccc2c3c([nH]c12)C1CCN(CC1)C3)\CCCc1ccccc1

Procedure:
A suspension of the product of Example 1B (110 mg, 0.38 mmol) and 5-phenyl-1-pentenylboronic acid pinacol ester (123 mg, 0.45 mmol; Alfa) was processed as described in Example 4 to provide the title compound: 1H NMR (500 MHz, methanol-d4) δ ppm 1.79-1.90 (m, 2 H), 2.00-2.14 (m, 4 H), 2.28-2.37 (m, 2 H), 2.69 (t, J=7.0 Hz, 2 H), 3.00-3.08 (m, 2 H), 3.08-3.11 (m, 1 H), 3.22 (ddd, J=14.1, 8.5, 5.8 Hz, 2 H), 4.20 (s, 2 H), 6.33 (dt, J=15.9, 7.0 Hz, 1 H), 6.77 (d, J=15.9 Hz, 1 H), 6.93 (t, J=7.6 Hz, 1 H), 7.12-7.17 (m, 3 H), 7.18-7.22 (m, 2 H), 7.22-7.28 (m, 2 H); MS (APCI) m/z 357 (M+H)+. Anal. Calcd. for C25H28N2.0.2H2O: C, 83.38; H, 7.95; N, 7.78. Found: C, 83.29; H, 7.66; N, 7.68.
Reaction SMILES: [BH4-].[Na+].[C:3]1(=[CH:15][C:16]#[N:17])[C:13]2=[C:14]3[C:9](=[CH:10][CH:11]=[CH:12]2)[CH:8]=[CH:7][CH:6]=[C:5]3[CH2:4]1>CO.Cl[Pd]Cl>[CH:3]1([CH2:15][C:16]#[N:17])[C:13]2=[C:14]3[C:9](=[CH:10][CH:11]=[CH:12]2)[CH:8]=[CH:7][CH:6]=[C:5]3[CH2:4]1
Reactant: N#CC=C1Cc2cccc3cccc1c23
Agent: Cl[Pd]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: N#CCC1Cc2cccc3cccc1c23
Reaction time: 0.25 h

Procedure:
The catalyst is prepared starting from 55 mg of PdCl2 in 5 ml of methanol treated with 25 mg of sodium borohydride. After 15 minutes' stirring, the compound obtained in Step A (1 g, 5.23.10−3 mol), diluted with methanol (15 ml), is incorporated. The mixture is purged with argon and placed under hydrogen. After 3 days' hydrogenation, the reaction mixture is filtered over Celite, rinsed and then evaporated under reduced pressure. The title product is isolated in the form of a light brown oil.
Reaction SMILES: [C:1]([C:5]1[C:10]2[O:11][CH2:12][CH2:13][C:9]=2[CH:8]=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:14](O)(=[O:19])[CH2:15][CH2:16][CH2:17]C>>[C:1]([C:5]1[C:10]2[O:11][CH2:12][CH2:13][C:9]=2[CH:8]=[C:7]([C:14](=[O:19])[CH2:15][CH2:16][CH3:17])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cccc2c1OCC2
Reactant: CCCCC(=O)O
Product: CCCC(=O)c1cc2c(c(C(C)(C)C)c1)OCC2

Procedure:
Substantially the method described in Example 1 is employed for the reaction between 7-tert-butyl-2,3-dihydrobenzo[b]furan and pentanoic acid, to provide 1-(7-tert-butyl-2,3-dihydrobenzo[b]furan-5-yl)-butan-1-one as a colorless oil.
Reaction SMILES: [BH4-].[Na+].C([O:5][C:6]([C:8]1[S:9][CH:10]=[C:11]([C:13](=[O:32])[NH:14][C@H:15]([CH3:31])[CH2:16][N:17]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[C:24]([Cl:30])[CH:23]=3)=[N:18]2)[N:12]=1)=O)C>C(O)C>[Cl:30][C:24]1[CH:23]=[C:22]([C:19]2[CH:20]=[CH:21][N:17]([CH2:16][C@H:15]([NH:14][C:13]([C:11]3[N:12]=[C:8]([CH2:6][OH:5])[S:9][CH:10]=3)=[O:32])[CH3:31])[N:18]=2)[CH:27]=[CH:26][C:25]=1[C:28]#[N:29]
Reactant: CCOC(=O)c1nc(C(=O)N[C@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)cs1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: C[C@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1csc(CO)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.6 %

Procedure:
Sodium borohydride (108 mg, 2.85 mmol) was added into a flask and the atmosphere was replaced with nitrogen. Dry ethanol was added and the reaction mixture was cooled to 0° C. (R)-ethyl-4-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-ylcarbamoyl)thiazole-2-carboxylate (632.8 mg, 1.426 mmol) was added and the reaction mixture was warmed slowly to RT while stirring overnight. The crude product was cooled to 0° C., the pH was adjusted to 6 and the mixture was evaporated. DCM and a few drops of ethanol were added and the crude product was washed with 1M Na2CO3 and with water. The final product was triturated using diethyl ether and DCM with some heptane added dropwise. Yield 46.6%. 1H-NMR (400 MHz; DMSO-d6): δ 1.12 (d, 3H), 4.31 (dd, 1H), 4.40 (dd, 1H), 4.43-4.51 (m, 1H), 4.78 (s, 2H), 6.20 (s, 1H), 6.95 (d, 1H), 7.84 (d, 1H), 7.95 (dd, 1H), 7.98 (dd, 1H), 8.08 (dd, 1H), 8.13 (s, 1H), 8.50 (d, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:12](=[O:15])[CH2:13]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27]([CH2:30][C:31]1[CH:47]=[CH:46][C:34]([O:35][CH2:36][CH2:37][NH:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[CH:33][CH:32]=1)(=[O:29])[NH2:28].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:39]([N:38]([CH2:37][CH2:36][O:35][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][C:27](=[O:29])[NH2:28])=[CH:47][CH:46]=1)[CH2:13][C:12](=[O:15])[C:11]1[CH:16]=[CH:17][C:18]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:10]=1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: NC(=O)Cc1ccc(OCCNCc2ccccc2)cc1
Reactant: O=C(CBr)c1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: NC(=O)Cc1ccc(OCCN(CC(=O)c2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)Cc2ccccc2)cc1

Procedure:
A mixture 3,4-dibenzyloxyphenacyl bromide (32.8 g.), N-[2-(4-carbamoylmethylphenoxy)ethyl]benzylamine (22.8 g.), anhydrous sodium carbonate (8.4 g.) and ethanol (1 liter) was boiled under reflux for 3 hours, then filtered hot to remove the inorganic sediment and evaporated in vacuo to afford a thick syrup. The latter was crystallized upon trituration in diethyl ether and a sample of the resultant solid was recrystallized from ethanol to give N-benzyl-N-(3,4-dibenzyloxybenzoyl)methyl-2-(4-carbamoylmethylphenoxy)ethylamine, m.p. 99°-101° C.
Reaction SMILES: [CH:1]1([O:4][CH2:5][CH2:6][CH2:7][OH:8])[CH2:3][CH2:2]1.ClCCl.C(N(CC)CC)C.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>C(Cl)(Cl)Cl>[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25]([O:8][CH2:7][CH2:6][CH2:5][O:4][CH:1]2[CH2:3][CH2:2]2)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: OCCCOC1CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)OCCCOC2CC2)cc1
Reaction time: 4 h
Yield: 44.9 %

Procedure:
To a mixture of 500 mg of 3-(cyclopropyloxy)propan-1-ol and 5 mL of dichloromethane were added 1.2 mL of triethylamine and 1.3 g of p-toluenesulfonic acid chloride under ice-cooling, followed by stirring for 4 hours. The reaction mixture was diluted with chloroform, washed with 1 M hydrochloric acid, a saturated aqueous sodium hydrogen carbonate solution, and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain 522 mg of 3-(cyclopropyloxy)propyl p-toluenesulfonate.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:17]1[N:22]=[CH:21][N:20]=[C:19]2[N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[N:24]=[CH:25][C:18]=12.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([N:14]([CH3:15])[C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[N:24]=[CH:25][C:18]=23)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN[C@@H]1CCCN(Cc2ccccc2)C1
Reactant: C[Si](C)(C)CCOCn1ncc2c(Cl)ncnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CN(c1ncnc2c1cnn2COCC[Si](C)(C)C)[C@@H]1CCCN(Cc2ccccc2)C1
Temperature: 60 °C
Reaction time: 8 h
Yield: 50.6 %

Procedure:
To a solution of (R)-1-benzyl-N-methylpiperidin-3-amine (500 mg, 2.4 mmol) and 4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidine (697 mg, 2.4 mmol) in DMF (10 mL) was added DIEA (1.26 g, 9.7 mmol) and the reaction mixture was stirred at 60° C. overnight. The reaction mixture was diluted with EtOAc (40 mL) and was washed with water (3×20 mL). The EtOAc layer was dried over Na2SO4 and evaporated in vacuo to give a residue that was purified by column chromatography (silica gel, gradient EtOAc in hexanes) to afford the titled intermediate (550 mg, 49%). 1H NMR (400 MHz, CDCl3): δ 8.37 (s, 1H), 7.98 (s, 1H), 7.34-7.20 (m, 5H), 5.71 (s, 2H), 3.62 (t, J=8.0 Hz, 2H), 3.55 (m, 2H), 3.24 (s, 3H), 2.91 (m, 2H), 2.17 (m, 1H), 1.99 (m, 2H), 1.79 (m, 2H), 1.41 (m, 1H), 1.27 (m, 1H), 0.92 (t, J=8.0 Hz, 2H), −0.054 (s, 9H). LC-MS: m/z [M+1]=453.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:8]([NH2:11])(=[O:10])=[O:9])=[C:5]([CH3:7])[N:6]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:53]1[CH:58]=[C:57]([O:59][CH3:60])[N:56]=[C:55]([S:61][CH2:62][C:63]2[CH:68]=[CH:67][CH:66]=[C:65]([F:69])[C:64]=2[F:70])[N:54]=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:1][C:2]1[S:3][C:4]([S:8]([NH:11][C:53]2[CH:58]=[C:57]([O:59][CH3:60])[N:56]=[C:55]([S:61][CH2:62][C:63]3[CH:68]=[CH:67][CH:66]=[C:65]([F:69])[C:64]=3[F:70])[N:54]=2)(=[O:10])=[O:9])=[C:5]([CH3:7])[N:6]=1
Reactant: COc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Reactant: Cc1nc(N)sc1S(N)(=O)=O
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COc1cc(NS(=O)(=O)c2sc(N)nc2C)nc(SCc2cccc(F)c2F)n1

Procedure:
The title compound was prepared according to the procedure outlined in example 1 step (iv) using a mixture of 2-amino-4-methyl-1,3-thiazole-5-sulfonamide (0.23 g), tris(dibenzylideneacetone)dipalladium (0) (73 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (38 mg), cesium carbonate (0.39 g) and 4-Chloro-2-[[(2,3-difluorophenyl)methyl]thio]-6-methoxypyrimidine (the product of Example 35, step i) (0.24 g) in dioxane (6 ml). The crude material was purified by column chromatography using EtOAc/isohexane (2:8 to 4.5:5.5 gradient) as eluent and trituration with Et2O to give the title compound as a beige solid. Yield: 0.15 g.