Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C=O.[N+:6]([C:9]1[N:10]=[C:11](SC2C=CC([N+]([O-])=O)=CC=2)[N:12]([CH2:14][C@:15]([OH:40])([CH3:39])[CH2:16][N:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][CH:27]=[CH:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=3)=[O:24])[CH2:19][CH2:18]2)[CH:13]=1)([O-:8])=[O:7].CC(C)([O-])C.[Na+].O>ClCCl.C(OCC)(=O)C.CO.C(OCC)(=O)C>[CH3:39][C@@:15]1([CH2:16][N:17]2[CH2:18][CH2:19][N:20]([C:23]([O:25][CH2:26][CH:27]=[CH:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:36])([F:38])[F:37])=[CH:31][CH:30]=3)=[O:24])[CH2:21][CH2:22]2)[O:40][C:11]2=[N:10][C:9]([N+:6]([O-:8])=[O:7])=[CH:13][N:12]2[CH2:14]1
Reactant: C[C@](O)(CN1CCN(C(=O)OCC=Cc2ccc(C(F)(F)F)cc2)CC1)Cn1cc([N+](=O)[O-])nc1Sc1ccc([N+](=O)[O-])cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C[C@]1(CN2CCN(C(=O)OCC=Cc3ccc(C(F)(F)F)cc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Reaction time: 0.33 h
Yield: 52.5 %

Procedure:
To N,N-dimethylformamide (1 ml) solution of 3-(4-trifluoromethylphenyl)-2-propenyl (S)-4-{3-[4-nitro-2-(4-nitrophenylthio)imidazol-1-yl]-2-hydroxy-2-methylpropyl}piperazin-1-carboxylate (100 mg) was added sodium tert-butoxide (19 mg) at 0° C., and stirred at the same temperature for 20 minutes. To the reaction mixture was added water and ethyl acetate, the organic layer was taken by separation. The ethyl acetate layer was washed with an aqueous solution of 5% potassium carbonate, water, and an aqueous solution being saturated with sodium chloride, then dried over anhydrous sodium sulfate. The residue obtained by removal of the solvent by distillation was purified by use of a basic silica gel chromatography (eluent: dichloroethane/ethyl acetate=9/1) and a slica gel column chromatography (eluent: dichloromethane/ethyl acetate/methanol=20/20/1), there was obtained 3-(4-trifluoromethylphenyl)-2-propenyl (S)-4-(2-methyl-6-nitro-2,3-dihydroimidazo-[2,1-b]oxazol-2-ylmethyl)piperazin-1-carboxylate (40 mg, yield: 54%) as yellow amorphous product.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C1COCC1>[CH3:22][S:23]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:25])=[O:24]
Reactant: OCCCCCOCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)OCCCCCOCc1ccccc1

Procedure:
The 5-benzyloxypentanol (Aldrich, 0.32 g, 1.7 mmol), triethylamine (0.67 mL, 5.0 mmol), and methanesulfonyl chloride (0.19 mL, 2.5 mmol) in 10 mL THF were processed as described in Example 1C to give the title compound that was used directly in the next reaction.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]2=[N:8][N:9]([CH3:12])[C:10]([CH3:11])=[C:4]2[CH:3]=1.[NH2:13][C:14]1[C:15](=[O:22])[N:16]([CH3:21])[CH:17]=[C:18]([Br:20])[CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Br:20][C:18]1[CH:19]=[C:14]([NH:13][C:2]2[N:7]=[CH:6][C:5]3=[N:8][N:9]([CH3:12])[C:10]([CH3:11])=[C:4]3[CH:3]=2)[C:15](=[O:22])[N:16]([CH3:21])[CH:17]=1
Reactant: Cc1c2cc(Br)ncc2nn1C
Reactant: Cn1cc(Br)cc(N)c1=O
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1c2cc(Nc3cc(Br)cn(C)c3=O)ncc2nn1C
Temperature: 25 °C
Yield: 23 %

Procedure:
A 100-mL round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 5-bromo-2,3-dimethyl-2H-pyrazolo[3,4-c]pyridine 326a from Example 325 (452 mg, 2.0 mmol), 3-amino-5-bromo-1-methylpyridin-2(1H)-one 325a (400 mg, 2.0 mmol), cesium carbonate (1.3 g, 4.0 mmol), and 1,4-dioxane (10 mL). After bubbling nitrogen through the suspension for 5 minutes, BINAP (124 mg, 0.2 mmol) and tris(dibenzylideneacetone)dipalladium(0) (140 mg, 0.2 mmol) were added. The system was subjected to three cycles of vacuum/nitrogen flush and heated at reflux for 2.5 h. It was then cooled to room temperature and filtered. The solid was washed with dichloromethane (3×10 mL). The combined filtrate was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with petroleum ether/ethyl acetate (2/1 to 100% ethyl acetate) to afford 326b (160 mg, 23%) as a yellow solid. MS-ESI: [M+H]+ 348.3
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([O:15][CH:16]([CH3:18])[CH3:17])=[C:11]([CH:14]=2)[C:12]#[N:13])=[N:4][CH:3]=1.[CH2:19]([C:21]1[C:26](/[CH:27]=[CH:28]/[O:29][CH3:30])=[CH:25][CH:24]=[CH:23][C:22]=1B1OC(C)(C)C(C)(C)O1)[CH3:20].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.O.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>[CH2:19]([C:21]1[C:26](/[CH:27]=[CH:28]/[O:29][CH3:30])=[CH:25][CH:24]=[CH:23][C:22]=1[C:2]1[S:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([O:15][CH:16]([CH3:18])[CH3:17])=[C:11]([CH:14]=2)[C:12]#[N:13])=[N:4][CH:3]=1)[CH3:20]
Reactant: CCc1c(/C=C/OC)cccc1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)Oc1ccc(-c2ncc(Br)s2)cc1C#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1c(/C=C/OC)cccc1-c1cnc(-c2ccc(OC(C)C)c(C#N)c2)s1
Temperature: 120 °C
Yield: 97.4 %

Procedure:
To a solution of 5-(5-bromo-1,3-thiazol-2-yl)-2-[(1-methylethyl)oxy]benzonitrile (D65) (500 mg), 2-{2-ethyl-3-[(E)-2-(methyloxy)ethenyl]phenyl}-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (401 mg) and tripotassium phosphate (591 mg) in N,N-dimethylformamide (DMF) (12 mL) and water (2 mL) stirred under nitrogen at room temperature was added Pd(Ph3P)4 (161 mg) in one charge. The reaction vessel was sealed and heated under microwave at 120° C. for 15 min. After cooling the reaction, the reaction mixture was filtered and the filtrate was partitioned between ethyl acetate (250 mL) and saturated brine (50 mL). The organic phase was dried over sodium sulphate and evaporated in vacuo. The crude product was purified by column chromatography to give 5-(5-{2-ethyl-3-[(E)-2-(methyloxy)ethenyl]phenyl}-1,3-thiazol-2-yl)-2-[(1-methylethyl)oxy]benzonitrile (D75) (548 mg) as a brown oil. MS (ES): C24H24N2O2S requires 404. found 405.2 (M+H+).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([OH:22])=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:23]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[CH3:24][O:25][C:26](=[O:32])[CH:27]([CH:29]1[CH2:31][CH2:30]1)O.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCOCC1>[CH3:24][O:25][C:26](=[O:32])[CH:27]([CH:29]1[CH2:31][CH2:30]1)[O:22][C:20]1[CH:19]=[CH:18][C:17]2[C:11]3[N:12]([CH2:13][CH2:14][O:15][C:16]=2[CH:21]=1)[CH:23]=[C:9]([C:8]1[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[CH:6][N:7]=1)[N:10]=3
Reactant: COC(=O)C(O)C1CC1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(O)cc1OCC2
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: C1COCCO1
Product: COC(=O)C(Oc1ccc2c(c1)OCCn1cc(-c3ncnn3C(C)C)nc1-2)C1CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 25.1 %

Procedure:
A mixture of 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-ol 490 (0.20 g, 0.64 mmol), cyclopropyl-hydroxy-acetic acid methyl ester (0.253 g, 1.28 mmol), triphenylphopshine (0.205 g, 1.28 mmol) and DIAD (252 μL, 1.28 mmol) in dioxane (6 mL) was stirred at RT for 18 h then concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 10% methanol in TBME) to give Cyclopropyl-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yloxy]-acetic acid methyl ester (0.068 g, 25%). LCMS: RT=3.43 min, [M+H]+=424.
Reaction SMILES: [CH2:1]([O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][O:7]1)[CH2:2][C:3]#[CH:4].[Li]CCCC.CCCCCC.[CH2:23]=[O:24]>C1COCC1>[O:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH:6]1[O:5][CH2:1][CH2:2][C:3]#[C:4][CH2:23][OH:24]
Reactant: C#CCCOC1CCCCO1
Reactant: C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OCC#CCCOC1CCCCO1
Reaction time: 0.5 h
Yield: 62 %

Procedure:
A solution of compound 2 (11.0 g, 71.3 mmol) in THF (80 mL) was treated with a 1.6 M solution of n-BuLi in hexane (58 mL, 92.8 mmol) dropwise at 0° C. for 20 min. After 30 min, paraformaldehyde (6.4 g) was added to the reaction mixture at 0° C. After 5 h, the reaction mixture was quenched with aq NH4Cl at 0° C. and diluted with EtOAc (200 mL) and washed with aq NH4Cl and brine. The organic layer was dried over MgSO4 and concentrated. The residue was purified with 20% EtOAc in hexanes by silica get column chromatography to give 8.15 g of compound 3 (44.2 mmol, 62% yield): 1H NMR (CDCl3) δ 4.63 (t, J=3.4 Hz, 1H), 4.22 (t, J=2.1 Hz, 2H), 3.91˜3.76 (m, 2H), 3.59˜3.46 (m, 2H), 2.51 (tt, J=7.1, 2.2 Hz, 2H), 1.86˜1.46 (m, 6H).
Reaction SMILES: Cl.[F:2][C:3]1[C:8]([O:9][CH2:10][CH2:11][OH:12])=[CH:7][C:6]([O:13][CH3:14])=[CH:5][C:4]=1[CH:15]([NH:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([NH2:35])=[NH:34])=[CH:31][CH:30]=1)[C:16]1[NH:20][C:19](=[O:21])[N:18]([C:22]2[N:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[N:17]=1.CO.C(N(CC)CC)C.[CH3:47][O:48][C@H:49]([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:50]([OH:52])=[O:51]>C(O)(=O)C>[CH3:47][O:48][C@H:49]([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:50]([OH:52])=[O:51].[F:2][C:3]1[C:8]([O:9][CH2:10][CH2:11][OH:12])=[CH:7][C:6]([O:13][CH3:14])=[CH:5][C:4]=1[C@@H:15]([NH:28][C:29]1[CH:30]=[CH:31][C:32]([C:33]([NH2:35])=[NH:34])=[CH:36][CH:37]=1)[C:16]1[NH:20][C:19](=[O:21])[N:18]([C:22]2[N:23]=[CH:24][CH:25]=[CH:26][N:27]=2)[N:17]=1
Reactant: COc1cc(OCCO)c(F)c(C(Nc2ccc(C(=N)N)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c1
Agent: CO[C@@H](C(=O)O)c1ccccc1
Agent: Cl
Solvent: CO
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: COc1cc(OCCO)c(F)c([C@@H](Nc2ccc(C(=N)N)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c1
Temperature: 60 °C
Yield: 38.8 %

Procedure:
A suspension of 4-{[[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl](5-oxo-1-pyrimidin-2-yl-4,5-dihydro-1H-[1,2,4]-triazol-3-yl)methyl]amino}benzamidine hydrochloride (4.73 g, purity 92%, 8.2 mmol) and methanol (131 mL) was heated to 60° C. to bring into solution. Triethylamine (1.71 mL, 12.3 mmol) was added thereto at 60° C., and the resulting mixture was stirred for minutes or more. To the suspension obtained, (R)-(−)-α-methoxyphenylacetic acid (2.73 g, 16.4 mmol) and acetic acid (4.35 mL) were added to bring the same into solution. The solution obtained was allowed to cool to 35° C., and a seed crystal of the captioned compound was added thereto, and the resulting mixture was stirred at room temperature for 20 hours and at 0° C. for 3 hours. The resulting solid was filtered, sequentially washed with ethanol (13 mL) and tert-butyl methyl ether (13 mL), and then dried at room temperature under reduced pressure to obtain the captioned compound (2.1 g) as a white solid.
Reaction SMILES: C(OC([N:8]([CH2:32][C:33]1[CH:51]=[CH:50][C:36]([C:37]([O:39][CH2:40][O:41]/[N:42]=[N+:43](\[O-:49])/[N:44]([CH2:47][CH3:48])[CH2:45][CH3:46])=[O:38])=[CH:35][CH:34]=1)[S:9]([C:12]1[CH:17]=[C:16]([C:18](=[O:30])[NH:19][N:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22][C@H:21]2[CH3:29])[CH:15]=[CH:14][C:13]=1[Cl:31])(=[O:11])=[O:10])=O)(C)(C)C>Cl.O1CCOCC1>[Cl:31][C:13]1[CH:14]=[CH:15][C:16]([C:18](=[O:30])[NH:19][N:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22][C@H:21]2[CH3:29])=[CH:17][C:12]=1[S:9]([NH:8][CH2:32][C:33]1[CH:34]=[CH:35][C:36]([C:37]([O:39][CH2:40][O:41]/[N:42]=[N+:43](\[O-:49])/[N:44]([CH2:45][CH3:46])[CH2:47][CH3:48])=[O:38])=[CH:50][CH:51]=1)(=[O:11])=[O:10]
Reactant: CCN(CC)/[N+]([O-])=N/OCOC(=O)c1ccc(CN(C(=O)OC(C)(C)C)S(=O)(=O)c2cc(C(=O)NN3c4ccccc4C[C@H]3C)ccc2Cl)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CCN(CC)/[N+]([O-])=N/OCOC(=O)c1ccc(CNS(=O)(=O)c2cc(C(=O)NN3c4ccccc4C[C@H]3C)ccc2Cl)cc1

Procedure:
Dissolve the compound obtained in Step D (1.47×10−3 mol) in 20 ml of a 4N solution of HCl in 1,4-dioxane and place under stirring. The initially yellowish reaction mixture becomes darker and darker until it is virtually black. After stirring for 18 hours at ambient temperature, the reaction mixture is evaporated to dryness under reduced pressure. The black residue obtained is chromatographed on a silica column using as eluant a 50/50 n-heptane/ethyl acetate mixture.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][NH:11][C:12]1[N:13]=[N:14][C:15]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[C:16]([CH3:19])[C:17]=1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:27][C@H:28]([CH3:32])[C:29](O)=[O:30].C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[CH2:1]([N:8]([CH2:9][CH2:10][NH:11][C:12]1[N:13]=[N:14][C:15]([C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)=[C:16]([CH3:19])[C:17]=1[CH3:18])[C:29](=[O:30])[C@H:28]([Cl:27])[CH3:32])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(NCCNCc2ccccc2)nnc(-c2ccc(F)cc2)c1C
Reactant: C[C@@H](Cl)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(NCCN(Cc2ccccc2)C(=O)[C@@H](C)Cl)nnc(-c2ccc(F)cc2)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.5 %

Procedure:
Sequentially treat a solution of N1-benzyl-N2-(6-(4-fluorophenyl)-4,5-dimethylpyridazin-3-yl)ethane-1,2-diamine (4.90 g, 13.98 mmol) in CH2Cl2 (70 mL) with (R)-(+)-2-chloropropionic acid (1.84 mL, 20.97 mmol), triethylamine (2.92 mL, 20.97 mmol), HOBT (3.21 g, 20.97 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.02 g, 20.97 mmol). Stir the resulting mixture at ambient temperature overnight. Wash the reaction mixture with saturated aqueous NaHCO3. Extract the aqueous layer with CH2Cl2. Combine the organic layers, dry over Na2SO4, filter, and concentrate under reduced pressure. Purify the residue by flash silica gel chromatography (20% EtOAc in hexanes) to afford the title compound as a yellow foam (4.59 g, 74%). ES/MS m/z 441.2 (M+1).
Reaction SMILES: [O:1]=[S:2]1(=[O:33])[C:8]2[CH:9]=[C:10]([O:15][CH3:16])[C:11]([S:13][CH3:14])=[CH:12][C:7]=2[N:6]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[C:5](=O)[C:4]([CH2:29][CH2:30][CH2:31][CH3:32])([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:3]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>CCOCC>[O:33]=[S:2]1(=[O:1])[C:8]2[CH:9]=[C:10]([O:15][CH3:16])[C:11]([S:13][CH3:14])=[CH:12][C:7]=2[N:6]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH2:5][C:4]([CH2:29][CH2:30][CH2:31][CH3:32])([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:3]1
Reactant: CCCCC1(CCCC)CS(=O)(=O)c2cc(OC)c(SC)cc2N(c2ccc(Cl)cc2)C1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CCCCC1(CCCC)CN(c2ccc(Cl)cc2)c2cc(SC)c(OC)cc2S(=O)(=O)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 67.6 %

Procedure:
To a solution of 1,1-dioxo-3,3-dibutyl-4-oxo-5-(4-chlorophenyl)-7-methylthio-8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (Method 97; 0.41 g, 0.79 mmol) in anhydrous ether (15 ml) was added LiAlH4 (0.15 g, 3.97 mmol) under nitrogen. The reaction mixture was stirred at room temperature for 2.5 hours. The reaction flask was cooled to 0° C. and the excess LiAlH4 was quenched by adding water (0.3 ml) and 2 M aqueous NaOH (0.3 ml). The mixture was filtered and the filtrate was dried and evaporated under reduced pressure. The crude product was purified by column chromatography using DCM as eluent to give the title compound 0.265 g (68%). NMR (300 MHz) 0.8–0.90 (m, 6H), 1.0–1.47 (m, 12H), 2.33 (s, 3H), 3.17 (s, 2H), 3.70 (s, 2H), 3.93 (s, 3H), 7.03–7.08 (m, 3H), 7.23–7.32 (m, 3H); m/z 496.
Reaction SMILES: [CH:1]1([CH2:5][OH:6])[CH2:4][CH2:3][CH2:2]1.[C:7]1([CH3:17])[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1>C(Cl)Cl.N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH3:17][C:7]1[CH:12]=[CH:11][C:10]([S:13]([O:6][CH2:5][CH:1]2[CH2:4][CH2:3][CH2:2]2)(=[O:15])=[O:14])=[CH:9][CH:8]=1
Reactant: OCC1CCC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2CCC2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 72.8 %

Procedure:
To a solution of cyclobutylmethanol (25 g, 290 mmol) in CH2Cl2 (200 mL) and pyridine (100 mL) was added 4-(dimethylamino)pyridine (1.8 g, 14.5 mmol) followed by p-toluenesulfonyl chloride (55.3 g, 290 mmol). The mixture was allowed to stir at ambient temperature for 20 hours then quenched with 5% aqueous HCl (30 mL). The layers were separated and the aqueous phase was extracted with CH2Cl2 (3×15 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by column chromatography (SiO2, 75% hexanes in EtOAc) afforded the title compound (50.8 g, 211 mmol, 73% yield). MS (DCI/NH3) m/z 258 (M+NH4)−.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:12])[O:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.C(O[CH:16]=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19])C>>[CH2:21]([O:20][C:18](=[O:19])[C:17](=[CH:16][NH:1][C:2]1[C:3](=[O:12])[O:4][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=2[CH:11]=1)[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH3:22]
Reactant: Nc1cc2ccccc2oc1=O
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)C(=CNc1cc2ccccc2oc1=O)C(=O)OCC
Temperature: 120 °C
Yield: 89.2 %

Procedure:
A mixture of 3-aminocoumarin (30.0 g, 0.186 mole) and diethyl ethoxymethylenemalonate (75.0 g, 0.347 mole) is heated at 120° C. for 4 hours under nitrogen. The reaction mixture is cooled and triturated with hexane. The product is filtered off and washed with hexane. Recrystallization from ethyl acetate gives white crystals (55.0 g, 89%), mp. 134-135.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:15])[N:5]([C:7]2[CH:12]=[C:11]([S:13][CH3:14])[N:10]=[CH:9][N:8]=2)[N:6]=1.Br[C:17]1[CH:18]=[C:19]([NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)[CH:20]=[CH:21][C:22]=1[CH3:23].C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1COCC1>[CH3:23][C:22]1[CH:17]=[CH:18][C:19]([NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:33])([F:34])[F:35])[CH:27]=2)=[CH:20][C:21]=1[NH:15][C:4]1[N:5]([C:7]2[CH:12]=[C:11]([S:13][CH3:14])[N:10]=[CH:9][N:8]=2)[N:6]=[C:2]([CH3:1])[CH:3]=1
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1Br
Reactant: CSc1cc(-n2nc(C)cc2N)ncn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CSc1cc(-n2nc(C)cc2Nc2cc(NC(=O)c3cccc(C(F)(F)F)c3)ccc2C)ncn1
Temperature: 25 °C

Procedure:
5-Methyl-2-(6-methylsulfanyl-pyrimidin-4-yl)-2H-pyrazol-3-ylamine (90 mg, 0.40 mmol) is mixed with N-(3-Bromo-4-methyl-phenyl)-3-trifluoromethyl-benzamide (228 mg, 0.64 mmol), palladium acetate (20 mg, 0.089 mmol), Xantophos (75 mg, 0.13 mmol) and cesium carbonate (420 mg, 1.28 mmol). 4 mL anhydrous 1,4-dioxane is added under a nitrogen environment and the mixture is subjected to microwave irradiation to 150° C. for 30 minutes. The reaction mixture is then cooled to room temperature, treated with 100 mL THF, passed through a celite column and concentrated. The crude product is purified by ISCO chromatography eluting with ethyl acetate in hexanes from 0% to 40% to afford N-{4-Methyl-3-[5-methyl-2-(6-methylsulfanyl-pyrimidin-4-yl)-2H-pyrazol-3-ylamino]-phenyl}-3-trifluoromethyl-benzamide: 1H NMR 400 MHz (d6-DMSO) δ 10.65 (s, 1H), 10.46 (s, 1H), 8.89 (s, 1H), 8.30-8.25 (m, 2H), 7.98 (d, J=7.5 Hz, 1H), 7.89 (s, 1H), 7.80 (t, J=7.5 Hz, 1H), 7.67 (s, 1H), 7.40 (d, J=7.5 Hz, 1H), 7.25 (d, J=8.2 Hz, 1H), 6.12 (s, 1H), 2.61 (s, 3H), 2.34 (s, 3H), 2.25 (s, 3H); MS m/z 499.14 (M+1).
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[C:6]([O:10][C:11](=[O:26])[NH:12][C:13]([CH3:25])([CH3:24])[CH2:14][NH:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[CH3:23])([CH3:9])([CH3:8])[CH3:7].C(=O)(O)[O-].[Na+]>CN(C)C(=O)C>[C:6]([O:10][C:11](=[O:26])[NH:12][C:13]([CH3:25])([CH3:24])[CH2:14][N:15]([C:3](=[O:4])[CH2:2][Br:1])[C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[CH3:23])([CH3:9])([CH3:8])[CH3:7]
Reactant: O=C(Br)CBr
Reactant: Cc1ccc(F)cc1NCC(C)(C)NC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1ccc(F)cc1N(CC(C)(C)NC(=O)OC(C)(C)C)C(=O)CBr
Reaction time: 0.17 h
Yield: 89.1 %

Procedure:
1.67 ml of bromoacetyl bromide (19.1 mmol) was added to a solution of 5.68 g of [1,1-dimethyl-2-(5-fluoro-2-methylphenylamino)ethyl]carbamic acid t-butyl ester obtained in Example (70a) (19.1 mmol) in N,N-dimethylacetamide (95 ml) under ice-cooling, and the mixture was stirred at the same temperature for 10 minutes. A saturated sodium bicarbonate aqueous solution was added to the reaction mixture, followed by extraction with ethyl acetate. Then, the organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. Hexane was added to the residue, and the solid was collected by filtration to obtain 7.1 g of the title compound (yield: 89%).
Reaction SMILES: [Si]([O:18][CH2:19][C:20]([CH3:53])([CH3:52])[CH2:21][NH:22][C@@H:23]([C:25]1[CH:30]=[CH:29][C:28]([C:31]2[C:40]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[CH:39][C:38]3[C:33](=[CH:34][CH:35]=[N:36][C:37]=3[C:47]3[CH:48]=[N:49][NH:50][CH:51]=3)[N:32]=2)=[CH:27][CH:26]=1)[CH3:24])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>C1COCC1>[CH3:53][C:20]([CH3:52])([CH2:21][NH:22][C@@H:23]([C:25]1[CH:30]=[CH:29][C:28]([C:31]2[C:40]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)=[CH:39][C:38]3[C:33](=[CH:34][CH:35]=[N:36][C:37]=3[C:47]3[CH:48]=[N:49][NH:50][CH:51]=3)[N:32]=2)=[CH:27][CH:26]=1)[CH3:24])[CH2:19][OH:18]
Reactant: C[C@@H](NCC(C)(C)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1ccc(-c2nc3ccnc(-c4cn[nH]c4)c3cc2-c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@@H](NCC(C)(C)CO)c1ccc(-c2nc3ccnc(-c4cn[nH]c4)c3cc2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 3-{[teri-butyl(diphenyl)silyl]oxy}-2,2-dimethyl-N-[(1R)-1-{4-[3-phenyl-5-(1H-pyrazol-4-yl)-1,6-naphthyridin-2-yl]phenyl}ethyl]propan-1-amine (2-5, 0.050 g, 0.070 mmol) in THF (1.0 mL) was added 1M tetrabutylammonium fluoride in THF (0.70 mL, 0.70 mmol) at room temperature and the reaction was stirred at room temperature for 15 hours. The reaction was poured into ethyl acetate, washed with water and brine. The organic layer was dried over sodium sulfate, filtered and concentrated under vacuum. Purification by reverse phase chromatography (5-95% acetonitrile/water/0.1% TFA; Water Sunfire C18) gave (2,2-dimethyl-3-{[(1R)-1-{4-[3-phenyl-5-(1H-pyrazol-4-yl)-1,6-naphthyridin-2-yl]phenyl}ethyl]amino}propan-1-ol (2-6) as a yellow solid. HRMS (M+H)+: calculated 478.2602; found 478.2626.