Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[O:2]1[C:8]2[CH:9]=[C:10]([N:13]3[CH2:18][CH2:17][N:16]([C:19](=[O:21])[CH3:20])[CH2:15][CH2:14]3)[CH:11]=[CH:12][C:7]=2[CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)C(C)C)(C)C.[C:31]1([CH2:37][S:38](Cl)(=[O:40])=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>ClCCl>[C:31]1([CH2:37][S:38]([N:5]2[CH2:6][C:7]3[CH:12]=[CH:11][C:10]([N:13]4[CH2:14][CH2:15][N:16]([C:19](=[O:21])[CH3:20])[CH2:17][CH2:18]4)=[CH:9][C:8]=3[O:2][CH2:3][CH2:4]2)(=[O:40])=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC(=O)N1CCN(c2ccc3c(c2)OCCNC3)CC1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1CCN(c2ccc3c(c2)OCCN(S(=O)(=O)Cc2ccccc2)C3)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.6 %

Procedure:
To a solution of 1-(4-(2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-8-yl)piperazin-1-yl)ethanone hydrochloride (80 mg, 0.26 mmol) and N,N-diisopropylethylamine (0.17 mL, 0.94 mmol) in dichloromethane (1.5 mL) was added phenylmethanesulfonyl chloride (76 mg, 0.39 mmol) and the reaction was stirred at ambient temperature for 16 hours. The reaction was then concentrated and purified by preparative reverse phase HPLC to yield 61 mg of 1-[4-(4-phenylmethanesulfonyl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-8-yl)-piperazin-1-yl]-ethanone. 1H NMR (400 MHz, DMSO) δ 7.38-7.27 (m, 5H), 7.03 (d, J=8.3 Hz, 1H), 6.63-6.58 (m, 1H), 6.58-6.55 (m, 1H), 4.36 (s, 2H), 4.22 (s, 2H), 3.96-3.90 (m, 2H), 3.59-3.51 (m, 4H), 3.51-3.46 (m, 2H), 3.18-3.12 (m, 2H), 3.12-3.04 (m, 2H), 2.02 (s, 3H); LCMS (m/z) ES+ 430.1 [M+1]+.
Reaction SMILES: O.Cl.C[O:4][C:5]1[C:10]([CH3:11])=[C:9]([CH3:12])[CH:8]=[C:7]([CH3:13])[C:6]=1[C:14](=O)[CH3:15].C(SCCC1(O)C(C)=C(C)C=C(C)C1)C>CN(C)C=O>[CH3:11][C:10]1[C:9]([CH3:12])=[CH:8][C:7]([CH3:13])=[C:6]([CH:14]=[CH2:15])[C:5]=1[OH:4]
Reactant: COc1c(C)c(C)cc(C)c1C(C)=O
Agent: CCSCCC1(O)CC(C)=CC(C)=C1C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: C=Cc1c(C)cc(C)c(C)c1O
Temperature: 25 °C
Yield: 16.2 %

Procedure:
Under nitrogen atmosphere, in dry N,N-dimethylformamide (8 mL) was suspended 270 mg (6.75 mmol) of 60% sodium hydride, and 0.60 mL (8.10 mmol) of ethanethiol was gradually added dropwise to the suspension. After stirring for 15 minutes, 400 mg (2.27 mmol) of 3-methoxy-1,2,5-trimethyl-4-vinylbenzene obtained in (4) and dissolved in dry N,N-dimethylformamide (1.5 mL) was added to the mixture, and the resulting mixture was refluxed for 1 hour. After cooling to room temperature, the reaction mixture was poured into water, made acidic by adding hydrochloric acid, and extracted with hexane. The organic layers were combined, washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (Wako gel C-100, hexane:ethyl acetate=20:1) and by preparative thin-layer chromatography (available from MERCK CO., 1.05744, developed by hexane:ethyl acetate=8:1) to obtain 63.0 mg (0.389 mmol, Yield from 1-(2-methoxy-3,4,6-trimethylphenyl)ethanone: 16.2%) of 2,3,5-trimethyl-6-vinylphenol and 330 mg (1.47 mmol, Yield from 1-(2-methoxy-3,4,6-trimethylphenyl)ethanone: 61.4%) of 2-[1-(ethylsulfanylethyl]-3,5,6-trimethylphenol.
Reaction SMILES: Cl.[F:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)=[N:8][O:9][C:5]=2[CH:4]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][C:30]=1[C:36](=[O:38])[CH3:37]>CN(C)C=O.C(#N)C>[F:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([CH:10]3[CH2:11][CH2:12][N:13]([CH2:25][CH2:26][CH2:27][O:28][C:29]4[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][C:30]=4[C:36](=[O:38])[CH3:37])[CH2:14][CH2:15]3)=[N:8][O:9][C:5]=2[CH:4]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: CC(=O)c1cc(C)ccc1OCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: CC(=O)c1cc(C)ccc1OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 95 °C
Yield: 46.2 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride (2.87 g, 11.23 mmol), K2CO3 (2.5 g), 1-[2-(3-bromopropoxy)-5-methylphenyl]ethanone (3.74 g, 13.8 mmol) in dimethylformamide (10 ml) and acetonitrile (50 ml) was heated at 95° C. for 6 hours. At the end of the reaction, the solvent was concentrated and the mixture was extracted into dichloromethane (300 ml). The organic solution was washed with water and brine, dried over MgSO4, then concentrated down to a crude oil. The purification was done by flash chromatography over a silica gel column (SiO2, 60 g, eluted with 1% CH3OH:dichloromethane: 1.2 l; 3% CH3OH:dichloromethane: 600 ml). The material thus obtained was crystallized from a small volume of ether and hexane to provide 2.13 g (46%) of off-white 1-[2-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-5-methylphenyl]ethanone, m.p.=92°-93° C.
Reaction SMILES: [O:1]1CCN=[CH:2]1.[F:6][C:7]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].[Li]C(CC)C.CN(C=O)C>C1COCC1>[F:6][C:7]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:8]=1[CH:9]([OH:11])[O:10][C:2]2=[O:1]
Reactant: C1=NCCO1
Reactant: O=C(O)c1cc(F)ccc1F
Agent: [Li]C(C)CC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C1OC(O)c2c(F)ccc(F)c21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
To a -78° C. solution of the oxazoline derivative (7.95 g, 37.7 mmol), prepared from 2,5-difluorobenzoic acid in the usual manner, in THF (50 mL) was added over 15 min sec-BuLi (29 mL of 1.3 M solution). After 30 min, DMF (6.0 mL) was added, and the reaction was stirred at -78° C. for 2 hr. The reaction was tnen quenched with concentrated HCl (5 mL). Tne solvents were removed in vacuo, and the residue was taken up in 5 N HCl (5 mL) and heated on the steam bath overnight. After cooling to room temperature, the reaction mixture was extracted with EtOAc (3×200 mL). Standard workup gave a light brown solid (6.5 g, 93%, mp 125°-128° C.).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:34])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:32][CH3:33])=[C:16]([CH2:19][N:20]([CH3:31])[C:21]4([C:27]([NH:29][CH3:30])=[O:28])[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>>[Cl:1][C:2]1[C:3]([F:34])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:32][CH3:33])=[C:16]([CH2:19][N:20]([CH3:31])[C:21]4([C:27]([NH:29][CH3:30])=[O:28])[CH2:26][CH2:25][CH2:24][N:23]([S:36]([CH3:35])(=[O:38])=[O:37])[CH2:22]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CNC(=O)C1(N(C)Cc2cc3c(Nc4cccc(Cl)c4F)ncnc3cc2OC)CCCNC1
Reactant: CS(=O)(=O)Cl
Product: CNC(=O)C1(N(C)Cc2cc3c(Nc4cccc(Cl)c4F)ncnc3cc2OC)CCCN(S(C)(=O)=O)C1

Procedure:
3-[({4-[(3-Chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]-N-methylpiperidine-3-carboxamide (Example 90.1, Isomer 2) was coupled with methanesulfonyl chloride using an analogous method to that described for the equivalent step in Example 89 to give (S or R)-3-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]-N-methyl-1-(methylsulfonyl)piperidine-3-carboxamide (Example 90, Isomer 2); 1H NMR Spectrum: (DMSO d6) 1.67 (m, 1H); 1.92 (m, 2H); 2.07 (m, 1H); 2.21 (s, 3H); 2.66 (d, 3H); 2.88 (s, 3H); 3.03 (m, 1H); 3.21 (m, 1H); 3.34 (d, 1H); 3.52 (d, 1H); 3.62 (d, 1H); 3.79 (d, 1H); 3.96 (s, 3H); 7.20 (s, 1H); 7.30 (dt, 1H); 7.50 (m, 1H); 7.62 (m, 2H); 8.32 (s, 1H); 8.44 (s, 1H); 9.57 (s, 1H); Mass Spectrum: (M+H)+ 565.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:10].B([C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=1)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=2)=[C:3]([CH3:10])[CH:4]=1)#[N:7]
Reactant: Cc1cc(C#N)ccc1Br
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1cc(C#N)ccc1-c1ccc(C(=O)O)cc1
Reaction time: 24 h
Yield: 67.4 %

Procedure:
4-bromo-3-methylbenzonitrile (5 g, 0.026 mol) was suspended in 1,2-dimethoxyethane (100 ml) and treated with 4-boronobenzoic acid (2.4 g, 0.026 mol) followed by a solution of sodium carbonate (11.65 g, 0.11 mmol) in water (100 ml). The mixture was flushed with argon and tetrakis(triphenylphosphine)palladium (0) (0.55 g) was added. The reaction mixture was then heated to reflux with stirring. After 24 h, the 1,2-dimethoxyethane was removed by evaporation under reduced pressure and the aqueous residue was washed with ethyl acetate. The aqueous layer was then acidified to pH 1 and the resultant solid was filtered off and was dried in vacuo to give the title compound as a white solid (4.16 g, 69%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]4[S:20][C:21]5[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=5[CH:23]=4)=[CH:15][C:13]=3[N:14]=2)[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[CH:28]1[C:33]([C:34]([OH:36])=[O:35])=[CH:32][C:31]2[C:37]([O:39][C:40](=O)[C:30]=2[CH:29]=1)=[O:38]>>[CH3:9][O:8][C:5]1[C:4]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]4[S:20][C:21]5[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=5[CH:23]=4)=[CH:15][C:13]=3[N:14]=2)=[CH:3][C:2]([N:1]2[C:37](=[O:38])[C:31]3[C:30](=[CH:29][CH:28]=[C:33]([C:34]([OH:36])=[O:35])[CH:32]=3)[C:40]2=[O:39])=[CH:7][CH:6]=1
Reactant: COc1ccc(N)cc1-c1nc2cc(-c3cc4ccccc4s3)ccc2o1
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Product: COc1ccc(N2C(=O)c3ccc(C(=O)O)cc3C2=O)cc1-c1nc2cc(-c3cc4ccccc4s3)ccc2o1

Procedure:
Prepared by the method of Example 15f), from 2-(3-amino-6-methoxyphenyl)-5-(2-benzothiophenyl)benzoxazole (140 mg, 0.38 mmol) and 1,2,4-benzenetricarboxylic anhydride (72 mg, 0.38 mmol) the title compound was obtained (100 mg, 22%). 1H NMR (DMSO) δ 13.79(s, 1H), 8.44(dd, 1H), 8.34(s, 1H), 8.22(m, 2H), 8.11(d, 1H), 8.01(d, 1H), 7.97(s, 1H), 7.92(d, 1H), 7.87(m, 2H), 7.73(dd, 1H), 7.48(d, 1H), 7.40(m, 2H), 4.04(s, 3H). MS 547.0 m/z (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[C:6]([CH3:9])[C:7]=1[CH3:8].[CH3:11][C:12](=[CH2:15])[CH2:13]O.C(O)=O>C(OC(C)C)(C)C>[CH3:11][C:12]1([CH3:15])[CH2:13][C:3]2[C:2]([CH3:1])=[C:7]([CH3:8])[C:6]([CH3:9])=[CH:5][C:4]=2[O:10]1
Reactant: Cc1cc(O)cc(C)c1C
Reactant: C=C(C)CO
Solvent: CC(C)OC(C)C
Solvent: O=CO
Product: Cc1cc2c(c(C)c1C)CC(C)(C)O2
Yield: 41.5 %

Procedure:
3,4,5-Trimethylphenol (5.0 g, 36.7 mmol) and 2-methyl-2-propenol (3.2 g, 44.0 mmol) were added to formic acid (50 ml). The mixture was heated under reflux for 3 hours. The reaction mixture was diluted with isopropyl ether, washed with water and saturated sodium bicarbonate solution, dried and concentrated. The residue was purified by column chromatography on silica gel (hexane-isopropyl ether, 97:3) to obtain the desired compound (2.9 g, yield: 41.5%) as oil.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([O:11][CH3:12])=[O:10])[CH2:5][CH2:4]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.CCOC(C)=O>[CH:2]([C@H:3]1[CH2:4][CH2:5][C@H:6]([C:9]([O:11][CH3:12])=[O:10])[CH2:7][CH2:8]1)=[O:1]
Reactant: COC(=O)[C@H]1CC[C@H](CO)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)[C@H]1CC[C@H](C=O)CC1
Temperature: 25 °C

Procedure:
To a flask containing methyl trans-4-(hydroxymethyl)cyclohexanecarboxylate (100 mg, 0.581 mmol) in CH2Cl2 (5.8 mL) at 0° C., was added Dess-Martin periodinane (493 mg, 1.16 mmol). The reaction was allowed to warm to room temperature over an hour and then was diluted with EtOAc (60 mL), washed with saturated K2CO3 solution (3×40 mL) and brine (40 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel (0 to 25% EtOAc/hexanes) afforded methyl trans-4-formylcyclohexanecarboxylate. Rf=0.87 (25% EtOAc/hexanes). 1H NMR (CDCl3, 500 MHz) δ 9.63 (s, 1H), 3.67 (s, 3H), 2.51-2.05 (m, 6H), 1.63-1.26 (m, 4H).
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH3:4].O>C(O)C>[CH2:3]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]([OH:16])[C:12]([F:14])([F:15])[F:13])[CH3:4]
Reactant: CCOCCCCCC(=O)C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOCCCCCC(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 93.4 %

Procedure:
2.6 g (0.07 mol) of sodium borohydride was added gradually to a solution of 30 g (0.14 mol) of 7-ethoxy-1,1,1-trifluoro-2-heptanone in 200 ml of ethanol at 0° C. The solution was stirred for 24 hours at room temperature. 200 ml of water was added and extracted with diethyl ether. The organic layer was washed with a small amount of water, dried over anhydrous magnesium sulfate and concentrated. The residue was distilled under the reduced pressure, to obtain 28 g of racemic 7-ethoxy-1,1,1-trifluoro-2-heptanol. Boiling point; 133-137° C. (50 mmHg).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[CH2:18]1[O:28][C:27]2[C:20](=[C:21]([CH:24]=[CH:25][CH:26]=2)[CH2:22]Br)[O:19]1>>[O:28]1[C:27]2[CH:26]=[CH:25][CH:24]=[C:21]([CH2:22][N:12]3[C:13]([CH3:17])([CH3:16])[C:14](=[O:15])[N:11]3[CH:2]3[CH:3]4[CH2:4][CH:5]5[CH2:6][CH:7]([CH2:8][CH:1]3[CH2:10]5)[CH2:9]4)[C:20]=2[O:19][CH2:18]1
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Reactant: BrCc1cccc2c1OCO2
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1Cc1cccc2c1OCO2

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 2,3-(methylenedioxy)benzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a white crystalline powder.
Reaction SMILES: C([O:8][C:9]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[S:11][CH:10]=1)C1C=CC=CC=1.ClC(Cl)(Cl)Cl.I[Si](C)(C)C>O>[OH:8][C:9]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[S:11][CH:10]=1
Reactant: FC(F)(F)c1cc(OCc2ccccc2)cs1
Agent: C[Si](C)(C)I
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: Oc1csc(C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 12 h

Procedure:
A mixture of 1G (7.75 g) and tetrachloromethane (50 ml) was treated with iodotrimethylsilane (12.30 ml) and heated to 60 ° C. for 12 hours. The reaction mixture was stirred at room temperature for 12 hours. Water (50 ml) was added and the resulting reaction mixture was extracted with dichloromethane three times. The combined organic phases were washed with water and dried. The crude reaction mixture was eluted through hexane (100 g/silica gel) to remove benzyliodide and then with diethyl ether. The ether phases were concentrated and distilled in vacuo to give the product (3.33 g, 74% having point of 65-66 ° C. at 4 mm.
Reaction SMILES: [CH3:1][C:2]1[C:10]([C:11](=O)[CH2:12][N:13]2[CH2:30][CH2:29][C:16]3([C:20](=[O:21])[N:19]([C:22]4[CH2:23][O:24][C:25](=[O:28])[C:26]=4[CH3:27])[CH2:18][CH2:17]3)[CH2:15][CH2:14]2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][O:5][C:6]2=[O:32].[CH:33]1([NH2:36])[CH2:35][CH2:34]1.[BH3-]C#N.[Na+]>CC(O)=O.C1COCC1>[CH:33]1([NH:36][CH:11]([C:10]2[C:2]([CH3:1])=[C:3]3[C:7](=[CH:8][CH:9]=2)[C:6](=[O:32])[O:5][CH2:4]3)[CH2:12][N:13]2[CH2:30][CH2:29][C:16]3([C:20](=[O:21])[N:19]([C:22]4[CH2:23][O:24][C:25](=[O:28])[C:26]=4[CH3:27])[CH2:18][CH2:17]3)[CH2:15][CH2:14]2)[CH2:35][CH2:34]1
Reactant: CC1=C(N2CCC3(CCN(CC(=O)c4ccc5c(c4C)COC5=O)CC3)C2=O)COC1=O
Reactant: NC1CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC1=C(N2CCC3(CCN(CC(NC4CC4)c4ccc5c(c4C)COC5=O)CC3)C2=O)COC1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of 8-(2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)-2-oxoethyl)-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one (25 mg, 0.057 mmol) and cyclopropanamine (6.5 mg, 0.114 mmol) in anhydrous 5% HOAc/THF (1 mL) was added NaCNBH3 (18 mg, 0.28 mmol). The reaction was sealed and shaken at ambient temperature for 16 h. LCMS showed that the product was formed. The reaction was quenched with water (0.5 mL) and the solvent was evaporated under reduced pressure. The residue was dissolved in DMSO (1.5 mL) and filtered. The crude product was purified by using reversed-phase HPLC (Acetonitrile with 0.1% TFA: water with 0.1% TFA from 10% to 60%) to give the title compound. LC-MS (IE, m/z): 480 [M+1]+.
Reaction SMILES: C1(C)C=CC(S([O:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])(=O)=O)=CC=1.C(N(CC)CC)C.[F:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:40]=[CH:39][N:38]([CH2:41][CH2:42][CH2:43]O)[C:37]=2[C:45]2[CH:50]=[CH:49][N:48]=[CH:47][CH:46]=2)=[CH:32][CH:31]=1>ClCCl>[F:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:40]=[CH:39][N:38]([CH2:41][CH2:42][CH2:43][O:10][S:11]([C:14]3[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=3)(=[O:12])=[O:13])[C:37]=2[C:45]2[CH:46]=[CH:47][N:48]=[CH:49][CH:50]=2)=[CH:32][CH:31]=1
Reactant: OCCCn1ccc(-c2ccc(F)cc2)c1-c1ccncc1
Reactant: Cc1ccc(S(=O)(=O)OS(=O)(=O)c2ccc(C)cc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCCn2ccc(-c3ccc(F)cc3)c2-c2ccncc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.4 %

Procedure:
1.99 g (6.09 mmol) of p-toluenesulfonic anhydride and 0.85 ml (6.09 mmol) of triethylamine were added to a solution of 1.64 g (5.53 mmol) of 3-(4-fluorophenyl)-1-(3-hydroxypropyl)-2-(pyridin-4-yl)-1H-pyrrole [prepared as described in step 22(ii) above] in 16 ml of dichloromethane. The resulting mixture was stirred at room temperature for 2 hours, after which the solvent was distilled off by evaporation under reduced pressure. The resulting residue was purified by chromatography on a silica gel column using a 1:1 by volume mixture of hexane and ethyl acetate as the eluant to afford 1.33 g (yield 53%) of the title compound as a yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C@@H:23]4[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]4)[N:17]=2)[CH:13]=[CH:12][O:11]3)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[Cl:38][C:39](Cl)([O:41]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C@@H:23]4[CH2:28][CH2:27][CH2:26][N:25]([C:39]([Cl:38])=[O:41])[CH2:24]4)[N:17]=2)[CH:13]=[CH:12][O:11]3)=[CH:4][CH:3]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Fc1ccc(-c2nc3occn3c2-c2ccnc(N[C@@H]3CCCNC3)n2)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cl)N1CCC[C@@H](Nc2nccc(-c3c(-c4ccc(F)cc4)nc4occn34)n2)C1
Yield: 95.8 %

Procedure:
To a solution of 4-[6-(4-fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]-N-[(3R)-piperidin-3-yl]pyrimidin-2-amine (200 mg, 0.45 mmol) and Hunig's base (145 μL, 0.90 mmol) in 10 mL DCM was added a solution of triphosgene (660 mg; 2.25 mmol) in 10 mL DCM dropwise over 10 min with stirring. The mixture was allowed to stir at ambient temperature for 1.5 hr. The reaction mixture was then concentrated under reduced pressure. The residue was diluted with 20 mL ether and concentrated under reduced pressure yielding (3R)-3-({4-[6-(4-fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]pyrimidin-2-yl}amino)piperidine-1-carbonyl chloride as an off-white solid (190 mg). The solid was diluted in 10 mL DCM. To the resulting solution was added morpholine (60 μL, 0.67 mmol) and triethylamine (70 μL, 0.50 mmol). The mixture was allowed to stir at ambient temperature for 20 hr. The reaction mixture was then concentrated under reduced pressure and the residue purified by flash chromatography on silica gel (1:4, ethyl acetate:hexanes) to yield 4-[6-(4-fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]-N-[(3R)-1-(morpholin-4-ylcarbonyl)piperidin-3-yl]pyrimidin-2-amine as an off-white solid (50.2 mg, 23%). 400 MHz 1H NMR (DMSO-d6) δ: 8.75 (s, 1H), 8.20 (s, 1H), 8.11 (d, J=5.2 Hz, 1H), 7.62-7.66 (m, 2H), 7.30-7.34 (m, 2H), 6.37 (s, 1H), 3.76 (m, 2H), 3.53 (m, 4H), 3.15 (m, 2H), 3.09 (m, 2H), 2.75 (m, 2H), 2.62 (m, 1H), 1.99 (s, 1H), 1.78 (br.s, 1H), 1.50-1.54 (m, 2H). LCMS: 492 [M+H].
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[CH2:12][C:13]1[C:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH3:30])=[CH:21][CH:20]=[C:19]2[C:14]=1[C:15]([CH3:33])=[CH:16][C:17]([CH3:32])([CH3:31])[NH:18]2.C(OCC)(=O)C>O1CCCC1>[CH2:3]([O:10][CH2:12][C:13]1[C:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH3:30])=[CH:21][CH:20]=[C:19]2[C:14]=1[C:15]([CH3:33])=[CH:16][C:17]([CH3:32])([CH3:31])[NH:18]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCc1ccccc1
Reactant: COc1ccccc1-c1ccc2c(c1CCl)C(C)=CC(C)(C)N2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccccc1-c1ccc2c(c1COCc1ccccc1)C(C)=CC(C)(C)N2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 6.7 %

Procedure:
60% Sodium hydride (30 mg, 0.75 mmol) was suspended in anhydrous tetrahydrofuran (1 mL), and benzylalcohol (78 μL, 0.75 mmol) was added thereto under argon atmosphere at 0° C. After the reaction mixture was stirred at room temperature for 30 minutes, a solution of 5-chloromethyl-6-(2-methoxyphenyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Reference Compound 5-1, 50 mg, 0.15 mmol) in anhydrous tetrahydrofuran solution (1.5 mL) was added thereto. The reaction mixture was stirred at 50° C. for 7 hours. After cooling down, ethyl acetate (50 mL) was added thereto. The whole was washed with water (50 mL) and saturated brine (30 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (4.0 mg) as a colorless solid. (Yield 7%)
Reaction SMILES: [C:1]1([C:7]2[NH:16][C:10]3=[N:11][CH:12]=[C:13]([NH2:15])[CH:14]=[C:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>N1C=CC=CC=1>[Cl:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([NH:15][C:13]1[CH:14]=[C:9]2[N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[NH:16][C:10]2=[N:11][CH:12]=1)=[O:21]
Reactant: Nc1cnc2[nH]c(-c3ccccc3)nc2c1
Reactant: O=C(Cl)c1ccccc1Cl
Solvent: c1ccncc1
Product: O=C(Nc1cnc2[nH]c(-c3ccccc3)nc2c1)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
100 mg 2-phenyl-3H-imidazo[4,5-b]pyridin-6-ylamine (0.38 mmol,) in 4 ml dry pyridine were cooled to −40° C. and treated with 92 mg (1.1 equivalents) 2-chlorobenzoyl chloride. The cooling bath was removed an the mixture stirred for 1 hr at room temperature. The solvent was evaporated and the residue purified by chromatography on silica in methanol/dichloromethane mixtures. Yield 35 mg.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[NH2:10].[CH2:11]=O.C[O-].[Na+].[BH4-].[Na+]>CO.C(OCC)(=O)C>[CH3:11][NH:10][C:3]1[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=1[CH3:1]
Reactant: C=O
Reactant: COc1ccc(N)c(C)c1
Agent: C[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CNc1ccc(OC)cc1C
Temperature: 50 °C
Yield: 91.1 %

Procedure:
A suspension of [2-methyl-4-(methyloxy)phenyl]amine (5 ml, 39.2 mmol), paraformaldehyde (5.88 g, 196 mmol), and sodium methoxide (10.58 g, 196 mmol) in methanol (100 ml) was maintained at 50° C. for 5 hours, cooled, and sodium borohydride (7.41 g, 196 mmol) was added portionwise. The resulting suspension was re-heated to 50° C. and maintained for 16 hours. The reaction was cooled, poured into ethyl acetate/saturated sodium bicarbonate, and the organic layer was dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and purified by column chromatography to afford N,2-dimethyl-4-(methyloxy)aniline (5.40 g, 35.7 mmol, 91% yield) as a pale orange oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 6.55-6.68 (m, 2 H), 6.34-6.40 (m, 1 H), 4.47-4.66 (m, 1 H), 3.62 (s, 3 H), 2.66 (d, J=5.0 Hz, 3 H), 2.04 (s, 3 H).