Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[C:6]([CH3:8])([CH3:7])[O:5][BH:4][O:3]1.[Cl:10][C:11]1[C:12]([CH3:23])=[C:13](I)[C:14]([O:20][CH3:21])=[C:15]([C:17](=[O:19])[CH3:18])[CH:16]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C(N(CC)CC)C>O1CCOCC1.CC#N.CC#N.Cl[Pd]Cl>[Cl:10][C:11]1[C:12]([CH3:23])=[C:13]([B:4]2[O:5][C:6]([CH3:8])([CH3:7])[C:2]([CH3:9])([CH3:1])[O:3]2)[C:14]([O:20][CH3:21])=[C:15]([C:17](=[O:19])[CH3:18])[CH:16]=1
Reactant: CC1(C)OBOC1(C)C
Reactant: COc1c(C(C)=O)cc(Cl)c(C)c1I
Agent: Cl[Pd]Cl
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COc1c(C(C)=O)cc(Cl)c(C)c1B1OC(C)(C)C(C)(C)O1
Temperature: 100 °C
Yield: 64.6 %

Procedure:
4,4,5,5-Tetramethyl-1,3,2-dioxaborolane (2.2 mL, 15 mmol) was added to a mixture of 1-(5-chloro-3-iodo-2-methoxy-4-methylphenyl)ethanone (2.0 g, 6.2 mmol, from Example 60, Step 2), bis(acetonitrile)palladium(II) chloride (32 mg, 0.12 mmol), 2-(dicyclohexylphosphino)-2′,6′-dimethoxy-1,1′-biphenyl (0.20 g, 0.49 mmol) and triethylamine (2.6 mL, 18 mmol) in 1,4-dioxane (3.7 mL) under N2 and then the mixture was degassed with N2. The reaction was then heated at 100° C. for 3 hours. The mixture was cooled to room temperature, filtered and purified on silica gel column (eluting with 0 to 20% EtOAc in hexanes) to give the desired product (1.3 g, 65%). LCMS calculated for C16H23BClO4 (M+H)+: m/z=325.1. found: 325.1.
Reaction SMILES: [F:1][CH:2]([F:30])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]3[CH2:25][CH2:24][S:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1.ClC1C=CC=C(C(OO)=[O:39])C=1.O>ClCCl>[F:30][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]3[CH2:25][CH2:24][S:23](=[O:39])[CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1
Reactant: FC(F)c1nc2ccccc2n1-c1nc(N2CCOCC2)nc(N2CCSCC2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: O
Product: O=S1CCN(c2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4ccccc43)n2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 42.9 %

Procedure:
0.61 g (1.4 mmol) of 2-(2-difluoromethylbenzimidazol-1-yl)-4-morpholino-6-thiomorpholino-1,3,5-triazine dissolved in dichloromethane (20 ml) was added with m-chloroperbenzoic acid (0.35 g, 2.0 mmol) and stirred at room temperature for 16 hours. The reaction solution was poured into water and extracted with ethyl acetate. The separated organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography to obtain 0.27 g (yield: 42%) of the titled compound as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([C:11]2[N:15]=[CH:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[N:12]=2)[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(N(CC)CC)C.P([N:50]=[N+:51]=[N-:52])(=O)(OC1C=CC=CC=1)OC1C=CC=CC=1>C(O)(C)C>[CH3:1][C:2]1[CH:10]=[C:9]([C:11]2[N:15]=[CH:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:24])[F:25])=[CH:18][CH:17]=3)[N:12]=2)[CH:8]=[CH:7][C:3]=1[C:4]([N:50]=[N+:51]=[N-:52])=[O:5]
Reactant: Cc1cc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)ccc1C(=O)O
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: Cc1cc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)ccc1C(=O)N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.8 %

Procedure:
To 2-methyl-4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzoic acid (0.412 g, 1.134 mmol) in a 100 mL round-bottomed flask equipped with a stir bar under N2 was added isopropyl alcohol (11 mL), triethylamine (0.205 ml, 1.474 mmol) and diphenyl phosphorazidate (0.319 ml, 1.474 mmol). The reaction was stirred at room temperature overnight. The resultant solid was filtered, washed with isopropyl alcohol followed by hexanes and dried under vacuum providing the title compound as a white solid (0.294 g, 0.757 mmol, 67%): 1H NMR (300 MHz, CDCl3) δ 8.60 (s, 1H), 8.13 (s, 1H), 8.11-8.02 (m, 2H), 7.84-7.77 (m, 2H), 7.40 (d, J=8.6 Hz, 2H), 2.74 (s, 3H); 19F NMR (376 MHz, CDCl3) δ −58.02; ESIMS m/z 389 ([M+H]+).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:10][C:9](=O)[NH:8][CH2:7]1)C.O1CCCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C.CCCCCC>ClCCl>[C:12]1([C:6]2([CH2:5][CH2:4][OH:3])[CH2:10][CH2:9][NH:8][CH2:7]2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)CC1(c2ccccc2)CNC(=O)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCCCCC
Solvent: ClCCl
Solvent: C1CCOC1
Product: OCCC1(c2ccccc2)CCNC1
Temperature: 5 °C
Reaction time: 18 h

Procedure:
Combine (3-phenyl-5-oxopyrrolidin-3-yl)acetic acid ethyl ester (301 g, 1.25 mol) and tetrahydrofuran (3.5 L). Cool to about 5° C. Slowly, add portionwise over about 45 minutes a solution of lithium aluminum hydride in tetrahydrofuran (3.9 L, 1M, 3.9 mol). After the addition is complete heat to 60° C. After 18 hours, cool in an ice-bath. Add water/tetrahydrofuran 1/1 (1.95 L) dropwise at such a rate that the temperature of the reaction mixture does not rise above 20° C. Dilute the reaction mixtur tetrahydrofura tetrahydrofuran (2.25 L) and stir. After 1.5 hours, filter the reaction mixture. Suspend the solids in diethyl ether (3 L) and filter. Combine the filtrates and concentrate the in vacuo to give a residue. Combine the residue and dichloromethane (4 L) and extract three times with water (1 L). Dry the organic layer over MgSO4, filter, and concentrate in vacuo to obtain a solid. Triturate the solid with diethyl ether (0.3 L), collect by filtration, rinse with diethyl ether, and dry to give the title compound: Rf =0.12 (silica gel dichloromethane/methanol/concentrated aqueous ammonia, 9/1/0.1).
Reaction SMILES: O[CH:2]([C:4]1[N:15]([C@@H:16]2[CH2:21][O:20][C@@H:19]([CH2:22][C:23]#[N:24])[CH2:18][CH2:17]2)[C:7]2=[C:8]3[S:14][CH:13]=[CH:12][C:9]3=[N:10][CH:11]=[C:6]2[N:5]=1)[CH3:3].[CH2:25]([N:27](CC)CC)C.CS(Cl)(=O)=O.[Cl-].C[NH3+]>C(Cl)Cl>[CH3:25][NH:27][CH:2]([C:4]1[N:15]([C@@H:16]2[CH2:21][O:20][C@@H:19]([CH2:22][C:23]#[N:24])[CH2:18][CH2:17]2)[C:7]2=[C:8]3[S:14][CH:13]=[CH:12][C:9]3=[N:10][CH:11]=[C:6]2[N:5]=1)[CH3:3]
Reactant: CCN(CC)CC
Reactant: CC(O)c1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CC#N)OC1
Agent: CS(=O)(=O)Cl
Agent: C[NH3+]
Agent: [Cl-]
Solvent: ClCCl
Product: CNC(C)c1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CC#N)OC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.1 %

Procedure:
To a cooled mixture of {(2R,5S)-5-[2-(1-hydroxyethyl)-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl]tetrahydro-2H-pyran-2-yl}acetonitrile (10.1 mg, 0.0295 mmol) and triethylamine (12 μL, 0.088 mmol) in methylene chloride (0.18 mL) was added methanesulfonyl chloride (2.7 μL, 0.035 mmol). The resulting mixture was allowed to warm to room temperature and stirred overnight. The mixture was diluted with dichloromethane and washed with water (2×). The layers were separated and the organic concentrated. To the concentrate was added methylene chloride (0.2 mL), triethylamine (18 μL), and methylammonium chloride (6.0 mg, 0.088 mmol). The resulting mixture was stirred at room temperature over the weekend (64 h) then heated to 40° C. for 3 h. The mixture was concentrated then purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give 2 mg (19%) of the desired product. LCMS calculated for C18H22N5OS (M+H)+: m/z=356.2. Found: 356.1.
Reaction SMILES: [CH3:1][CH:2]([CH3:23])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21]O)=[CH:17][CH:16]=3)[N:11]=2)=[CH:6][CH:5]=1.[NH:24]1[CH2:27][CH:26]([C:28]([OH:30])=[O:29])[CH2:25]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH3:1][CH:2]([CH3:23])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:16]=[CH:17][C:18]([CH2:21][N:24]4[CH2:27][CH:26]([C:28]([OH:30])=[O:29])[CH2:25]4)=[CH:19][CH:20]=3)[N:11]=2)=[CH:8][CH:9]=1
Reactant: O=C(O)C1CNC1
Reactant: CC(C)Cc1ccc(-c2nc(-c3ccc(CO)cc3)no2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)Cc1ccc(-c2nc(-c3ccc(CN4CC(C(=O)O)C4)cc3)no2)cc1
Reaction time: 1 h
Yield: 73.6 %

Procedure:
A solution of 3.06 g (10.0 mmol) of Aldehyde 1, 1.06 g (10.5 mmol) of 3-azetidine carboxylic acid and 5 mL of acetic acid in 150 mL of methanol was stirred for 20 min at rt. A solution of sodium cyanoborohydride (380 mg, 5.0 mmol) in 20 mL of methanol was added. The reaction mixture was stirred for 1 h then was filtered. The solids were washed with 30 ml of methanol and dried to afford 2.88 g (74%) of the title compound: 1H NMR (400 Mhz, CD3OD) δ 0.95 (d, J=6.6, 6H), 1.96 (m, 1H), 2.62 (d, J=7.3, 2H), 3.42 (m, 1H), 4.19 (m, 4H), 4.41 (s, 2H), 7.43 (d, J=8.0, 2H), 7.64 (d, J=8.2, 2H), 8.14 (d, J=8.0, 2H), 8.23 (d, J=8.2, 2H); ESI-MS 392 (M+H); LC-1: 3.0 min.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]([CH3:6])[CH3:5].[N+:7]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)([O-:9])=[O:8].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:5][CH:4]([CH3:6])[CH2:3][CH2:2][O:16][C:13]1[CH:14]=[CH:15][C:10]([N+:7]([O-:9])=[O:8])=[CH:11][CH:12]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CC(C)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)CCOc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.3 %

Procedure:
1-Bromo-3-methylbutane (7.07 g, 5.60 mL, 46.8 mmol) was added in one portion to a stirred suspension of 4-nitrophenol (5.00 g, 35.9 mmol) and potassium carbonate (5.46 g, 49.5 mmol) in dimethylformamide (50 mL) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 16 h then the volatiles were evaporated. The residue was partitioned between diethyl ether (50 mL) and water (50 mL) and the phases separated. The aqueous phase was extracted with ether (2×50 mL) then the organic extracts were combined and dried (magnesium sulfate). The solvent was evaporated and the residue chromatographed on silica gel (10% diethyl ether:cyclohexane) to give the title compound as a pale yellow oil (6.63 g, 88%). LC/MS: 3.69 min. 1H NMR (400 MHz; CDCl3): 0.95 (6H), 1.75 (2H), 1.85 (1H), 4.05 (2H), 6.95 (2H), 8.20 (2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[C:6]([NH2:13])[CH:5]=1.CCN(CC)CC.[Cl:22][CH2:23][CH2:24][CH2:25][C:26](Cl)=[O:27]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[C:6]([NH:13][C:26](=[O:27])[CH2:25][CH2:24][CH2:23][Cl:22])[CH:5]=1
Reactant: O=C(Cl)CCCCl
Reactant: COC(=O)c1cc(N)cc([N+](=O)[O-])c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(NC(=O)CCCCl)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
To a solution of 3-amino-5-nitro-benzoic acid methyl ester (D1) (38 g, 194 mmol, 1 equiv) in CH2Cl2 (350 ml) was added NEt3 (32 ml, 230 mmol, 1.2 equiv) followed by 4-chlorobutyryl chloride (24.7 ml, 220 mmol, 1.13 equiv) dropwise over 20 nm. The resulting mixture was allowed to warm to room temperature and stirred for 30 min. The organic phase was then washed with 2N aqueous HCl solution, dried over MgSO4 and concentrated in vacuo. The residue was triturated with iso-hexane and Et2O to give 3-(4-chloro-butanoylamino)-5-nitro-benzoic acid methyl ester D2 (56 g, 96%) as a brown solid.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:21])[CH2:9][S:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=2)(=[O:12])=[O:11])=[CH:4][CH:3]=1.[I:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1>>[I:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:21])/[C:9](/[S:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=2)(=[O:11])=[O:12])=[CH:27]\[C:26]2[CH:29]=[CH:30][C:23]([I:22])=[CH:24][CH:25]=2)=[CH:6][CH:7]=1
Reactant: O=C(CS(=O)(=O)Cc1ccc(I)cc1)c1ccc(I)cc1
Reactant: O=Cc1ccc(I)cc1
Product: O=C(/C(=C\c1ccc(I)cc1)S(=O)(=O)Cc1ccc(I)cc1)c1ccc(I)cc1

Procedure:
The title compound is prepared by the methods described in Synthesis Example 10. A solution of 1-(4-iodophenyl)-2-(4-iodobenzylsulfonyl)ethanone (10 mmol) and 4-iodobenzaldehyde (10 mmol) was subjected to the procedure described as Method A in part C of Synthesis Example 10 and the product obtained was purified by column chromatography.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[NH:7]1[CH:11]=[N:10][CH:9]=[N:8]1.[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C@@:20]1([O:25][CH2:24]1)[C@H:21]([OH:23])[CH3:22]>CN(C)C=O>[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C@@:20]([OH:25])([C@H:21]([OH:23])[CH3:22])[CH2:24][N:7]1[CH:11]=[N:10][CH:9]=[N:8]1
Reactant: c1nc[nH]n1
Reactant: C[C@@H](O)[C@]1(c2ccc(F)cc2F)CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@@H](O)[C@@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 80 °C
Yield: 38 %

Procedure:
To an ice cooled suspension of anhydrous K2CO3 (0.691 g, 0.005 mole) in N,N-dimethylformamide (7 ml), 1H-1,2,4-triazole (0.345, 0.005 mole) was added in small portions under art atmosphere of nitrogen. The mixture was slowly brought to room temperature and a solution of compound 7c (2R, 3S)-3-(2,4-Difluorophenyl)-3,4-epoxy-2-butanol (0.5 g, 0.0025 mole) in N,N-dimethylformamide (1 ml) was added. The resulting mixture was heated at 80° C. for 2 hours. The solvent was removed under reduced pressure and 25 g of crushed ice was added to the residue. The so formed mixture was extracted with ethyl acetate (50 ml, 2×25 ml). The combined organic layers were washed with water (10 ml) brine (25 ml) and dried over MgSO4. The solvent was removed in vacuo and the residue was chromatographed on silica gel. Elution with methanol in chloroform (0% -3%) gave the title compound 9c as an amorphous solid (0.26 g, 38%).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[F:25][C:26]([F:41])([F:40])[C:27]1[CH:28]=[C:29]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[C:30](Cl)=[O:31]>C1COCC1>[CH3:1][N:2]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:30](=[O:31])[C:29]1[CH:33]=[C:34]([C:36]([F:37])([F:38])[F:39])[CH:35]=[C:27]([C:26]([F:25])([F:40])[F:41])[CH:28]=1
Reactant: CNc1cnccc1-c1ccccc1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 33.9 %

Procedure:
To a solution of methyl-(4-phenyl-pyridin-3-yl)-amine (160 mg, 0.87 mmol) in THF (4 mL) under nitrogen was added LiHMDS (1.3 mL, 1.3 mmol, 1M solution in THF) at −78° C. and the resulting reaction mixture was stirred for 30 min at −78° C. Then 3,5-bis(trifluoromethyl)-benzoyl chloride (480 mg, 1.74 mmol, CAS RN 1271-19-8) in THF (1 mL) was added to the reaction mixture at −78° C. and the reaction mixture was stirred for another 12 hours at 25° C. The reaction mixture was quenched with 10 mL saturated NH4Cl solution and extracted with EtOAc (2×20 mL). The combined organic layers were dried and evaporated. The crude product was purified by preparative HPLC (ammonium acetate/acetonitrile) to furnish the desired compound as off-white solid (125 mg, 34%). MS (ESI): m/z=425.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH:10]([C:14]3[NH:15][CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=4)[N:18]=3)[CH2:9]2)[N:5]=[C:4]([NH2:27])[N:3]=1.[F:28][C:29]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[CH:33][C:30]=1[C:31]#[N:32].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[NH2:27][C:4]1[N:3]=[C:2]([C:35]2[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[C:29]([F:28])[CH:36]=2)[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH:10]([C:14]3[NH:15][CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=4)[N:18]=3)[CH2:9]2)[N:5]=1
Reactant: CC1(C)OB(c2ccc(C#N)c(F)c2)OC1(C)C
Reactant: COc1ccc(-c2c[nH]c(C3CN(c4cc(Cl)nc(N)n4)CCO3)n2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(-c2c[nH]c(C3CN(c4cc(-c5ccc(C#N)c(F)c5)nc(N)n4)CCO3)n2)cc1
Temperature: 140 °C
Reaction time: 1 h
Yield: 55.3 %

Procedure:
A mixture of 4-chloro-6-(2-{4-[4-(methyloxy)phenyl]-1H-imidazol-2-yl}-4-morpholinyl)-2-pyrimidinamine (1.0 g, 2.59 mmol), 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (0.83 g, 3.36 mmol), Na2CO3 (0.685 g, 6.46 mmol) and Pd(PPh3)4 (0.30 g, 0.26 mmol) in 1,4-dioxane (8 mL) and water (2 mL) was heated at 140° C. under microwave conditions with stirring for 1 hour. The reaction mixture was filtered, washed by ethyl acetate (100 mL), and concentrated. The resulting residue was purified by silica gel chromatography using EtOAc/petroleum ether (3:1) to afford the title compound (675 mg) as a yellow solid. LC-MS (ES) m/z=472 [M+H]+.
Reaction SMILES: CS(Cl)(=O)=O.[N:6]1([CH2:19][CH:20](O)[CH3:21])[CH:10]=[CH:9][C:8]2[CH2:11][S:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:7]1=2.C(N(CC)CC)C.[N-:30]=[N+:31]=[N-:32].[Na+]>ClCCl.C(OCC)C.CN(C)C=O.O>[N:30]([CH:20]([CH3:21])[CH2:19][N:6]1[CH:10]=[CH:9][C:8]2[CH2:11][S:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:7]1=2)=[N+:31]=[N-:32]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(O)Cn1ccc2c1-c1ccccc1SC2
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: O
Product: CC(Cn1ccc2c1-c1ccccc1SC2)N=[N+]=[N-]
Yield: 59 %

Procedure:
1.15 ml of methanesulfonyl chloride were added dropwise while stirring to a solution, cooled to 0°, of 1.8 g of (RS)-1-(1,4-dihydro-[1]benzothiopyrano[4,3-b]pyrrol-1-yl)-propan-2-ol and 4.1 ml of triethylamine in 50 ml of anhydrous dichloromethane and the mixture was stirred at this temperature for an additional 1.5 hours. The reaction mixture was subsequently diluted with 180 ml of diethyl ether, washed twice with 70 ml of saturated sodium hydrogen carbonate solution each time and the combined aqueous phases were extracted once with 70 ml of diethyl ether. The combined organic phases were washed with 140 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated in a vacuum. The brown oil obtained was dissolved in 50 ml of anhydrous dimethylformamide, treated with 0.96 g of sodium azide and the reaction mixture was heated to 600 while stirring for 17 hours. After cooling, the solution was poured into 100 ml of water and extracted twice with 120 ml of diethyl ether each time. The combined organic phases were washed once with 100 ml of water and once with 100 ml of saturated sodium chloride solution, dried over magnesium sulfate and the solution was concentrated in a vacuum. The brown oil obtained was purified by column chromatography on silica gel (toluene). 1.17 g (59%) of (RS)-1-(2-azido-propyl)-1,4-dihydro-[1]benzothiopyrano[4,3-b]pyrrole were obtained as a light yellow oil.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:30]=[CH:29][C:9]3[N:10]=[C:11]([N:13]4[CH2:18][CH2:17][CH:16]([O:19][CH2:20][C:21](N5CCOCC5)=[O:22])[CH2:15][CH2:14]4)[O:12][C:8]=3[CH:7]=2)[CH2:3][CH2:2]1.[CH3:31][Mg]Cl.[Cl-].[NH4+]>C1COCC1>[CH:1]1([CH2:4][O:5][C:6]2[CH:30]=[CH:29][C:9]3[N:10]=[C:11]([N:13]4[CH2:14][CH2:15][CH:16]([O:19][CH2:20][C:21](=[O:22])[CH3:31])[CH2:17][CH2:18]4)[O:12][C:8]=3[CH:7]=2)[CH2:2][CH2:3]1
Reactant: C[Mg]Cl
Reactant: O=C(COC1CCN(c2nc3ccc(OCC4CC4)cc3o2)CC1)N1CCOCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)COC1CCN(c2nc3ccc(OCC4CC4)cc3o2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 6-(cyclopropylmethoxy)-2-{4-[2-(morpholin-4-yl)-2-oxoethoxy]piperidin-1-yl}-1,3-benzoxazole (2.10 g) in THF (17 mL) was added methylmagnesium chloride (3.0 M THF solution, 5.06 mL), and the mixture was stirred at room temperature for 3 hr. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (1.31 g).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]#[N:12])=[CH:6][CH:5]=1.Cl[CH2:14][CH2:15][N:16]([CH2:24][CH2:25]Cl)[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20].[Cl-].[NH4+]>C1COCC1>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:11]#[N:12])[CH2:25][CH2:24][N:16]([C:17]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:23])[CH2:15][CH2:14]2)=[CH:6][CH:5]=1
Reactant: N#CCc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N(CCCl)CCCl
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccc(Cl)cc2)CC1
Reaction time: 8 h

Procedure:
A suspension of 4.4 g of sodium hydride at a concentration of 60% in oil in 300 ml of THF is admixed rapidly at AT with 7.51 g of 4-chlorophenylacetonitrile and then with 12 g of tert-butyl bis(2-chloroethyl)carbamate, heated at 40° C. for 28 hours and then left with stirring at AT overnight. Saturated ammonium chloride solution is added to the reaction mixture, which is then concentrated under vacuum to remove the THF, after which the aqueous phase which remains is extracted with ether, the organic phase is washed with a buffer solution pH=2 and with saturated NaCl solution and dried over Na2SO4 and the solvent is evaporated under vacuum. This gives 12 g of the expected product, which is used as it is.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH:12]1[CH2:14][CH2:13]1)[CH2:7][CH2:6][C:5]2([CH3:16])[CH3:15].[CH3:17][Si:18]([C:21]#[CH:22])([CH3:20])[CH3:19].C(N(CC)CC)C>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH:12]1([N:8]2[C:9]3[C:4](=[CH:3][C:2]([C:22]#[C:21][Si:18]([CH3:20])([CH3:19])[CH3:17])=[CH:11][CH:10]=3)[C:5]([CH3:16])([CH3:15])[CH2:6][CH2:7]2)[CH2:14][CH2:13]1
Reactant: CC1(C)CCN(C2CC2)c2ccc(Br)cc21
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1(C)CCN(C2CC2)c2ccc(C#C[Si](C)(C)C)cc21

Procedure:
Following general procedure D and using 6-bromo-1-cyclopropyl-4,4-dimethyl-1,2,3,4-tetrahydro quinoline (Intermediate 51, 0.8 g, 2.86 mmol), (trimethylsilyl)acetylene (5 mL, 35 mmol), triethyl amine (10 mL), anhydrous tetrahydrofuran, copper(I)iodide (0.080 g, 0.42 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.240 g, 0.34 mmol), the title compound was obtained as an oil (0.67 g, 79%).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]([OH:19])=[C:8]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[C:10]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:5]=2[O:4][C:3]=1[C:20]([O:22]CC)=[O:21].[OH-].[K+]>O.CO>[CH3:1][C:2]1[C:6]2[C:7]([OH:19])=[C:8]([C:15]([CH3:17])([CH3:16])[CH3:18])[CH:9]=[C:10]([C:11]([CH3:12])([CH3:13])[CH3:14])[C:5]=2[O:4][C:3]=1[C:20]([OH:22])=[O:21]
Reactant: CCOC(=O)c1oc2c(C(C)(C)C)cc(C(C)(C)C)c(O)c2c1C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1c(C(=O)O)oc2c(C(C)(C)C)cc(C(C)(C)C)c(O)c12

Procedure:
Ethyl 3-methyl-4-hydroxy-5,7-di-tert-butylbenzofuran-2-carboxylate (0.475 g, 1.43 mmol) was refluxed in a solution of KOH (0.241 g, 4.29 mmol) in water (10 mL) and methanol (2 mL) for two hours. Acidification of the cooled mixture led to precipitation of the product. 3-Methyl-4-hydroxy-5,7-di-tert-butylbenzofuran-2-carboxylic acid, compound 9, was collected by filtration and vacuum dried. This material was decarboxylated without further purification. mp 241°-243° C.; 1H NMR (DMSO-d6) d 1.40 (18H, s), 2.71 (3H, s), 7.18 (1H, s), 8.35 (1H, s).