Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[CH2:9][C:10]1[N:14]([CH3:15])[C:13]2[C:16]([NH2:20])=[CH:17][CH:18]=[CH:19][C:12]=2[N:11]=1.[CH:22](=O)[CH3:23].[C:25](O)(=O)[CH3:26].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>CO>[CH2:25]([N:20]([CH2:22][CH3:23])[C:16]1[C:13]2[N:14]([CH3:15])[C:10]([CH2:9][C:2]3[C:3]([CH3:8])=[CH:4][C:5]([CH3:7])=[CH:6][C:1]=3[CH3:21])=[N:11][C:12]=2[CH:19]=[CH:18][CH:17]=1)[CH3:26]
Reactant: CC=O
Reactant: CC(=O)O
Reactant: Cc1cc(C)c(Cc2nc3cccc(N)c3n2C)c(C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CCN(CC)c1cccc2nc(Cc3c(C)cc(C)cc3C)n(C)c12
Temperature: 25 °C
Reaction time: 14 h
Yield: 98.6 %

Procedure:
To a solution of 2-(mesitylmethyl)-1-methyl-1H-benzimidazol-7-amine (200 mg, 0.717 mmol), acetaldehyde (0.400 mL, 7.17 mmol) and acetic acid (0.330 mL, 5.78 mmol) in methanol (5.0 mL) was added sodium triacetoxyborohydride (1.52 g, 7.17 mmol) portionwise at 0° C. The mixture was warmed to room temperature and stirred for 14 hr. Saturated aqueous sodium bicarbonate solution (50 mL) was added to the mixture and the mixture was extracted with ethyl acetate (25 mL, three times). Combined organic layers were washed with saturated aqueous sodium bicarbonate solution (20 mL) and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford the title compound (237 mg, 0.707 mmol, 97%) as a colorless solid. The resulting solid was recrystallized from n-hexane/ethyl acetate to give the title compound (145 mg, 0.433 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][C:5]1[N:10]=[C:9]([C:11](=[NH:14])OC)[CH:8]=[CH:7][CH:6]=1.[Cl-].[NH4+:20]>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][C:5]1[N:10]=[C:9]([C:11]([NH2:20])=[NH:14])[CH:8]=[CH:7][CH:6]=1
Reactant: [NH4+]
Reactant: COC(=N)c1cccc(Cc2ccccc2Cl)n1
Agent: [Cl-]
Solvent: CCO
Product: Cl
Product: N=C(N)c1cccc(Cc2ccccc2Cl)n1

Procedure:
A mixture of methyl 6-(o-chlorobenzyl)-2-picoline imidate 5.5 g, 0.021 moles) and ammonium chloride (1.28 g, 0.024 moles) in ethanol (40 ml) was refluxed for 4 hours. The ethanol was removed in vacuo to give 6-(o-chlorobenzyl)-2-picoline amidine hydrochloride which was used in the final stage without further purification.
Reaction SMILES: C(Cl)Cl.[C-:4]#[N:5].[Na+].Cl[C:8]([O:10][CH2:11][CH:12]([CH2:17][CH3:18])[CH2:13][CH2:14][CH2:15][CH3:16])=[O:9]>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].O>[C:4]([C:8]([O:10][CH2:11][CH:12]([CH2:17][CH3:18])[CH2:13][CH2:14][CH2:15][CH3:16])=[O:9])#[N:5]
Reactant: [C-]#N
Reactant: CCCCC(CC)COC(=O)Cl
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCCCC(CC)COC(=O)C#N
Temperature: -60 °C
Yield: 94.9 %

Procedure:
A solution of 600 ml. of methylene chloride and 4 grams (0.01 moles) of Aliquat 336 was charged into a 2 1. 3-neck round bottom flask and cooled to approximately -60° C. with a dry ice/acetone bath. An aqueous solution of 120 grams (2.45 moles) of sodium cyanide in 250 ml. of water was added dropwise to the reaction mixture to provide a slurry of reactants. Next, 385.38 grams (2.0 moles) of 2-ethylhexyl chloroformate was added to the mixture while maintaining the temperature below approximately -40° C. The external cooling was then removed from the reaction flask and the mixture was allowed to warm slowly. After 19 minutes the mixture had warmed to -25° C. and the external cooling was replaced. After 9 more minutes the temperature of the reaction mixture was -17° C. at which point 100 ml. of water, 200 ml. of carbon tetrachloride and 100 ml. of ice was added and the layers were allowed to separate. The organic phase was separated, and the aqueous phase was extracted twice with methylene chloride. The organic extracts were combined and dried over anhydrous magnesium sulfate. The organic phase was concentrated under reduced pressure and the residue was distilled under vacuum to provide 347.85 grams of 99.7% pure 2-ethylhexyl cyanoformate (94.9% yield). bp=95° C. (12- 15 mm).
Reaction SMILES: [CH3:1][C@@:2]1([CH2:16][CH2:17][OH:18])[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([CH3:15])[C:6]([CH3:14])=[C:7]([OH:13])[C:8]=2[CH3:12])[O:3]1.[CH2:19]=[C:20]([CH3:22])[CH3:21].S(=O)(=O)(O)O>C(Cl)Cl>[CH3:1][C@@:2]1([CH2:16][CH2:17][O:18][C:20]([CH3:22])([CH3:21])[CH3:19])[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([CH3:15])[C:6]([CH3:14])=[C:7]([OH:13])[C:8]=2[CH3:12])[O:3]1
Reactant: Cc1c(C)c2c(c(C)c1O)CC[C@@](C)(CCO)O2
Reactant: C=C(C)C
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: Cc1c(C)c2c(c(C)c1O)CC[C@@](C)(CCOC(C)(C)C)O2
Reaction time: 0.25 h

Procedure:
5 g of (S)-2,5,7,8-tetramethyl-6-hydroxy-2-(2-hydroxyethyl)-chroman were suspended in 250 ml of methylene chloride, and isobutene was passed through the suspension. After 15 minutes, 1 ml of concentrated sulfuric acid was added, and stirring was then continued for a further 4 hours at room temperature, while a gentle stream of isobutene was passed through. The mixture was then left to stand overnight in a closed vessel. The organic phase was washed with sodium bicarbonate solution and with water, and was then dried and evaporated down. The crude product was purified over silica gel, using a 5:1 hexane/acetone solvent mixture. 4.5 g of (S)-2,5,7,8-tetramethyl-6-hydroxy-2-(2-tert.-butoxyethyl)-chroman were obtained as a colorless oil. [α]36520 =+4.23° (c=2, ethanol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH2:11][CH2:10][NH:9][C:8](=[O:13])[C:7]=2[CH:14]=1.[H-].[Na+].[CH3:17]N(C=O)C>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH2:11][CH2:10][N:9]([CH3:17])[C:8](=[O:13])[C:7]=2[CH:14]=1
Reactant: COc1ccc2c(c1)C(=O)NCCC2
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: COc1ccc2c(c1)C(=O)N(C)CCC2
Reaction time: 0.17 h

Procedure:
A mixture of 8-Methoxy-2,3,4,5-tetrahydro-benzo[c]azepin-1-one (283 mgs, 1.48 mmol) in DMF (5 mL) was treated with NaH (60% dispersion in mineral oil, 75 mgs, 1.85 mmol) and stirred for 10 min. The mixture was quenched with water and extracted with ether. The organic layers were washed with brine and the organic layer dried (MgSO4), filtered and concentrated to give 8-Methoxy-2-methyl-2,3,4,5-tetrahydro-benzo[c]azepin-1-one (227 mgs). 1H-NMR (CDCl3) δ 7.14 (d, J=2.7 Hz, 1H), 6.96 (d, J=8.1 Hz, 1H), 6.83-6.81 (m, 1H), 3.74 (s, 3H), 3.14 (t, J=6.6 Hz, 2H), 3.10 (s, 3H), 2.64 (t, J=8.1 Hz, 2H), 1.97-1.91 (m, 2H); LC/MS (ESI+): 273 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:18][C:19]=2[CH3:20])=[CH:8][C:7]=1[CH2:27][CH2:28][NH:29]C(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O.O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:37])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[O:18][C:19]=2[CH3:20])=[CH:8][C:7]=1[CH2:27][CH2:28][NH2:29]
Reactant: COC(=O)CCc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1CCNC(=O)OC(C)(C)C
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)CCc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1CCN
Temperature: 25 °C
Reaction time: 18 h
Yield: 58.1 %

Procedure:
A solution of 3-{2-(2-tert-butoxycarbonylamino-ethyl)-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid methyl ester (0.90 g, 1.77 mmol) in CH2Cl2 (10 mL) at 0° C. was treated with TFA (5.0 mL) and water (0.2 mL). The resulting solution was allowed to warm gradually to ambient temperature. After 18 h, the mixture was concentrated. The residue was partitioned between CH2Cl2 (30 mL) and 5N NaOH (2 mL), and the aqueous layer was extracted with CH2Cl2 (3×30 mL). The combined organics were dried (K2CO3) and concentrated to a residue, which was purified by silica gel chromatography (CH2Cl2/MeOH/NH4OH, 8/2/0.05) to afford the title compound as a colorless oil (0.42 g, 58%). 1H NMR (400 MHz, CDCl3): δ 2.34 (s, 3H), 2.52 (t, 2H, J=7.8 Hz), 2.81 (t, 2H, J=7.8 Hz), 2.91 (t, 4H, J=6.4 Hz), 3.06 (t, 2H, J=7.3 Hz), 3.60 (s, 3H), 4.20 (t, 2H, J=6.8 Hz), 6.68 (br s, 1H), 6.71 (d, 1H, J=8.3 Hz), 7.01 (d, 1H, J=8.3 Hz), 7.37-7.39 (m, 3H), 7.89-7.92 (m, 2H).
Reaction SMILES: [Zn](CC)CC.F[C:7](F)(F)[C:8]([OH:10])=O.C(I)I.[Br:16][C:17]1[CH:22]=[C:21]([CH:23]=C)[CH:20]=[C:19](OCOC)[CH:18]=1>CCCCCCC.C(Cl)Cl>[Br:16][C:17]1[CH:22]=[C:8]([OH:10])[CH:7]=[C:19]([CH:20]2[CH2:21][CH2:23]2)[CH:18]=1
Reactant: O=C(O)C(F)(F)F
Reactant: C=Cc1cc(Br)cc(OCOC)c1
Agent: CC[Zn]CC
Solvent: CCCCCCC
Solvent: ClCCl
Solvent: ICI
Product: Oc1cc(Br)cc(C2CC2)c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 30.9 %

Procedure:
To anhydrous CH2Cl2 (10 mL) was added ZnEt2 (12.34 of a 1.0 M in heptane, 12.34 mmol) under nitrogen. The solution was cooled to 0° C., and a solution of trifluoroacetic acid (0.95 mL, 12.34 mmol) in anhydrous CH2Cl2 (4 mL) was added very slowly. After stirring the reaction mixture for 20 m, a solution of CH2I2 (0.99 mL, 12.34 mmol) in CH2Cl2 (4 mL) was added. After an additional 20 m stirring, a solution of the 1-bromo-3-methoxymethoxy-5-vinyl-benzene (1.20 g, 4.94 mmol) in CH2Cl2 (6 mL) was added, and the reaction was allowed to warm to RT. After 1.5 h, the reaction was quenched with saturated aqueous NH4Cl (30 mL) and hexanes (50 mL), and the layers were separated. The aqueous layer was extracted with Et2O (2×40 mL), and the combined organic layers were washed with H2O (30 mL), brine (30 mL), and dried with anhydrous MgSO4. The solvents were evaporated, and the remaining oil was partially purified by flash chromatography on silica gel (0% to 5% EtOAc/hexanes). The partially purified material was placed in i-PrOH (10 mL), and 2 mL of 1.0 M HCl was added. The mixture was aged at 50° C. for 14 h, cooled to RT, and added to H2O (25 mL). The aqueous mixture was extracted with Et2O (3×40 mL), and the combined organics were washed with brine (30 mL), and dried over anhydrous MgSO4. The solvents were evaporated, and the remaining oil was purified by flash chromatography on silica gel (0% to 10% EtOAc/hexanes) to afford 325 mg (31%) of 3-bromo-5-cyclopropyl-phenol (114).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][N:11]3[C:14](=[O:17])[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.ClC1C=CC(C2N=CN=C(NNC(OC(Cl)(Cl)Cl)=O)C=2C2C=CC=CC=2)=CC=1.Br[CH2:53][C:54]1[CH:59]=[CH:58][C:57]([C:60]2[O:64][N:63]=[CH:62][CH:61]=2)=[CH:56][CH:55]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[O:64]1[C:60]([C:57]2[CH:58]=[CH:59][C:54]([CH2:53][N:15]3[C:14](=[O:17])[N:11]4[CH:12]=[N:13][C:8]([C:5]5[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=5)=[C:9]([C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)[C:10]4=[N:16]3)=[CH:55][CH:56]=2)=[CH:61][CH:62]=[N:63]1
Reactant: BrCc1ccc(-c2ccno2)cc1
Reactant: O=c1[nH]nc2c(-c3ccccc3)c(-c3ccc(Cl)cc3)ncn12
Agent: O=C(NNc1ncnc(-c2ccc(Cl)cc2)c1-c1ccccc1)OC(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=c1n(Cc2ccc(-c3ccno3)cc2)nc2c(-c3ccccc3)c(-c3ccc(Cl)cc3)ncn12
Temperature: 60 °C

Procedure:
To a stirred solution of 7-(4-chlorophenyl)-8-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one and/or trichloromethyl 2-(6-(4-chlorophenyl)-5-phenylpyrimidin-4-yl)hydrazinecarboxylate (16.0 mg, 0.05 mmol) in acetone (5 mL) at room temperature under argon was added 5-(4-(bromomethyl)phenyl)isoxazole (23.8 mg, 0.10 mmol), followed by K2CO3 (13.8 mg, 0.10 mmol). The resulting mixture was heated at 60° C. for 17 h. Insoluble material was filtered and rinsed with CH2Cl2. The filtrate was concentrated under reduced pressure and purified by reverse phase preparative HPLC (without TFA). Further purification was performed by silica gel column chromatography eluting with EtOAc-hexanes. Pure product was lyophilized from 1,4-dioxane to obtain the title compound (3.5 mg) as an off-white lyophilate. HPLC/MS: retention time=3.88 min, [M+H]30 =480. 1H NMR (CDCl3): δ 8.71 (s, 1H), 8.28 (d, J=1.2 Hz, 1H), 7.81 (d, J=7.3 Hz, 2H), 7.45 (d, J=7.3 Hz, 2H), 7.26-7.42 (m, 7H), 7.18 (d, J=7.2 Hz, 2H), 6.51(d, J=1.2 Hz, 1H), 5.18 (s, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([CH2:13]O)=[N:6][CH:7]=[C:8]([O:10][CH2:11][CH3:12])[CH:9]=1)[CH3:2].O=S(Cl)[Cl:17]>C(Cl)Cl.C1(C)C=CC=CC=1>[Cl:17][CH2:13][C:5]1[C:4]([O:3][CH2:1][CH3:2])=[CH:9][C:8]([O:10][CH2:11][CH3:12])=[CH:7][N:6]=1.[ClH:17]
Reactant: CCOc1cnc(CO)c(OCC)c1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCOc1cnc(CCl)c(OCC)c1
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (3,5-diethoxy-pyridin-2-yl)-methanol (166 mg, 0.84 mmol) in CH2Cl2 (5 mL) is added 2.0 M solution of SOCl2 (1 mL) in CH2Cl2. The reaction mixture is stirred at room temperature for 30 minutes, diluted with toluene and concentrated to afford 2-chloromethyl-3,5-diethoxy-pyridine as HCl salt which is directly used for the next step.
Reaction SMILES: [C:1]([C:5]1[O:6][C:7]2[C:13]([S:14](Cl)(=[O:16])=[O:15])=[C:12]([Cl:18])[CH:11]=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>C1COCC1>[C:1]([C:5]1[O:6][C:7]2[C:13]([S:14]([N:30]3[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]3)(=[O:16])=[O:15])=[C:12]([Cl:18])[CH:11]=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc2ccc(Cl)c(S(=O)(=O)Cl)c2o1
Reactant: CN1CCNCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN1CCN(S(=O)(=O)c2c(Cl)ccc3nc(C(C)(C)C)oc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.5 %

Procedure:
To a solution of 2-tert-butyl-6-chloro-benzooxazole-7-sulfonyl chloride (2.69 g, 8.73 mmol) and triethylamine (2.44 mL, 17.5 mmol) in THF (60 mL) at 0° C. was added 1-methylpiperazine (0.98 mL, 8.83 mmol). The reaction was warmed to room temperature and allowed to stir overnight. The solution was concentrated and then diluted with water and extacted with ethyl acetate (3 times). The combined organic layers were dried with MgSO4, filtered, and concentrated. Flash chromatography (80% ethyl acetate/20% Ethanol) on silica gel gave the title compound (2.45 g, 76%). EI-MS m/z 372(M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][CH:10]=[O:11])=[C:4]([CH3:12])[C:3]=1[CH3:13].[OH-].[K+].S(OC)(O[CH3:20])(=O)=O>CO>[CH3:20][O:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][CH:10]=[O:11])=[C:4]([CH3:12])[C:3]=1[CH3:13]
Reactant: COS(=O)(=O)OC
Reactant: Cc1cc(O)c(C)c(C)c1NC=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(C)c(NC=O)c(C)c1C

Procedure:
N-(4-Hydroxy-2,3,6-trimethylphenyl)formamide (30.0 g, 167 mmol) was dissolved into a mixed solvent of a 4 N aqueous solution of potassium hydroxide (100 ml) and methanol (300 ml) and dimethyl sulfate (42.0 g, 334 mmol) was added to the resulting solution at room temperature. The resulting mixture was refluxed with heating for 14 hours. After the reaction solution was cooled down, the crystals precipitated were collected by filtration to obtain N-(4-methoxy-2,3,6-trimethylphenyl)formamide as a crude product. To a suspension of this compound in methanol (200 ml) was added concentrated hydrochloric acid (50 ml) and the resulting mixture was refluxed with heating for 3 hours. The reaction mixture was cooled down and neutralized with an 8 N aqueous solution of sodium hydroxide. The product was extracted twice with ethyl acetate. The combined extracts were washed with a 10% aqueous solution of sodium hydrosulfite, dried on magnesium sulfate, and then concentrated under reduced pressure. The residue was crystallized from isopropyl ether to obtain 21.0 g (yield 76%) of the title compound. Melting point: 70-72° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][S:6]([CH3:9])(=[O:8])=[O:7].[H-].[Na+].Br[CH2:13][C:14]1[S:22][C:21]2[C:20]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[N:19][C:18]([Cl:29])=[N:17][C:16]=2[CH:15]=1>O1CCCC1>[Cl:29][C:18]1[N:19]=[C:20]([N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)[C:21]2[S:22][C:14]([CH2:13][N:5]([CH2:4][CH2:3][O:2][CH3:1])[S:6]([CH3:9])(=[O:8])=[O:7])=[CH:15][C:16]=2[N:17]=1
Reactant: Clc1nc(N2CCOCC2)c2sc(CBr)cc2n1
Reactant: COCCNS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCN(Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74 %

Procedure:
To a solution of N-(2-Methoxy-ethyl)-methanesulfonamide (61 mg) in tetrahydrofuran (1.5 ml) under nitrogen was added sodium hydride, 60% dipersion in mineral oil, (18 mg). The reaction mixture was stirred at room temperature for 30 minutes. 6-Bromomethyl-2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (140 mg) was added. The reaction mixture was stirred at room temperature for 2 hours and then 50° C. for 5 hours. The solvents were removed in vacuo to give a crude product. This was purified by flash chromatography to give N-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-N-(2-methoxy-ethyl)-methanesulfonamide (124 mg).
Reaction SMILES: Cl[C:2]1[C:3]2[NH:11][N:10]=[N:9][C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1.C([Sn](CCCC)(CCCC)[C:17]1[O:18][CH:19]=[CH:20][CH:21]=1)CCC>CN1CCCC1=O.CCOC(C)=O.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>[O:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[C:2]1[C:3]2[NH:11][N:10]=[N:9][C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Reactant: Nc1nc(Cl)c2[nH]nnc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Nc1nc(-c2ccco2)c2[nH]nnc2n1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
A solution of 7-chloro-1H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine (570 mg, 3.34 mmol) in N-methyl-2-pyrrolidinone (4 mL) was treated with PdCl2(PPh3)2 (117 mg, 0.17 mmol) and 2-(tributylstannyl)furan (1.05 mL, 1 mmol), stirred at 80° C. for 5 h, diluted with EtOAc, filtered through a silica pad and concentrated in vacuo. The residue was triturated with diethyl ether and the title compound isolated as a yellow solid (438 mg, 65%).
Reaction SMILES: C(OC(N1CCCC1C1C=CC(N)=CC=1)=O)(C)(C)C.[N+:20]([C:23]1[CH:36]=[CH:35][C:26]([CH2:27][N:28]2[CH2:32][CH2:31][CH2:30][CH:29]2[CH:33]=[CH2:34])=[CH:25][CH:24]=1)([O-])=O>>[CH2:33]([CH:29]1[CH2:30][CH2:31][CH2:32][N:28]1[CH2:27][C:26]1[CH:25]=[CH:24][C:23]([NH2:20])=[CH:36][CH:35]=1)[CH3:34]
Reactant: C=CC1CCCN1Cc1ccc([N+](=O)[O-])cc1
Agent: CC(C)(C)OC(=O)N1CCCC1c1ccc(N)cc1
Product: CCC1CCCN1Cc1ccc(N)cc1
Yield: 44 %

Procedure:
Using the same procedure described for the preparation of 2-(4-Amino-phenyl)-pyrrolidine-1-carboxylic acid tert-butyl ester, the title compound is prepared from 1-(4-Nitro-benzyl)-2-vinyl-pyrrolidine (220 mg, 0.95 mmol) in 44% yield.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]1([CH3:27])[C:13]([CH3:15])([CH3:14])[O:12][B:11]([C:16]2[CH:17]=[CH:18][C:19]3[O:25][CH2:24][CH2:23][N:22]=[CH:21][C:20]=3[CH:26]=2)[O:10]1.Cl[C:29]1[C:34]([CH2:35][C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)=[C:33]([CH3:43])[N:32]=[CH:31][N:30]=1.C(N(CC)C(C)C)(C)C>CN1CCCC1=O>[F:42][C:39]1[CH:38]=[CH:37][C:36]([CH2:35][C:34]2[C:29]([N:22]3[CH2:21][C:20]4[CH:26]=[C:16]([B:11]5[O:10][C:9]([CH3:27])([CH3:8])[C:13]([CH3:14])([CH3:15])[O:12]5)[CH:17]=[CH:18][C:19]=4[O:25][CH2:24][CH2:23]3)=[N:30][CH:31]=[N:32][C:33]=2[CH3:43])=[CH:41][CH:40]=1
Reactant: Cc1ncnc(Cl)c1Cc1ccc(F)cc1
Reactant: CC1(C)OB(c2ccc3c(c2)C=NCCO3)OC1(C)C
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1ncnc(N2CCOc3ccc(B4OC(C)(C)C(C)(C)O4)cc3C2)c1Cc1ccc(F)cc1
Temperature: 25 °C
Yield: 42 %

Procedure:
A mixture of 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1,4-benzoxazepine trifluoroacetate salt (2.9 g, 8.00 mmol, 4-chloro-5-[(4-fluorophenyl)methyl]-6-methylpyrimidine (reagent preparation 5) (1.9 g, 8.00 mmol) and N,N-diisopropylethylamine (7.0 mL, 40.0 mmol) in N-methyl-2-pyrrolidone (10 mL) was reacted in a microwave apparatus (250 W) for 2 h at 150° C. After cooling to room temperature the reaction mixture was partitioned between ethyl acetate (500 mL) and brine (100 mL). The organic layer was separated, washed with brine (100 mL), dried over sodium sulfate then filtered and concentrated. Column chromatography of the residue on silica (gradient 20 to 40% ethyl acetate in hexane) gave 4-{5-[(4-fluorophenyl)methyl]-6-methylpyrimidin-4-yl}-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine (1.6 g, 42% yield). 1H NMR (400 MHz, DMSO-D6): 8.58 (s, 1H), 7.62 (dd, 1H), 7.08 (m, 4H), 7.02 (d, 1H), 6.96 (d, 1H), 4.36 (s, 2H), 4.30 (m, 2H), 3.92 (s, 2H), 3.84 (m, 2H), 2.26 (s, 3H), 1.36 (s, 12H); MS (EI) for C27H31BFN3O3: 476 (MH+).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[C:3]=1[I:12].[CH3:13][O-:14].[Na+].[CH3:16][OH:17]>>[I:12][C:3]1[C:4]([O:14][CH3:13])=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[O:17][CH3:16]
Reactant: O=[N+]([O-])c1ccc(F)c(I)c1F
Reactant: C[O-]
Reactant: CO
Agent: [Na+]
Product: COc1ccc([N+](=O)[O-])c(OC)c1I

Procedure:
1,3-Difluoro-2-iodo-4-nitrobenzene (5.0 g, 17.5 mmol) was dissolved in 50 ml of methanol, and NaOMe (3.79 g, 70.1 mmol) was added. The solution was heated under reflux for 16 h. After concentration, the residue was chromatographed on silica gel using petroleum ether/ethyl acetate. This gave 2-iodo-1,3-dimethoxy-4-nitrobenzene (3 g) as a yellowish powder.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][CH:19]([N:22]4[CH2:25][CH:24]([N:26]([CH3:28])[CH3:27])[CH2:23]4)[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[CH:4][CH:3]=1.[F:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][C:39]([N:41]=[C:42]=[O:43])=[O:40])=[CH:34][CH:33]=1.C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)C.CCCCCC>[F:31][C:32]1[CH:33]=[CH:34][C:35]([CH2:38][C:39]([NH:41][C:42](=[O:43])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([O:6][C:7]3[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]4[CH2:17][CH2:18][CH:19]([N:22]5[CH2:23][CH:24]([N:26]([CH3:28])[CH3:27])[CH2:25]5)[CH2:20][CH2:21]4)=[O:15])[CH:8]=3)=[CH:29][CH:30]=2)=[O:40])=[CH:36][CH:37]=1
Reactant: O=C=NC(=O)Cc1ccc(F)cc1
Reactant: CN(C)C1CN(C2CCN(C(=O)Nc3cc(Oc4ccc(N)cc4)ccn3)CC2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN(C)C1CN(C2CCN(C(=O)Nc3cc(Oc4ccc(NC(=O)NC(=O)Cc5ccc(F)cc5)cc4)ccn3)CC2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27 %

Procedure:
To a solution of 4-(3-dimethylaminoazetidin-1-yl)piperidine-1-carboxylic acid [4-(4-aminophenoxy)pyridin-2-yl]amide (60 mg) in tetrahydrofuran (5.0 ml) was added a solution of 2-(4-fluorophenyl)acetyl isocyanate in tetrahydrofuran (0.25 M, 1.75 ml) at room temperature, followed by stirring at room temperature for 0.5 hr. To the reaction mixture was added a saturated aqueous solution of sodium hydrogencarbonate, followed by stirring at room temperature for 0.5 hr. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated to give a residue, which was then purified by silica gel column chromatography (FUJI Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=10:1). Fractions containing a target compound were concentrated to give a solid, which was suspended in diethyl ether (1 ml) and hexane (2 ml). The solid was filtered off, washed with diethyl ether:hexane=1:2, and dried under aeration to provide the titled compound (23.2 mg, 27%) as white powder.