Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:6][CH2:7][N:8]([C:17](=[O:25])[C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=3)[C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[C:11]=2[N:12]=1.C(N(CC)CC)C.[CH3:33][C:34]1[CH:42]=[CH:41][CH:40]=[CH:39][C:35]=1[C:36](Cl)=[O:37]>C(Cl)Cl>[CH3:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:6][CH2:7][N:8]([C:17]([C:18]3[CH:19]=[CH:20][C:21]([NH:24][C:36](=[O:37])[C:35]4[CH:39]=[CH:40][CH:41]=[CH:42][C:34]=4[CH3:33])=[CH:22][CH:23]=3)=[O:25])[C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[C:11]=2[N:12]=1
Reactant: Cc1ccccc1C(=O)Cl
Reactant: Cc1ncc2c(n1)-c1ccccc1N(C(=O)c1ccc(N)cc1)CC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ncc2c(n1)-c1ccccc1N(C(=O)c1ccc(NC(=O)c3ccccc3C)cc1)CC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 0.216 mg of 6,7-dihydro-2-methyl-7-(4-aminobenzoyl)-5H-pyrimido[5,4-d][1]benzazepine in 6 ml of methylene chloride under argon is added 100 μl of triethylamine followed by a solution of 94 μl of 2-methylbenzoyl chloride in 1.5 ml of methylene chloride. The reaction mixture is stirred at room temperature for 18 hours, washed with water, saturated NaHCO3 and the separated organic layer treated with activated carbon and filtered through MgSO4. The filtrate is evaporated to a residue which is dissolved in ethyl acetate and evaporated in vacuo to give 300 mg of the desired product as a pale yellow foam.
Reaction SMILES: [CH3:1][C:2]([CH:4]([CH3:6])[CH3:5])=O.Cl.[N+:8]([C:11]1[CH:12]=[C:13]([NH:17][NH2:18])[CH:14]=[CH:15][CH:16]=1)([O-:10])=[O:9].O.O.O.C([O-])(=O)C.[Na+]>O.CCO>[N+:8]([C:11]1[CH:12]=[C:13]([NH:17]/[N:18]=[C:2](/[CH:4]([CH3:6])[CH3:5])\[CH3:1])[CH:14]=[CH:15][CH:16]=1)([O-:10])=[O:9]
Reactant: CC(=O)C(C)C
Reactant: NNc1cccc([N+](=O)[O-])c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C/C(=N\Nc1cccc([N+](=O)[O-])c1)C(C)C
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of isopropyl methyl ketone (2.5 g, 29 mol), 3-nitrophenylhydrazine hydrochloride (6.1 g, 32 mmol) and sodium acetate trihydrate (4.8 g, 35 mmol) in H2O (50 mL) and EtOH (50 mL) was stirred at 80° C. for 1 h. The reaction mixture was cooled and then concentrated under reduced pressure. The residue was partitioned between saturated aqueous NaHCO3 (100 mL) and CHCl3 (150 mL). The organic layer was removed and the aqueous phase was further extracted with CHCl3 (100 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound. MS: m/z=222 (M+1).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:21]=[CH:20][C:6]([NH:7][CH:8]=[C:9]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:5]([I:22])[CH:4]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24].O>C(O)(=O)C>[C:23]([O:1][CH2:2][C:3]1[CH:21]=[CH:20][C:6]([NH:7][CH:8]=[C:9]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:5]([I:22])[CH:4]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)C(=CNc1ccc(CO)cc1I)C(=O)OCC
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C(=CNc1ccc(COC(C)=O)cc1I)C(=O)OCC
Temperature: 25 °C
Yield: 87 %

Procedure:
A solution of diethyl 2-{[4-(hydroxymethyl)-2-iodoanilino]methylene}malonate (0.20 g) and acetic anhydride (0.054 mL) in acetic acid (0.24 mL) is heated at 80° C. overnight. The reaction is cooled to room temperature and poured into 50 mL of water. The resulting solid is filtered and dried to yield 0.19 g (87%) of diethyl 2-({4-[(acetyloxy)methyl]-2-iodoanilino} methylene)malonate as a white solid, m.p. 128-131° C.
Reaction SMILES: [Br:1][C:2]1[O:6][CH:5]=[C:4]([C:7]([OH:9])=O)[CH:3]=1.[NH2:10][C@@H:11]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]([F:34])([F:33])[F:32])[CH2:12][N:13]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]1=[O:23].C(N(C(C)C)CC)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Br:1][C:2]1[O:6][CH:5]=[C:4]([C:7]([NH:10][C@@H:11]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]([F:34])([F:32])[F:33])[CH2:12][N:13]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]2=[O:23])=[O:9])[CH:3]=1
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Reactant: O=C(O)c1coc(Br)c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O)c1coc(Br)c1
Reaction time: 16 h
Yield: 55 %

Procedure:
To a solution of 5-bromo-3-furancarboxylic acid (0.30 g, 1.57 mmol) [prepared according to J. Org. Chem. 1976, 41, 2350.], 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (0.60 g, 1.73 mmol) [from Preparation 5] and diisopropylethyl amine (0.82 mL, 4.7 mmol) in DCM (50 mL) at 25° C. was added PyBrOP (1.09 g, 2.36 mmol) in one portion. After 16 h, the solution was partitioned between H2O and washed with DCM. The combined organic fractions were dried (Na2SO4), concentrated and purified via column chromatography (silica, hexanes/EtOAc, 1:1) affording the title compound (0.45 g, 55%) as a white solid: LC-MS (ES) m/z=521 (WH)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[N:3]=1.[CH2:20]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[CH3:21].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:20]([N:22]1[CH2:27][CH2:26][N:25]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[C:4]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[N:3]=2)[CH2:24][CH2:23]1)[CH3:21]
Reactant: COc1ccc(-c2cc3ccccc3c(Cl)n2)cc1
Reactant: CCN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN1CCN(c2nc(-c3ccc(OC)cc3)cc3ccccc23)CC1
Yield: 89 %

Procedure:
A mixture of 1-chloro-3-(4-methoxyphenyl)isoquinoline (0.89 g), N-ethylpiperazine (0.86 g) and potassium carbonate (1.10 g) was heated in dimethylformamide (20 ml) at 90° C. for 12 hr. The reaction mixture was evaporated, water was added to the resulting residue, and then it was extracted with ethyl acetate. The resulting organic layer was washed with water and brine, dried over magnesium sulfate, and then the solvent was removed. The resulting residue was purified by silica gel column chromatography (methylene chloride/methanol system), to give the tilte compound as a pale brown oil (1.02 g, yield; 88%).
Reaction SMILES: [C:1]([C:3]1[CH:7]=[N:6][NH:5][C:4]=1[NH2:8])#[N:2].CN(C)[CH:11]=[CH:12][C:13]([C:15]1[CH:16]=[C:17]([N:21]([CH2:26][CH3:27])[S:22]([CH3:25])(=[O:24])=[O:23])[CH:18]=[CH:19][CH:20]=1)=O.C(OCC)(=O)C>C(O)(=O)C>[C:1]([C:3]1[CH:7]=[N:6][N:5]2[C:13]([C:15]3[CH:16]=[C:17]([N:21]([CH2:26][CH3:27])[S:22]([CH3:25])(=[O:24])=[O:23])[CH:18]=[CH:19][CH:20]=3)=[CH:12][CH:11]=[N:8][C:4]=12)#[N:2]
Reactant: N#Cc1cn[nH]c1N
Reactant: CCN(c1cccc(C(=O)C=CN(C)C)c1)S(C)(=O)=O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCN(c1cccc(-c2ccnc3c(C#N)cnn23)c1)S(C)(=O)=O
Yield: 52.1 %

Procedure:
A mixture of 0.196 g (1.82 mmol) of 4-cyano-2H-pyrazol-3-ylamine and 0.54 g (1.82 mmol) of N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-N-ethyl-methanesulfonamide in 10 ml of glacial acetic acid was refluxed for 8 hours and then the solvent was removed by reduced pressure distillation. To the resulting residue were added 10 ml of dichloromethane and 10 ml of saturated sodium bicarbonate solution. The two layers were separated, and the aqueous layer was washed with 10 ml of dichloromethane. The organic layers were washed with 10 ml of water and dried over magnesium sulfate. The dichloromethane layer was evaporated to dryness to yield an oil which, in the presence of ethyl acetate, gave 324 mg of N-[3-(3-cyano-pyrazolo[1,5-a]pyrimidin-7-yl)-phenyl]-N-ethyl-methanesulfonamide as a yellow solid (yield 52.4%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][NH:12][CH2:11][CH:10]2[CH:14]([O:16][C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][N:18]=2)[CH3:15])[CH:5]=[CH:6][C:7]=1[Cl:8].CCN(CC)CC.[Br:32][CH2:33][C:34](Cl)=[O:35]>C(Cl)Cl>[Br:32][CH2:33][C:34]([N:12]1[CH2:13][CH:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH:10]([CH:14]([O:16][C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][N:18]=2)[CH3:15])[CH2:11]1)=[O:35]
Reactant: CC(Oc1ccc(C#N)cn1)C1CNCC1c1ccc(Cl)c(Cl)c1
Reactant: O=C(Cl)CBr
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(Oc1ccc(C#N)cn1)C1CN(C(=O)CBr)CC1c1ccc(Cl)c(Cl)c1
Yield: 703.7 %

Procedure:
To a stirred solution of 6-{(SR)-1-[(3RS,4SR)-4-(3,4-Dichloro-phenyl)-pyrrolidin-3-yl]-ethoxy}-nicotinonitrile (XV-B-4) 30 mg (0.083 mmol) in CH2Cl2 (3 mL) at RT, 0.013 ml (0.01 mmol) of Et3N and 0.0083 mL (0.01 mmol) of bromo-acetyl chloride were added. Stirring was continued over night and then concentrated under vacuo. The crude residue was dissolved in EtOAc, washed with H2O. The organic phase was dried over Na2SO4 and the product was purified by flash chromatography (SiO2, EtOAc) to yield the title product 34 mg (85%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)=[O:7])=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][C:33](Cl)=[O:34].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][C:33]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)=[O:7])=[CH:23][CH:24]=1)=[O:34]
Reactant: O=C(Cl)Cc1ccccc1Cl
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Cc1ccccc1Cl)Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 38.5 %

Procedure:
A mixture of 0.471 g (1.5 mmol) of 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine, 0.340 g (1.8 mmol) of 2-chlorophenylacetyl chloride, 0.20 g of triethylamine and 9 mg of 4-(dimethylamino)pyridine in 10 ml of dichloromethane is stirred at room temperature for 48 hours. An additional 0.27 g of 2-chlorophenylacetyl chloride is added and the mixture stirred at room temperature for 2.5 hr. The mixture is washed with 1N HCl, H2O, 1M NaHCO3, brine and dried (Na2SO4). The solvent is removed and the solid recrystallized from dichloromethane to give 0.27 g of crystals;, m.p. 191°-194° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([OH:33])[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:24]([CH2:29][CH:30]3[CH2:32][CH2:31]3)[S:25]([CH3:28])(=[O:27])=[O:26])[CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:36](Br)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([O:33][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:24]([CH2:29][CH:30]3[CH2:32][CH2:31]3)[S:25]([CH3:28])(=[O:26])=[O:27])[CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)N(CC1CC1)c1ccccc1N1CCN(C(=O)[C@@H](O)Cc2ccc(Cl)cc2)CC1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CS(=O)(=O)N(CC1CC1)c1ccccc1N1CCN(C(=O)[C@H](Cc2ccc(Cl)cc2)OCc2ccccc2)CC1
Reaction time: 0.08 h
Yield: 74.4 %

Procedure:
To a 15-mL round-bottomed flask equipped with a magnetic stir bar and containing (2S)-3-(4-chlorophenyl)-1-(4-{2-[(cyclopropylmethyl)-(methylsulfonyl)amino]phenyl}-piperazinyl)-2-hydroxy-propan-1-one (Step 3) (0.075 g, 0.15 mmol) in 2 mL THF at RT was added NaH (Aldrich) (0.007 g of 60% dispersion in oil, 0.17 mmol). Gas evolution was observed and after 5 min benzyl bromide (Aldrich) (20 ml, 0.17 mmol) was added. After stirring for 18 h, the mixture was quenched with aq. NaHCO3 and extracted with Et2O. The combined ether extracts were washed with H2O and brine, dried (Na2SO4) and concentrated onto silica gel. Purification by chromatography (30-55% EtOAc/hexanes) afforded (2S)-3-(4-chlorophenyl)-1-(4-{2-[(cyclopropylmethyl)-(methylsulfonyl)amino]-phenyl}piperazinyl)-2-(phenyl-methoxy)propan-1-one as a colorless oil (0.065 g). MS (ESI, pos. ion) m/z 582 (M+1). Calc'd for C31H36ClN3O4S: 581.21.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH2:11][CH2:10]2)[CH:6]=[CH:5][C:4]=1[NH2:21].CS([C:25]1[N:30]=[CH:29][C:28]2=[CH:31][CH:32]=[C:33]([C:34]3[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=3)[N:27]2[N:26]=1)=O.[F-].[Cs+].C(N(CC)C(C)C)(C)C>C(O)(C)(C)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH2:11][CH2:10]2)[CH:6]=[CH:5][C:4]=1[NH:21][C:25]1[N:30]=[CH:29][C:28]2=[CH:31][CH:32]=[C:33]([C:34]3[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=3)[N:27]2[N:26]=1
Reactant: COc1cc(N2CCC(N3CCOCC3)CC2)ccc1N
Reactant: CS(=O)c1ncc2ccc(-c3cccnc3)n2n1
Agent: [Cs+]
Agent: [F-]
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(N2CCC(N3CCOCC3)CC2)ccc1Nc1ncc2ccc(-c3cccnc3)n2n1
Temperature: 130 °C
Yield: 33.1 %

Procedure:
Into a 8-dram vial, 2-Methoxy-4-(4-morpholin-4-yl-piperidin-1-yl)-phenylamine (40.0 mg, 0.137 mmol), 2-Methanesulfinyl-7-pyridin-3-yl-pyrrolo[2,1-f][1,2,4]triazine (80.9 mg, 0.313 mmol), Cesium fluoride (41.7 mg, 0.274 mmol), tert-Butyl alcohol (0.80 mL) and N,N-Diisopropylethylamine (0.0478 mL, 0.274 mmol) were added. The reaction mixture was heated at 130° C. overnight. HPLC suggested little if any SM. The reaction mixture was purified via HPLC reverse phase chromatography with 0.1% TFA in Water and 0.1% TFA in ACN. The collected fractions were lyophilized to give a [2-Methoxy-4-(4-morpholin-4-yl-piperidin-1-yl)-phenyl]-(7-pyridin-3-yl-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-amine yellow solid (22 mg, 33%). LCMS (E/I+) 486.18 (M+H). NMR 1H (DMSO-d6)-9.35 (s, 1H), 8.97 (s, 1H), 8.65 (d, 1H, J=8.50 Hz), 8.55 (s, 1H), 7.97 (s, 1H), 7.69 (d, 1H, J=8.50 Hz), 7.50 (t, 1H, J=5.95 Hz), 7.31 (d, 1H, J=4.25 Hz), 6.97 (d, 1H, J=4.25 Hz), 6.73 (s, 1H), 6.58 (d, 1H, J=9.35 Hz), 4.05 (d, 2H, J=11.87 Hz), 3.91 (d, 2H, J=11.87 Hz), 3.83 (s. 3H), 3.67 (t, 2H, J=11.87 Hz), 3.52 (d, 2H, J=11.87 Hz), 3.13 (d, 2H, J=11.87 Hz), 2.73 (t, 2H, J=11.87 Hz), 2.16 (d, 2H, J=11.87 Hz), 1.71 (q, 2H, J=11.87 Hz).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:17])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1)([CH3:4])[CH3:3].[CH:18]([S:26](Cl)(=[O:28])=[O:27])=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:4][C:2]([CH3:1])([O:5][C:6]([NH:7][CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][S:26]([CH:18]=[CH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:28])=[O:27])=[CH:14][CH:15]=1)=[O:17])[CH3:3]
Reactant: O=S(=O)(Cl)C=Cc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(N)cc1
Product: CC(C)(C)OC(=O)NCCc1ccc(NS(=O)(=O)C=Cc2ccccc2)cc1

Procedure:
In a manner analogous to that of Example 5, the title compound was prepared from the Boc amine from Example 4 and β-styrenesulfonyl chloride: 1H NMR (400 MHz, CDCl3) δ7.47 (d, 1H, J =15.4 Hz), 7.42-7.33 (m, 5H), 7.11 (s, 4H), 6.77 (d, 1H, J=15.4 Hz), 6.56 (br s, 1H), 4.48 (br s, 1H), 4.10 (br m, 2H), 2.72 (t, 2H, J=7.1 Hz), 1.39 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[CH:3]=1.C1C(=O)N([Br:16])C(=O)C1>C(Cl)(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][Br:16])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(Br)ccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1cc(Br)ccn1
Temperature: 100 °C
Yield: 36 %

Procedure:
A mixture of 4-bromo-2-methylpyridine (2.0 g, 11.63 mmol), NBS (2.69 g, 15.11 mmol), and diphenylperoxyanhydride (0.282 g, 1.163 mmol) in carbon tetrachloride (50 mL) was heated to 100° C. overnight. Cooled to RT, diluted with saturated NaHCO3, and extracted with ethyl acetate (3×). The combined organic extracts were washed with saturated NaCl (2×), dried over Na2SO4, filtered, and concentrated. The residue was purified via silica gel chromatography (ISCO, 120 g silica, 60 mL/min, 0-80% EtOAc/Hexanes over 45 min) to afford 4-bromo-2-(bromomethyl)pyridine (1.05 g, 36%). MS (m/z) 251.9.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[CH:9])[CH:3]=1.[CH3:10][C:11]([CH3:20])([CH3:19])[C:12]([O:14][CH2:15][N:16]=[N+:17]=[N-:18])=[O:13].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>CC(O)(C)C.O.O>[CH3:10][C:11]([CH3:20])([CH3:19])[C:12]([O:14][CH2:15][N:16]1[CH:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[N:18]=[N:17]1)=[O:13]
Reactant: C#Cc1cccc(Br)c1
Reactant: CC(C)(C)C(=O)OCN=[N+]=[N-]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: CC(C)(C)C(=O)OCn1cc(-c2cccc(Br)c2)nn1
Temperature: 25 °C
Reaction time: 25 h

Procedure:
To a mixture of 1-bromo-3-ethynylbenzene (0.430 g; 2.38 mmol; Note 1), and azidomethyl 2,2-dimethylpropanoate (0.391 g; 2.49 mmol; Note 2) in t-BuOH/water (3.5/3.0 mL respectively) at room temperature was added a solution of CuSO4.5H2O in water (0.030 g/0.5 mL), followed by sodium ascorbate (0.141 g; 0.71 mmol) in one portion. The mixture was stirred 25 h at room temperature, diluted with water and extracted with EtOAc (×3). Combined organics were washed (5% NH4OH, water, brine), dried over Na2SO4 and concentrated in vacuo affording the title compound as a tan solid which was used without further purification. LC/MS (method B) 2.77 min, m/z 338, 340 (M+H, Br isotopes).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=[O:7].C(N(CC)C(C)C)(C)C.[C:17](Cl)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C>[C:17]([N:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=[O:7])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ncc[nH]1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=Cc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 30 °C
Reaction time: 21 h
Yield: 46.3 %

Procedure:
To a suspension of imidazole-2-carboxaldehyde (1.00 g, 10.4 mmol) in DMF (16 mL) was added N,N-diisopropylethylamine (4.0 mL, 23.0 mmol) followed by a solution of trityl chloride (3.19 g, 11.4 mmol) in DMF (10 mL), and the mixture was stirred at 30° C. for 21 h. The mixture was concentrated in vacuo then dissolved in EtOAc (60 mL). The solution was washed with saturated NaHCO3(aq) (2×30 mL) and brine (15 mL) then dried (MgSO4) and concentrated in vacuo. Purification of the crude material by column chromatography on silica gel (20% EtOAc/hexanes) gave a yellow solid (1.63 g, 46%). 1H NMR (CDCl3) δ 7.03 (s, 1H), 7.12 (m, 6H), 7.32 (m, 10H), 9.23 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[C:4]([C:6]1[C:11]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([C:23]([F:26])([F:25])[F:24])[CH:17]=2)(=[O:15])=[O:14])=[CH:10][C:9]([Cl:27])=[CH:8][N:7]=1)=O.[Si]([N:36]=[C:37]=[O:38])(C)(C)C>C1COCC1.CC(O)=O>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([S:13]([NH:12][C:11]2[C:6]([C:4]3[C:3]4[C:2](=[CH:31][CH:30]=[CH:29][CH:28]=4)[NH:1][C:37](=[O:38])[N:36]=3)=[N:7][CH:8]=[C:9]([Cl:27])[CH:10]=2)(=[O:15])=[O:14])=[CH:17][C:18]=1[C:23]([F:24])([F:25])[F:26]
Reactant: C[Si](C)(C)N=C=O
Reactant: Nc1ccccc1C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=c1nc(-c2ncc(Cl)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)c2ccccc2[nH]1
Temperature: 65 °C

Procedure:
To a stirred solution of N-[2-(2-amino-benzoyl)-5-chloro-pyridin-3-yl]-4-chloro-3-trifluoromethyl-benzenesulfonamide (48 mg, 0.097 mmol) in anhydrous THF (2 mL) and AcOH (400 μL) was added TMS isocyanate (32 μL, 0.22 mmol) and the resulting mixture was heated at 65° C. overnight. The crude reaction mixture was directly purified by HPLC to provide 4-Chloro-N-[5-chloro-2-(2-oxo-1,2-dihydro-quinazolin-4-yl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide. 1H NMR (400 MHz, CDCl3) δ 10.50 (br s, 1 H), 8.58 (d, J=2.4 Hz, 1 H), 8.19 (d, J=2.4 Hz, 1 H), 8.06 (d, J=7.6 Hz, 1 H), 7.92 (d, J=2.4 Hz, 1 H), 7.80-7.76 (m, 1 H), 7.65 (dd, J=8.4, 2.4 Hz, 1 H), 7.41 (d, J=8.0 Hz, 1 H), 7.23-7.22 (m, 2 H); Mass spectrum m/z: 515.0 (M+H).
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:13](Cl)(=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15]>C(OCC)C>[C:1]([NH:5][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 98 %

Procedure:
A 1 L three-necked round-bottomed flask was charged with diethylether (500 mL), tert-butylamine (11.3 mL, 105 mmol), and triethylamine (14.9 mL, 105 mmol). To this vigorously stirred solution at 0° C. was slowly added pivaloyl chloride (8.9 mL, 100 mmol) and the resultant white slurry was stirred for 18 h at ambient temperature. This slurry was then filtered with a water aspirator pump and the volatile components of the filtrate were removed under reduced pressure. The resultant crystalline solid was sublimed at 55° C./0.05 Torr to afford LtBu,tBuH as white crystals (15.41 g, 98%): mp 116-118° C.
Reaction SMILES: C1(C)C=C[C:4]([S:7](O)(=[O:9])=[O:8])=CC=1.[CH3:12][C:13]1([CH3:32])[CH:15]([CH:16](OS(C)(=O)=O)[C:17]([C:20]([F:23])([F:22])[F:21])([Br:19])[Cl:18])[CH:14]1[C:29]([O-:31])=[O:30]>C(Cl)Cl>[CH3:32][C:13]1([CH3:12])[CH:15]([CH:16]([S:7]([CH3:4])(=[O:9])=[O:8])[C:17]([C:20]([F:21])([F:22])[F:23])([Br:19])[Cl:18])[CH:14]1[C:29]([OH:31])=[O:30]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC1(C)C(C(=O)[O-])C1C(OS(C)(=O)=O)C(Cl)(Br)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)C(C(=O)O)C1C(C(Cl)(Br)C(F)(F)F)S(C)(=O)=O
Temperature: 40 °C

Procedure:
30 mg of p-toluene sulfonic acid were added at 40° C. to a solution of 1 g of the product of Step B and 10 ml of methylene chloride and the reaction mixture was heated for 5 hours at 40° C., then poured on to ice, and decanted. The organic phase was washed with water, dried on sodium sulfate and evaporated to dryness under reduced pressure to obtain 860 mg of [1R-[1α-, 3α-(RS*,RS*)]] 2,2-dimethyl-3-[2-trifluoromethyl-2-bromo-2-chloro-1-methylsulfonylethyl]-cyclopropane carboxylic acid melting at 138° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:24]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]2)=[C:8]([NH2:26])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH:28]([CH3:30])[CH3:29]>>[NH2:26][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:24])[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][N:20]([CH:28]([CH3:30])[CH3:29])[CH2:19]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCNC3)c2n1
Reactant: CC(C)I
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCC3CCCN(C(C)C)C3)c2n1

Procedure:
Prepared similarly to Example 14 from 2-(butyloxy)-8-(methyloxy)-9-[3-(3-piperidinyl)propyl]-9H-purin-6-amine and 2-iodopropane.
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[CH3:9][O:10][CH:11]([O:15][CH3:16])[C:12](=[O:14])[CH3:13]>>[CH3:3][N:4]([CH3:6])[CH:5]=[CH:13][C:12](=[O:14])[CH:11]([O:15][CH3:16])[O:10][CH3:9]
Reactant: COC(OC)C(C)=O
Reactant: COC(OC)N(C)C
Product: COC(OC)C(=O)C=CN(C)C
Temperature: 80 °C

Procedure:
A mixture of 1,1-dimethoxy-N,N-dimethylmethanamine (5.0 g, 41.96 mmol) and 1,1-dimethoxypropan-2-one (5.0 g, 41.96 mmol) was heated to 80° C. for 16 h. The solvent was removed under reduced pressure to afford 4-(dimethylamino)-1,1-dimethoxybut-3-en-2-one as a black colored liquid. The material was used without further purification.