Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([N:9]2[C:13]3=[C:14]4[S:20][CH:19]=[CH:18][C:15]4=[N:16][CH:17]=[C:12]3[N:11]=[C:10]2[CH2:21][C:22]#[N:23])[CH2:5][CH2:4]1.C(N(CC)CC)C.Cl[C:32]([O:34][CH2:35][CH3:36])=[O:33]>C(Cl)Cl>[C:22]([CH2:21][C:10]1[N:9]([C@H:6]2[CH2:7][CH2:8][C@H:3]([CH2:2][NH:1][C:32](=[O:33])[O:34][CH2:35][CH3:36])[CH2:4][CH2:5]2)[C:13]2=[C:14]3[S:20][CH:19]=[CH:18][C:15]3=[N:16][CH:17]=[C:12]2[N:11]=1)#[N:23]
Reactant: N#CCc1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CN)CC1
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)NC[C@H]1CC[C@H](n2c(CC#N)nc3cnc4ccsc4c32)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of {1-[trans-4-(aminomethyl)cyclohexyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl}acetonitrile (9.5 mg, 0.029 mmol) and triethylamine (20. μL, 0.14 mmol) in methylene chloride (1 mL) was added ethyl chloroformate (3.3 μL, 0.035 mmol). The mixture was stirred at room temperature for 1 h, then stripped to dryness and purified on prep-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (1.9 mg, 16%). LCMS calculated for C20H24N5O2S (M+H)+: m/z=398.2. Found: 397.8.
Reaction SMILES: C1(C)C=CC(S(O[C:11]2[N:16]=[C:15]([NH:17][C:18]([O:20][CH3:21])=[O:19])[N+:14]([O-:22])=[C:13]([NH:23][C:24]([O:26][CH3:27])=[O:25])[CH:12]=2)(=O)=O)=CC=1.[NH:29]1[CH2:34][CH2:33][CH:32]=[CH:31][CH2:30]1>C(Cl)(Cl)Cl.C(Cl)Cl>[N:29]1([C:11]2[N:16]=[C:15]([NH:17][C:18]([O:20][CH3:21])=[O:19])[N+:14]([O-:22])=[C:13]([NH:23][C:24]([O:26][CH3:27])=[O:25])[CH:12]=2)[CH2:30][CH:31]=[CH:32][CH2:33][CH2:34]1
Reactant: C1=CCNCC1
Reactant: COC(=O)Nc1cc(OS(=O)(=O)c2ccc(C)cc2)nc(NC(=O)OC)[n+]1[O-]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COC(=O)Nc1cc(N2CC=CCC2)nc(NC(=O)OC)[n+]1[O-]

Procedure:
1.0 g of dimethyl 6-[(p-tolylsulfonyl)oxy]-2,4-pyrimidinedicarbamate-3-oxide is dissolved in 20 ml of chloroform and the solution is heated at reflux with 1 ml of 1,2,5,6-tetrahydropyridine. The cooled mixture is diluted with methylene chloride and washed with water. The organic phase is dried over sodium sulfate and concentrated. The residue is recrystallized from methylene chloride and methanol, there being obtained pure dimethyl 6-[3,6-dihydro-1(2H)-pyridyl]-2,4-pyrimidinedicarbamate-3-oxide of melting point 185°-187°.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[CH3:39][C:40]1[O:44][C:43]([C:45]2[CH:46]=[C:47]([OH:60])[CH:48]=[C:49](B3OC(C)(C)C(C)(C)O3)[CH:50]=2)=[N:42][N:41]=1.C(=O)([O-])[O-].[Na+].[Na+]>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>[OH:60][C:47]1[CH:48]=[C:49]([C:2]2[C:10]3[C:9]([NH:11][C@H:12]([C:14]4[N:19]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:18](=[O:26])[C:17]5=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]5[N:15]=4)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=3[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=2)[CH:50]=[C:45]([C:43]2[O:44][C:40]([CH3:39])=[N:41][N:42]=2)[CH:46]=1
Reactant: Cc1nnc(-c2cc(O)cc(B3OC(C)(C)C(C)(C)O3)c2)o1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
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+]
Product: Cc1nnc(-c2cc(O)cc(-c3cn(COCC[Si](C)(C)C)c4ncnc(N[C@@H](C)c5nn6ccc(C)c6c(=O)n5-c5ccccc5)c34)c2)o1
Temperature: 100 °C
Reaction time: 48 h
Yield: 17.3 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (250 mg, 0.42 mmol) was treated with 3-(5-methyl-1,3,4-oxadiazol-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (200 mg, 0.66 mmol), tetrakis(triphenylphosphine)palladium(0) (40 mg, 0.03 mmol) and aqueous solution 2M of sodium carbonate (500 μl, 4.7 mmol) in N,N-dimethylformide (5 ml) according to the method described in Preparation 186 but stirring at 100° C. for 48 h. The crude was purified using SP1® Purification System (hexane-ethyl acetate) to obtain 50 mg (16% yield) of the title compound as a oil. Purity 95%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C@H:4](OS(C)(=O)=O)[C@@H:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=1)[CH3:6].[N-:21]=[N+:22]=[N-:23].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:20])[C@@H:4]([N:21]=[N+:22]=[N-:23])[C@@H:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=1)[CH3:6]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)[C@H](OS(C)(=O)=O)[C@H](C)c1ccc(Cl)c(Cl)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](N=[N+]=[N-])[C@H](C)c1ccc(Cl)c(Cl)c1
Temperature: 55 °C
Yield: 71.1 %

Procedure:
To a solution of (2R,3R)-3-(3,4-dichloro-phenyl)-2-methanesulfonyloxy-butyric acid methyl ester (0.70 g, 2.05 mmol) in DMF (10 mL) was added NaN3 (0.27 g, 4.10 mmol). The reaction was heated at 55° C. overnight. The mixture was quenched with water and extracted with EtOAc. The organic phase was washed with water (2×), dried (MgSO4), and concentrated. The product was purified by flash chromatography to give 0.42 g (71%) of product. 1H NMR (500 MHz, CDCl3): 7.39 (d, J=8.3, 1H), 7.35 (d, J=2.1, 1H), 7.10 (dd, J=8.3, 2.1, 1H), 3.96 (d, J=6.4, 1H), 3.71 (s, 3H), 3.29 (m, 1H), 1.33 (d, J=7.0, 3H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9][F:10].[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]>C(#N)C>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([CH2:8][CH2:9][F:10])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: FCCBr
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(CCF)CC1
Yield: 56.9 %

Procedure:
Potassium carbonate (1.85 g, 13.4 mmol) and 1-bromo-2-fluoroethane (440 PI, 5.9 mmol) were added to a solution of tert-butyl-1-piperazinecarboxylate (1 g, 5.4 mmol) in acetonitrile (12 ml). The reaction mixture was stirred at 65° C. for 3.5 hours after which time more 1-bromo-2-fluoroethane (160 μl, 2.1 mmol) was added. The reaction was heated for a further 3 hours then filtered to remove the inorganic solids. The filtrate was concentrated and the crude product was purified using column chromatography eluting with ethyl acetate to give 4-(2-fluoroethyl)-piperazine-1-carboxylic acid tert-butyl ester (714 mg, 57%).
Reaction SMILES: [CH3:1][N:2]([C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)[CH2:3][CH2:4][C:5](Cl)=[O:6].C(N(CC)CC)C.[CH3:24][C:25]1[CH:30]=[C:29]([CH3:31])[N:28]=[C:27]([NH:32][CH3:33])[CH:26]=1>ClCCl>[CH3:24][C:25]1[CH:30]=[C:29]([CH3:31])[N:28]=[C:27]([N:32]([CH3:33])[C:5](=[O:6])[CH2:4][CH2:3][N:2]([CH3:1])[C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[CH:26]=1
Reactant: CNc1cc(C)cc(C)n1
Reactant: CN(CCC(=O)Cl)c1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)nc(N(C)C(=O)CCN(C)c2ccc([N+](=O)[O-])cc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.4 %

Procedure:
A solution of 3-[methyl-(4-nitro-phenyl)-amino]-propionyl chloride (550 mg, 4.04 mmol) in dichloromethane (5 mL) was cooled to 0° C., triethylamine (1.12 mL, 8.08 mmol) was added followed, after 5 min, by (4,6-dimethyl-pyridin-2-yl)-methyl-amine (1.14 g, 4.73 mmol). The reaction mixture was warmed to room temperature and stirred for 30 min then partitioned between water and dichloromethane. The organic phase was separated, washed with saturated bicarbonate solution, brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue which was purified by column chromatography over silica gel (60-120 mesh) using 20% ethyl acetate in hexane as eluent to afford N-(4,6-dimethyl-pyridin-2-yl)-N-methyl-3-[methyl-(4-nitro-phenyl)-amino]-propionamide (600 mg, 43%) as a yellow solid.
Reaction SMILES: [C:1]12([NH:11][Si:12](Cl)([CH3:14])[CH3:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:16][C:17]1[CH-:18][C:19]2[C:24]([C:25]=1[CH3:26])=[CH:23][CH:22]=[CH:21][CH:20]=2.[Li+]>C1COCC1>[CH3:16][C:17]1[CH:18]([Si:12]([NH:11][C:1]23[CH2:10][CH:5]4[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]4)[CH2:2]2)[CH2:8]3)([CH3:13])[CH3:14])[C:19]2[C:24]([C:25]=1[CH3:26])=[CH:23][CH:22]=[CH:21][CH:20]=2
Reactant: C[Si](C)(Cl)NC12CC3CC(CC(C3)C1)C2
Reactant: Cc1[cH-]c2ccccc2c1C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1=C(C)C([Si](C)(C)NC23CC4CC(CC(C4)C2)C3)c2ccccc21
Reaction time: 8 h

Procedure:
(1-adamantylamino)chlorodimethylsilane (5.48 g, 0.0225 moles) was stirred in THF (100 mL) as lithium 2.3-dimethylindenide (3.40 g, 0.0225 moles) in THF (25 mL) was added dropwise. This mixture was allowed to stir for 8 hours. After the reaction period the volatiles were removed and the residue extracted and filtered using hexane. Removal of the hexane resulted in the isolation of the desired product as a solid. (7.69 g, 97.0 percent).
Reaction SMILES: Cl.[C@H:2]12[CH2:8][C@H:5]([O:6][CH2:7]1)[CH2:4][NH:3]2.[Br:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Br)=[CH:12][CH:11]=1.C(N(CC)CC)C>CN(C)C=O>[Br:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][N:3]2[CH2:4][C@@H:5]3[CH2:8][C@H:2]2[CH2:7][O:6]3)=[CH:12][CH:11]=1
Reactant: C1O[C@@H]2CN[C@H]1C2
Reactant: BrCc1ccc(Br)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Brc1ccc(CN2C[C@@H]3C[C@H]2CO3)cc1
Yield: 76.7 %

Procedure:
(1S,4S)-(+)-2-Aza-5-oxabicyclo[2.2.1]heptane hydrochloride (1.26 g), 4-bromobenzyl bromide (2.32 g) and triethylamine (3.88 ml) were stirred in dimethylformamide (30 ml) for 18 h. The mixture was partitioned between diethyl ether (60 ml) and water (60 ml) and the organic phase was washed further with water (60 ml), dried (MgSO4), concentrated in vacuo and purified by Bondelute® chromatography, eluting with 0-100% ethyl acetate/iso-hexane to give the product as an orange oil (1.91 g).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[C:11]([CH3:12])=[CH:10][NH:9][CH:8]=1)=[O:6].Cl[C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][N:15]=1.O>CN(C)C=O>[C:14]1([N:9]2[CH:10]=[C:11]([CH3:12])[C:7]([C:5]([O:4][CH3:3])=[O:6])=[CH:8]2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][N:15]=1
Reactant: COC(=O)c1c[nH]cc1C
Reactant: Clc1nccc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cn(-c2nccc3ccccc23)cc1C
Temperature: 40 °C
Reaction time: 0.3 h

Procedure:
0.208 g (6.5 mmol) of sodium hydride, at 75% by weight in liquid petroleum jelly, is added at a temperature in the region of 20° C. under an argon atmosphere to a solution of 0.903 g (6.5 mmol) of 3-methoxycarbonyl-4-methyl-1H-pyrrole in 20 mL of dimethylformamide. After stirring at a temperature in the region of 40° C. for 0.3 hour, 1.07 g (6.5 mmol) of 1-chloroisoquinoline and 10 mL of dimethylformamide are added. After stirring at a temperature in the region of 120° C. for 4 hours, the reaction mixture is poured into 200 mL of salt water and then extracted with 100 mL of ethyl acetate. The organic phase is partially concentrated under reduced pressure. 100 mL of salt water are added to the residue, which is then extracted with 50 mL of ethyl acetate. The organic phase is dried over anhydrous magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) to give a solid which is purified by silica gel chromatography [eluent: cyclohexane/dichloromethane/ethyl acetate (60/36/4 by volume)]. After concentrating the fractions under reduced pressure (2.7 kPa), 1.5 g of 1-(isoquinol-1-yl)-3-methoxycarbonyl-4-methyl-1H-pyrrole are obtained. Mass spectrum (EI): m/e 266 (M+.), m/e 235.
Reaction SMILES: [N-]=[C:2]=[O:3].CC(OI1(OC(C)=O)(OC(C)=O)O[C:15](=O)[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]1=2)=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl.CCOC(C)=O>[C:15]1([C:14]2([CH:2]=[O:3])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]2)[CH:11]=[CH:10][CH:9]=[CH:14][CH:13]=1
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Reactant: [N-]=C=O
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=CC1(c2ccccc2)CCCCC1
Reaction time: 2 h
Yield: 150.3 %

Procedure:
To compound 2 (5.0 g, 26.3 mmol) in CH2Cl2 (50 mL) was added 13.4 g (31.6 mmol) of Dess-Martin periodinane. After 2 h, sodium thiosulfate (58 g) followed by sat. NaHCO3 (200 mL) was added. After stirring for 1 h, the reaction mixture was diluted with EtOAc then washed with H2O, brine and dried over anhydrous sodium sulfate. Purification by flash chromatography (3:1, hexane-EtOAc) gave 1-phenyl-cyclohexanecarbaldehyde (4.47 g, 90%) as a colorless oil. Mass Spec [M+H]+=189.1.
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:6]=1[C:7]1[C:8](=[O:18])[CH2:9][CH2:10][CH2:11][C:12]=1[NH:13]2)([O:3][CH3:4])=[O:2].[CH:19]1[CH:24]=[C:23]([F:25])[C:22]([F:26])=[C:21]([CH2:27]Br)[CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[F:26][C:22]1[C:23]([F:25])=[CH:24][CH:19]=[CH:20][C:21]=1[CH2:27][N:13]1[C:12]2[CH2:11][CH2:10][CH2:9][C:8](=[O:18])[C:7]=2[C:6]2[C:14]1=[CH:15][CH:16]=[CH:17][C:5]=2[C:1]([O:3][CH3:4])=[O:2]
Reactant: Fc1cccc(CBr)c1F
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CCC3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2c1c1c(n2Cc2cccc(F)c2F)CCCC1=O
Temperature: 25 °C
Reaction time: 73 h
Yield: 70.4 %

Procedure:
A suspension of 5-carbomethoxy-1,2-dihydro-9H-carbazol-4(3H)-one (973 mg, 4.0 mM), a-bromo-2,3-difluorotoluene (1.01 g, 4.8 mM), and potassium carbonate (553 mg, 4.0 mM) in 10 mL DMF was stirred at room temperature for 73 hours. The mixture was diluted with ethyl acetate, washed with H2O, 1 N HCl, H2O, saturated NaHCO3, H2O, and saturated brine, dried over anhydrous magnesium sulfate, filtered, concentrated. The residue was purified by column chromatography on silica gel (elution with methylene chloride/ethyl acetate) to afford 1.04 g (70%) of the 9-[(2,3-difluorophenyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one as a tan solid. 1H NMR (CDCl3) δ 7.4 (d, 1H, J=8 Hz), 7.35 (d, 1H, J=8 Hz), 7.15-6.9 (m, 5H), 6.35 (t, 1H, J=8 Hz), 5.4 (s, 2H), 4.05 (s, 3H), 2.9 (t, 2H, J=6 Hz), 2.6 (t, 2H, J=6 Hz), and 2.25 (m, 2H). IR (KBr, cm−1) 1719 and 1650. MS (ES) m/e 368, 370.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:12][C@H:11]([C:13]([OH:15])=[O:14])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:10][C@H:11]([C:13]([O:15][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:14])[CH2:12]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](C(=O)O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1C[C@H](C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A suspension of trans-3-(tert-butoxycarbonylamino)cyclobutanecarboxylic acid (0.5 g, 2.323 mmol) and potassium carbonate (0.321 g, 2.323 mmol) in dimethylformamide (2.323 ml) was treated with (bromomethyl)benzene (0.401 g, 2.346 mmol) added from a syringe over 3 minutes. The reaction mixture was stirred at room temperature for 17 hours and water was added. The suspension was filtered and the solid collected was washed with water and dried under vacuum to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([CH2:34][C:35]1[NH:44][C:43](=[O:45])[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[N:36]=1)(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[S:31]([CH2:34][C:35]3[NH:44][C:43](=[O:45])[C:42]4[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=4)[N:36]=3)(=[O:33])=[O:32])=[CH:7][C:2]=2[F:1])=[CH:18][N:19]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Reactant: O=c1[nH]c(CS(=O)(=O)c2ccccc2Br)nc2ccccc12
Product: Nc1ncc(-c2ccc(-c3ccccc3S(=O)(=O)Cc3nc4ccccc4c(=O)[nH]3)cc2F)cn1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 6 utilizing 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrimidin-2-amine and 2-(((2-bromophenyl)sulfonyl)methyl)quinazolin-4(3H)-one. MS (ESI): mass calcd. for C25H18FN5O3S, 487.11; m/z found, 487.9 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 12.36 (s, 1H), 8.60-8.43 (d, J=1.4, 2H), 8.12-8.02 (dd, J=8.0, 1.5, 1H), 7.96-7.89 (dd, J=8.0, 1.3, 1H), 7.84-7.71 (m, 2H), 7.66-7.42 (m, 4H), 7.42-7.22 (m, 3H), 6.91 (s, 2H), 4.37 (s, 2H).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]3[C:20]([NH2:21])=[CH:19][CH:18]=[CH:17][N:16]=3)[CH2:11][CH2:10]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](Cl)=[O:27]>CN(C)C=O>[Cl:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26]([NH:21][C:20]1[C:15]([N:12]2[CH2:11][CH2:10][CH:9]([CH2:8][CH2:7][N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[CH2:14][CH2:13]2)=[N:16][CH:17]=[CH:18][CH:19]=1)=[O:27]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: Nc1cccnc1N1CCC(CCN2CCCCC2)CC1
Solvent: CN(C)C=O
Product: O=C(Nc1cccnc1N1CCC(CCN2CCCCC2)CC1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 35.1 %

Procedure:
To a solution of 0.029 g (0.10 mmol) of 4-(2-piperidin-1-yl-ethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-ylamine in N,N-dimethylformamide (1 mL) is added 0.017 g (0.10 mmol) of 3-chlorobenzoyl chloride. The mixture is stirred at room temperature for 6 hours and then purified by preparative reverse phase HPLC to provide 0.015 g (35%) of the title compound (44) as a colorless solid. [M+H]+=427.1.
Reaction SMILES: [F:1][C:2]1([F:17])[CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][CH2:5][N:4]([CH3:16])[CH2:3]1.O1CCOCC1.[Cl:24]CCl>Cl>[F:1][C:2]1([F:17])[CH2:3][N:4]([CH3:16])[CH2:5][CH2:6][NH:7][CH2:8]1.[ClH:24]
Reactant: CN1CCN(C(=O)OC(C)(C)C)CC(F)(F)C1
Reactant: ClCCl
Agent: Cl
Solvent: C1COCCO1
Product: CN1CCNCC(F)(F)C1
Temperature: 20 °C
Reaction time: 21 h

Procedure:
Combined a solution of tert-butyl 6,6-difluoro-4-methyl-1,4-diazepane-1-carboxylate (50 mg, 0.200 mmol) in dichloromethane (2 mL) and 4 M HCl in dioxane (0.4 mL, 1.6 mmol) and the solution stirred at 20° C. for 21 h. The reaction was then concentrated in vacuo to give the title compound as a hydrochloride acid salt which was used without further purification. MS: 151 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([OH:13])=O)[NH:8][C:5]2=[CH:6][N:7]=1.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.Cl.[CH2:33]([O:35][C:36](=[O:47])[CH:37]([NH2:46])[C:38](=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH3:34].CN1CCOCC1>C1COCC1>[CH2:33]([O:35][C:36](=[O:47])[CH:37]([NH:46][C:11]([C:9]1[NH:8][C:5]2=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]2[CH:10]=1)=[O:13])[C:38](=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH3:34]
Reactant: CCOC(=O)C(N)C(=O)c1ccccc1
Reactant: O=C(O)c1cc2cc(Cl)ncc2[nH]1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CCOC(=O)C(NC(=O)c1cc2cc(Cl)ncc2[nH]1)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (100 mg, 0.51 mmol) and 4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride (DMTMM) (183 mg, 0.66 mmol) were dissolved in THF (20 ml). After 5 min, 2-amino-3-oxo-3-phenylpropionic acid ethyl ester hydrochloride (Tetrahedron Lett., 1993, 34(2), 211–214; 124 mg, 0.51 mmol) and 4-methylmorpholine (56 μl, 0.51 mmol) were added and the reaction mixture stirred at rt for 72 h. The solvent was removed in vacuo and the residue partitioned between water (40 ml) and EtOAc (3×30 ml). The combined organics were dried (MgSO4), concentrated in vacuo and purified by chromatography on silica gel eluting with methanol:dichloromethane (1:19). This material was further triturated with methanol:diethyl ether (1:19) to give the title compound as a pale yellow solid. m/z (ES+)=386 [M+H]+; RT=3.56 min.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH:10]1[CH2:14][CH2:13][CH:12]([O:15][C:16]([N:18]2[CH2:23][CH2:22][CH:21]([O:24][C:25]3[CH:30]=[C:29]([N:31]4[C:39]5[C:34](=[CH:35][C:36]([S:40]([CH3:43])(=[O:42])=[O:41])=[CH:37][CH:38]=5)[CH2:33][CH2:32]4)[N:28]=[CH:27][N:26]=3)[CH2:20][CH2:19]2)=[O:17])[CH2:11]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.C(Cl)Cl>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][N:10]1[CH2:14][CH2:13][CH:12]([O:15][C:16]([N:18]2[CH2:23][CH2:22][CH:21]([O:24][C:25]3[CH:30]=[C:29]([N:31]4[C:39]5[C:34](=[CH:35][C:36]([S:40]([CH3:43])(=[O:42])=[O:41])=[CH:37][CH:38]=5)[CH2:33][CH2:32]4)[N:28]=[CH:27][N:26]=3)[CH2:20][CH2:19]2)=[O:17])[CH2:11]1
Reactant: CS(=O)(=O)c1ccc2c(c1)CCN2c1cc(OC2CCN(C(=O)OC3CCNC3)CC2)ncn1
Reactant: O=Cc1ccccc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc2c(c1)CCN2c1cc(OC2CCN(C(=O)OC3CCN(Cc4ccccc4F)C3)CC2)ncn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Fluoro-benzaldehyde (11 μL, 0.1 mmol) was dissolved in 1 mL of DCE with 21b (49 mg, 0.1 mmol) and NaBH(OAc)3 (30 mg, 0.14 mmol). The mixture was stirred for 8 h at room temperature then was diluted with DCM and quenched with saturated NaHCO3. The organic layer was washed with saturated NaHCO3 followed by brine. The organic layer was dried, filtered and evaporated. The residue was purified by preparative HPLC to afford 21-1, LCMS 596.2 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1.[CH:13]1([CH3:25])[CH2:18][CH2:17][CH:16]([CH:19]([CH3:21])[CH3:20])[CH:15]([C:22](Cl)=[O:23])[CH2:14]1.C(Cl)Cl.Cl>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH:7][C:22]([CH:15]2[CH2:14][CH:13]([CH3:25])[CH2:18][CH2:17][CH:16]2[CH:19]([CH3:21])[CH3:20])=[O:23])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Reactant: CC1CCC(C(C)C)C(C(=O)Cl)C1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(NC(=O)C2CC(C)CCC2C(C)C)c([N+](=O)[O-])c1
Temperature: 50 °C
Reaction time: 6 h
Yield: 81.4 %

Procedure:
4-Methoxy-2-nitroaniline (5 g, 0.018 mol) was dissolved in pyridine (50) and treated with menthoyl chloride (3.57 g, 0.018 mol). The reaction mixture was heated to 50° C. and stirred vigorously for 6 h. The reaction mixture was cooled to room temperature and poured into a mixture of CH2Cl2 (100 mL) and 1N HCl (100 mL)). The heterogeneous mixture was transferred to a reparatory funnel where the aqueous phase was separated and re-extracted with CH2Cl2 (2×100 mL). The organic phases were combined and washed with 1N HCl (8×100 mL), H2O (1×100 mL), 1N NaOH (2×100 mL), brine (100 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (20 to 50% ethyl acetate/hexane for elution) provided the title compounds as colorless solid (4.9 g, 83%).