Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC(N(C)C)=C(C)C.[Si:9]([O:16][C@@H:17]([CH2:21][O:22][CH:23]1[CH2:26][CH2:25][CH2:24]1)[C:18]([OH:20])=O)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].N1C=CC=CC=1.[CH3:33][C:34]1[CH:35]=[CH:36][C:37]([NH2:40])=[N:38][CH:39]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[Si:9]([O:16][C@@H:17]([CH2:21][O:22][CH:23]1[CH2:26][CH2:25][CH2:24]1)[C:18]([NH:40][C:37]1[CH:36]=[CH:35][C:34]([CH3:33])=[CH:39][N:38]=1)=[O:20])([C:12]([CH3:13])([CH3:14])[CH3:15])([CH3:10])[CH3:11]
Reactant: Cc1ccc(N)nc1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](COC1CCC1)C(=O)O
Agent: CC(C)=C(Cl)N(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(NC(=O)[C@H](COC2CCC2)O[Si](C)(C)C(C)(C)C)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.8 %

Procedure:
1-Chloro-N,N,2-trimethylprop-1-en-1-amine (0.133 mL, 1.00 mmol) was added to a stirred solution of (S)-2-(tert-butyldimethylsilyloxy)-3-cyclobutoxypropanoic acid (Intermediate R4) (250 mg, 0.91 mmol) in DCM (5 mL) at room temperature under nitrogen. The resulting solution was stirred at room temperature for 30 minutes. Pyridine (0.147 mL, 1.82 mmol) was added followed by a solution of 5-methylpyridin-2-amine (108 mg, 1.00 mmol) in DCM (5 mL) and the resulting solution was stirred at ambient temperature for 1 hour. 1M citric acid (10 mL) and DCM (50 mL) were added and the phases were separated. The organic phase washed with water (10 mL) and brine (10 mL), dried (MgSO4), filtered and evaporated. The crude product was purified by flash silica chromatography, eluting with 0 to 30% ethyl acetate in isohexane to afford the product (195 mg, 58.7%). 1H NMR (400 MHz, DMSO) δ 0.01 (d, 6H), 0.80 (s, 9H), 1.24-1.37 (m, 1H), 1.43-1.53 (m, 1H), 1.59-1.72 (m, 2H), 1.94-2.06 (m, 2H), 2.13 (s, 3H), 3.33-3.44 (m, 2H), 3.77-3.87 (m, 1H), 4.29-4.34 (m, 1H), 7.49-7.54 (m, 1H), 7.86 (d, 1H), 8.02-8.06 (m, 1H), 9.25 (s, 1H); m/z (ESI+) (M+H)+=365.47; HPLC tR=3.60 min.
Reaction SMILES: C(N=C(N(C)C)N(C)C)(C)(C)C.Br[CH2:14][CH:15]([CH3:17])[CH3:16].[F:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[N:30]=2)(=[O:27])=[O:26])=[CH:21][CH:20]=1>C(#N)C>[F:18][C:19]1[CH:20]=[CH:21][C:22]([S:25]([N:28]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[N:30]=2)(=[O:27])=[O:26])=[CH:23][CH:24]=1
Reactant: CC(C)CBr
Reactant: COc1cccc(NS(=O)(=O)c2ccc(F)cc2)n1
Agent: CN(C)C(=NC(C)(C)C)N(C)C
Solvent: CC#N
Product: COc1cccc(N(CC(C)C)S(=O)(=O)c2ccc(F)cc2)n1
Temperature: 150 °C
Reaction time: 0.25 h
Yield: 63.8 %

Procedure:
A mixture of 2-(tert-butyl)-1,1,3,3-tetramethylguanidine (0.121 ml, 0.581 mmol), 1-bromo-2-methylpropane (0.126 ml, 1.162 mmol) and 4-fluoro-N-(6-methoxypyridin-2-yl)benzenesulfonamide (164 mg, 0.581 mmol) was prepared and dissolved in acetonitrile (4 mL). The reaction was heated by microwaves to 150° C. for 30 minutes, then again for a further 15 minutes. After cooling the reaction was quenched with sodium hydroxide in ethanol and concentrated in vacuo. The product was extracted to the organic phase of an acidic work up between ethyl acetate and 5% citric acid. The organic phase was dried by passing through a hydrophobic frit, concentrated in vacuo and purified by flash silica (Si) chromatography (0-25% ethyl acetate-cyclohexane gradient), to give the title compound (125.5 mg). LCMS (2 min, formic) Rt 1.33 min, m/z (ES+) 339 (M+H).
Reaction SMILES: CO.[OH-].[K+].[Cl:5][C:6](Cl)([Cl:22])[CH:7]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)[C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.Cl>O>[Cl:5][C:6]([Cl:22])=[C:7]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)[C:8]1[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=1
Reactant: Oc1ccc(C(c2ccc(O)cc2)C(Cl)(Cl)Cl)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Oc1ccc(C(=C(Cl)Cl)c2ccc(O)cc2)cc1
Temperature: 20 °C

Procedure:
A 4-necked 5-liter flask, equipped with a mechanical stirrer, a thermometer, and a condenser, is charged with methanol (800 g). Potassium hydroxide (440 g) is added in portions to the methanol solution. After the addition, the solution is cooled to 20° C. To this stirring solution, 1,1,1-trichloro-2,2-bis(4-hydroxyphenyl)ethane (420 g) is added in portions. The reaction temperature is kept below 40° C. After the addition, the temperature is raised to 50° C. and maintained for 2.5 hours. The reaction mixture is cooled to 20° C. and neutralized with 25% HCl solution. After the neutralization, the mixture is heated to reflux and water (480 g) is added. The mixture is allowed to cool to the room temperature. The precipitates are filtered and dried to afford 1,1-dichloro-2,2-bis(4-hydroxyphenyl)ethene as white solids with slight tan color.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH:10]2[CH2:15][CH:14]3[CH2:16][CH:11]2[CH:12]=[CH:13]3)=[CH:4][CH:3]=1.CCCCC.[C:22]1([P:28]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[Si](C)(C)C)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1(C)C=CC=CC=1.CC#N.CC#N.Cl[Pd]Cl>[CH:11]12[CH2:16][CH:14]([CH:13]=[CH:12]1)[CH2:15][CH:10]2[CH2:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([P:28]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:3][CH:4]=1
Reactant: C[Si](C)(C)P(c1ccccc1)c1ccccc1
Reactant: Ic1ccc(OCC2CC3C=CC2C3)cc1
Agent: Cl[Pd]Cl
Solvent: CCCCC
Solvent: CC#N
Solvent: Cc1ccccc1
Product: C1=CC2CC1CC2COc1ccc(P(c2ccccc2)c2ccccc2)cc1
Temperature: 70 °C
Yield: 14.7 %

Procedure:
Bis(acetonitrile)dichloropalladium(II) (1 mmol) was placed in a Schlenk flask, stoppered with a septum and evacuated and purged with nitrogen three times. To this flask was then added a solution of 8 (0.038 mol) in 100 mL of anhydrous toluene and 9.6 g of diphenyl(trimethylsilyl)phosphine. The resulting deep purple solution was heated at 70° C. overnight, then cooled to room temperature and the solvent evaporated under reduced pressure. The residue was chromatographed on a column of silica gel using first hexane and then 9:1 hexane ethyl acetate as eluent to collect the product. After evaporation of the solvent, the product 9 (10 g), a mixture of endo and exo isomers, was obtained as white gummy material. Addition of 50 mL of hot pentane to this compound resulted in the separation of white crystalline compound (2.1 g). 1H NMR (500 MHz, 25° C., CDCl3): δ (endo isomer, ˜85%) 7.30 (m, 12H, Ar—H), 6.88 (m, 2H, Ar—H), 6.18 (m, 1H, olefinic), 5.98 (m, 1H, olefinic), 3.72 (m, 1H, nor-CH2), 3.57 (m 1H, nor-CH2), 3.04 (br s 1H), 2.88 (br s, 1H), 2.53 (m, 1H), 1.92 (m, 1H), 1.51 (d, |J|=8.0 Hz), 1.32 (d, |J|=8.2 Hz, 1H), 0.65 (m, 1H); (exo isomer, partial) 6.92 (m, 2H, Ar—H), 4.05 (m, 1H), 3.88 (m, 1H). 31P {1H} NMR (200 MHz, 25° C., CDCl3): δ −6.57
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:17]=[C:18]([CH2:22][C:23]([O:25]C)=[O:24])[CH:19]=[CH:20][CH:21]=2)=[C:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[S:6]1(=[O:34])=[O:33])([CH3:4])([CH3:3])[CH3:2].[Li+].[I-].CCOC(C)=O>N1C=CC=CC=1>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:17]=[C:18]([CH2:22][C:23]([OH:25])=[O:24])[CH:19]=[CH:20][CH:21]=2)=[C:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[S:6]1(=[O:33])=[O:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)Cc1cccc(OCCCNC2=C(c3ccccc3)S(=O)(=O)N(C(C)(C)C)C2=O)c1
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)(C)N1C(=O)C(NCCCOc2cccc(CC(=O)O)c2)=C(c2ccccc2)S1(=O)=O
Temperature: 120 °C
Yield: 39 %

Procedure:
A mixture of methyl (3-{3-[(2-tert-butyl-1,1-dioxido-3-oxo-5-phenyl-2,3-dihydroisothiazol-4-yl)amino]propoxy}phenyl)acetate (Example 21) (0.087 g, 0.179 mmol) and LiI (0.239 g, 1.788 mmol) in pyridine (2 ml) was heated at 120° C. for 18 h. EtOAc was added and the mixture was washed with 1N HCl, evaporated to dryness and the residue was purified by silica gel column chromatography (Horizons Biotage) using 0-12% MeOH (+1% AcOH) in EtOAc as eluent to give the title compound (0.033 g, 39%). 1H NMR (500 MHz CDCl3): δ 7.54-7.46 (m, 2H), 7.45-7.40 (m, 3H), 7.25 (t, 1H), 6.89 (dd, 1H), 6.82-6.75 (m, 2H), 5.73 (t, 1H), 3.87 (t, 2H), 3.63 (s, 2H), 3.10-3.04 (m, 2H), 1.87-1.79 (m, 2H), 1.74 (s, 9H); 13C NMR (125 MHz CDCl3): δ 176.7, 159.8, 158.7, 135.4, 135.0, 131.8, 129.9, 129.8, 128.8, 125.3, 122.4, 115.7, 113.6, 107.2, 65.9, 61.7, 42.3, 41.2, 29.0, 27.8; Mass Spectrum: M2H+ 472.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[O:8][C:7]2([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[O:6][CH:5]1[CH:14]=[N:15][OH:16].[Cl:17]N1C(=O)CCC1=O>CN(C=O)C>[OH:16][N:15]=[C:14]([Cl:17])[C@H:5]1[C@H:4]([CH2:3][O:2][CH3:1])[O:8][C:7]2([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[O:6]1
Reactant: COCC1OC2(CCCCC2)OC1C=NO
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: COC[C@@H]1OC2(CCCCC2)O[C@H]1C(Cl)=NO
Temperature: 25 °C
Yield: 93.1 %

Procedure:
3-(Methoxymethyl)-1,4-dioxaspiro[4.5]decane-2-carbaldehyde oxime (33.2 g, 145 mmol) was dissolved in DMF (600 mL) and cooled in an ice bath. 1-Chloropyrrolidine-2,5-dione (19.3 g, 145 mmol) was added and the reaction allowed to slowly warm to ambient temperature overnight. Most of the DMF was removed under reduced pressure and the remaining material was partitioned between water and EtOAc. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated to afford (2R,3S)-N-hydroxy-3-(methoxymethyl)-1,4-dioxaspiro[4.5]decane-2-carbimidoyl chloride (35.6 g, 135 mmol, 93.2% yield) which was taken forward without further purification.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[S:10][C:11]([Cl:14])=[CH:12][CH:13]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li]C(CC)C.S([N:30]=[N+:31]=[N-:32])(C1C=CC(C)=CC=1)(=O)=O>O1CCCC1>[N:30]([C:13]1[CH:12]=[C:11]([Cl:14])[S:10][C:9]=1[S:6]([NH:5][C:1]([CH3:4])([CH3:2])[CH3:3])(=[O:7])=[O:8])=[N+:31]=[N-:32]
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(Cl)s1
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CC(C)(C)NS(=O)(=O)c1sc(Cl)cc1N=[N+]=[N-]
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
A solution of Example 311A (1.01 g, 3.99 mmol) in tetrahydrofuran (32 mL) at −78° C. was treated with dropwise addition of sec-BuLi (1.4 M in hexane, 2.1 equivalents). The reaction was warmed to −20° C. and stirred for 30 minutes, treated with a solution of tosyl azide (1.1 equivalent) in tetrahydrofuran (7 mL) at −20° C., stirred at 25° C. for 18 hours. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel, eluting with a gradient of 30% dichloromethane in hexane to 100% dichloromethane to give approximately a 2:1 mixture of starting material to the title compound.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9])=[O:4].[F:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.CN(C=O)C.[OH-].[K+]>O>[F:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][CH2:2][C:3]([NH:5][C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[C:8]([OH:10])=[O:9])=[O:4])=[CH:18][CH:17]=1
Reactant: O=C(CBr)Nc1ccccc1C(=O)O
Reactant: Nc1ccc(F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CNc1ccc(F)cc1)Nc1ccccc1C(=O)O
Yield: 89.3 %

Procedure:
A solution of 2-(N-bromoacetylamino)benzoic acid from Example 79 (8.00 g, 31.0 mmol), para-fluoroaniline (7.34 mL, 77.5 mmol) and DMF (80 mL) was heated to 75° C. for 8 h. The mixture was cooled, poured over H2O (1 L) and 5% KOH (300 mL) and washed with CH2Cl2 (3×300 mL). The aqueous layer was acidified to pH 2 with 2 N HCl, cooled below room temperature and filtered. The filter cake was rinsed with water (60 mL) and dried under high vacuum at 45° C. to yield 7.98 g (89%) of the title compound as an off-white solid; 1H NMR (DMSO-d6) δ 13.45 (broad s, 1H), 12.00 (s, 1H), 8.72 (d, J=8, 1H), 7.94 (dd, J=8, J=1.2, 1H), 7.59 (td, J=7.2, J=1.6, 1H), 7.13 (td, J=7.2, J=0.8, 1H), 6.95 (m, 2H), 6.58 (m, 2H), 6.47 (s, 1H), 3.82 (s, 2H); 13C NMR (DMSO-d6) δ 170.73, 169.04, 154.95 (J=232.0), 144.78, 140.54, 134.15, 131.13, 122.69, 119.43, 116.00, 115.38 (J=21.9), 113.22 (J=7.6), 49.31.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][CH:9]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH2:8][C@H:7]1[CH2:19]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:5])[CH3:2].[F:31][C:32]1[CH:37]=[CH:36][C:35]([CH:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)=[CH:34][CH:33]=1.[I-].[Na+].C(N(CC)CC)C>CN(C)C=O>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C@@H:9]([O:11][Si:12]([C:15]([CH3:16])([CH3:17])[CH3:18])([CH3:14])[CH3:13])[CH2:8][C@H:7]1[CH2:19][N:41]1[CH2:42][CH2:43][CH:38]([C:35]2[CH:34]=[CH:33][C:32]([F:31])=[CH:37][CH:36]=2)[CH2:39][CH2:40]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CC(O[Si](C)(C)C(C)(C)C)C[C@H]1COS(=O)(=O)c1ccc(C)cc1
Reactant: Fc1ccc(C2CCNCC2)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CN1CCC(c2ccc(F)cc2)CC1
Yield: 40.8 %

Procedure:
A solution of (1R,2R)-4-(tert-Butyl-dimethyl-silanyloxy)-2-(toluene-4-sulfonyloxymethyl)-cyclopentanecarboxylic acid ethyl ester (example 148, step 1, epimeric mixture, 410 mg), 4-(4-Fluoro-phenyl)-piperidine (cas # 6716-98-9, 291 mg), sodium iodide (1.36 g) and triethylamine (545 mg) in N,N-dimethylformamide (2.8 mL) was stirred at 90° C. over 6 h. The reaction mixture was partitioned between ethyl acetate and an aqueous saturated solution of sodium hydrogenocarbonate. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel with a gradient of cyclohexane/ethyl acetate (9:1 to 1:1 v/v) as eluant to afford the title compound (170 mg, 41%) as a yellow liquid. MS (EI): 464.4 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH3:30])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N:16]=C(C2C=CC=CC=2)C2C=CC=CC=2)[CH:11]=1)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[NH2:7][CH:8]([CH3:30])[CH2:9][C:10]1[CH:11]=[C:12]([NH2:16])[CH:13]=[CH:14][CH:15]=1
Reactant: CC(Cc1cccc(N=C(c2ccccc2)c2ccccc2)c1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(N)Cc1cccc(N)c1
Reaction time: 0.33 h

Procedure:
A solution {2-[3(Benzhydrylidene-amino)-phenyl]-1-methyl-ethyl}-carbamic acid tert-butyl ester (200 mg, 0.48 mmol) in dichloromethane (5 mL) and trifluoroacetic acid (5 mL) was stirred for 45 min at room temperature. Solvents removed under vacuum and residue suspended in 5 N hydrochloric acid at 60° C. for 20 min. Biphasic system washed with ether and organics discarded. The pH of the aqueous layer was then adjusted to 14 with 10 N sodium hydroxide. Aqueous was then washed three times with dichloromethane (10 mL). Combined organics dried over magnesium sulfate, and product isolated as an amber film after removal of solvent under vacuum. M+1=151.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]1.C(O)C.Cl.[NH2:20][OH:21]>C(N(CC)CC)C>[OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH2:13][C:12](=[N:20][OH:21])[CH2:11][CH2:10]1
Reactant: NO
Reactant: O=C1CCC(c2ccc(O)cc2O)CC1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: ON=C1CCC(c2ccc(O)cc2O)CC1
Yield: 98.7 %

Procedure:
To a round bottomed flask, equipped with magnetic stirrer was added 4-(2,4-dihydroxyphenyl)cyclohexanone (100 mg, 0.49 mmol), anhydrous ethanol (5 ml), triethylamine (102 ml) and hydroxylamine hydrochloride (51 mg, 0.73 mmol). The reaction mixture was heated under reflux for 3 hr, then evaporated in vacuo. The resulting solid was purified by flash column chromatography, (SiO2, ethyl acetate/petroleum ether, 35:65, v/v), furnishing the title compound as short white needles (107 mg, 100%). δH (CD3OD) 1.44-1.61 (2H, m), 1.81-1.88 (1H, m), 1.94-2.00 (2H, m), 2.19-2.27 (1H, m), 2.43 (1H, d), 3.04-3.10 (1H, m), 3.38 (1H, m), 6.22-6.25 (1H, m), 6.28 (1H, d), 6.84-6.86 (1H, m); m/z (EI−) 220.
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]4[C:26]([C:27]5[C:28]([CH3:45])=[C:29]([NH:33][CH2:34][C:35]6[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][C:36]=6[C:37](O)=[O:38])[CH:30]=[CH:31][CH:32]=5)=[CH:25][N:24]=[C:23]([C:46](=[O:48])[NH2:47])[C:19]=4[NH:20]3)=[CH:16][CH:15]=2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.CCOC(C)=O>[Si:1]([O:8][CH:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]4[C:26]([C:27]5[CH:32]=[CH:31][CH:30]=[C:29]([N:33]6[CH2:34][C:35]7[C:36](=[CH:40][C:41]([Cl:44])=[CH:42][CH:43]=7)[C:37]6=[O:38])[C:28]=5[CH3:45])=[CH:25][N:24]=[C:23]([C:46]([NH2:47])=[O:48])[C:19]=4[NH:20]3)=[CH:16][CH:15]=2)[CH2:10]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: Cc1c(NCc2ccc(Cl)cc2C(=O)O)cccc1-c1cnc(C(N)=O)c2[nH]c3cc(N4CCC(O[Si](C)(C)C(C)(C)C)C4)ccc3c12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1c(-c2cnc(C(N)=O)c3[nH]c4cc(N5CCC(O[Si](C)(C)C(C)(C)C)C5)ccc4c23)cccc1N1Cc2ccc(Cl)cc2C1=O
Temperature: 25 °C
Yield: 44.7 %

Procedure:
A solution of 2-((3-(7-(3-(tert-butyldimethylsilyloxy)pyrrolidin-1-yl)-1-carbamoyl-9H-pyrido[3,4-b]indol-4-yl)-2-methylphenylamino)methyl)-5-chlorobenzoic acid (0.104 g, 0.152 mmol), DIPEA (0.080 mL, 0.456 mmol), N-methylmorpholine (0.134 mL, 1.216 mmol) and BOP (0.175 g, 0.395 mmol) in DMF (1.520 mL) under nitrogen was heated at 45° C. for 1 h. The reaction was cooled to room temperature, dissolved in EtOAc (100 mL) and washed with water (3×25 mL) and brine (25 mL), dried over MgSO4, filtered and concentrated in vacuo to give a residue which was purified by flash chromatography using an ISCO 12 g column eluting with 0-20 EtOAc/hexanes. Appropriate fractions were collected and concentrated in vacuo to give the desired product (0.0456 g, 0.068 mmol, 45.0% yield) as a light orange solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[C:10]=1Br.[Li]CCCC.CN(CCN(C)C)C.[CH:37]1[CH:42]=[C:41]([CH:43]=[O:44])[N:40]=[CH:39][CH:38]=1>CCOCC>[N:40]1[CH:39]=[CH:38][CH:37]=[CH:42][C:41]=1[CH:43]([C:10]1[C:9]([CH2:8][O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:15][O:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1)[OH:44]
Reactant: O=Cc1ccccn1
Reactant: Brc1c(COC2CCCCO2)cccc1COC1CCCCO1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Product: OC(c1ccccn1)c1c(COC2CCCCO2)cccc1COC1CCCCO1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 72.6 %

Procedure:
To a solution of 2,6-di(tetrahydro-2H-2-pyranyloxymethyl)-phenyl bromide (15.5 g, 39 mmol) in ether at -30° C. was added n-BuLi (2.5M, 16.4 ml, 41 mmol) and the mixture was allowed to warm to room temperature and stirred for 1.5 hours. The mixture was cooled to 0° C., and TMEDA (4.56 g, 37 mmol) was added, and the resulting mixture was cooled to -50° C. After stirring for 20 minutes, 2-pyridylcarboxaldehyde (6.31 g, 58 mmol) was added. The above mixture was warmed to room temperature over a period of 2 hours, quenched with saturated sodium bicarbonate, and diluted with ethyl acetate with stirring. The organic layer was washed with brine and concentrated in vacuo to afford 11.7 g (73%) of 1-(2-pyridyl)-1-[2,6-di(tetrahydro-2H-2-pyranyloxymethyl)phenyl]-methanol as an oil.
Reaction SMILES: [CH2:1]([N:4]1[CH2:10][CH:9]([CH3:11])[C:8](=[O:12])[NH:7][C:6]2[CH:13]=[N:14][C:15]([Cl:17])=[N:16][C:5]1=2)[CH:2]=[CH2:3].I[CH3:19].[H-].[Na+]>CN(C)C=O>[CH2:1]([N:4]1[CH2:10][CH:9]([CH3:11])[C:8](=[O:12])[N:7]([CH3:19])[C:6]2[CH:13]=[N:14][C:15]([Cl:17])=[N:16][C:5]1=2)[CH:2]=[CH2:3]
Reactant: C=CCN1CC(C)C(=O)Nc2cnc(Cl)nc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCN1CC(C)C(=O)N(C)c2cnc(Cl)nc21
Reaction time: 2 h
Yield: 100.3 %

Procedure:
To a mixture of 1.37 g (0.00542 mole) of (rac)-9-allyl-2-chloro-7-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-65), 0.51 mL (0.00813 mole) of iodomethane and 15 mL of N,N-dimethyl-formamide at 0 degrees, was added 0.33 g (0.00813 mole) of 60% oil dispersion of sodium hydride. The mixture was stirred at 0 degrees for 2 hours and then partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed successively with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with hexanes-ethyl acetate (100:0-60:40) to give 1.45 g of (rac)-9-allyl-2-chloro-5,7-dimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-65). HRMS (ES+) m/z Calcd for C12H15CIN4O+H [(M+H)+]: 267.1007. Found: 267.1007.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([O:14]C)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(O)(=O)C.Br>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(-c2cccc(Cl)c2)cc1
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: Oc1ccc(-c2cccc(Cl)c2)cc1
Yield: 76.9 %

Procedure:
A mixture of 3'-chloro-4-methoxybiphenyl (2.00 g), acetic acid (25 ml) and concentrated hydrobromic acid (25 ml) was heated at reflux for 6 hours. After cooling the reaction was added to water (200 ml) and the solution extracted with ether (300 ml). The ethereal solution was washed with saturated aqueous sodium hydrogencarbonate solution (2×150 ml), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with dichloromethane:hexane (1:1) then dichloromethane to give the sub-title compound as a white solid (1.44 g).
Reaction SMILES: [H-].[Na+].[F:3][CH:4]([F:42])[C:5]1[N:9]([C:10]2[N:15]=[C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[N:13]=[C:12]([C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:24][CH:23]=3)[N:11]=2)[C:8]2[CH:36]=[CH:37][CH:38]=[C:39]([O:40][CH3:41])[C:7]=2[N:6]=1.I[CH3:44]>CN(C=O)C.O>[F:42][CH:4]([F:3])[C:5]1[N:9]([C:10]2[N:15]=[C:14]([N:16]3[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)[N:13]=[C:12]([C:22]3[CH:23]=[CH:24][C:25]([N:28]([CH3:44])[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:26][CH:27]=3)[N:11]=2)[C:8]2[CH:36]=[CH:37][CH:38]=[C:39]([O:40][CH3:41])[C:7]=2[N:6]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(-c2ccc(NC(=O)OC(C)(C)C)cc2)nc(N2CCOCC2)n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(-c2ccc(N(C)C(=O)OC(C)(C)C)cc2)nc(N2CCOCC2)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 84.4 %

Procedure:
NaH (95%, 11 mg, 0.435 mmol) was added to a suspension of tert-butyl 4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]phenylcarbamate (Example 74) (120 mg, 0.217 mmol) in DMF (3 mL) at 0° C. After stirring at 0° C. for 15 min, iodomethane (0.020 mL, 0.321 mmol) was added. The reaction mixture was warmed to room temperature, stirred for additional 17 hrs, and then diluted with H2O. The resulting precipitate was collected by filtration and dried to give tert-butyl 4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]phenyl(methyl)carbamate (104 mg, 85%): mp (CH2Cl2/MeOH) 205-208° C.; 1H NMR (CDCl3) δ 8.42 (d, J=8.8 Hz, 2H), 8.09 (dd, J=8.4, 0.6 Hz, 1H), 7.63 (t, JHF=53.5 Hz, 1H), 7.45-7.40 (m, 3H), 6.86 (d, J=7.8 Hz, 1H), 4.13 (m, 2H), 4.07 (s, 3H), 4.00 (m, 2H), 3.86 (m, 4H), 3.35 (s, 3H), 1.50 (s, 9H); Anal. Calcd. for C28H31F2N7O4: C, 59.25; H, 5.5; N, 17.3. Found: C, 59.0; H, 5.3; N, 17.2%.