Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C@H:9]([CH3:35])[C@@H:10]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[C:28]([Cl:34])[CH:27]=1)[C:11]([NH:13][NH:14][C:15](=O)[C:16]1[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=1)=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.II.CCN(CC)CC>C(Cl)Cl>[Si:1]([O:8][C@H:9]([CH3:35])[C@@H:10]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[C:28]([Cl:34])[CH:27]=1)[C:11]1[O:12][C:15]([C:16]2[CH:17]=[CH:18][C:19]([C:22]#[N:23])=[CH:20][CH:21]=2)=[N:14][N:13]=1)([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:3])[CH3:2]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](Nc1ccc(C#N)c(Cl)c1)C(=O)NNC(=O)c1ccc(C#N)cc1
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](Nc1ccc(C#N)c(Cl)c1)c1nnc(-c2ccc(C#N)cc2)o1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 100.6 %

Procedure:
A solution of N′-((2R,3R)-3-(tert-butyldimethylsilyloxy)-2-(3-chloro-4-cyanophenylamino)butanoyl)-4-cyanobenzohydrazide (1.02 g, 1.98 mmol) in CH2Cl2 (30 mL) was added to a pre-cooled (0° C.) mixture of PPh3 (1.04 g, 3.97 mmol), iodine (1.01 g, 3.97 mmol) and Et3N (1.11 mL, 7.94 mmol). The reaction mixture was warmed to room temperature, stirred for 25 min and quenched with sat, aq. sodium thiosulfate (300 mL). The solution was extracted with CH2Cl2 (200 mL). The organic extract was washed with sat. aq. sodium thiosulfate (2×150 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide a brown oil, which was purified by flash chromatography over silica gel (20% EtOAc in hexanes) to provide the title compound as a light yellow oil (984 mg, 100%): 1H NMR (400 MHz, acetone-d6, δ in ppm) 8.22 (dm, J=8.6 Hz, 2H), 8.03 (dm, J=8.8 Hz, 2H), 7.55 (d, J=8.8 Hz, 1H), 7.07 (d, J=2.4 Hz, 1H), 6.92 (dd, J=2.3, 8.8 Hz, 1H), 6.67 (d, J=9.0 Hz, 1H), 5.10 (dd, J=7.2, 9.2 Hz, 1H), 4.52 (dq, J=6.1, 7.2 Hz, 1H), 1.45 (d, J=6.1 Hz, 3H), 0.75 (s, 9H), 0.09 (s, 3H), −0.07 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[CH2:8][CH2:7][C:6]3[C:12]([C:16]([NH:18][C:19]4[C:24]([CH2:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:20]=4[CH2:27][CH3:28])=[O:17])=[N:13][N:14]([CH3:15])[C:5]=3[C:4]=2[N:3]=1.[C:29]([N:36]1[CH2:41][CH2:40][C:39](=O)[CH2:38][CH2:37]1)([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30].C(O)(C(F)(F)F)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+]>CN(C)C=O>[CH2:27]([C:20]1[CH:21]=[CH:22][CH:23]=[C:24]([CH2:25][CH3:26])[C:19]=1[NH:18][C:16]([C:12]1[C:6]2[CH2:7][CH2:8][C:9]3[CH:10]=[N:11][C:2]([NH:1][CH:39]4[CH2:40][CH2:41][N:36]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:37][CH2:38]4)=[N:3][C:4]=3[C:5]=2[N:14]([CH3:15])[N:13]=1)=[O:17])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CCc1cccc(CC)c1NC(=O)c1nn(C)c2c1CCc1cnc(N)nc1-2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CCc1cccc(CC)c1NC(=O)c1nn(C)c2c1CCc1cnc(NC3CCN(C(=O)OC(C)(C)C)CC3)nc1-2
Reaction time: 20 h
Yield: 80 %

Procedure:
To a solution of 8-amino-N-(2,6-diethylphenyl)-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (1.0 g, 2.66 mmol) in dry dimethylformamide (20 mL), were added 1-Boc-4-piperidone (1.06 g mL, 5.32 mmol), CF3COOH (1.7 mL, 22.7 mmol) and NaBH(OAc)3 (1.12 g, 5.32 mmol). After 20 hours, NaOH 2N (12 mL, 24 mmol) was added dropwise to the mixture. The precipitate was filtered, washed with water and dried. The crude material was purified by flash chromatography on silica gel eluted with dichloromethane/methanol 97:3 to give the 1.2 g of to the pure title compound (80% yield).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([N:10]3[CH2:15][CH2:14][CH:13]([O:16][CH2:17][C@@H:18]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH3:19])[CH2:12][CH2:11]3)=[N:7][C:6]=2[CH:28]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][CH:37]1[CH2:39][CH2:38]1>CN(C=O)C.C(OCC)(=O)C>[CH:37]1([CH2:36][O:1][C:2]2[CH:3]=[CH:4][C:5]3[O:9][C:8]([N:10]4[CH2:15][CH2:14][CH:13]([O:16][CH2:17][C@@H:18]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:26])[CH3:25])[CH3:19])[CH2:12][CH2:11]4)=[N:7][C:6]=3[CH:28]=2)[CH2:39][CH2:38]1
Reactant: C[C@@H](COC1CCN(c2nc3cc(O)ccc3o2)CC1)NC(=O)OC(C)(C)C
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H](COC1CCN(c2nc3cc(OCC4CC4)ccc3o2)CC1)NC(=O)OC(C)(C)C
Temperature: 60 °C

Procedure:
To a solution of tert-butyl [(1S)-2-{[1-(5-hydroxy-1,3-benzoxazol-2-yl)piperidin-4-yl]oxy}-1-methylethyl]carbamate (345 mg) in DMF (5 mL) were added potassium carbonate (366 mg) and (bromomethyl)cyclopropane (0.171 mL), and the mixture was stirred with heating at 60° C. for 1.5 hr under a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (375 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]1[CH:21]=O.N1CCCCC1>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:21][C:13]1[NH:12][C:20]2[C:15]([CH:14]=1)=[CH:16][CH:17]=[CH:18][CH:19]=2
Reactant: O=Cc1cc2ccccc2[nH]1
Reactant: O=C1Cc2cc(Br)ccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1Nc2ccc(Br)cc2C1=Cc1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 5-bromo-2-oxindole (212 mg), indole-2-carbaldehyde (174 mg) (prepared according to Synthetic Communications, 1993, 23, 3109) and piperidine (10 mg) in ethanol was held in a sealed tube at 95° C. for 4 hours. The mixture was cooled to room temperature. The solid was collected by vacuum filtration, washed with cold ethanol and dried in a vacuum oven to give 5-bromo-3-(1H-indol-2-ylmethylene)-1,3-dihydroindol-2-one.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[SH:8][C:9]1([CH2:19][CH2:20][OH:21])[CH:16]2[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:18][CH:10]1[CH2:11]3)[CH2:15]2>C1(C)C=CC=CC=1>[SH:8][C:9]1([CH2:19][CH2:20][O:21][C:4]([CH2:3][CH2:2][C:1]([OH:6])=[O:7])=[O:5])[CH:16]2[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:18][CH:10]1[CH2:11]3)[CH2:15]2
Reactant: OCCC1(S)C2CC3CC(C2)CC1C3
Reactant: O=C1CCC(=O)O1
Solvent: Cc1ccccc1
Product: O=C(O)CCC(=O)OCCC1(S)C2CC3CC(C2)CC1C3

Procedure:
A solution of succinic anhydride (10 mmol, 1.00 g) and 2-(2-sulfanyladamantan-2-yl)ethan-1-ol (2.214 g, 10.4 mmol) in toluene (30 mL) was heated at 70° C. for 16 hours. Removal of the solvent under vacuum provided a low-melting solid, 3.12 g, 10 mmol. 1H NMR (CDCl3, 300 MHz): δ4.44 (t, J=7.4 Hz, 2H), 2.68 (m, 2H), 2.63 (m, 2H), 2.43 (m, 2H), 2.25 (t, J=7.4 Hz, 2H), 2.11 (m, 2H), 1.88-1.62 (m, 10H); MS (CI/NH3) (m/e) 330 (M+NH4), 279 (M-SH), 195, 161.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[CH:3]=1.O.[NH2:14][NH2:15]>C(O)C>[NH:14]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[CH:3]=1)[NH2:15]
Reactant: Cc1cc(Cl)c2ccccc2n1
Reactant: NN
Solvent: O
Solvent: CCO
Product: Cc1cc(NN)c2ccccc2n1
Temperature: 25 °C

Procedure:
A solution of 4-chloro-2-methylquinoline (5.01 g, 28.2 mmol) and 80% hydrazine hydrate (8 ml) solution was refluxed in ethanol (30 mL) for 8 h. The resulting solution was cooled to room temperature and the solid formed was collected by filtration, washed with ethanol, and dried to yield known 4-hydrazino-2-methylquinoline,54,55 4.712 g (79.70%); mp 195-197° C.; 1H NMR (DMSO-d6) δ 2.64 (3H, s, Me), 5.15 (2H, brs, exchangeable, NH2), 6.99 (1H, s, ArH), 7.58 (1H, t, J=7.6 Hz, ArH), 7.86 (1H, t, J=7.6 Hz, ArH), 7.85 (1H, d, J=8.4 Hz, ArH), 8.42 (1H, d, J=8.2 Hz, ArH), 10.64 (1H, s, exchangeable, NH), Anal. Calcd. for (C10H12N3.HCl): C, 57.28; H, 5.77; N, 20.04. Found: C, 57.28; H, 5.77; N, 20.04.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH:9]([CH3:11])[CH3:10])[C:4]=1[OH:12].O.C(=O)(O)[O-].[Na+].[Br:19][C@H:20]([CH:24]([CH3:26])[CH3:25])[C:21](Cl)=[O:22]>C(OCC)(=O)C>[Br:19][C@H:20]([CH:24]([CH3:26])[CH3:25])[C:21]([NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH:9]([CH3:10])[CH3:11])[C:4]=1[OH:12])=[O:22]
Reactant: CC(C)[C@@H](Br)C(=O)Cl
Reactant: CC(C)c1cccc(N)c1O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)c1cccc(NC(=O)[C@H](Br)C(C)C)c1O
Reaction time: 0.5 h
Yield: 76 %

Procedure:
To a stirred, ice-cooled mixture of 2-amino-6-isopropylphenol hydrochloride (15.0 g), ethyl acetate (200 ml), water (100 ml), and sodium bicarbonate (20.0 g), was added dropwise a solution of (R)-2-bromo-3methylbutyryl chloride (16.0 g) in ethyl acetate (30 ml). The whole was stirred for 30 minutes, and the ethyl acetate layer was separated, washed with water and dried over MgSO4. Removal of the solvent gave (R)-2-(2-bromo-3-methylbutyryl)amino-6-isopropylphenol as crystals (19.1 g, 76.1%). Recrystallization from isopropyl ether afforded colorless needles, mp 108°-109° C. [α]D23 +44.8° (c=0.82, MeOH).
Reaction SMILES: C([O:3][C:4](=[O:19])[C:5]1[CH:10]=[CH:9][C:8]([P:11]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][CH:6]=1)C.[OH-].[Li+]>CO.O>[CH2:17]([O:16][P:11]([C:8]1[CH:9]=[CH:10][C:5]([C:4]([OH:19])=[O:3])=[CH:6][CH:7]=1)([O:13][CH2:14][CH3:15])=[O:12])[CH3:18]
Reactant: CCOC(=O)c1ccc(P(=O)(OCC)OCC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCOP(=O)(OCC)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-(diethoxyphosphoryl)-benzoic acid ethyl ester (2b) (2.46 g, 8.59 mmol) in methanol (86 mL) was slowly added lithium hydroxide (monohydrate, 0.36 g, 8.59 mmol) in water (86 mL). The resulting reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated to remove methanol and diluted with brine, then extracted with EtOAc (3×100 mL) until the aqueous layer showed little or no evidence of product by HPLC. The combined organics were dried over Na2SO4 and concentrated on a rotary evaporator. The desired product was purified by crystallization from hexane/ethyl acetate (2.37 g), m.p. 101° C. 1H NMR (300 MHz, CDCl3) δ(ppm)): 1.27 (t, J=7.03 Hz, 6H), 4.03 (q, J=7.03 Hz, 4H), 7.85 (m, 2H), 8.09 (m, 2H), 12.65 (bs, 1H). 31P NMR (121 MHz, CDCl3) δ 21.611.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[C:8]([CH2:10][N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)[CH:7]=[CH:6][C:5]=1[OH:18].CS(O[CH:24]1[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:25]1)(=O)=O.[OH-].[Na+]>CN(C=O)C.O>[CH3:3][C:4]1[CH:9]=[C:8]([CH2:10][N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)[CH:7]=[CH:6][C:5]=1[O:18][CH:24]1[CH2:25][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:27]1
Reactant: Cc1cc(CN2CCN(C)CC2)ccc1O
Reactant: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(CN2CCN(C)CC2)ccc1OC1CN(C(=O)OC(C)(C)C)C1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 63.8 %

Procedure:
A mixture of NaH (55-65% disp. in oil, 0.50 g, 11.5 mmol) in dry DMF (10 mL) under nitrogen was cooled by an ice-water bath. A solution of 9A (2.0 g, 9.1 mmol) in DMF (15 mL) was added drop-wise over 15 minutes. The mixture was stirred for 15 minutes and then tert-butyl 3-[(methylsulfonyl)oxy]azetidine-1-carboxylate (3.0 g, 11.8 mmol) in DMF (15 mL) was added. The mixture was heated to 80° C. over night and then cooled to RT. Water and some aqueous NaOH were added and the mixture was extracted three times with DCM. The combined organic solutions were dried (MgSO4) and evaporated. The residue was purified by column chromatography on SiO2 using 5% triethylamine in EtOAc as eluent. There was obtained 2.18 g (64%) of 9B as a colorless oil. 1H NMR (500 MHz, CDCl3): δ 1.45 (s, 9H), 2.22 (s, 3H), 2.28 (s, 3H), 2.30-2.63 (bm, 8H), 3.40 (s, 2H), 3.96-4.04 (m, 2H), 4.24-4.34 (m, 2H), 4.79-4.89 (m, 1H), 6.37 (d, 1H), 7.03 (d, 1H), 7.11 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([Br:12])=[CH:7][C:3]=1[C:4](O)=[O:5].[NH2:13][C:14](N)=[O:15]>>[Br:12][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][C:9]=1[Cl:11])[NH:1][C:14](=[O:15])[NH:13][C:4]2=[O:5]
Reactant: Nc1cc(Cl)c(Br)cc1C(=O)O
Reactant: NC(N)=O
Product: O=c1[nH]c(=O)c2cc(Br)c(Cl)cc2[nH]1

Procedure:
Prepared according to general method C from 2-amino-5-bromo-4-chlorobenzoic acid (987 mg) and urea (2.36 g). Yield: 1.00 g (92%) of a solid. 1H-NMR (DMSO-δ6) δ (ppm) 8.01 (s, 1H), 7.36 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH2:6][C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=1)([CH3:9])[CH3:8])[CH3:2].C1(S(N2C(C3C=CC=CC=3)O2)(=O)=[O:26])C=CC=CC=1.[Cl-].[NH4+]>O1CCCC1.C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([OH:26])[CH2:6][C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=1)([CH3:8])[CH3:9])[CH3:2]
Reactant: CCOC(=O)CCC(C)(C)c1cccc(OC)c1
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(O)CC(C)(C)c1cccc(OC)c1
Temperature: -70 °C
Reaction time: 2 h
Yield: 72.2 %

Procedure:
27.2 g (108.65 mmol) of ethyl-4-(3-methoxyphenyl)-4-methylpentanoate is dissolved in 380 ml of tetrahydrofuran, and the reaction mixture is cooled to −70° C. to −65° C. Within two hours, 304 ml of a 0.5 molar solution of potassium-bis-(trimethylsilylamide) in toluene is added in drops, and the reaction mixture is then stirred for 75 more minutes at −70° C. 39.7 g (152.11 mmol) of Davis reagent, dissolved in 380 ml of tetrahydrofuran, is now added in drops within 90 minutes. After two hours of stirring at −70° C., 195 ml of saturated ammonium chloride solution is slowly added in drops, the cold bath is removed and it is stirred vigorously for thirty minutes. After extraction with diethyl ether (twice with 800 ml each), the combined organic extracts are treated as usual with water and brine. After the solvent is spun off, the residue is chromatographed on silica gel (mobile solvent ethyl acetate/hexane). 20.9 g (72.4%) of the desired compound is isolated.
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:10]([CH2:22][CH3:23])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH:13]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([NH:33][CH2:34][CH2:35][C:36]([O:38]CC)=[O:37])=[O:32])=[CH:27][CH:26]=1>>[CH:1]1([CH:7]([NH:24][C:25]2[CH:26]=[CH:27][C:28]([C:31]([NH:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[O:32])=[CH:29][CH:30]=2)[C:9]2[C:10]([CH2:22][CH3:23])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCNC(=O)c1ccc(N)cc1
Reactant: CCc1nn(-c2ccc(OC)cc2)cc1C(O)C1CCCCC1
Product: CCc1nn(-c2ccc(OC)cc2)cc1C(Nc1ccc(C(=O)NCCC(=O)O)cc1)C1CCCCC1
Yield: 0 %

Procedure:
Using cyclohexyl[3-ethyl-1-(4-methoxyphenyl)-1H-pyrazol-4-yl]methanol (0.5 g) synthesized above and ethyl 3-{[(4-aminophenyl)carbonyl]amino}propanoate (0.38 g) synthesized in Example 1(2) and in the same manner as in Example 1(7), the title object compound (0.35 mg, 43%) was obtained as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([F:15])=[CH:10][C:9]=1[Br:16])([CH3:4])([CH3:3])[CH3:2].[C:18](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C)C=O>[C:1]([O:5][C:6](=[O:17])[N:7]([C:8]1[CH:13]=[C:12]([F:14])[C:11]([F:15])=[CH:10][C:9]=1[Br:16])[CH3:18])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(F)cc1Br
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1cc(F)c(F)cc1Br
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of Example 144A (12.37 g, 40.1 mmol) in anhydrous N,N-dimethylformamide (100 mL) was added cesium carbonate (19.62 g, 60.2 mmol) and iodomethane (5.02 mL, 80 mmol) at room temperature. The reaction mixture was stirred at room temperature for 4 hours, and was partitioned between ethyl acetate and brine. The organic phase was washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated and the residue was separated by flash chromatography on silica gel (Teledyne CombiFlash Rf, 40% to 100% ethyl acetate in hexane) to provide the title compound. MS (ESI+) m/z 322 (M+1).
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]([N:34]([CH2:38][CH2:39][OH:40])[CH:35]([CH3:37])[CH3:36])(=[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[C:26]([S:31]([N:34]([CH2:38][CH2:39][OH:40])[CH:35]([CH3:36])[CH3:37])(=[O:33])=[O:32])=[CH:27][CH:28]=[CH:29][CH:30]=3)=[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: CC(C)N(CCO)S(=O)(=O)c1ccccc1Br
Product: CC(C)N(CCO)S(=O)(=O)c1ccccc1-c1ccc(-c2cnc(N)nc2)c(F)c1

Procedure:
The title compound was prepared using methods analogous to those described in Example 376 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine and 2-bromo-N-(2-hydroxyethyl)-N-isopropylbenzene-sulfonamide. MS (ESI): mass calcd. for C21H23FN4O3S, 430.15; m/z found, 431.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.56 (d, J=1.4, 2H), 8.10 (dd, J=8.0, 1.4, 1H), 7.65-7.57 (m, 1H), 7.58-7.49 (m, 1H), 7.49-7.38 (m, 1H), 7.37-7.28 (m, 3H), 5.22 (s, 2H), 3.72 (p, J=6.7, 1H), 3.65-3.50 (m, 2H), 2.99 (t, J=6.0, 2H), 2.19 (d, J=7.0, 1H), 1.04 (d, J=6.7, 6H).
Reaction SMILES: [ClH:1].[NH2:2][C:3]([CH3:14])([CH3:13])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.F[C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C.C(OCC)(=O)C>[ClH:1].[NH2:2][C:3]([CH3:14])([CH3:13])[CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=2)=[CH:10][CH:11]=1
Reactant: CC(C)(N)CCc1ccc(O)cc1
Reactant: N#Cc1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CC(C)(N)CCc1ccc(Oc2ccc(C#N)cc2)cc1
Temperature: 110 °C
Reaction time: 16 h
Yield: 61.9 %

Procedure:
4-(3-Amino-3-methylbutyl)phenol hydrochloride (1.14 g, 5.3 mmol), 4-fluorobenzonitrile (0.77 g, 6.4 mmol, 1.2 eq.) and potassium carbonate (1.65 g, 11.6 mmol, 2.2 eq.) were suspended in N,N-dimethyl-acetamide (15 ml) and stirred for 16 hours at 110° C. After this time, the darkened mixture was allowed to cool to ambient temperature. The suspension was diluted with ethyl acetate (100 ml) and washed with 1N NaOH (2×100 ml). The organic layer was treated with 5N HCl (100 ml), producing a white precipitate at the biphasic interface. The solid material was filtered and dried, triturated with pentane and dried in vacuo for 14 hours to produce a white solid (1.04 g, 71%). NMR, MS
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.Br[C:17]1[C:18]([NH2:24])=[N:19][CH:20]=[C:21]([Br:23])[N:22]=1.CCN(CC)CC>CS(C)=O>[NH2:24][C:18]1[C:17]([NH:1][CH2:2][CH:3]2[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]2)=[N:22][C:21]([Br:23])=[CH:20][N:19]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(CN)C1
Reactant: Nc1ncc(Br)nc1Br
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCC(CNc2nc(Br)cnc2N)C1
Temperature: 130 °C
Reaction time: 8 h
Yield: 25.3 %

Procedure:
tert-butyl 3-(aminomethyl)piperidine-1-carboxylate (4.97 g, 22.40 mmol) was dissolved in DMSO (80 ml), and then 3,5-dibromopyrazine-2-amine (8.5 g, 33.60 mmol) and Et3N (6.3 ml) were added, followed by stirring at 130° C. overnight. After the completion of the reaction, the reaction mixture was extracted with H2O, EA, and brine, followed by drying (Na2SO4), filtration, and concentration under reduced pressure, and the residue was purified by column chromatography (EA:Hex=1:1), to give tert-butyl 3-(((3-amino-6-bromopyrazine-2-yl)amino)methyl)piperidine-1-carboxylate (2.19 g, two steps: 26%).
Reaction SMILES: [C:1]1([CH:11]=[CH:12][C:13]([OH:15])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:19])=O>>[C:1]1([CH:11]=[CH:12][C:13]([Cl:19])=[O:15])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)C=Cc1cccc2ccccc12
Product: O=C(Cl)C=Cc1cccc2ccccc12
Yield: 99 %

Procedure:
3-(1-Naphthalenyl)-2-Propenoic acid (7.5 g, 0.038 mol) was slurried in 15 ml of oxalyl chloride and refluxed for 2 hr. The resulting solution was evaporated to yield 8.0 g (99 percent) of yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[S:9][C:10]1[O:11][C:12]([CH3:15])=[N:13][N:14]=1.C1C=C(Cl)C=C(C(OO)=[O:24])C=1>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[S:9]([C:10]1[O:11][C:12]([CH3:15])=[N:13][N:14]=1)=[O:24]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1nnc(Sc2c(C)cccc2C)o1
Solvent: ClCCl
Product: Cc1nnc(S(=O)c2c(C)cccc2C)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.1 %

Procedure:
To an ice-cooled solution of 2-(2,6-dimethylphenyl)thio-5-methyl-1,3,4-oxadiazole (0.350 g, 0.0016 mol) in CH2Cl2 (10 ml) was added dropwise m-CPBA (0.530 g, 0.002 mol, 65% pure) in CH2Cl2 (5 ml). The ice bath was removed and the reaction mixture was stirred at rt for 2 h and treated with sat. aq. Na2S2O3 (2.5 ml) solution and sat. aq. Na2CO3 (10 ml). The organic layer was separated and then the aqueous layer was extracted with CH2Cl2 (2×25 ml), dried (MgSO4) and the solvent evaporated in vacuo. Chromatography on silica gel using ethyl acetate/hexanes (1/1) as the eluant gave 2-(2,6-dimethylphenyl)sulfinyl-5-methyl-1,3,4-oxadiazole (78) (0.125 g, 23%) as a white solid; mp 79°-80° C.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[H-].[Na+].CS([C:12]1[N:13]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]([F:35])([F:34])[F:33])=[CH:26][CH:25]=2)[C:14](=[O:23])[C:15]2[CH2:21][CH2:20][C:19](=[O:22])[NH:18][C:16]=2[N:17]=1)=O.O>O1CCCC1>[F:1][C:2]([F:6])([F:5])[CH2:3][O:4][C:12]1[N:13]([C:24]2[CH:25]=[CH:26][C:27]([O:30][CH2:31][C:32]([F:35])([F:34])[F:33])=[CH:28][CH:29]=2)[C:14](=[O:23])[C:15]2[CH2:21][CH2:20][C:19](=[O:22])[NH:18][C:16]=2[N:17]=1
Reactant: CS(=O)c1nc2c(c(=O)n1-c1ccc(OCC(F)(F)F)cc1)CCC(=O)N2
Reactant: OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C1CCc2c(nc(OCC(F)(F)F)n(-c3ccc(OCC(F)(F)F)cc3)c2=O)N1
Reaction time: 0.08 h

Procedure:
To a solution of 2,2,2-trifluoroethanol (0.472 mL) in tetrahydrofuran (20 mL) was added sodium hydride (60% in oil, 0.184 g). The reaction mixture was stirred for 5 min, 2-(methylsulfinyl)-3-[4-(2,2,2-trifluoroethoxy)phenyl]-5,6-dihydropyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (0.88 g) was added thereto, and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and recrystallized from ethyl acetate/hexane to give the title compound (0.80 g).