Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([N:13]2[C:17]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[O:25][CH:26]=[CH:27][CH:28]=4)=[CH:20][CH:19]=3)=[CH:16][C:15]([C:29]([F:32])([F:31])[F:30])=[N:14]2)[CH:6]=[CH:7][C:8]=1[S:9]([CH3:12])(=[O:11])=[O:10].[C:33]1(=[O:43])[NH:37][C:36](=[O:38])[C:35]2=[CH:39][CH:40]=[CH:41][CH:42]=[C:34]12.[K].O>CN(C=O)C>[O:25]1[CH:26]=[CH:27][CH:28]=[C:24]1[C:21]1[CH:20]=[CH:19][C:18]([C:17]2[N:13]([C:5]3[CH:6]=[CH:7][C:8]([S:9]([CH3:12])(=[O:10])=[O:11])=[C:3]([CH:4]=3)[CH2:2][N:37]3[C:33](=[O:43])[C:34]4[C:35](=[CH:39][CH:40]=[CH:41][CH:42]=4)[C:36]3=[O:38])[N:14]=[C:15]([C:29]([F:31])([F:32])[F:30])[CH:16]=2)=[CH:23][CH:22]=1
Reactant: CS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(-c3ccco3)cc2)cc1CCl
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(-c3ccco3)cc2)cc1CN1C(=O)c2ccccc2C1=O
Temperature: 90 °C
Yield: 751.3 %

Procedure:
A mixture of 1-[3-chloromethyl-4-(methylsulfonyl)phenyl]-5-[4-(2-furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole from step 1 of Example 160 (280 mg, 0.58 mmol) and potassium phthalimide (10 mg, 0.054 mmol) in DMF was heated at 90° C. for 1 hour. After cooled to room temperature, the mixture was poured into water (30 mL), and extracted with ether (30 mL×2), washed with water (30 mL) and brine (30 mL), dried over MgSO4, and concentarted in vacuo to give the title compound (240 mg, 70%).
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[C:17]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:16]=[C:15]([CH3:23])[C:3]=1[O:4][Si:5]([CH:12]([CH3:14])[CH3:13])([CH:9]([CH3:11])[CH3:10])[CH:6]([CH3:8])[CH3:7].[Li]CCCC.[P:29](Cl)(=[O:36])([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32]>C1COCC1>[CH3:23][C:15]1[CH:16]=[C:17]([S:19]([CH2:22][P:29](=[O:36])([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])(=[O:21])=[O:20])[CH:18]=[C:2]([CH3:1])[C:3]=1[O:4][Si:5]([CH:6]([CH3:7])[CH3:8])([CH:9]([CH3:10])[CH3:11])[CH:12]([CH3:14])[CH3:13]
Reactant: Cc1cc(S(C)(=O)=O)cc(C)c1O[Si](C(C)C)(C(C)C)C(C)C
Reactant: CCOP(=O)(Cl)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOP(=O)(CS(=O)(=O)c1cc(C)c(O[Si](C(C)C)(C(C)C)C(C)C)c(C)c1)OCC
Temperature: -78 °C
Reaction time: 1 h
Yield: 15.4 %

Procedure:
To a stirring solution of (2,6-dimethyl-4-methanesulfonylphenoxy)triisopropylsilane (0.47 g, 1.32 mmol) in THF (15 mL) at −78° C. was added n-BuLi (2.5 M in hexanes, 0.58 mL), the reaction mixture was stirred at −78° C. for 1 hr, then diethyl phosphorochloridate (0.25 mL, 1.72 mmol) was added at −78° C. The reaction mixture was stirred at room temperature for 16 hrs. The reaction mixture was quenched with saturated NH4Cl and diluted with diethyl ether. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate-hexanes (1:1) to afford diethyl (3,5-dimethyl-4-triisopropylsilanyloxy-benzenesulfonyl)methylphosphonate as a colorless oil (0.1 g, 15%): 1H NMR (200 MHz, CDCl3-d6): δ 7.57 (s, 2 H), 4.17 (m, 4 H), 3.71 (d, J=17.2 Hz, 2H), 2.29 (s, 6 H), 1.33 (m, 9 H), 1.10 (d, J=7.2 Hz, 18 H). TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=ethyl acetate-hexanes (1:1); Rf=0.45.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14](C#N)[CH:15]=3)[N:10]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][O:20]3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:25]([O:28][C@@H:29]([CH3:33])[C:30](O)=[O:31])(=[O:27])[CH3:26].Cl.[CH3:35][N:36](C)CCCN=C=NCC>ClCCl>[C:25]([O:28][C@H:29]([C:30](=[O:31])[NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH:19]3[CH2:24][CH2:23][CH:22]([C:35]#[N:36])[CH2:21][O:20]3)[N:9]=2)[CH:3]=1)[CH3:33])(=[O:27])[CH3:26]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(=O)O[C@@H](C)C(=O)O
Reactant: N#Cc1ccc2c(c1)c(-c1cccc(N)c1)nn2C1CCCCO1
Agent: Cl
Solvent: ClCCl
Product: CC(=O)O[C@@H](C)C(=O)Nc1cccc(-c2nn(C3CCC(C#N)CO3)c3ccccc23)c1
Reaction time: 12 h
Yield: 85 %

Procedure:
To a solution of 3-(3-aminophenyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile (0.400 g, 1.25 mmol) in dichloromethane (50 mL), was added (S)-(−)-2-acetoxy propionic acid (0.128 mL, 1.38 mmol) and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (EDCI) (0.287 g, 1.5 mmol). After overnight reaction at room temperature, 0.6 equivalent of carboxylic acid and EDCI were added. After 12 hours at room temperature, the reaction was complete. The reaction mixture was partitioned between dichloromethane and water. The organic phase was dried under vacuum and the title product was used in the subsequent step without further purification (0.460 g, 85% yield): ES-MS (m/z) 433 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([NH:23][CH2:24][CH:25]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:20][CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:5][CH:4]=1)#[N:2].I[CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41]>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([N:23]([CH2:24][CH:25]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:20][CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:7][CH:8]=1)#[N:2]
Reactant: CCOC(=O)CI
Reactant: N#Cc1ccc(CCC(=O)N2CCCc3cc(NCC(c4ccccc4)c4ccccc4)ccc32)cc1
Product: CCOC(=O)CN(CC(c1ccccc1)c1ccccc1)c1ccc2c(c1)CCCN2C(=O)CCc1ccc(C#N)cc1

Procedure:
Prepared from 1-[3-(4-cyano-phenyl)-propionyl]-6-(2,2-diphenyl-ethylamino)-1,2,3,4-tetrahydro-quinoline (see Example 14(4)) and ethyl iodoacetate
Reaction SMILES: [OH:1][N:2]=[C:3]([CH3:12])[C:4]([C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)=O.O.[NH3:14].[CH3:15][O:16][C:17]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:18]=1[CH:19]=O>O1CCOCC1.C(O)C>[OH:1][N:2]1[C:3]([CH3:12])=[C:4]([C:6]2[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=2)[N:14]=[C:19]1[C:18]1[CH:21]=[CH:22][C:23]([O:25][CH3:26])=[CH:24][C:17]=1[O:16][CH3:15]
Reactant: CC(=NO)C(=O)c1ccncc1
Reactant: COc1ccc(C=O)c(OC)c1
Reactant: N
Solvent: O
Solvent: CCO
Solvent: C1COCCO1
Product: COc1ccc(-c2nc(-c3ccncc3)c(C)n2O)c(OC)c1
Temperature: 25 °C

Procedure:
To a suspension of 4-(2-hydroxyiminopropionyl)pyridine (2.0 g) in a mixture of dioxane (40 ml) and ethanol were added conc. ammonia water (58 ml) and 2,4-dimethoxybenzaldehyde (2.02 g), and the mixture was stirred at ambient temperature for 1 week. After evaporation, the mixture was triturated with chloroform to give 1-hydroxy-2-(2,4-dimethoxyphenyl)-5-methyl-4-(4-pyridyl)imidazole (3.01 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[N:10]=[C:4]2[N:3]=1.[C:15]([C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][C:18]=1[F:26])#[N:16]>>[N:3]1[C:4]2[N:5]([C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[N:10]=2)[CH:6]=[CH:7][C:2]=1[C:21]1[CH:20]=[CH:19][C:18]([F:26])=[C:17]([CH:22]=1)[C:15]#[N:16].[N:3]1[C:4]2[N:5]([C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[N:10]=2)[CH:6]=[CH:7][C:2]=1[C:20]1[CH:21]=[CH:22][C:17]([C:15]#[N:16])=[C:18]([F:26])[CH:19]=1
Reactant: N#Cc1ccc(B(O)O)cc1F
Reactant: Brc1ccn2c(n1)nc1ccccc12
Product: N#Cc1cc(-c2ccn3c(n2)nc2ccccc23)ccc1F
Product: N#Cc1ccc(-c2ccn3c(n2)nc2ccccc23)cc1F
Yield: 41 %

Procedure:
The title compound was prepared using General Experimental Procedure A (Suzuki coupling reaction) from 2-bromobenzo[4,5]imidazo[1,2-a]pyrimidine and (4-cyano-3-fluorophenyl)boronic acid on a 0.1 mmol scale. The residue was washed with water (3×5 mL), EtOAc (3×2 mL), and DCM (3×2 mL) and dried under high vacuum to afford 4-(Benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)-2-fluorobenzonitrile (T747) as a orange solid (12 mg, 41%). 1H NMR (400 MHz, DMSO-d6): δ 9.67 (d, J=7.2 Hz, 1H), 8.86 (dd, J=5.6, 2.0 Hz, 1H), 8.74 (m, 1H), 8.33 (d, J=7.6 Hz, 1H), 7.91 (d, J=7.2 Hz, 1H), 7.84 (d, J=9.2 Hz, 1H), 7.760 (t, J=8.8 Hz, 1H), 7.54 (t, J=7.2 Hz, 1H), 7.42 (t, J=7.6 Hz, 1H); MS (ESI) m/z [M+H]+289.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:7]=1.[OH-].[NH4+:13]>C1COCC1>[F:9][C:8]([F:11])([F:10])[C:5]1[N:4]=[N:3][C:2]([NH2:13])=[CH:7][CH:6]=1
Reactant: FC(F)(F)c1ccc(Cl)nn1
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Nc1ccc(C(F)(F)F)nn1
Temperature: 100 °C
Yield: 93 %

Procedure:
A mixture of 3-chloro-6-trifluoromethylpyridazine (1.6 g, 8.80 mmol) and ammonium hydroxide (9 mL) in THF (3 mL) was heated at 100° C. in a microwave reactor for 1 h. After this period, the reaction mixture was evaporated and the residue was extracted with dichloromethane. The combined extract was dried over with MgSO4, filtered, and evaporated under reduce pressure to afford 301a (1.3 g, 93%) as a white solid. MS-ESI: [M+H]+ 164.1
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][NH:6][C:7](=[O:33])[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:19]=[C:18]([NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[Cl:30])[N:17]=[C:16]([O:31][CH3:32])[N:15]=2)[CH:9]=1)C.[OH-].[Li+].Cl>C1COCC1.CO.O>[Cl:30][C:24]1[CH:25]=[C:26]([Cl:29])[CH:27]=[CH:28][C:23]=1[CH2:22][CH2:21][NH:20][C:18]1[N:17]=[C:16]([O:31][CH3:32])[N:15]=[C:14]([C:10]2[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=2)[C:7]([NH:6][CH2:5][C:4]([OH:34])=[O:3])=[O:33])[CH:19]=1
Reactant: CCOC(=O)CNC(=O)c1cccc(-c2cc(NCCc3ccc(Cl)cc3Cl)nc(OC)n2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1nc(NCCc2ccc(Cl)cc2Cl)cc(-c2cccc(C(=O)NCC(=O)O)c2)n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 43 %

Procedure:
A mixture of (3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-benzoylamino)-acetic acid ethyl ester [120 mg, 0.24 mmol, Example 58], lithium hydroxide (20 mg, 0.48 mmol) in THF (1 mL), MeOH (1 mL) and water (1 mL) is stirred for 20 hours at ambient temperature. The mixture is acidified to pH 1 with 10% hydrochloric acid and extracted three times with EtOAc (25 mL). The organic extracts are combined and dried over magnesium sulfate, filtered and concentrated by rotary evaporator to provide (3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-benzoylamino)-acetic acid [49 mg, 43%, Example 59]. LCMS: RT=2.77 minutes, MS: 475 (M+H). IC50=0.8 nM
Reaction SMILES: F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[O:23]1[CH2:27][CH2:26][CH2:25][C@H:24]1[C:28]([OH:30])=O.C(N(C(C)C)CC)(C)C.[OH:40][C:41]([CH3:71])([CH3:70])[CH2:42][C@@:43]1([C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)[O:48][C:47](=[O:49])[N:46]([C@H:50]([C:52]2[CH:57]=[CH:56][C:55]([CH:58]3[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]3)=[CH:54][CH:53]=2)[CH3:51])[CH2:45][CH2:44]1>CN(C)C=O>[OH:40][C:41]([CH3:70])([CH3:71])[CH2:42][C@@:43]1([C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)[O:48][C:47](=[O:49])[N:46]([C@H:50]([C:52]2[CH:57]=[CH:56][C:55]([CH:58]3[CH2:63][CH2:62][N:61]([C:28]([C@@H:24]4[CH2:25][CH2:26][CH2:27][O:23]4)=[O:30])[CH2:60][CH2:59]3)=[CH:54][CH:53]=2)[CH3:51])[CH2:45][CH2:44]1
Reactant: O=C(O)[C@@H]1CCCO1
Reactant: C[C@@H](c1ccc(C2CCNCC2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](c1ccc(C2CCN(C(=O)[C@@H]3CCCO3)CC2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (125 mg) was added to a solution of (S)-tetrahydro-furan-2-carboxylic acid (45 mg) and diisopropylethyl-amine (200 μL) in N,N-dimethylformamide (2 mL) at room temperature. The resulting solution was stirred for 30 min, before (S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-3-[(S)-1-(4-piperidin-4-yl-phenyl)-ethyl]-[1,3]oxazinan-2-one (150 mg) dissolved in dimethylformamide (1 mL) was added. The resulting solution was stirred at room temperature overnight and then concentrated under reduced pressure. The crude product was purified by HPLC on reversed phase (MeCN/H2O/NH3) to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[N:6][C:5]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])=[C:4]([CH3:18])[N:3]=1.Cl.Cl[C:21]([NH2:23])=[NH:22]>COCCOCCOC>[NH2:23][C:21]1[N:22]=[C:8]([NH2:9])[C:7]2[C:2](=[N:3][C:4]([CH3:18])=[C:5]([C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:11])[N:6]=2)[N:1]=1
Reactant: Cc1nc(N)c(C#N)nc1C(=O)c1ccccc1
Reactant: N=C(N)Cl
Agent: Cl
Solvent: COCCOCCOC
Product: Cc1nc2nc(N)nc(N)c2nc1C(=O)c1ccccc1

Procedure:
This compound is prepared in a manner analogous to that of Step C of Example 7, using 2.1 grams (0.009 mole) of 2-amino-3-cyano-6-methyl-5-phenylcarbonylpyrazine and 0.9 gram (0.009 mole) chloroformamidine hydrochloride in 20 mL of diglyme, yielding 2,4-diamino-7-methyl-6-phenylcarbonylpteridine.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:12])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C1COCC1.Cl.[CH2:19]([S:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](O)=[O:25])[CH3:20].C(=O)([O-])O.[Na+]>O>[CH2:19]([S:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24]([NH:1][C:2]1[C:3]([OH:12])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1)=[O:25])[CH3:20]
Reactant: CCSc1ccccc1C(=O)O
Reactant: Nc1cc(C(F)(F)F)cnc1O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCSc1ccccc1C(=O)Nc1cc(C(F)(F)F)cnc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a mixture of 3-amino-5-trifluoromethylpyridin-2-ol (0.75 g) and THF (5 ml), 2-ethylsulfanylbenzoic acid hydrochloride (0.93 g) was added under ice-cooling, heated to room temperature, and stirred for 2 hours. After the mixture was allowed to stand overnight, the mixture was heated to 50° C., and stirred with heating for 6 hours. To the mixture, sodium hydrogen carbonate (0.35 g) was added, and stirred with heating for further 2.5 hours. After the mixture was allowed to stand, water was poured thereinto, and the precipitated solid was collected by filtration. The obtained solid was washed with water, and dried to give 1.37 g of 2-ethylsulfanyl-N-(2-hydroxy-5-trifluoromethylpyridin-3-yl)-benzamide (Compound (1B)-506).
Reaction SMILES: [F:1][C:2]([F:25])([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=1)[C:3]1[N:12]=[C:11](O)[C:10]2[C:5](=[CH:6][C:7]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:8][CH:9]=2)[N:4]=1.P(Br)(Br)(Br)=O.CCN(C(C)C)C(C)C.[CH3:40][C:41]1[NH:45][N:44]=[C:43]([NH2:46])[CH:42]=1>CN(C=O)C.C1(C)C=CC=CC=1>[F:1][C:2]([F:25])([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=1)[C:3]1[N:12]=[C:11]([NH:46][C:43]2[CH:42]=[C:41]([CH3:40])[NH:45][N:44]=2)[C:10]2[C:5](=[CH:6][C:7]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:8][CH:9]=2)[N:4]=1
Reactant: CS(=O)(=O)c1ccc2c(O)nc(C(F)(F)c3ccc(F)cn3)nc2c1
Reactant: Cc1cc(N)n[nH]1
Agent: O=P(Br)(Br)Br
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nc(C(F)(F)c3ccc(F)cn3)nc3cc(S(C)(=O)=O)ccc23)n[nH]1
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 42.5 %

Procedure:
To 2-(difluoro(5-fluoropyridin-2-yl)methyl)-7-(methylsulfonyl)quinazolin-4-ol (76 mg, 0.21 mmol) were added phosphoryl tribromide (1.21 g), toluene (0.5 mL), and DIEA (0.072 mL, 0.42 mmol), and the mixture was heated at 100° C. for 10 min. The mixture was cooled and partitioned between EtOAc and saturated aq sodium bicarbonate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. To the residue was added a solution of 5-methyl-1H-pyrazol-3-amine (59 mg, 0.6 mmol) in DMF (3 mL) and the mixture was stirred at rt for 20 min. The crude mixture was purified by preparative HPLC (Phenomenex C-18 reverse phase column, eluting with a gradient of solvent B=0.05% HOAc/ACN and solvent A=0.05% HOAc/H2O) to afford 2-(difluoro(5-fluoropyridin-2-yl)methyl)-N-(5-methyl-1H-pyrazol-3-yl)-7-(methylsulfonyl)quinazolin-4-amine (40 mg, 45%). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.19 (s, 3H) 3.39 (s, 3H) 6.06 (s, 1H) 7.97-8.05 (m, 2H) 8.09 (d, J=7.72 Hz, 1H) 8.33 (s, 1H) 8.67 (s, 1H) 8.97 (d, J=8.48 Hz, 1H) 11.10 (br s, 1H) 12.28 (br s, 1H); LC-MS (ESI) m/z 449 (M+H)+.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:21]3[C:16](=[CH:17][C:18]([N:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)=[CH:19][CH:20]=3)[N:15]([C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)[CH:14]=2)=[CH:9][CH:8]=1.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>C(Cl)Cl>[N:22]1([C:18]2[CH:17]=[C:16]3[C:21]([C:13]([C:10]4[CH:11]=[CH:12][C:7]([OH:6])=[CH:8][CH:9]=4)=[CH:14][N:15]3[C:28]3[CH:29]=[CH:30][N:31]=[CH:32][CH:33]=3)=[CH:20][CH:19]=2)[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]1
Reactant: COc1ccc(-c2cn(-c3ccncc3)c3cc(N4CCNCC4)ccc23)cc1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Oc1ccc(-c2cn(-c3ccncc3)c3cc(N4CCNCC4)ccc23)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 90 %

Procedure:
Boron tribromide (BBr3, 17 μL, 0.182 mmol) was added to a mixture solution of 3-(4-methoxyphenyl)-6-(piperazin-1-yl)-1-(pyridin-4-yl)-1H-indole (14 mg, 0.036 mmol) in methylene chloride (0.5 mL) at −78° C. After stirring at room temperature for 15 hours, the reaction solution was added to a mixture solution of saturated sodium bicarbonate aqueous solution and ethyl acetate and then extracted with ethyl acetate. The collected organic layer was washed with brine and concentrated under reduced pressure by drying with anhydrous magnesium sulfate. The target compound (12 mg) was obtained as yellow solid.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH:4]([N:7]([C:14]#[N:15])[NH:8][C:9]([O:11]CC)=O)([CH3:6])[CH3:5]>C(O)C>[CH3:1][N:2]([CH3:3])[C:14]1[N:7]([CH:4]([CH3:5])[CH3:6])[NH:8][C:9](=[O:11])[N:15]=1
Reactant: CNC
Reactant: CCOC(=O)NN(C#N)C(C)C
Solvent: CCO
Product: CC(C)n1[nH]c(=O)nc1N(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a solution of 100 ml of 33 % strength dimethylamine in absolute ethanol are added dropwise 35 g (0.2 mol) of ethyl 2-isopropyl-2-cyano-hydrazinecarboxylate. The solution is first stirred for 8 hours at room temperature and then for 1.5 hours at the reflux temperature. Concentration in a rotary evaporator gives an oily residue which slowly crystallizes on standing. Recrystallization from cyclohexane/ethyl acetate (4:1 by vol.) gives 30 g (88 % of theory) of 5-dimethylamino-1-isopropyl-1,2-dihydro-3H-1,2,4-triazol -3-one having a melting point of 111° C.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C:14](=[O:15])[N:13]([CH2:16][CH:17]2[CH2:20][CH2:19][O:18]2)[C:12]2[C:7]1=[N:8][C:9]([C:21]1[C:29]3[C:24](=[N:25][CH:26]=[CH:27][CH:28]=3)[N:23]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[F:37])[N:22]=1)=[N:10][CH:11]=2.C([SiH](CC)CC)C.O.C(=O)([O-])O.[Na+]>FC(F)(F)C(O)=O.C(OCC)(=O)C>[F:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[CH2:30][N:23]1[C:24]2=[N:25][CH:26]=[CH:27][CH:28]=[C:29]2[C:21]([C:9]2[N:8]=[C:7]3[C:12]([N:13]([CH2:16][CH:17]4[CH2:20][CH2:19][O:18]4)[C:14](=[O:15])[NH:6]3)=[CH:11][N:10]=2)=[N:22]1
Reactant: COc1ccc(Cn2c(=O)n(CC3CCO3)c3cnc(-c4nn(Cc5ccccc5F)c5ncccc45)nc32)c(OC)c1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=c1[nH]c2nc(-c3nn(Cc4ccccc4F)c4ncccc34)ncc2n1CC1CCO1
Yield: 48.9 %

Procedure:
476 mg (0.82 mmol) of the compound from example 86A were dissolved in 15 ml of trifluoroacetic acid, 953 mg (8.20 mmol) of triethylsilane were added and the mixture was heated to reflux for 18 h. The reaction mixture was admixed with water and ethyl acetate, and neutralized with saturated aqueous sodium hydrogencarbonate solution. The organic phase was dried over sodium sulfate and concentrated on a rotary evaporator. The residue was dried under high vacuum, and purified by means of preparative HPLC (eluent: methanol/water with 0.1% trifluoroacetic acid, gradient 30:70→90:10). 173 mg of the title compound were obtained (49% of theory).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][Cl:5].Cl.CN(CCCl)P(Cl)(Cl)=O.[CH3:16][C:17]1([CH3:32])[O:21][CH:20]([CH2:22][CH2:23][P:24]([Cl:31])(N(C)CCBr)=[O:25])[CH2:19][O:18]1>>[CH3:16][C:17]1([CH3:32])[O:21][CH:20]([CH2:22][CH2:23][P:24]([Cl:31])([N:2]([CH3:1])[CH2:3][CH2:4][Cl:5])=[O:25])[CH2:19][O:18]1
Reactant: CNCCCl
Reactant: CN(CCBr)P(=O)(Cl)CCC1COC(C)(C)O1
Agent: CN(CCCl)P(=O)(Cl)Cl
Agent: Cl
Product: CN(CCCl)P(=O)(Cl)CCC1COC(C)(C)O1
Yield: 61 %

Procedure:
This compound was prepared from N-methyl-N-chloroethylamine.HCl via N-methyl-N-(2-chloroethyl)phosphoramidic dichloride, as described for 16a (14 mmol scale). The crude residue was purified by chromatography (1:4 EtOAc:hexanes) to give 16b as an oil (2.72 g, 61%): Rf 0.75 (1:1 EtOAc:hexanes); 1H NMR (CDCl3) 4.22(m, 4H), 3.60(m, 3H), 3.42(m, 2H), 2.80(d, 3H, J=12.85 Hz), 1.99(dt, 2H, J=6.11 Hz), 1.36(d, 6H, J=15.82 Hz)ppm; -P NMR (CDCl3) -7.69, -7.92 ppm (1:1 ratio of diastereomers).
Reaction SMILES: [CH3:1][CH:2]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Na].[Br:14][C:15]1[CH:22]=[CH:21][C:18](CBr)=[CH:17][CH:16]=1>C(O)C>[Br:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:1][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:17][CH:16]=1
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: BrCc1ccc(Br)cc1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(Cc1ccc(Br)cc1)C(=O)OCC
Reaction time: 72 h
Yield: 91.7 %

Procedure:
A solution of diethyl methylmalonate (87 g) in absolute ethanol (100 ml) was added to a pre-formed solution of sodium (11.5 g) in ethanol (400 ml) under argon. A hot solution of p-bromobenzylbromide (125 g) in absolute alcohol (200 ml) was added rapidly with vigorous stirring, which was continued for 3 days and the solid so formed was removed by filtration. The filtrate was evaporated and the residue dissolved in ethyl acetate (1 l), washed with brine (250 ml), dried (MgSO4) and evaporated. The residual oil was distilled under vacuum to give diethyl (4-bromophenyl)methylmalonate (150.7 g) b.p. 130-133/0.03 mm Hg; 1H NMR (d6 -DMSO): 1.33 (t, 6 H), 1.4 (s, 3 H), 3.27 (s, 2 H), 4.30 (q, 4 H), 7.23 (d, 2 H), 7.6 (d, 2 H)
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Cl:4][C:5]1[CH:20]=[CH:19][C:8]([O:9][C:10]2[N:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](Cl)=[O:13])=[CH:7][CH:6]=1>O.C1C=CC=CC=1>[Cl:4][C:5]1[CH:20]=[CH:19][C:8]([O:9][C:10]2[N:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([N:2]([CH3:3])[CH3:1])=[O:13])=[CH:7][CH:6]=1
Reactant: O=C(Cl)c1cccnc1Oc1ccc(Cl)cc1
Reactant: CNC
Solvent: O
Solvent: c1ccccc1
Product: CN(C)C(=O)c1cccnc1Oc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a rapidly stirred mixture of 10 mL of benzene and dimethylamine (2.6 mL of a 40% solution) was added a slurry of 2-(4-chlorophenoxy)nicotinoyl chloride (0.536 g, 2 mmol, Maybridge Chemical Co.) over 5 min. The biphasic mixture was stirred at room temperature for 18 h and then diluted with water and benzene. The aqueous layer was further extracted with benzene and the organic layers were combined and washed (brine, water), dried (Na2SO4) and concentrated in vacuo to produce the product as a pale yellow oil (0.432 g); δH (CDCl3, 400 MHz) 8.14 (dd, 1H), 7.72 (dd, 1H), 7.33 (m, 2H), 7.03 (m, 3H), 3.12 (s, 3H), 2.99 (s, 3H); MS m/z279, 277 (MH+).
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([CH:8]([OH:10])[CH3:9])[CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].O>C(Cl)Cl>[CH3:20][C:19]([Si:16]([CH3:18])([CH3:17])[O:10][CH:8]([C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([F:1])[N:7]=1)[CH3:9])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(O)c1cccc(F)n1
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: CC(O[Si](C)(C)C(C)(C)C)c1cccc(F)n1
Yield: 86 %

Procedure:
(+/−)-1-(6-Fluoro-2-pyridinyl)ethanol (0.707 g, 5.01 mmol) was dissolved in 50 mL of DCM with stirring, imidazole (0.750 g, 11.0 mmol) and tert-butyldimethylsilyl chloride (0.831 g, 5.51 mmol) were added. The reaction was stirred for 16 h and poured into water. The layers were separated, and the aqueous layer was washed with 1:1 EtOAc/hexanes. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to provide 1.10 g (86%) of the title compound, 1H NMR (400 MHz, DMSO-d6) δ 7.97 (m, 1H), 7.37 (m, 1H), 7.00 (m, 1H), 4.79 (q, J=6.4 Hz, 1H), 1.34 (d, 6.4 Hz, 3H), 0.85 (s, 9H), 0.04 (s, 3H), 0.03 (s, 3H).