Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C.[N:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:46]=[CH:45][C:41]([C:42]([OH:44])=O)=[CH:40][CH:39]=2)=[CH:34][CH:33]=1.[CH:47]1([NH:50][CH:51]2[CH2:56][CH2:55][N:54]([C:57]3[O:61][N:60]=[C:59]([C:62]4[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=4)[N:58]=3)[CH2:53][CH2:52]2)[CH2:49][CH2:48]1>CN(C)C=O>[CH:47]1([N:50]([CH:51]2[CH2:52][CH2:53][N:54]([C:57]3[O:61][N:60]=[C:59]([C:62]4[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=4)[N:58]=3)[CH2:55][CH2:56]2)[C:42](=[O:44])[C:41]2[CH:40]=[CH:39][C:38]([C:35]3[CH:34]=[CH:33][N:32]=[CH:37][CH:36]=3)=[CH:46][CH:45]=2)[CH2:49][CH2:48]1
Reactant: O=C(O)c1ccc(-c2ccncc2)cc1
Reactant: c1ccc(-c2noc(N3CCC(NC4CC4)CC3)n2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1ccc(-c2ccncc2)cc1)N(C1CC1)C1CCN(c2nc(-c3ccccc3)no2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (75 mg) and ethyldiisopropylamine (74 μL) are added to a solution of 4-pyridin-4-yl-benzoic acid (42 mg) in N,N-dimethylformamide (5 mL) at room temperature. The solution is stirred for 10 min prior to the addition of cyclopropyl-[1-(3-phenyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-amine (60 mg). The resulting mixture is stirred at 60° C. for 5 h, cooled to room temperature and concentrated in vacuo. The crude product is purified by HPLC (H2O/MeOH/TFA). LC (method 6): tR=1.44 min; Mass spectrum (ESI+): m/z=466 [M+H]+.
Reaction SMILES: [CH3:1][C:2]12[O:13][C:8]([CH3:14])([CH2:9][C:10](=[O:12])[CH2:11]1)[CH:7]1[CH:3]2[O:4][C:5]([CH3:16])([CH3:15])[O:6]1.C([N-]C(C)C)(C)C.[Li+].[F:25][C:26]([F:41])([C:37]([F:40])([F:39])[F:38])[C:27]([F:36])([F:35])[C:28]([F:34])([F:33])[S:29](F)(=[O:31])=[O:30]>C1COCC1.O>[CH3:14][C:8]12[O:13][C:2]([CH3:1])([CH:11]=[C:10]([O:12][S:29]([C:28]([F:33])([F:34])[C:27]([F:35])([F:36])[C:26]([F:25])([F:41])[C:37]([F:40])([F:39])[F:38])(=[O:31])=[O:30])[CH2:9]1)[CH:3]1[CH:7]2[O:6][C:5]([CH3:16])([CH3:15])[O:4]1
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CC1(C)OC2C(O1)C1(C)CC(=O)CC2(C)O1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)OC2C(O1)C1(C)CC(OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)=CC2(C)O1
Temperature: -78 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
A solution of 1,4,4,7-tetramethyl-3,5,11-trioxa-tricyclo[5.3.1.02,6]undecan-9-one (Bulletin of the Chemical Society of Japan (1983), 56(9), 2680-99, 386 mg, 1.71 mmol) in THF (10 mL) was cooled to −78° C. under Ar and treated with lithium diisopropylamide (LDA) (1.00 mL of 2M in heptane/THF/ethylbenzene, 2 mmol). The resulting mixture was stirred at −78° C. for 2 h and treated dropwise with nonafluoro-1-butanesulfonylfluoride (0.60 mL, 3.4 mmol). The reaction mixture was allowed to warm to RT and stirred overnight and diluted with water (10 mL). The product was extracted with ether (4×10 mL). The organic layers were combined, dried (Na2SO4) and the product was purified on silica gel (0-2% EtOAc/hexane) to give the title compound (546 mg, 63%). 1H-NMR (CDCl3; 400 MHz): δ 5.78 (br s, 1H), 4.37 (d, 1H, J=5.5 Hz), 4.28 (d, 1H, J=5.5 Hz), 2.52 (dd, 1H, J=17.6, 2.0 Hz), 2.04 (d, 1H, J=17.6, 1.4 Hz), 1.43 (s, 3H), 1.38 (s, 3H), 1.32 (s, 3H), 1.25 (s, 3H).
Reaction SMILES: B(F)(F)F.[F:5][C:6]1[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=1.[Cl:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19](Cl)=[O:20].O>C(OCC)C>[Cl:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([C:9]1[CH:10]=[CH:11][C:6]([F:5])=[CH:7][C:8]=1[OH:12])=[O:20]
Reactant: O=C(Cl)CCCCCCl
Reactant: Oc1cccc(F)c1
Agent: FB(F)F
Solvent: CCOCC
Solvent: O
Product: O=C(CCCCCCl)c1ccc(F)cc1O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 85.3 %

Procedure:
Reaction under N2 atmosphere. BF3 in diethylether (215 ml) was cooled to 0° C. 3-Fluoro-phenol (0.25 mol) was added. 6-Chloro-hexanoyl chloride (0.51 mol) added and the resulting reaction mixture was stirred for 15 min at 0° C., then allowed to warm to room temperature. The reaction mixture was then stirred overnight at 130° C. The mixture was cooled room temperature. Water was added while cooling. This mixture was extracted twice with diisopropyl ether. The separated organic layer was dried, filtered and the solvent evaporated. The residue was by column chromatography over silica gel (eluent: CH2Cl2/hexane 50/50), then by HPLC (eluent: CH2Cl2/hexane 50/50). The fractions were collected and the solvent was evaporated, yielding 52.2 g of 6-chloro-1-(4-fluoro-2-hydroxyphenyl)-1-hexanone (interm 17).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([OH:8])[CH:7]=1.[CH2:11](Br)[CH2:12][Br:13].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:13][CH2:12][CH2:11][O:8][C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[O:9][CH3:10]
Reactant: COc1ccc(F)cc1O
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(F)cc1OCCBr
Temperature: 80 °C
Yield: 66.2 %

Procedure:
A suspension of 10.0 g of 5-fluoro-2-methoxyphenol, 52.9 g of ethylenebromide and 14.6 g of potassium carbonate in 50 ml of N,N-dimethylformamide was heated for 11 hours at 80° C. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and evaporated. The residue was chromatographed on silica gel using 50% chloroform-n-hexane as an eluent to give 11.6 g of the desired compound as a colorless oil.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[H-].[Na+].[Br:8][C:9]1[CH:10]=[C:11]([CH2:29]OS(C)(=O)=O)[C:12]2[O:21][C:20]3[CH2:19][CH2:18][N:17]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:16][C:15]=3[C:13]=2[CH:14]=1>O1CCCC1>[N:1]1([CH2:29][C:11]2[C:12]3[O:21][C:20]4[CH2:19][CH2:18][N:17]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[CH2:16][C:15]=4[C:13]=3[CH:14]=[C:9]([Br:8])[CH:10]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: CC(C)(C)OC(=O)N1CCc2oc3c(COS(C)(=O)=O)cc(Br)cc3c2C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2oc3c(Cn4cccn4)cc(Br)cc3c2C1
Temperature: 25 °C
Yield: 35.6 %

Procedure:
To a solution of 1H-pyrazole (20 mg, 0.52 mmol) in tetrahydrofuran (3 mL) at 0° C. was added sodium hydride (60% dispersion in oil, 26 mg, 0.39 mmol). After stirring the mixture for 1 h the product of step A (120 mg, 0.26 mmol) was added and the reaction warmed to ambient temperature over 2 h. The reaction mixture was quenched with 5% sodium bicarbonate solution and then extracted with ethyl acetate (3×20 mL). The combined organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (95:5 hexanes/ethyl acetate) to give tert-butyl 6-((1H-pyrazol-1-yl)methyl)-8-bromo-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (40 mg, 35%) as a yellow solid: 1H NMR (CDCl3, 300 MHz) δ 7.55 (d, J=1.5 Hz, 1H), 7.48 (d, J=1.8 Hz, 2H), 7.14 (d, J=1.5 Hz, 1H), 6.28 (t, J=2.1 Hz, 1H), 5.55 (s, 2H), 4.50 (s, 2H), 3.82 (t, J=5.4 Hz, 2H), 2.87 (t, J=5.4 Hz, 2H), 1.50 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.Cl.[H][H].O>CO.[Pt]>[NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][NH:4][C@H:3]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: [H][H]
Reactant: Nc1cccnc1-c1ccccc1
Agent: [Pt]
Agent: Cl
Solvent: CO
Solvent: O
Product: N[C@H]1CCCN[C@H]1c1ccccc1
Yield: 87.3 %

Procedure:
In a bottle were placed 2.65 g (15.6 mmol) of 3-amino-2-phenylpyridine, 10.6 g of 5% platinum/carbon and 106 mL of 1.5 M HCl in methanol. The mixture was shaken under an atmosphere (ca. 40 p.s.i.) of hydrogen for 2.5 hours. Water was added to the system, the mixture was filtered through a pad of diatomaceous earth and the pad was rinsed with ca. 700 mL of water. The filtrate was made basic with solid sodium hydroxide and extracted with two portions of dichloromethane. The combined organic fractions were washed with water, dried (sodium sulfate) and concentrated with a rotary evaporator to obtain 2.4 g of the title compound as a yellow oil.
Reaction SMILES: [C:1]([CH:5]1[N:9]([CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[C:8](=[O:15])[C:7]([C:16]2[NH:21][C:20]3[CH:22]=[CH:23][C:24]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][C:19]=3[S:18](=[O:32])(=[O:31])[CH:17]=2)=[C:6]1[OH:33])([CH3:4])([CH3:3])[CH3:2].C(C1[N:42](CC2C=CC(F)=C(C)C=2)[C:41](=O)C(C2NC3C=CC(NS(C)(=O)=O)=CC=3S(=O)(=O)C=2)=C1O)(C)(C)C>>[C:1]([CH:5]1[N:9]([CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[C:8](=[O:15])[C:7]([C:16]2[NH:21][C:20]3[CH:22]=[CH:23][C:24]([NH:26][S:27]([CH3:30])(=[O:28])=[O:29])=[CH:25][C:19]=3[S:18](=[O:32])(=[O:31])[C:17]=2[C:41]#[N:42])=[C:6]1[OH:33])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)CCN1C(=O)C(C2=CS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)C1C(C)(C)C
Reactant: Cc1cc(CN2C(=O)C(C3=CS(=O)(=O)c4cc(NS(C)(=O)=O)ccc4N3)=C(O)C2C(C)(C)C)ccc1F
Product: CC(C)CCN1C(=O)C(C2=C(C#N)S(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)C1C(C)(C)C

Procedure:
N-{3-[5-tert-Butyl-4-hydroxy-1-(3-methyl-butyl)-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-2-cyano-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,4]thiazin-7-yl}-methanesulfonamide was prepared from N-{3-[5-tert-butyl-4-hydroxy-1-(3-methyl-butyl)-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,4]thiazin-7-yl}-methanesulfonamide (15c, R3=Me2CH(CH2)2) to afford 28 mg (27%) of I-26: LCMS RT 2.48 min, M−H.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][N:8]=[C:7]([NH:10][CH2:11][CH2:12][NH:13][C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[C:6]=2[CH:22]=1.C(N(CC)CC)C.[C:30](Cl)(=[O:32])[CH3:31]>ClCCl>[C:30]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][N:8]=[C:7]([NH:10][CH2:11][CH2:12][NH:13][C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[C:6]=2[CH:22]=1)(=[O:32])[CH3:31]
Reactant: Nc1ccc2snc(NCCNC(=O)c3ccccn3)c2c1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1ccc2snc(NCCNC(=O)c3ccccn3)c2c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
N-(2-(5-Aminobenzo[d]isothiazol-3-ylamino)ethyl)picolinamide (95 mg, 0.30 mmol) was dissolved in anhydrous dichloromethane (5 mL) with triethylamine (50 μL, 0.36 mmol). The solution was cooled on an ice-water bath and a solution of acetyl chloride (26 μL, 0.36 mmol) in dichloromethane (0.5 mL) was added dropwise. The reaction mixture was allowed to stir for 2.5 h while warming to room temperature. The solution was diluted with dichloromethane, washed with saturated sodium bicarbonate solution, then dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under reduced pressure to yield N-(2-(5-acetamidobenzo[d]isothiazol-3-ylamino)ethyl) picolinamide as a white solid. 1H NMR (300 MHz, CDCl3): 8.48 (d, 1H), 8.30 (s, 1H), 8.20 (d, 1H), 7.80 (t, 1H), 7.52 (s, 1H), 7.42 (m, 1H), 7.31 (d, 1H), 7.18 (s, 1H), 6.82 (d, 1H), 3.70 (m, 2H), 3.50 (m, 2H), 2.20 ppm (s, 3H). MW=355 confirmed by LC-MS, tr=9.35 min (Method Y) MH+=356.
Reaction SMILES: CO[C:3]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[C:5](=[O:15])[CH:4]=1.[CH2:16]([CH2:18][NH2:19])[OH:17]>CO>[OH:17][CH2:16][CH2:18][NH:19][C:3]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[C:5](=[O:15])[CH:4]=1
Reactant: NCCO
Reactant: COc1cc(=O)c2ccccc2[nH]c1=O
Solvent: CO
Product: O=c1[nH]c2ccccc2c(=O)cc1NCCO
Temperature: 25 °C
Yield: 63 %

Procedure:
To a solution of 3-methoxy-2,5-dioxo-2,5-dihydro-1H-benz[b]azepine (1.0 g) in methanol (20 mL) was added ethanolamine (0.36 g). The mixture was heated to reflux until a precipitate formed. The reaction mixture was cooled to room temperature, filtered, and the resulting solid was recrystallized from ethanol to give the title compound (0.72 g); mp 207° C.; NMR: 5.91 (s,1); MS(EI): m/z=232(M). Analysis for C12H12N2O3.0.2 H2O: Calculated: C, 61.11; H, 5.30; N, 11.88; Found: C, 61.13; H, 5.20; N, 11.72.
Reaction SMILES: [Cl:1]Cl.[CH:3]1([C:6]2[NH:7][C:8]([CH:13]([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])=[CH:9][C:10](=[O:12])[N:11]=2)[CH2:5][CH2:4]1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[Cl:1][C:9]1[C:10](=[O:12])[N:11]=[C:6]([CH:3]2[CH2:4][CH2:5]2)[NH:7][C:8]=1[CH:13]([O:14][CH2:15][CH3:16])[O:17][CH2:18][CH3:19]
Reactant: CCOC(OCC)c1cc(=O)nc(C2CC2)[nH]1
Reactant: ClCl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(OCC)c1[nH]c(C2CC2)nc(=O)c1Cl
Temperature: 29 °C
Yield: 98 %

Procedure:
Chlorine was carefully passed through 2-cyclopropyl-6-(diethoxymethyl)-4(1H)-pyrimidinone (i.e. the product of Example 3) (46.0 g, 0.193 mol) and sodium acetate (18.8 g, 0.229 mol) in acetic acid (185 mL). The temperature was maintained in the range of about 28-30° C. When the starting material had been consumed, the flow of chlorine was stopped immediately. Toluene (185 mL) was added, and the mixture was evaporated under reduced pressure. The process was repeated. The mixture was partitioned between ethyl acetate (450 mL) and water (50 mL). The organic layer was further washed with water (4×50 mL), dried and evaporated to leave the product as an off-white solid (51.75 g, 98% yield). Product recrystallized from hexanes had a melting point of 109-111° C.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][NH:7][C:8](=[O:28])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:18]=[CH:17][C:16]=2[NH2:27])[CH:10]=1.[OH:34][C:35]1[CH:36]=[C:37]([CH:41]=[CH:42][CH:43]=1)[C:38](O)=[O:39].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:34][C:35]1[CH:36]=[C:37]([CH:41]=[CH:42][CH:43]=1)[C:38]([NH:27][C:16]1[CH:17]=[CH:18][C:19]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:20][C:15]=1[C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][N:12]=1)[C:8]([NH:7][CH2:6][C:5]1[CH:29]=[CH:30][CH:31]=[C:3]([C:2]([F:1])([F:32])[F:33])[CH:4]=1)=[O:28])=[O:39]
Reactant: Nc1ccc(N2CCCCC2)cc1-c1cc(C(=O)NCc2cccc(C(F)(F)F)c2)ccn1
Reactant: O=C(O)c1cccc(O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(N3CCCCC3)ccc2NC(=O)c2cccc(O)c2)c1
Reaction time: 18 h
Yield: 29.6 %

Procedure:
To a mixture of 4.1c (91 mg, 0.20 mmol), 3-hydroxybenzoic acid (28 mg, 0.20 mmol), and diisopropylethylamine (104 □L, 0.60 mmol) in DMF (2 mL) was added HATU (76 mg, 0.20 mmol) and the solution stirred for 18 h. The solvent was removed and the resulting residue purified by reverse-phase HPLC eluting with a water/acetonitrile gradient containing 0.1% TFA and lyophilized to give 34 mg (30%) of the product.
Reaction SMILES: [OH-:1].[Na+].[CH2:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[CH2:15]C)[O:11][C:10](=O)[C:9]([N+]([O-])=O)=[C:8]2[OH:21])C>O>[CH3:15][C:14]1[C:5]([CH3:3])=[C:6]2[C:7]([C:8]([OH:21])=[CH:9][C:10](=[O:11])[O:1]2)=[CH:12][CH:13]=1
Reactant: CCc1cc2oc(=O)c([N+](=O)[O-])c(O)c2cc1CC
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc2c(O)cc(=O)oc2c1C

Procedure:
Dilute sodium hydroxide solution was added to a suspension of 6,7-diethyl-4-hydroxy-3-nitrocoumarin (2.90g) in water (20 ml) till the pH of the solution reached 14. Filtration gave the product as a monohydrate, m.p. 249°-251°(d), (C13H12NO5Na.H2O requires C, 51.49; H, 4.65; N, 4.62; Na, 7.58. Found: C, 52.08; H, 4.65; N, 4.83; Na, 7.81) after washing with water and drying under vacuum.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[CH:10]=[CH:11][C:12](=O)[NH:13][N:14]=2)[CH:4]=1.P(Cl)(Cl)([Cl:20])=O>>[F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[N:14]=[N:13][C:12]([Cl:20])=[CH:11][CH:10]=2)[CH:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1ccc(-c2cccc(C(F)(F)F)c2)n[nH]1
Product: FC(F)(F)c1cccc(-c2ccc(Cl)nn2)c1

Procedure:
A mixture of 12.6 g. of 6-(α,α,α-trifluoro-m-tolyl)-3(2H)-pyridazinone and 200 ml. of phosphorus oxychloride is heated on a steam bath for 18 hours. The mixture is concentrated under vacuum and the residue triturated with cold water. The resulting solid is washed with water and air dried to give 13.5 g. of cream colored crystals, m.p. 131°-133° C. Recrystallization from methanol gives 6-(α,α,α-trifluoro-m-tolyl)-3-chloropyridazine as white crystals, m.p. 131°-133° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[NH:7][C:8](=[O:15])[C:9]3[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=3[C:5]=2[C:4]([C@H:16]2[CH2:20][CH2:19][CH2:18][NH:17]2)=[N:3]1.[CH:21](=O)[CH2:22][CH3:23].C([BH3-])#N.[Na+]>CO>[CH3:1][N:2]1[C:6]2[NH:7][C:8](=[O:15])[C:9]3[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=3[C:5]=2[C:4]([C@H:16]2[CH2:20][CH2:19][CH2:18][N:17]2[CH2:21][CH2:22][CH3:23])=[N:3]1
Reactant: CCC=O
Reactant: Cn1nc([C@H]2CCCN2)c2c3c(c(=O)[nH]c21)CCCC3
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCCN1CCC[C@@H]1c1nn(C)c2[nH]c(=O)c3c(c12)CCCC3
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.3 %

Procedure:
To a 250 mL of reaction flask were added the compound of Example 4F (1.39 g, 5.1 mmol), propanal (0.888 g, 15.31 mmol) and methanol (90 mL). The mixture was stirred for 2 hr at room temperature. Sodium cyanoborohydride (1.0 g, 15.9 mmol) was added to the mixture. The reaction was kept overnight with stirring. The reaction was stopped. The product was concentrated by rotary-evaporation and purified by column chromatography to give 1.4 g of the title compound. Yield: 87.5%. MS (ESI): m/z 315 (M+H)+
Reaction SMILES: [CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([Cl:19])=[CH:14][CH:15]=2)[N:10]([C:20]([CH:22]2[CH2:26][CH2:25][CH2:24][NH:23]2)=O)C1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27]1([CH3:35])[CH:32]=[CH:31][C:30]([CH:33]=O)=[CH:29][CH:28]=1>ClCCl>[CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([Cl:19])=[CH:14][CH:15]=2)[N:10]=[C:20]1[CH:22]1[CH2:26][CH2:25][CH2:24][N:23]1[CH2:33][C:30]1[CH:31]=[CH:32][C:27]([CH3:35])=[CH:28][CH:29]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2ccc(Cl)cc2N(C(=O)C2CCCN2)CN1Cc1ccccc1
Reactant: Cc1ccc(C=O)cc1
Solvent: ClCCl
Product: Cc1ccc(CN2CCCC2c2nc3cc(Cl)ccc3c(=O)n2Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 23.7 %

Procedure:
Formula I where U—V is —N(R6)—CReRf—; R1, R2, R4, and Ra to Rf are H; R3 is chloro; R5 is benzyl: and R6 is p-methyl-benzyl: Crude 3-benzyl-7-chloro-1-(pyrrolidine-2-carbonyl)-2,3-dihydro-1H-quinazoline-4-one (170 mg, 0.50 mmol) dissolved in dichloromethane (5 mL) was treated with p-tolualdehyde (80 μL, 0.7 mmol) and NaHB(OAc)3 (350 mg, 1.65 mmol), and the mixture was stirred for 40 minutes at room temperature. The reaction was quenched with saturated NaHCO3 (2.2 mL) and the aqueous phase extracted with dichloromethane (25 mL). The organic layers were combined and dried over Na2SO3, filtered and concentrated under vacuum. The crude residue was purified by silica gel chromatography using a stepwise gradient of 20% ethyl acetate/hexanes to 50% methanol/ethyl acetate as eluent to give 52.5 mg (24% yield) of desired product of Formula I, 3-benzyl-7-chloro-2-[1-(4-methyl-benzyl)-pyrrolidin-2-yl]-3Hquinazolin4-one. LRMS (MH+) m/z 445.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C:9](=[O:10])[N:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][C:13]=2[CH3:22])[C:7]2[CH:23]=[CH:24][C:25]([C:27]#[N:28])=[CH:26][C:6]=2[N:5]([C:29](=[O:35])[CH2:30][S:31]([CH3:34])(=[O:33])=[O:32])[C@H:4]1[CH3:36].[C:37]([O:41][C:42]([N:44]([CH3:51])[C@@H:45]([CH2:49][CH3:50])[C:46](O)=[O:47])=[O:43])([CH3:40])([CH3:39])[CH3:38].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:27]([C:25]1[CH:24]=[CH:23][C:7]2[N:8]([CH2:11][C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=[CH:14][C:13]=3[CH3:22])[C:9](=[O:10])[C@@H:3]([NH:2][C:46](=[O:47])[C@@H:45]([N:44]([CH3:51])[C:42](=[O:43])[O:41][C:37]([CH3:38])([CH3:39])[CH3:40])[CH2:49][CH3:50])[C@H:4]([CH3:36])[N:5]([C:29](=[O:35])[CH2:30][S:31]([CH3:34])(=[O:33])=[O:32])[C:6]=2[CH:26]=1)#[N:28]
Reactant: Cc1ccc2ccccc2c1CN1C(=O)[C@@H](N)[C@H](C)N(C(=O)CS(C)(=O)=O)c2cc(C#N)ccc21
Reactant: CC[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC[C@@H](C(=O)N[C@@H]1C(=O)N(Cc2c(C)ccc3ccccc23)c2ccc(C#N)cc2N(C(=O)CS(C)(=O)=O)[C@H]1C)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To a rt solution of (3S,4S)-3-amino-4-methyl-1-((2-methylnaphthalen-1-yl)methyl)-5-(2-(methylsulfonyl)acetyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbonitrile hydrochloride (100 mg, 190 μmol) in DMF (632 μl) was added (S)-2-(tert-butoxycarbonyl(methyl)amino)butanoic acid (45.3 mg, 209 μmol), N,N-diisopropylethylamine (131 μl, 759 μmol), and HBTU (79.2 mg, 209 μmol). The reaction was stirred at rt for 30 min, then purified by reverse phase preparative HPLC to provide tert-butyl(S)-1-((3S,4S)-7-cyano-4-methyl-1-((2-methylnaphthalen-1-yl)methyl)-5-(2-(methylsulfonyl)acetyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxobutan-2-yl(methyl)carbamate (118 mg, 90%) as a white solid. MS m/z 712 (MNa)+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[NH:7][C:8]([CH2:12][C:13]([N:15]([CH3:17])[CH3:16])=[O:14])=[N:9]2)=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].[Br:24]Br.O>C(O)(=O)C>[Br:24][CH:12]([C:8]1[NH:7][C:6](=[O:18])[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=1)[C:13]([N:15]([CH3:17])[CH3:16])=[O:14]
Reactant: CN(C)C(=O)Cc1nc2cc(Cl)ccc2c(=O)[nH]1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CN(C)C(=O)C(Br)c1nc2cc(Cl)ccc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2-(7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-N,N-dimethylacetamide and sodium acetate (930 mg, 3 eq.) in acetic acid (15 ml), was added bromine (190 ul, 1 eq.). The reaction mixture was stirred at room temperature overnight. Water was added and the product was extracted into ethyl acetate. The ethyl acetate layer was washed several times with water, saturated sodium bicarbonate, saturated sodium chloride, dried over magnesium sulfate, filtered, and concentrated to give 2-bromo-2-(7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-N,N-dimethylacetamide (0.95 g) as a brown solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[OH:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=[CH:12][CH:11]=1>CCOC(C)=O.C1CCCCC1>[Cl:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([O:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[CH:12][CH:11]=2)[N:3]=1
Reactant: Clc1cncc(Cl)n1
Reactant: Oc1ccnc2ccccc12
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: Clc1cncc(Oc2ccnc3ccccc23)n1
Yield: 14 %

Procedure:
Using Method DD with 2,6-dichloropyrazine (250 mg, 1.69 mmol) and 4-hydroxyquinoline (270 mg, 1.49 mmol), and purification by column chromatography (AcOEt cyclohexane, 1:1), the title compound was obtained (60 mg). Yield: 14%. 1H NMR (250 MHz, DMSO-d6) δ 7.45 (d, 1H, Harom 3, J=4.9 Hz), 7.67 (t, 1H, Harom 7, J=7.6 Hz), 7.86 (t, 1H, Harom 6, J=7.8 Hz), 8.12 (d, 2H, Harom 3+5, J=8.7 Hz), 8.67 (s, 1H, HPz 5), 8.82 (s, 1H, HPz 3), 8.94 (d, 1H, Harom 2, J=4.9 Hz). m/z: 258.0 [(M+H)+, calcd for C13H8ClN3O 257.0].