Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[N:5]2[CH:11]=[N:10][CH:9]=[C:6]2[S:7][CH:8]=1.C(N(CC)C(C)C)(C)C.[S:21](Cl)(=[O:24])(=[O:23])[NH2:22]>CN(C=O)C>[NH2:22][S:21]([N:2]([CH2:3][C:4]1[N:5]2[CH:11]=[N:10][CH:9]=[C:6]2[S:7][CH:8]=1)[CH3:1])(=[O:24])=[O:23]
Reactant: NS(=O)(=O)Cl
Reactant: CNCc1csc2cncn12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(Cc1csc2cncn12)S(N)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 47 mg potion of 3-(N-methylamino)methylimidazo[5,1-b]thiazole was dissolved in 1 ml of DMF, and 0.305 ml of N,N-diisopropylethylamine and 100 mg of sulfamoyl chloride were further added at -45° C., followed by stirring for 8 hours, while the solution was heated up to room temperature. Then, the reaction solution was concentrated under reduced pressure, and 10 ml of water and an aqueous sodium hydrogencarbonate solution were then added to adjust the solution to pH 9.0. Afterward, extraction was carried out four times with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and then filtered, and the solvent was evaporated under reduced pressure. The resulting residue was purified by a silica gel column chromatograph to obtain 37.4 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:14]2[CH2:18][CH:17]([CH2:19][NH:20][C:21](=O)[CH3:22])[O:16][N:15]=2)[CH:5]=[C:6]([F:13])[C:7]=1[N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:33]2)=CC=1.C(Cl)Cl>O1CCOCC1.O>[F:1][C:2]1[CH:3]=[C:4]([C:14]2[CH2:18][CH:17]([CH2:19][NH:20][C:21](=[S:33])[CH3:22])[O:16][N:15]=2)[CH:5]=[C:6]([F:13])[C:7]=1[N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(=O)NCC1CC(c2cc(F)c(-n3ccnc3)c(F)c2)=NO1
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: CC(=S)NCC1CC(c2cc(F)c(-n3ccnc3)c(F)c2)=NO1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.7 %

Procedure:
A mixture of the final product of Example 28 (150 mg) and [2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (Lawesson's Reagent) (189 mg) in 1,4-dioxane (5 mL) is heated at reflux for 1.5 hours and stirred at ambient temperature. After 18 hours, TLC analysis (5% CH3 0H--CH2Cl2) indicated the reaction to be complete. The mixture is diluted with water (50 mL), extracted with EtOAc (3×25 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to a light yellow solid. The crude material is recrystallized from 5%CH3OH/EtOAc to give 119 mg of the title compound as a white solid, mp 238-240° C. dec and MS(ES) 337 (M+H)+ [α]25D.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][C@@H:15]1[CH2:17][O:16]1)[N:9]=[CH:8][CH:7]=[C:6]2[O:18][C:19]1[C:20]([CH3:29])=[N:21][C:22]2[C:27]([CH:28]=1)=[CH:26][CH:25]=[CH:24][CH:23]=2.FC(F)(F)C(O)=[O:33].C(=O)([O-])O.[Na+]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][C@@H:15]([OH:16])[CH2:17][OH:33])[N:9]=[CH:8][CH:7]=[C:6]2[O:18][C:19]1[C:20]([CH3:29])=[N:21][C:22]2[C:27]([CH:28]=1)=[CH:26][CH:25]=[CH:24][CH:23]=2
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OC[C@@H]1CO1
Reactant: O=C(O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OC[C@@H](O)CO
Temperature: 25 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
(S)-6-Methoxy-4-(2-methyl-quinolin-3-yloxy)-7-oxiranylmethoxy-quinoline (30 mg) was dissolved in dichloromethane (1 ml) to prepare a solution. Trifluoroacetic acid (1 ml) was added dropwise to the solution at 0° C. The mixture was then stirred at room temperature for 3 hr. The reaction solution was made alkaline by the addition of a saturated aqueous sodium hydrogencarbonate solution and was extracted with ethyl acetate. The ethyl acetate layer was washed with water and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (24 mg, yield 76%).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([P:22](Cl)(Cl)=[O:23])=[CH:18][CH:17]=1>>[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([P:22]2(=[O:23])[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[CH2:1][N:8]2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:18][CH:17]=1
Reactant: c1ccc(CNc2ccccc2)cc1
Reactant: Cc1ccc(P(=O)(Cl)Cl)cc1
Product: Cc1ccc(P2(=O)c3ccccc3CN2c2ccccc2)cc1
Yield: 7 %

Procedure:
The procedure of Example 26 was employed utilizing N-benzylaniline and 4-methylphenyl phosphonic dichloride to yield 1-(4-methylphenyl)-2-phenyl-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide (0.65 g, 7% yield) as a white solid having a melting point of 180°-181° C. and the following analysis:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2.[Br:13]Br.S(=O)(O)[O-].[Na+]>C(O)(=O)C>[Br:13][C:4]1[C:3]([O:2][CH3:1])=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2
Reactant: BrBr
Reactant: COc1ccc2ncccc2c1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc2ncccc2c1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.7 %

Procedure:
To a solution of 6-methoxyquinoline (5 g, 31.4 mmol) in acetic acid (50 mL) was slowly added Br2 neat (1.62 mL, 31.4 mmol). The reaction mixture was stirred at ambient temperature for 1 hour and then poured onto ice. Saturated aqueous sodium bisulfite was added, and the resulting slurry was extracted into EtOAc (2×200 mL). The organic fractions were combined, dried over Na2SO4, concentrated, and purified by column chromatography (5% MeOH/CH2Cl2) affording 4.39 g of the title compound as the acetate salt. The free base was prepared by washing the salt with 1 N NaOH (50 mL) and H2O (100 mL) and extracting into CH2Cl2 (200 mL). The organic fractions were concentrated affording 3.89 g (52%) of the title compound as a pink solid.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([NH2:10])=[O:9])=[N:6][CH:7]=1.[NH2:11][CH2:12][CH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CS(C)=O.O>[C:8]([C:5]1[N:6]=[CH:7][C:2]([NH:11][CH2:12][CH2:13][CH:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]2)=[N:3][CH:4]=1)(=[O:9])[NH2:10]
Reactant: NC(=O)c1cnc(Cl)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(CCN)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(CCNc2cnc(C(N)=O)cn2)CC1
Temperature: 100 °C
Yield: 79.6 %

Procedure:
A mixture of 1.12 g (7.15 mmol) of 5-chloropyrazine-2-carboxamide, 1.95 g (8.58 mmol) of tert-butyl 4-(2-aminoethyl)piperidine-1-carboxylate and 1.18 g (8.58 mmol) of potassium carbonate in 1.4 ml of dimethyl sulphoxide is heated during 5 hours at 100° C. under an argon atmosphere and with stirring. After cooling to ambient temperature, 25 ml of ethyl acetate and 25 ml of water are added. The organic phase is separated by settling and washed 3 times with 25 ml of water and then 25 ml of a saturated aqueous sodium chloride solution. It is dried over sodium sulphate and evaporated to dryness. The residue is purified by chromatography on silica gel, elution being carried out with a 97:3, then 95:5 and 93:7 mixture of dichloromethane and methanol, in order to obtain 1.99 g (5.69 mmol) of product in the form of a light-yellow paste.
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][C@@H:3]([CH2:7][NH:8][C:9]([C:11]1[N:18]3[C:14]([S:15][CH:16]=[CH:17]3)=[N:13][C:12]=1[CH3:19])=[O:10])[NH:2]2.[F:20][C:21]1[CH:22]=[C:23]([C:27]2[S:31][C:30]([CH3:32])=[N:29][C:28]=2[C:33](O)=[O:34])[CH:24]=[CH:25][CH:26]=1>>[F:20][C:21]1[CH:22]=[C:23]([C:27]2[S:31][C:30]([CH3:32])=[N:29][C:28]=2[C:33]([N:2]2[C@H:3]([CH2:7][NH:8][C:9]([C:11]3[N:18]4[C:14]([S:15][CH:16]=[CH:17]4)=[N:13][C:12]=3[CH3:19])=[O:10])[CH2:4][C@H:5]3[C@@H:1]2[CH2:6]3)=[O:34])[CH:24]=[CH:25][CH:26]=1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@@H]1C[C@@H]2C[C@@H]2N1
Reactant: Cc1nc(C(=O)O)c(-c2cccc(F)c2)s1
Product: Cc1nc(C(=O)N2[C@H](CNC(=O)c3c(C)nc4sccn34)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid [(1S,3S,5S)-2-aza-bicyclo[3.1.0]hex-3-ylmethyl]-amide with 5-(3-fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid. LC-MS (basic): tR=1.30 min; [M+H]+=496.1.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([NH:10][C:11]2[CH:16]=[C:15]([O:17][C:18]3[CH:19]=[N:20][C:21]([N+:24]([O-])=O)=[CH:22][CH:23]=3)[CH:14]=[CH:13][N:12]=2)=[O:9])[CH2:4][CH2:3]1>[Ni].CO>[NH2:24][C:21]1[N:20]=[CH:19][C:18]([O:17][C:15]2[CH:14]=[CH:13][N:12]=[C:11]([NH:10][C:8]([N:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]3)=[O:9])[CH:16]=2)=[CH:23][CH:22]=1
Reactant: CN1CCN(C(=O)Nc2cc(Oc3ccc([N+](=O)[O-])nc3)ccn2)CC1
Agent: [Ni]
Solvent: CO
Product: CN1CCN(C(=O)Nc2cc(Oc3ccc(N)nc3)ccn2)CC1
Yield: 99 %

Procedure:
A suspension of 4-methyl-N-(4-((6-nitropyridin-3-yl)oxy)pyridin-2-yl)piperazine-1-carboxamide, DN-01540-085-1 (6.40 g, 17.86 mmol) and Raney Nickel (1.00 g, 17.26 mmol) in MeOH (100 mL) was hydrogenated (40 psi) in a Parr shaker flask at RT for 2 h. The catalyst from the reaction mixture was removed by filtration and washed with MeOH. The filtrate was evaporated to provide N-(4-((6-aminopyridin-3-yl)oxy)pyridin-2-yl)-4-methylpiperazine-1-carboxamide (5.80 g, 99%) as light brownish solid. MS (ESI) m/z: 329.2 (M+H+).
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][C@@H:12]1[C:34](=[O:35])[N:14]2[CH:15]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=3)=[O:22])[C:16]([CH3:20])([CH3:19])[S:17](=[O:18])[C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:36]N1C(=O)CCC1=O.ClC(Cl)CCl>>[CH3:19][C:16](=[CH2:20])[CH:15]([N:14]1[C:34](=[O:35])[CH:12]([NH:11][C:9](=[O:10])[CH2:8][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:13]1[S:17]([Cl:36])=[O:18])[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1)=[O:22]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC1(C)C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@@H](NC(=O)COc3ccccc3)[C@H]2S1=O
Solvent: ClCC(Cl)Cl
Product: C=C(C)C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C(NC(=O)COc2ccccc2)C1S(=O)Cl

Procedure:
A solution of 500 mg. (1 mmol.) of p-nitrobenzyl 6β-phenoxyacetamido-2,2-dimethylpenam-3-carboxylate-1-oxide and 134 mg. (1 mmol.) of N-chlorosuccinimide in 40 ml. of well dried 1,1,2-trichloroethane was refluxed for 90 minutes. The mixture was cooled, washed with water and brine, dried, and the solvent evaporated in vacuo. According to the nmr spectrum the title compound was obtained in nearly quantitative yield.
Reaction SMILES: [CH2:1]([CH:4]([CH2:15][CH2:16][CH3:17])[CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=[O:11])[CH2:2][CH3:3].[C:18](#[N:20])[CH3:19]>>[OH:11][CH:10]([C:9]1[CH:12]=[CH:13][CH:14]=[C:7]([O:6][CH2:5][CH:4]([CH2:1][CH2:2][CH3:3])[CH2:15][CH2:16][CH3:17])[CH:8]=1)[CH2:19][C:18]#[N:20]
Reactant: CC#N
Reactant: CCCC(CCC)COc1cccc(C=O)c1
Product: CCCC(CCC)COc1cccc(C(O)CC#N)c1

Procedure:
Reaction of 3-(2-propylpentyloxy)benzaldehyde with acetonitrile was conducted following the method used for Example 20. Purification by flash chromatography (20% EtOAc-hexanes) gave 3-hydroxy-3-(3-(2-propylpentyloxy)phenyl)propanenitrile as a clear oil. Yield (1.05 g, 59%): 1H NMR (DMSO-d6) δ 7.21 (t, J=8.0 Hz, 1H), 6.92-6.95 (m, 2H), 6.81 (ddd, J=8.0, 2.4, 0.8 Hz, 1H), 5/87 (br s, 1H), 4.82 (t, J=6.4 Hz, 1H), 3.81 (d, J=5.6 Hz, 1H), 2.86 (dd, J=16.8, 5.0 Hz, 1H), 2.77 (dd, J=17.2, 6.8 Hz, 1H), 1.74 (quint., J=5.6 Hz, 1H), 1.26-1.40 (m, 8H), 0.84-0.87 (m, 6H).
Reaction SMILES: [F:1][CH:2]([F:24])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[N:16]=[C:15]([O:17][CH3:18])[C:14]([C:19](OCC)=[O:20])=[CH:13][N:12]=2)=[CH:6][CH:5]=1.CC(C[AlH]CC(C)C)C>C1COCC1>[F:24][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[N:16]=[C:15]([O:17][CH3:18])[C:14]([CH2:19][OH:20])=[CH:13][N:12]=2)=[CH:6][CH:5]=1
Reactant: CCOC(=O)c1cnc(Nc2ccc(OC(F)F)cc2)nc1OC
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: COc1nc(Nc2ccc(OC(F)F)cc2)ncc1CO
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92.6 %

Procedure:
A solution of ethyl 2-((4-(difluoromethoxy)phenyl)amino)-4-methoxypyrimidine-5-carboxylate (0.37 g, 1.090 mmol) in THF (11 mL) was cooled to −78° C. and DIBAL-H (4.36 mL, 4.36 mmol) was added. The cold bath was removed and mixture was stirred for 1.5 h while warming to room temperature. The reaction mixture was diluted with THF (30 mL) and quenched with Na2SO4.10H2O, followed by a few drops of water. After stirring at room temperature for 18 h, the mixture was filtered through a pad of celite topped with silica gel. The pad was washed several times with methanol and the filtrate was concentrated. The residue was purified by flash chromatography on silica gel using 30-100% ethyl acetate in hexanes. The desired fractions were concentrated to give (2-((4-(difluoromethoxy)phenyl)amino)-4-methoxypyrimidin-5-yl)methanol as an off-white solid (0.3 g, 93%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.57 (s, 1H), 8.16 (s, 1H), 7.89-7.67 (m, 2H), 7.38-6.83 (m, 3H), 4.98 (t, J=5.5 Hz, 1H), 4.36 (d, J=5.5 Hz, 2H), 3.95 (s, 3H). LCMS: R.T.=0.70; [M+H]+=298.2.
Reaction SMILES: C(OC([N:8]([CH2:51][CH2:52][N:53]([C:55](OC(C)(C)C)=O)C)[C@H:9]1[CH2:14][CH2:13][C@H:12]([CH:15]([CH2:49][OH:50])[C:16]([NH:18][C@H:19]([B:36]2[O:44]C3C(C)(C4CC(C3)C4(C)C)[O:37]2)[CH2:20][C:21]2[C:22](OC)=[C:23]([CH:31]=[CH:32][CH:33]=2)[C:24]([O:26]C(C)(C)C)=[O:25])=[O:17])[CH2:11][CH2:10]1)=O)(C)(C)C.B(Cl)(Cl)Cl>>[OH:37][B:36]1[C@@H:19]([NH:18][C:16](=[O:17])[CH:15]([C@H:12]2[CH2:13][CH2:14][C@H:9]([NH:8][CH2:51][CH2:52][NH:53][CH3:55])[CH2:10][CH2:11]2)[CH2:49][OH:50])[CH2:20][C:21]2[CH:33]=[CH:32][CH:31]=[C:23]([C:24]([OH:26])=[O:25])[C:22]=2[O:44]1
Reactant: COc1c(C[C@H](NC(=O)C(CO)[C@H]2CC[C@H](N(CCN(C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CC2)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)OC(C)(C)C
Agent: ClB(Cl)Cl
Product: CNCCN[C@H]1CC[C@H](C(CO)C(=O)N[C@H]2Cc3cccc(C(=O)O)c3OB2O)CC1

Procedure:
Prepared from tert-butyl 3-((2R)-2-(2-(trans-4-(tert-butoxycarbonyl(2-(tert-butoxycarbonyl(methyl)amino)ethyl)amino)cyclohexyl)-3-hydroxypropanamido)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)ethyl)-2-methoxybenzoate and BCl3 following the procedure described in Step 2 of Example 1. The crude product was purified by reverse phase preparative HPLC and dried using lyophilization. ESI-MS m/z 434 (MH)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH:15]([C:17]#[N:18])[CH3:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N-]C(C)C)(C)C.[Li+].Br[CH2:28][CH2:29][CH2:30][CH2:31]CBr.O>O1CCCC1>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][C:15]2([C:17]#[N:18])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:16]2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCCCCCBr
Reactant: CC(C#N)CN1CCN(Cc2ccccc2)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: N#CC1(CN2CCN(Cc3ccccc3)CC2)CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of l-[(4-benzyl-1-piperazinyl)methyl]ethanecarbonitrile (9.0 g/39.3 mmol) in tetrahydrofuran (300 ml) was added dropwise 2.0 M solution of lithium diisopropylamide (98 ml/197 mmol) at −78° C., and then the resulting mixture was stirred for 30 minutes. 1,5-Dibromopentane (8 ml/59 mmol) was added to the mixture in one portion and the resulting mixture was allowed to warm to ambient temperature. The mixture was stirred for 3 hours. Then, H2O (150 ml) was added for quenching. The mixture was extracted with ethyl acetate (200 ml×2). The combined extracts were washed with brine (50 ml), dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (Si, 230-400 mesh/150 g/dichloromethane:methanol=100:0-100:4) to give a brown solid (11 g/94%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[N:25]([CH3:26])[CH:24]=[N:23][N:5]2[C:6](=[N:17][CH2:18][C:19]([F:22])([F:21])[F:20])[C:7]=1[C:8]1[C:13]([F:14])=[CH:12][C:11]([F:15])=[CH:10][C:9]=1[F:16].[H-].[Na+]>CS(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([C:8]2[C:9]([F:16])=[CH:10][C:11]([F:15])=[CH:12][C:13]=2[F:14])=[C:6]([NH:17][CH2:18][C:19]([F:21])([F:22])[F:20])[N:5]=[C:4]([N:25]([CH3:26])[C:24]#[N:23])[N:3]=1
Reactant: Cn1cnn2c(=NCC(F)(F)F)c(-c3c(F)cc(F)cc3F)c(Cl)nc12
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CN(C#N)c1nc(Cl)c(-c2c(F)cc(F)cc2F)c(NCC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.6 %

Procedure:
To a solution of N-[5-chloro-3-methyl-6-(2,4,6-trifluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7(3H)-ylidene]-2,2,2-trifluoroethanamine (345 mg, 0.87 mmol) in 1 mL of dimethylsulfoxide at room temperature is added sodium hydride (60% in mineral oil, 35 mg, 0.87 mmol). The mixture is then stirred at room temperature for 2 h, and diluted with ethyl acetate. The organic layer is washed with water and saturated sodium chloride, dried over magnesium sulfate, and concentrated. The residue is chromatographed over silica gel, eluting with 10% ethyl acetate in hexanes. Concentration provides 4-chloro-6-[(2,2,2-trifluoroethyl)amino]-5-(2,4,6-trifluorophenyl)pyrimidin-2-yl(methyl)cyanamide as a white solid (157 mg). MS: m/z 396.1 (M+H).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH2:7][C@H:6]([NH:10][C:11]2[C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=[C:13](Cl)[CH:12]=2)[CH2:5]1)(=[O:3])[CH3:2].[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1.C([O-])([O-])=O.[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O.C(#N)C.C(O)(C(F)(F)F)=O.CC([O-])=O.CC([O-])=O.[Pd+2].O1CCOCC1>[C:1]([N:4]1[CH2:9][CH2:8][CH2:7][C@H:6]([NH:10][C:11]2[C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=[C:13]([NH:29][C:26]3[CH:27]=[CH:28][C:23]([O:22][CH3:21])=[CH:24][CH:25]=3)[CH:12]=2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC[C@H](Nc2cc(Cl)ncc2C(N)=O)C1
Reactant: COc1ccc(N)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: COc1ccc(Nc2cc(N[C@H]3CCCN(C(C)=O)C3)c(C(N)=O)cn2)cc1
Temperature: 100 °C
Yield: 6.1 %

Procedure:
(S)-4-(1-acetylpiperidin-3-ylamino)-6-chloronicotinamide (50 mg, 0.17 mmol), p-anisidine (31 mg, 0.26 mmol), Cs2CO3 (111 mg, 0.34 mmol), BINAP (16 mg, 0.026 mmol), and Pd(OAc)2 (4 mg, 0.017 mmol) and degassed dioxane (4 mL) were heated to 100° C. under Argon overnight. The following morning the mixture was determined to be complete by UPLC. The reaction was diluted with water, acetonitrile, and TFA, then purified by HPLC affording 4 mg of the desired product after lyophilization. MS found for C20H25N5O3 as (M+H)+ 384.3. UV: λ=202, 257 nm. 1H NMR: (CD3OD) (mixture of rotamers) δ 8.12 (s, 0.4H), 8.06 (s, 0.6H), 7.24 (dd, 2H), 7.06 (dd, 2H), 5.98 (s, 0.7H), 5.89 (s, 0.3H), 3.84 (s, 3H), 3.40-3.68 (m, 5H), 2.13 (s, 2H), 2.03 (m, 1H), 1.98 (s, 1H), 1.52-1.93 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:20]#[N:21])[C:17]([OH:19])=[CH:18][C:13]=2[NH:12][C:11](=[O:22])[CH2:10][N:9]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl[CH2:30][CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:20]#[N:21])[C:17]([O:19][CH2:30][CH2:31][CH2:32][N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:18][C:13]=2[NH:12][C:11](=[O:22])[CH2:10][N:9]=1
Reactant: ClCCCN1CCOCC1
Reactant: N#Cc1cc2c(cc1O)NC(=O)CN=C2c1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cc2c(cc1OCCCN1CCOCC1)NC(=O)CN=C2c1ccccc1Cl
Temperature: 50 °C
Reaction time: 24 h
Yield: 44 %

Procedure:
A mixture of 0.322 g (0.00103 mole) of 5-(2-chlorophenyl)-7-cyano-1,3-dihydro-8-hydroxy-2H-1,4-benzodiazepin-2-one (Iqq), 6 mL of dimethylformamide, 0.132 g (0.00124 mole) of sodium carbonate and 0.2028 g (0.00124 mole) of 4-(3-chloropropyl)-morpholine was stirred 50° C. under an atmosphere of argon for 24 hours. The mixture was then cooled and partitioned between ethyl acetate and water. The aqueous phase was reextracted with ethyl acetate and the ethyl acetate extracts were then dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel eluting with acetonitrile-methanol (90:10), to provide 0.199 g of 5-(2-chlorophenyl)-7-cyano-1,3-dihydro-8-(3-(4-morpholinyl)propoxy)-2H-1,4-benzodiazepin-2-one (Ik). MH+/Z=439.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([NH:15][NH2:16])=[O:14].[F:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=O)=[C:20]([O:27][CH3:28])[CH:19]=1>>[F:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]2[O:14][C:13]([C:3]3[C:4]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:15][N:16]=2)=[C:20]([O:27][CH3:28])[CH:19]=1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NN
Reactant: COc1cc(F)ccc1C(=O)O
Product: COc1cc(F)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Yield: 49 %

Procedure:
As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (2.00 g, 9.12 mmol) was converted using 4-fluoro-2-methoxy-benzoic acid instead of o-toluic acid to the title compound (SiO2, heptane:ethyl acetate:dichloromethane=70:10:20 to 40:40:20, 1.59 g, 49%) which was obtained as a white solid. MS: m/e=352.3 [M+H]+.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([F:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH:28][CH2:29][CH2:30][NH2:31].C(N(CC)CC)C>CCO>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([F:17])[C:10]([F:16])=[C:11]([NH:31][CH2:30][CH2:29][NH:28][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=4)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)c(F)c2c1=O
Reactant: NCCNc1ccccn1
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(O)c1cn(C2CC2)c2c(F)c(NCCNc3ccccn3)c(F)c(F)c2c1=O
Temperature: 25 °C
Yield: 56.4 %

Procedure:
A solution of 1-cyclopropyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (3.70 g, 12.3 mmol), N-2-pyridyl-1,2-ethanediamine (1.77 g, 12.9 mmol) and triethylamine (3.50 mL) in EtOH (50 mL) was stirred at room temperature for 3 h, and refluxed for 1 h. The reaction mixture was cooled at room temperature. The resulting precipitate was combined by filtration. The cake washed with EtOH and collected by filtration and then dried to give 1-cyclopropyl-1,4-dihydro-5,6,8-trifluoro-4-oxo-7-[2-(2-pyridylamino)ethylamino]quinoline-3-carboxylic acid (2.90 g, 56%) as a pale yellow solid.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]2[C:11](=[C:12]([OH:17])[CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1)(=O)=O.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.[C:56]([O:59][CH2:60][CH3:61])(=[O:58])C>CN(C)C=O.C(O)C.O>[OH:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[CH:10]=[CH:9][CH:8]=[C:7]2[C:56]([O:59][CH2:60][CH3:61])=[O:58]
Reactant: O=S(=O)(Oc1cccc2c(O)cccc12)C(F)(F)F
Reactant: CCOC(C)=O
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cccc2c(O)cccc12
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a mixture of 5-hydroxy-1-naphthyl trifluoromethane-sulfonate (8.0 g) in N,N-dimethylformamide (35 ml) and ethanol (5.0 ml) were added 1,3-bis(diphenylphosphino)-propane (621 mg), palladium acetate(II) (3.7 mg) and triethylamine (1.35 g), and the mixture was stirred at 100° C. for 1 hour under carbon-monoxide. The mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=5/1) to give ethyl 5-hydroxy-1-naphthoate (1.7 g) as a colorless oil.