Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]=O.C(C=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(OC)=O.CCCCCC.[C:45]([O:48]CC)(=[O:47])[CH3:46]>C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]=[CH:46][C:45]([OH:48])=[O:47]
Reactant: O=CCCCCCCCCCCCBr
Reactant: CCOC(C)=O
Agent: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCCCCC
Solvent: ClCCl
Product: O=C(O)C=CCCCCCCCCCCCBr
Reaction time: 4 h

Procedure:
To 12-bromododecanol (5 g) dissolved in methylene chloride (30 ml) were added Celite (5.0 g) and pyridinium chlorochromate (5.2 g), and the mixture was stirred at room temperature for 12 hours. Then, the reaction mixture was filtered and subjected to chromatography on a silica gel column with an eluent system of n-hexane-ethyl acetate (30:1) to give 12-bromododecanal (4.4 g). To 12-bromododecanal (4.4 g) dissolved in methylene chloride (50 ml) was added (carbomethoxymethylene)-triphenylphosphorane (6.75 g), and the mixture was stirred for 4 hours. Then, the reaction mixture was concentrated, and the residue thus obtained was subjected to chromatography on a silica gel column with an eluent system of n-hexane-ethyl acetate (30:1) to give the methyl ester of 14-bromo-2-tetradecenoic acid (4.91 g). The product was dissolved in acetonitrile (30 ml), and 1M tetra-n-butylammonium chloride in THF (27 ml) and potassium fluoride (7.6 g) were added. The mixture was heated under reflux for 12 hours. The reaction mixture was concentrated and subjected to chromatography on a silica gel column with an eluent system of n-hexane-ethylacetate 100:1 to give the methyl ester of 14-fluoro-3-tetradecenoic acid (3.3 g).
Reaction SMILES: [C:1]([C:4]1[CH:8]=[C:7]([C:9]([OH:11])=O)[NH:6][N:5]=1)(=[O:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.CN(C=O)C.[CH2:50]([O:52][C:53](=[O:73])[C@H:54]([OH:72])[CH2:55][C@H:56]([NH2:71])[CH2:57][C:58]1[CH:63]=[CH:62][C:61]([C:64]2[CH:69]=[CH:68][CH:67]=[C:66]([Cl:70])[CH:65]=2)=[CH:60][CH:59]=1)[CH3:51]>C(Cl)Cl>[CH2:50]([O:52][C:53](=[O:73])[C@H:54]([OH:72])[CH2:55][C@H:56]([NH:71][C:9]([C:7]1[CH:8]=[C:4]([C:1](=[O:3])[CH3:2])[NH:5][N:6]=1)=[O:11])[CH2:57][C:58]1[CH:63]=[CH:62][C:61]([C:64]2[CH:69]=[CH:68][CH:67]=[C:66]([Cl:70])[CH:65]=2)=[CH:60][CH:59]=1)[CH3:51]
Reactant: CCOC(=O)[C@H](O)C[C@H](N)Cc1ccc(-c2cccc(Cl)c2)cc1
Reactant: CC(=O)c1cc(C(=O)O)[nH]n1
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
Solvent: ClCCl
Product: CCOC(=O)[C@H](O)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1cc(C(C)=O)[nH]n1
Temperature: 25 °C
Yield: 13.8 %

Procedure:
To a stirred solution of 3-acetyl-1H-pyrazole-5-carboxylic acid (50.9 mg, 330 μmol), HATU (125 mg, 330 μmol), and DIPEA (104 μL, 0.6 mmol) in DMF (0.6 mL, 7.7 mmol), was added (2R,4R)-4-amino-5-(3′-chlorobiphenyl-4-yl)-2-hydroxypentanoic acid ethyl ester (104 mg, 300 μmol). The resulting mixture was stirred at room temperature until the reaction was complete. The mixture was diluted with DCM and washed with saturated aqueous NaHCO3. The organics were dried over Na2SO4, and the solvent removed. Half of material was then purified by preparative HPLC to yield the title compound (20 mg) as a TFA salt. MS m/z [M+H]+ calc'd for C25H26ClN3O5, 484.16. found 484.1.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][N:3]=1.[CH3:11][Mg+].[Br-]>C1COCC1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:10])([CH3:11])[CH3:9])=[CH:4][N:3]=1
Reactant: C[Mg+]
Reactant: CC(=O)c1cnc(Cl)nc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(C)(O)c1cnc(Cl)nc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 51.1 %

Procedure:
To a solution of 1-(2-chloropyrimidin-5-yl)ethanone (268 mg, 1.7 mmol) in THF (20 mL) was added MeMgBr (2.68 mL, 8.04 mmol) at −78° C. under nitrogen. The solution was stirred at −78° C. for 20 min, quenched with satd aq NH4Cl, and extracted with EtOAc. The combined organic layer was dried over anhydrous Na2SO4 and concentrated to give an oil, which was purified by prep TLC (PE:EA 3:1) to give 2-(2-chloropyrimidin-5-yl)propan-2-ol (150 mg, yield 51%).
Reaction SMILES: Br[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:20]([C:22]1[O:26][CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=1)=[O:21].C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:20]([C:22]1[O:26][CH:25]=[C:24]([C:2]2[C:12]3[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH:23]=1)=[O:21]
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)cccc2C1
Reactant: CC1(C)OB(c2coc(C=O)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCOc2c(cccc2-c2coc(C=O)c2)C1
Temperature: 85 °C
Reaction time: 12 h
Yield: 72.8 %

Procedure:
A mixture of tert-butyl 9-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (1.18 g, 3.60 mmol), 5-formylfuran-3-boronic acid pinacol ester (800 mg, 3.60 mmol), saturated aqueous sodium carbonate solution (15 ml), and tetrakis(triphenylphosphine)palladium(0) (118 mg, 0.102 mmol) in ethylene glycol dimethyl ether (20 ml) was stirred under a nitrogen atmosphere at 85° C. for 12 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the desired product (900 mg, 72.6%) as an oil.
Reaction SMILES: [F:1][C:2]([F:9])([CH3:8])[CH2:3][CH2:4][C:5]([OH:7])=O.CN(C=O)C.C(Cl)(=O)C(Cl)=O.[CH2:21]([C@H:28]1[CH2:32][O:31][C:30](=[O:33])[NH:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Li]CCCC>C(Cl)Cl.C1COCC1>[CH2:21]([C@H:28]1[CH2:32][O:31][C:30](=[O:33])[N:29]1[C:5](=[O:7])[CH2:4][CH2:3][C:2]([F:1])([F:9])[CH3:8])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(F)(F)CCC(=O)O
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Agent: O=C(Cl)C(=O)Cl
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(F)(F)CCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.1 %

Procedure:
In a 100 mL round-bottomed flask was added 4,4-difluoropentanoic acid (1.7 g, 12.31 mmol) and DMF (0.019 mL, 0.246 mmol) in DCM (9 mL) to give a colorless solution. Oxalyl chloride (1.077 mL, 12.31 mmol) was added slowly and the resulting mixture was stirred at room temperature for 3 hours. The resulting mixture was concentrated to dryness. A separate 100 mL round-bottomed flask was charged with (S)-4-benzyloxazolidin-2-one (2.181 g, 12.31 mmol) in THF (23 mL) and then cooled to −78° C. Next, n-BuLi (4.92 mL, 12.31 mmol) was added slowly over 5 min. A solution of the above acid chloride in THF (10 mL) was slowly added to the reaction at −78° C. The reaction mixture was stirred at −78° C. for about 1 h and then allowed to warm to room temperature and stirred under nitrogen overnight. The reaction mixture was quenched with about 60 mL of saturated aqueous NH4Cl solution. The resulting mixture was diluted with 200 mL of EtOAc and about 60 mL of water. The layers were separated and the aqueous layer was extracted with 250 mL of EtOAc. The combined EtOAc extracts were dried (MgSO4), filtered and concentrated in vacuo to give a dark yellowish oil. The crude material was purified by silica gel chromatography (80 g ISCO column. A: hexane, B: DCM, 20% to 100% elution) to give Intermediate S-5A (1.65 g, 5.55 mmol, 45.1% yield). 1H NMR (400 MHz, chloroform-d) δ ppm 7.23-7.39 (3 H, m), 7.17-7.24 (2 H, m), 4.67 (1 H, ddd, J=9.85, 3.69, 3.41 Hz), 4.13-4.26 (2 H, m), 3.29 (1 H, dd, J=13.42, 3.30 Hz), 3.16 (2 H, ddd, J=13.98, 8.47, 6.82 Hz), 2.77 (1 H, dd, J=13.31, 9.57 Hz), 2.19-2.41 (2 H, m), 1.53-1.75 (3 H, m).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[S:24]1(=[O:29])(=[O:28])[CH2:27][CH2:26][NH:25]1>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:25]4[CH2:26][CH2:27][S:24]4(=[O:29])=[O:28])=[CH:3][CH:4]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3)CC2)c(C)c1
Reactant: O=S1(=O)CCN1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCS4(=O)=O)cc3)CC2)c(C)c1
Yield: 2 %

Procedure:
Using (4-bromophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (188 mg) described in Preparation Example 165 and [1,2]thiazetidine 1,1-dioxide (54 mg) and by the reaction and treatment in the same manner as in Example 536, the title compound (4 mg) was obtained.
Reaction SMILES: N1CCOCC1.[N:7]1([CH2:12][C:13]([N:15]2[C@H:19]([C:20](=[O:36])[NH:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=4)=[CH:24][CH:23]=3)[CH2:18][C@H:17]([NH:37]C(=O)OCC3C4C=CC=CC=4C4C3=CC=CC=4)[CH2:16]2)=[O:14])[CH:11]=[N:10][CH:9]=[N:8]1.CN(C=O)C>O>[N:7]1([CH2:12][C:13]([N:15]2[CH2:16][C@@H:17]([NH2:37])[CH2:18][C@H:19]2[C:20]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([O:28][C:29]3[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=3)=[CH:26][CH:27]=2)=[O:36])=[O:14])[CH:11]=[N:10][CH:9]=[N:8]1
Reactant: O=C(N[C@H]1C[C@@H](C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)N(C(=O)Cn2cncn2)C1)OCC1c2ccccc2-c2ccccc21
Solvent: C1COCCN1
Solvent: O
Solvent: CN(C)C=O
Product: N[C@H]1C[C@@H](C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)N(C(=O)Cn2cncn2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.7 %

Procedure:
Step (a) Morpholine (10 mL) was added to a flask charged with the (9H-fluoren-9-yl)methyl (3S,5S)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-5-(4-(4-fluorophenoxy)phenylcarbamoyl)pyrrolidin-3-ylcarbamate (0.859 g, 1.33 mmol), prepared as in prepared as in Example 1, and DMF (10 mL). The reaction mixture was stirred at ambient temperature for 30 minutes and then diluted with deionized water (20 mL). The dilution was extracted with ethyl acetate (60 mL) and the extract was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give (2S,4S)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-4-amino-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (0.465 g, 1.10 mmol), which was carried forward without further purification.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[C:9]([C:11]2[CH:12]=[CH:13][C:14]([Cl:33])=[C:15]([CH:32]=2)[C:16]([NH:18][C:19]2[N:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:22]=[C:21]([C:30]#[N:31])[CH:20]=2)=[O:17])[CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-:35].[K+].[K+].OO.Cl>CS(C)=O.O>[C:1]([NH:4][C:5]1[N:10]=[C:9]([C:11]2[CH:12]=[CH:13][C:14]([Cl:33])=[C:15]([CH:32]=2)[C:16]([NH:18][C:19]2[N:23]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:22]=[C:21]([C:30]([NH2:31])=[O:35])[CH:20]=2)=[O:17])[CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)Nc1cccc(-c2ccc(Cl)c(C(=O)Nc3cc(C#N)nn3-c3ccccc3)c2)n1
Agent: Cl
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)Nc1cccc(-c2ccc(Cl)c(C(=O)Nc3cc(C(N)=O)nn3-c3ccccc3)c2)n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 62.2 %

Procedure:
To a solution of 5-(6-acetamidopyridin-2-yl)-2-chloro-N-(3-cyano-1-phenyl-1H-pyrazol-5-yl)benzamide (Example 88, 100 mg, 0.22 mmol) in dimethylsulfoxide (3 mL) was added potassium carbonate (60 mg, 0.44 mmol) followed by hydrogen peroxide (30% w/w solution in water, 441 μL, 4.4 mmol) and the reaction was stirred at room temperature for 2.5 hours. Additional hydrogen peroxide was added (882 μL, 8.8 mmol) and the reaction was stirred for 1 hour. The reaction was diluted with water (5 mL) then neutralised with 2M aqueous hydrochloric acid and extracted into ethyl acetate (3×10 mL). The combined organic extracts were dried over magnesium sulphate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 80% ethyl acetate in heptanes to furnish the title compound as a colourless solid (65 mg, 62%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][C:9]1[CH:14]=[C:13]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:12]=[CH:11][C:10]=1[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:21][N:20]=1.Cl[C:34]([O:36][CH:37]([CH3:39])[CH3:38])=[O:35].C(N(CC)CC)C>C(Cl)Cl>[C:3]([OH:5])([C:2]([F:7])([F:6])[F:1])=[O:4].[C:34](=[O:35])([O-:16])[O-:36].[CH3:8][C:9]1[CH:14]=[C:13]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:12]=[CH:11][C:10]=1[C:19]1[N:20]=[CH:21][C:22]([O:25][CH2:26][CH:27]2[CH2:32][CH2:31][N:30]([C:34]([O:36][CH:37]([CH3:39])[CH3:38])=[O:35])[CH2:29][CH2:28]2)=[CH:23][CH:24]=1
Reactant: CC(C)OC(=O)Cl
Reactant: Cc1cc(S(C)(=O)=O)ccc1-c1ccc(OCC2CCNCC2)cn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(S(C)(=O)=O)ccc1-c1ccc(OCC2CCN(C(=O)OC(C)C)CC2)cn1
Product: O=C([O-])[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.9 %

Procedure:
A mixture of 2-[2-methyl-4-(methylsulfonyl)phenyl]-5-[(4-piperidinylmethyl)oxy]pyridine trifluoroacetate (80 mg, 0.169 mmol), isopropyl chloroformate (1M in toluene, 0.169 mL, 0.169 mmol), and triethylamine (0.070 mL, 0.506 mmol) in CH2Cl2 (3 mL) was stirred at ambient temperature for 1 h, then concentrated. The crude product was purified by reverse-phase preparative HPLC using CH3CN:H2O gradient (5:95 to 90:10) with 0.05% TFA as a modifier, then free-based in CH2Cl2 with MP-Carbonate to give 26 mg (35%) of the title compound as a clear oil. 1H NMR (400 MHz, CDCl3): δ 8.38 (d, 1H, J=2.5 Hz), 7.86-7.76 (m, 2H), 7.55 (d, 1H, J=7.9 Hz), 7.37-7.31 (m, 1H), 7.29-7.25 (m, 1H), 4.92 (septet, 1H, J=6.2 Hz), 4.22 (bs, 2H), 3.90 (d, 2H, J=6.3 Hz), 3.05 (s, 3H), 2.90-2.70 (m, 2H), 2.43 (s, 3H), 2.09-1.95 (m, 1H), 1.95-1.80 (m, 2H), 1.39-1.22 (m, 8H); LRMS (ESI), m/z 447 (M+H).
Reaction SMILES: C[O-].[Na+].CO.[CH2:6]([N:8]1[C:12]([CH3:13])=[C:11]([NH:14][S:15]([C:18]2[N:28]=[C:21]3[CH:22]=[C:23]([CH3:27])[CH:24]=[C:25](Cl)[N:20]3[N:19]=2)(=[O:17])=[O:16])[C:10]([C:29]([F:32])([F:31])[F:30])=[N:9]1)[CH3:7].[C:33](O)(=[O:35])C>CS(C)=O>[CH2:6]([N:8]1[C:12]([CH3:13])=[C:11]([NH:14][S:15]([C:18]2[N:28]=[C:21]3[CH:22]=[C:23]([CH3:27])[CH:24]=[C:25]([O:35][CH3:33])[N:20]3[N:19]=2)(=[O:17])=[O:16])[C:10]([C:29]([F:32])([F:31])[F:30])=[N:9]1)[CH3:7]
Reactant: CC(=O)O
Reactant: CCn1nc(C(F)(F)F)c(NS(=O)(=O)c2nc3cc(C)cc(Cl)n3n2)c1C
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CO
Product: CCn1nc(C(F)(F)F)c(NS(=O)(=O)c2nc3cc(C)cc(OC)n3n2)c1C
Reaction time: 18 h

Procedure:
A 25 percent solution of sodium methoxide in methanol (1.65 g, 5.4 mmol) was added to a solution of 1.14 g (2.70 mmol) of N-(1-ethyl-5-methyl-3-(trifluoromethyl)-4-pyrazolyl)-5-chloro-7-methyl[1,2,4]triazolo[1,5-a]pyridine-2-sulfonamide in 25 mL of dimethyl sulfoxide (DMSO) at ambient temperature with stirring. After 18 hours, 1.0 mL of acetic acid was added and the resulting mixture was concentrated by evaporation under reduced pressure. The residue was diluted with 25 mL of water and the resulting slurry was stirred for 10 min and then the insoluble solids collected by filtration, washed twice with 10 mL portions of water and then with 25 mL of ether, and dried under reduced pressure at 40° C. overnight. The resulting white solid, which amounted to 1.03 g (92 percent of theory) and melted at 230°-231° C. (d), was the title compound (Compound 2).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[C:16](Cl)=[N:17][C:18]3[C:23]([CH:24]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)(O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH2:26]>Cl>[CH2:1]([N:8]1[CH2:13][CH:12]=[C:11]([C:15]2[C:16](=[O:26])[NH:17][C:18]3[C:23]([CH:24]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O
Reactant: OC1(c2cc3ccccc3nc2Cl)CCN(Cc2ccccc2)CC1
Agent: Cl
Product: O=c1[nH]c2ccccc2cc1C1=CCN(Cc2ccccc2)CC1

Procedure:
3-(1-Benzyl-4-hydroxypiperidin-4-yl)-2-chloroquinoline (11.0 g, 31.1 mmol) was refluxed in 6 N hydrochloric acid for 8 h. The solution was cooled and water (100 mL) added. The precipitated solid was collected and dried to give the title compound, 7.9 g. MS: m/z=317 (M+1). 1H NMR (500 MHz, CD3OD) δ 7.97 (s, 1H), 7.70 (d, J=7 Hz, 1H), 7.60 (m, 2H), 7.55 (m, 4H), 7.35 (d, J=9 Hz, 1H), 7.27 (t, J=8 Hz, 1H), 6.50 (m, 1H), 4.49 (ABq, J=13 Hz, Δν=16 Hz, 2H), 3.92 (m, 2H), 3.76 (dt, J=12.4 Hz, 1H), 3.40 (m, 1H), 2.96 (m, 2H).
Reaction SMILES: C([N:3](CC)CC)C.[C:8](Cl)(=[O:18])[C:9]1[C:10](=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:11](Cl)=[O:12]>CN(C1C=CN=CC=1)C.ClCCl.C(OCC)(=O)C>[C:8]1(=[O:18])[NH:3][C:11](=[O:12])[C:10]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:9]12
Reactant: CCN(CC)CC
Reactant: O=C(Cl)c1ccccc1C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C1NC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of MCH17-1 (520 mg), triethyl amine (0.82 mL) and DMAP (24 mg) in 10 mL dichloromethane at 0° C. was added phthaloyl chloride (0.36 mL). The mixture was stirred overnight at rt, diluted with ethyl acetate and washed with 1N HCl, aq. NaHCO3 and brine. It was dried over anhydrous MgSO4, filtered, concentrated and purified by chromatography eluting with 0% to 50% ethyl acetate in hexane to provide 338 mg of phthalimide protected intermediate which was stirred with 5 mL of trifluoroacetic acid at rt for 40 min. The reaction mixture was evaporated to dryness, the residue was suspended in aq. NaHCO3 and extracted 3× with ethyl acetate. The combined organic layer was washed with brine, dried over MgSO4, filtered and evaporated to dryness to obtain 220 mg MCH 17-2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].CO[CH:13](OC)[N:14]([CH3:16])[CH3:15].C(#N)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH:9]=[CH:13][N:14]([CH3:16])[CH3:15]
Reactant: CC(=O)c1ccccc1Cl
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Solvent: CC#N
Product: CN(C)C=CC(=O)c1ccccc1Cl
Temperature: 83 °C
Yield: 101.6 %

Procedure:
To a 5 liter, 3-necked flask equipped with a mechanical stirrer, thermometer, reflux condenser capped with a nitrogen inlet, and a heating mantle were added o-chloroacetophenone (305.8 g, 1.98 mol), N,N-dimethylformamide dimethyl acetal (707.0 g, 5.93 mol), and acetonitrile (dried over molecular sieves, 3.0 L) at room temperature, giving an orange solution. The mixture was heated gradually to reflux (83° C.) over 1.5 hours, then maintained at reflux for 18 hours. After the dark red solution was cooled to room temperature, the acetonitrile was evaporated, leaving a heavy red oil. The oil was redissolved in toluene (1 L). The toluene was evaporated to afford the crude enamine which was further dried under high vacuum overnight to afford 2'-chloro-3-dimethylaminopropenophenone (422 g, quantitative) which was used without further purification.
Reaction SMILES: C(N1[CH:12]=[CH:11]N=C1)(N1C=CN=C1)=O.[NH2:13][C:14]1[CH2:20][N:19]=[C:18]([C:21]2[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=2[F:28])[C:17]2[CH:29]=[C:30]([N+:33]([O-:35])=[O:34])[CH:31]=[CH:32][C:16]=2[N:15]=1.[O:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1.CN(C)C=O>>[N+:33]([C:30]1[CH:31]=[CH:32][C:16]2[N:15]3[C:39]([CH2:40][CH2:11][CH3:12])=[CH:38][C:37](=[O:36])[N:13]=[C:14]3[CH2:20][N:19]=[C:18]([C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=3[F:28])[C:17]=2[CH:29]=1)([O-:35])=[O:34]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C1CCOC1
Reactant: NC1=Nc2ccc([N+](=O)[O-])cc2C(c2c(F)cccc2F)=NC1
Solvent: CN(C)C=O
Product: CCCc1cc(=O)nc2n1-c1ccc([N+](=O)[O-])cc1C(c1c(F)cccc1F)=NC2

Procedure:
In the manner given in Example 16, carbonyldiimidazole, p-hexynoic acid and 2-amino-7-nitro-5-(2,6-difluorophenyl)-3H-1,4-benzodiazepine were stirred in tetrahydrofuran-dimethylformamide to give 9-nitro-1-propyl-7-(2,6-difluorophenyl)pyrimido[1,2-a][1,4]benzodiazepin-3(5H)-one.
Reaction SMILES: N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[Cl:19][C:20]1[CH:39]=[CH:38][C:23]([NH:24][C:25]2[C:34]3[C:29](=[CH:30][C:31]([OH:37])=[C:32]([O:35][CH3:36])[CH:33]=3)[N:28]=[CH:27][N:26]=2)=[C:22]([F:40])[CH:21]=1.O[CH2:42][C:43]1[CH:48]=[CH:47][N:46]=[C:45]([NH:49][CH3:50])[CH:44]=1.C(P(CCCC)CCCC)CCC>C(Cl)Cl>[ClH:19].[Cl:19][C:20]1[CH:39]=[CH:38][C:23]([NH:24][C:25]2[C:34]3[C:29](=[CH:30][C:31]([O:37][CH2:42][C:43]4[CH:48]=[CH:47][N:46]=[C:45]([NH:49][CH3:50])[CH:44]=4)=[C:32]([O:35][CH3:36])[CH:33]=3)[N:28]=[CH:27][N:26]=2)=[C:22]([F:40])[CH:21]=1
Reactant: CNc1cc(CO)ccn1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: ClCCl
Product: CNc1cc(COc2cc3ncnc(Nc4ccc(Cl)cc4F)c3cc2OC)ccn1
Product: Cl
Temperature: 25 °C
Yield: 82.9 %

Procedure:
1,1'-(azodicarbonyl)dipiperidine (1.68 g, 6 mmol) was added in portions to a mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (640 mg, 2 mmol), 4-hydroxymethyl-2-(methylamino)pyridine (385 mg, 2.8 mmol) and tributylphosphine (1.6 ml, 6 mmol) in methylene chloride (50 ml) at 0° C. The mixture was allowed to warm to ambient temperature over 2 hours, the insolubles were removed by filtration and the filtrate was washed with water and brine, dried (Na2SO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol (10:0 increasing to 9:1). The purified product was dissolved in acetone/methanol and a 1M solution of ethereal hydrogen chloride was added. The resulting precipitate was collected by filtration and dried to give 4-(4-chloro-2-fluoroanilino)-7-(2-(methylamino)pyrid-4-yl)methoxy-6-methoxyquinazoline hydrochloride (395 mg, 45%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[C:16](F)[CH:15]=3)=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][C:3]=1[CH3:24].[O:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][NH2:33])[CH2:27][CH2:26]1.C([O-])([O-])=O.[K+].[K+]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[C:16]([NH:33][CH2:32][CH2:31][N:28]4[CH2:29][CH2:30][O:25][CH2:26][CH2:27]4)[CH:15]=3)=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][C:3]=1[CH3:24]
Reactant: NCCN1CCOCC1
Reactant: Cc1cc(-c2ncccc2-c2ccc([N+](=O)[O-])c(F)c2)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1cc(-c2ncccc2-c2ccc([N+](=O)[O-])c(NCCN3CCOCC3)c2)ccc1F
Temperature: 60 °C

Procedure:
To solution of 2-(4-fluoro-3-methylphenyl)-3-(3-fluoro-4-nitrophenyl)pyridine (100 mg) in 2 ml, THF was added 2-morpholinoethanamine (64 uL) and K2CO3 (76 mg). The reaction was heated at 60° C. for 15 hours in a sealed vial. The reaction mixture was cooled to room temperature, concentrated by rotary evaporation under vacuum and partitioned the concentrate between CH2Cl2/water. The organic layer was separated, dried with anhydrous Na2SO4, filtered and evaporated. The crude residue of 5-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-N-(2-morpholinoethyl)-2-nitrobenzenamine was used in the next step with no further purification.