Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:19])[N:9]([CH3:18])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[CH2:16][OH:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.CI.[CH3:22]N(C)C=O.[H-].[Na+]>O>[Cl:1][C:2]1[C:7]2[C:8](=[O:19])[N:9]([CH3:18])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[CH2:16][O:17][CH3:22])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: CN1Cc2c(CO)ncn2-c2cccc(Cl)c2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: COCc1ncn2c1CN(C)C(=O)c1c(Cl)cccc1-2
Temperature: 25 °C
Reaction time: 23 h

Procedure:
A mixture of 2.22 g (8 mmol) of 7-chloro-4,5-dihydro-3-(hydroxymethyl)-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one, 0.6 ml (10 mmoL) of methyl iodide and 20 ml of dry dimethylformamide is treated with 0.4 g (9 mmol) of sodium hydride (55 percent oil dispersion, washed with n-hexane) and the mixture is stirred at room temperature for 23 hours. The mixture is poured into 50 ml of water and extracted four times with methylene chloride. The methylene chloride solution is dried over magnesium sulphate and evaporated. The crude product is chromatographed on silica gel using methylene chloride containing 1% of methanol for the elution. By subsequent recrystallization from ethyl acetate/n-hexane there is obtained 7-chloro-4,5-dihydro-3-(methoxymethyl)-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 143°-144°.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([I:8])[N:5]=[CH:4][N:3]=1.[F:9][C:10]1[CH:11]=[C:12]([CH:14]=[CH:15][CH:16]=1)[NH2:13].C(N(CC)C(C)C)(C)C.C(O)CCC>O>[F:9][C:10]1[CH:11]=[C:12]([NH:13][C:2]2[CH:7]=[C:6]([I:8])[N:5]=[CH:4][N:3]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: Nc1cccc(F)c1
Reactant: Ic1cc(I)ncn1
Solvent: CCCCO
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Fc1cccc(Nc2cc(I)ncn2)c1
Temperature: 120 °C
Reaction time: 4 h
Yield: 71.7 %

Procedure:
A mixture of 4,6-diiodopyrimidine (1.0 g, 3.01 mmol), 3-fluoroaniline (290 μL, 3.01 mmol), N,N-diisopropylethylamine (782 μL, 4.52 mmol) and n-butanol (3 mL) under nitrogen was stirred at 120° C. for 4 h. After cooling to room temperature, the solution was poured into water and extracted with ethyl acetate. The organic layer was washed once with 1 N hydrochloric acid, followed by brine, dried and concentrated to yield 0.68 g of title compound.
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=O)[CH:10]=2)=[CH:7][C:6]([CH2:17][NH:18][C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([NH:29][CH2:30][C:31]3[C:32]([NH:44][CH:45]4[CH2:50][CH2:49][O:48][CH2:47][CH2:46]4)=[C:33]4[CH:41]=[N:40][N:39]([CH2:42][CH3:43])[C:34]4=[N:35][C:36]=3[CH2:37][CH3:38])=[O:28])[CH:22]=2)=[O:20])=[CH:5][CH:4]=1)#[N:2].[CH3:51][N:52]1[CH2:58][CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O>C(Cl)Cl>[C:1]([C:3]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:55]3[CH2:56][CH2:57][CH2:58][N:52]([CH3:51])[CH2:53][CH2:54]3)[CH:10]=2)=[CH:7][C:6]([CH2:17][NH:18][C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([NH:29][CH2:30][C:31]3[C:32]([NH:44][CH:45]4[CH2:50][CH2:49][O:48][CH2:47][CH2:46]4)=[C:33]4[CH:41]=[N:40][N:39]([CH2:42][CH3:43])[C:34]4=[N:35][C:36]=3[CH2:37][CH3:38])=[O:28])[CH:22]=2)=[O:20])=[CH:5][CH:4]=1)#[N:2]
Reactant: CN1CCCNCC1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(C#N)c(-c3cccc(C=O)c3)c2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(C#N)c(-c3cccc(CN4CCCN(C)CC4)c3)c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-[(6-Cyano-3′-formyl-3-biphenylyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,3-benzenedicarboxamide (182 mg, 0.000272 mol) in DCM (4 mL) and 1-methylhexahydro-1H-1,4-diazepine (43.4 mg, 0.00038 mol) were mixed with sodium triacetoxyborohydride (115 mg, 0.00054 mol) and AcOH (19.5 mg, 19 μL). The solution was stirred overnight at room temperature. LC-MS showed that the reaction was complete. The reaction was quenched with sat. aq. NaHCO3, then extracted with DCM (2×). Combined organic extracts were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a glassy foam (150 mg). Purification was carried out on Gilson instrument with acetonitrile-water (0.1% TFA) gradient; C18-RP column. Fractions containing the clean desired product were combined; diluted with EtOAc; washed with sat. aq. NaHCO3; and the aq. phase was back-extracted with EtOAc. Combined organic layers were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a residue. It was taken up in a small amount of DCM and transferred to a vial and pumped down to afford the title compound as a solid. Further purification of the material was needed and this was carried out on a Chomatotron utilizing silica gel [DCM-MeOH-conc. aq. NH3, (90:7:3)] to afford 42 mg of the title compound as a glassy solid. LC-MS m/z 768.7 (M+H)+.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].CN1CCOCC1.C(O[C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])C.[C:21]1([C:27](Cl)([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>ClCCl>[F:19][C:16]([F:17])([F:18])[C:15]([NH:4][CH2:3][CH2:1][O:2][C:27]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:20]
Reactant: NCCO
Reactant: CCOC(=O)C(F)(F)F
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=C(NCCOC(c1ccccc1)(c1ccccc1)c1ccccc1)C(F)(F)F
Reaction time: 0.5 h
Yield: 22.5 %

Procedure:
To 200 mL of dichloromethane was added 100 mmole of ethanolamine, 200 mmole of N-methylmorpholine and 105 mmole of ethyltrifluoroacetate. This solution was allowed to stir for 30 minutes and then 105 mmol of triphenylmethyl chloride was added. After stirring overnight, the solution was transferred to a separatory fimnel and washed twice with water. The organic layer was dried with sodium sulfate, filtered and evaporated to a yellow oil. The product was determined to be impure and was redissolved in DCM and washed with 5% monobasic sodium phosphate and then a mixture of 10% citric acid and 5% monobasic sodium phosphate. The organic layer was dried with sodium sulfate, filtered and evaporated to a yellow oil. The residue was crystallized from methanol but this caused the impurity to crystallized. The mother liquor was then recrystallized from hexanes/ethyl acetate to yield 9.0 g of crystaline N-(trifluoroacetyl)-O-(trityl)-ethanolamine.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15](O)=[O:16])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(OCC)=O.[BH4-].[Na+]>O1CCCC1.CO>[OH:16][CH2:15][CH:11]1[CH2:12][CH2:13][CH2:14][CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH2:10]1
Reactant: CC(C)(C)OC(=O)NC1CCCC(C(=O)O)C1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1CCCC(CO)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 89.7 %

Procedure:
To a mixture of 3-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylic acid (from Alfa Aesar, 3.3 g, 14 mmol) and triethylamine (3.8 mL, 27 mmol) in tetrahydrofuran (40 mL) at 0° C. was added dropwise ethyl chloroformate (1.9 mL, 20 mmol). The mixture was stirred at 0° C. for 10 min and then at room temperature for 20 min. The mixture was filtered to remove the white solid and then cooled to 0° C. A mixture of sodium tetrahydroborate (1.0 g, 27 mmol) and methanol (1 mL) was added slowly. The mixture was stirred at room temperature for 1 h. The mixture was quenched with 1N aq. HCl solution and extracted with EtOAc. The extracts were concentrated and purified on silica gel column (eluting with 75% EtOAc in hexanes) to give the desired product (2.88 g, 92%). LCMS calculated for C13H23NO3Na (M+Na)+: m/z=252.2. Found: 252.1.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:6][B:5]([OH:7])[C:4]2[CH:8]=[C:9]([N+:12]([O-])=O)[CH:10]=[CH:11][C:3]1=2.CCN(CC)CC.[Cl:23][C:24]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27].CCOC(C)=O.Cl>C1COCC1.[Pd]>[Cl:23][C:24]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:25]=1[C:26]([NH:12][C:9]1[CH:10]=[CH:11][C:3]2[C:2]([CH3:15])([CH3:1])[O:6][B:5]([OH:7])[C:4]=2[CH:8]=1)=[O:27]
Reactant: CC1(C)OB(O)c2cc([N+](=O)[O-])ccc21
Reactant: O=C(Cl)c1ccc(F)cc1Cl
Agent: [Pd]
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC1(C)OB(O)c2cc(NC(=O)c3ccc(F)cc3Cl)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.2 %

Procedure:
A solution of 3,3-dimethyl-6-nitro-3H-benzo[c][1.2]oxaborol-1-ol (500 mg, 2.4 mmol) in THF (60 mL) was pass through H-Cube equipped with a 10% Pd/C Catcart (30×4 mm). The flow rate was set at 1.0 mL/min and TLC indicated complete consumption of starting material after one run. To the obtained light yellow solution was added Et3N (1.1 mL, 7.7 mmol, 3.2 equiv.), followed by drop wise addition of 2-cloro-4-fluoro-benzoyl chloride (0.51 mL, 3.8 mmol, 1.6 equiv.). The mixture was allowed to stir at room temperature over 18 h before poured into a 1:1 mixture of EtOAc/HCl (1 N). The layers were separated and the aqueous phase was extracted with EtOAc (3×). Combined organics was washed with H2O, brine and concentrated under reduced pressure to give a white solid. The solid was dissolved in minimal amount of THF and treated with heptanes. The precipitate was collected by filtration and washed with heptanes to give the title compound as a white solid. LCMS (M/Z): 334 (M+H); 1H NMR (DMSO-d6) δ: 10.49 (s, 1H), 9.06 (s, 1H), 8.01 (d, J=1.7 Hz, 1H), 7.60-7.65 (m, 2H), 7.55 (dd, J=9.0, 2.5 Hz, 1H), 7.28-7.37 (m, 2H), 1.40 (s, 6H). Amount obtained: 726 mg, (91.2% yield).
Reaction SMILES: CC(O[CH2:5][C:6]1[C:11]2=[CH:12][CH:13]=[C:14](C=O)[C:10]2=[CH:9]OC=1)=O.[NH2:17]CCC[N:21]1[CH:25]=[CH:24][N:23]=[CH:22]1>C(Cl)(Cl)Cl>[CH:9]1[NH:17][CH:5]=[CH:6][C:11]2[C:10]=1[CH:14]=[CH:13][CH:12]=2.[NH:21]1[CH:25]=[CH:24][N:23]=[CH:22]1
Reactant: CC(=O)OCc1cocc2c(C=O)ccc1-2
Reactant: NCCCn1ccnc1
Solvent: ClC(Cl)Cl
Product: c1c[nH]cn1
Product: c1cc2cc[nH]cc-2c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Baldrinal (2) (2.7 g) was reacted with 1-(3-aminopropyl)-imidazole (2.94 g) in 2 ml of chloroform. After stirring for 10 min at room temperature, no baldrinal was detected in the reaction mixture. Compound (5) was separated on column with silica using 20:1 CHCl3:MeOH solvent system, and 26.7 mg of product was collected.
Reaction SMILES: [I:1][CH3:2].[CH2:3]([O:6][C:7]([N:9]1[C@H:13]([CH:14]([OH:23])[C:15]2[N:16]3[CH:22]=[N:21][CH:20]=[C:17]3[S:18][CH:19]=2)[CH2:12][C@H:11]([S:24][C:25]2[C@H:26]([CH3:42])[C@@H:27]3[C@@H:37]([C@H:38]([OH:40])[CH3:39])[C:36](=[O:41])[N:28]3[C:29]=2[C:30]([O:32][CH2:33][CH:34]=[CH2:35])=[O:31])[CH2:10]1)=[O:8])[CH:4]=[CH2:5]>>[I-:1].[OH:40][C@@H:38]([C@H:37]1[C:36](=[O:41])[N:28]2[C:29]([C:30]([O:32][CH2:33][CH:34]=[CH2:35])=[O:31])=[C:25]([S:24][C@H:11]3[CH2:12][C@@H:13]([CH:14]([OH:23])[C:15]4[N+:16]5[C:17](=[CH:20][N:21]([CH3:2])[CH:22]=5)[S:18][CH:19]=4)[N:9]([C:7]([O:6][CH2:3][CH:4]=[CH2:5])=[O:8])[CH2:10]3)[C@H:26]([CH3:42])[C@H:27]12)[CH3:39]
Reactant: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](C(O)c3csc4cncn34)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Reactant: CI
Product: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](C(O)c3csc4cn(C)c[n+]34)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Product: [I-]
Temperature: 25 °C
Reaction time: 14 h
Yield: 95.2 %

Procedure:
Iodomethane (1.70 g) is added to 70.6 mg of allyl(1R,5S,6S)-2-[(3S,5S)-1-allyloxycarbonyl-5-[1-hydroxy-1-(imidazo[5,1-b]thiazol-3-yl)methyl]pyrrolidin-3-yl]thio-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate (stereoisomer A) described in Example 6-b), and the mixture is stirred in an argon atmosphere at room temperature in a light-shielded state for 14 hr. The excess reagent is removed by evaporation under reduced pressure, and the residue is purified by column chromatography on Sephadex LH-20 (chloroform:methanol=1: 1) to give 83.4 mg of allyl(1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[(3S,5S)-1-allyloxycarbonyl-5-[1-hydroxy-1-(6-methylimidazo[5,1-b]thiazolium-3-yl)methyl]pyrrolidin-3-yl]thio-1-methylcarbapen-2-em-3-carboxylate iodide (stereoisomer A) as a light yellow amorphous material.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[OH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[O:10].[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([F:44])=[C:20]([C:22]([CH:24]2[CH2:29][CH2:28][N:27]([C:30]3[N:31]=[C:32]4[CH2:43][CH2:42][NH:41][CH2:40][C:33]4=[N:34][C:35]=3[NH:36][CH:37]([CH3:39])[CH3:38])[CH2:26][CH2:25]2)=[O:23])[CH:21]=1.N1C=CC=CC=1>C(Cl)Cl>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([F:44])=[C:20]([CH:21]=1)[C:22]([CH:24]1[CH2:25][CH2:26][N:27]([C:30]2[N:31]=[C:32]3[CH2:43][CH2:42][N:41]([C:5](=[O:7])[CH3:6])[CH2:40][C:33]3=[N:34][C:35]=2[NH:36][CH:37]([CH3:39])[CH3:38])[CH2:28][CH2:29]1)=[O:23].[C:9]([OH:10])([C:11]([F:14])([F:13])[F:12])=[O:8]
Reactant: CC(C)Nc1nc2c(nc1N1CCC(C(=O)c3cc(Cl)ccc3F)CC1)CCNC2
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)N1CCc2nc(N3CCC(C(=O)c4cc(Cl)ccc4F)CC3)c(NC(C)C)nc2C1
Reaction time: 1 h

Procedure:
Acetic anhydride (3 μL, 0.029 mmol) was added to a solution of (5-chloro-2-fluorophenyl)(1-(3-(isopropylamino)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-yl)piperidin-4-yl)methanone TFA salt (8.0 mg, 0.015 mmol) and pyridine (4 μL, 0.044 mmol) in DCM (150 μL) at rt. After 1 h, the mixture was purified by HPLC Method A to give the title compound as a TFA salt (3.6 mg, 42%) as a yellow solid. 1H NMR (400 MHz, methanol-d4, mixture of rotamers) δ ppm 1.26-1.32 (m, 6H), 1.84-1.96 (m, 2H), 1.97-2.06 (m, 2H), 2.19 (s, 1.1H), 2.21 (s, 1.9H), 2.70-2.76 (m, 0.7H), 2.80-2.86 (m, 1.3H), 2.87-3.00 (m, 2H), 3.34-3.41 (m, 1H), 3.46-3.56 (m, 2H), 3.79-3.84 (m, 1.3H), 3.84-3.89 (m, 0.7H), 4.07-4.18 (m, 1H), 4.57 (s, 1.1H), 4.62 (s, 0.9H), 7.28 (dd, J=10.4, 8.8 Hz, 1H), 7.61 (ddd, J=8.9, 4.2, 2.9 Hz, 1H), 7.76 (dd, J=6.1, 2.8 Hz, 1H); ESI-MS m/z [M+H]+ 474.3.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.[C:10]([O:14][C:15]([N:17]1[CH2:23][CH2:22][CH2:21][C@H:18]1[CH2:19]O)=[O:16])([CH3:13])([CH3:12])[CH3:11].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:10]([O:14][C:15]([N:17]1[CH2:23][CH2:22][CH2:21][CH:18]1[CH2:19][O:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][C:4]=1[CH3:9])=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: Cc1cc(I)ccc1O
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(I)ccc1OCC1CCCN1C(=O)OC(C)(C)C
Temperature: 70 °C
Reaction time: 13 h
Yield: 77.8 %

Procedure:
To a stirred solution of 4-iodo-2-methylphenol (465 mg, 1.987 mmol), N-tert-butoxycarbonylprolinol (400 mg, 1.987 mmol), and Ph3P (625 mg, 2.384 mmol) in THF (7 mL) was added dropwise DIAD (0.5 mL, 2.404 mmol) at room temp, and the mixture was stirred for 13 hr at 70° C. The reaction mixture was concentrated in vacuo and the residue was chromatographed on silica-gel with n-hexane-EtOAc (9:1, v/v) as eluent to give 645.3 mg (78%) 4-[1-(tert-butoxycarbonyl)-2-pyrrolidinyl]methoxy-1-iodo-3-methylbenzene as a pale yellow oil. 1H-NMR (400 MHz, CDCl3) δ 1.47 (s, 9H), 1.83–1.89 (m, 1H), 1.96–2.04 (m, 3H), 2.16 (s, 3H), 3.37–3.43 (br m, 2H), 3.81, 3.94 (br m each, 1H), 4.08–4.18 (m, 2H), 6.62 (br s, 1H), 7.42 (s, 2H); MS (FAB) m/z 418 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14](I)[CH:15]=[C:16]([CH2:21][CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:32][N:33]([CH2:35][C:36]#[CH:37])[CH3:34]>C(NCC)C.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([C:37]#[C:36][CH2:35][N:33]([CH3:34])[CH3:32])[CH:15]=[C:16]([CH2:21][CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CC3CCOCC3)cc(I)c21
Reactant: C#CCN(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCNCC
Product: CN(C)CC#Cc1cc(CC2CCOCC2)cc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Yield: 70 %

Procedure:
A solution of N-(4-chlorobenzyl)-8-iodo-1-methyl-4-oxo-6-(tetrahydro-2H-pyran-4-ylmethyl)-1,4-dihydro-3-quinolinecarboxamide (0.070 g), copper iodide (0.013 g), Pd(PPh3)2Cl2 (0.007 g) and N,N-dimethylpropargylamine (0.020 mL) in 7 mL diethylamine is stirred at room temperature for 3 days. The reaction is partitioned between CH2Cl2 and H20. The aqueous layer is extracted 3× with CH2Cl2. The organics are combined, dried over Na2SO4, filtered and concentrated. The residue is dissolved in CH2Cl2 and adsorbed onto silica. Purification by Biotage Flash 40S (eluent CH2Cl2 (1L), 1% MeOH/CH2Cl2 (1L), 2% MeOH/CH2Cl2 (1L), 3% MeOH/CH2Cl2 (1L), 4% MeOH/CH2Cl2 (1L), 5% MeOH/CH2Cl2 (1L)) affords the product as a tan residue. Recrystallization with CH2Cl2/hexanes affords the desired product (0.046 g, 70%).
Reaction SMILES: [C:1]([C:3]1([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:8][O:7][C:6]([CH3:10])([CH3:9])[O:5][CH2:4]1)#[CH:2].C#CCCCCCC.Br[C:28]1[CH:33]=[CH:32][C:31]([S:34]([NH:37][CH:38]2[CH2:43][CH2:42][CH:41]3[CH2:44][CH:39]2[C:40]3([CH3:46])[CH3:45])(=[O:36])=[O:35])=[CH:30][CH:29]=1.IC1C=C2C(=CC=1)CN(C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C2>>[C:14]([O:13][C:12](=[O:18])[NH:11][C:3]1([C:1]#[C:2][C:28]2[CH:29]=[CH:30][C:31]([S:34](=[O:35])(=[O:36])[NH:37][CH:38]3[CH2:43][CH2:42][CH:41]4[CH2:44][CH:39]3[C:40]4([CH3:45])[CH3:46])=[CH:32][CH:33]=2)[CH2:8][O:7][C:6]([CH3:10])([CH3:9])[O:5][CH2:4]1)([CH3:17])([CH3:16])[CH3:15]
Reactant: C#CC1(NC(=O)OC(C)(C)C)COC(C)(C)OC1
Reactant: CC1(C)C2CCC(NS(=O)(=O)c3ccc(Br)cc3)C1C2
Agent: C#CCCCCCC
Agent: Ic1ccc2c(c1)CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2
Product: CC(C)(C)OC(=O)NC1(C#Cc2ccc(S(=O)(=O)NC3CCC4CC3C4(C)C)cc2)COC(C)(C)OC1
Yield: 46 %

Procedure:
When tert-butyl 5-ethynyl-2,2-dimethyl-1,3-dioxan-5-ylcarbamate was substituted for 1-octyne and the product of Step A was substituted for 5-iodo-2-tritylisoindoline in Example 2, Step D, the similar process afforded the title compound in 46% yield, as a creamy paste. 1H-NMR (CDCl3) 0.85 (s, 3H); 1.1 (s, 3H); 1.44 (s, 3H); 1.46 (s, 9H); 1.48 (s, 3H); 1.63-1.65 (m, 2H); 1.79-1.86 (m, 5H); 2.05-2.08 (m, 1H); 2.27-2.32 (m, 1H); 2.89 (tr, 2H, J=6.59 Hz); 4.0-4.13 (m, 4H); 4.6 (broad s, 1H); 5.23 (s, 1H); 7.52 (d, 2H, J=8.25 Hz); 7.75 (d, 2H, J=8.46 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2=[CH:9][CH:10]=[C:11]3[C:20]([N:19]=[C:18]4[C:13]([CH:14]=[CH:15][CH:16]=[C:17]4[C:21](O)=[O:22])=[N:12]3)=[C:7]2[CH:6]=[CH:5][N:4]=1.[CH3:24][N:25]([CH3:30])[CH2:26][C@H:27]([NH2:29])[CH3:28]>>[CH3:24][N:25]([CH3:30])[CH2:26][C@H:27]([NH:29][C:21]([C:17]1[C:18]2[C:13](=[N:12][C:11]3[C:20]([N:19]=2)=[C:7]2[CH:6]=[CH:5][N:4]=[C:3]([O:2][CH3:1])[C:8]2=[CH:9][CH:10]=3)[CH:14]=[CH:15][CH:16]=1)=[O:22])[CH3:28]
Reactant: C[C@@H](N)CN(C)C
Reactant: COc1nccc2c1ccc1nc3cccc(C(=O)O)c3nc12
Product: COc1nccc2c1ccc1nc3cccc(C(=O)N[C@H](C)CN(C)C)c3nc12

Procedure:
4-Methoxypyrido[4,3-α]phenazine-11-carboxylic acid (2-dimethylamino-1(R)-methylethyl)-amide was prepared from 4-methoxypyrido[4,3-α]phenazine-11-carboxylic acid (II.4) and (R)-N1,N1-Dimethyl-propane-1,2-diamine
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:19]=[CH:18][C:12]([CH:13]=[CH:14][C:15]([OH:17])=[O:16])=[CH:11][CH:10]=1.CN(C)C1C=CC=CC=1.[C:29](Cl)(=[O:32])[CH:30]=[CH2:31].C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C>O1CCOCC1>[C:29]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:13]=[CH:14][C:15]([OH:17])=[O:16])=[CH:18][CH:19]=1)(=[O:32])[CH:30]=[CH2:31]
Reactant: O=C(O)C=Cc1ccc(OCCCCCCO)cc1
Reactant: C=CC(=O)Cl
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: CN(C)c1ccccc1
Solvent: C1COCCO1
Product: C=CC(=O)OCCCCCCOc1ccc(C=CC(=O)O)cc1
Temperature: 60 °C

Procedure:
A mixture of 21.15 g (0.08 mole) of 4-(6-hydroxyhexyloxy)cinnamic acid (13), 11.63 g (0.096 mole) of N,N-dimethylaniline 8.69 g (0.096 mole) of acryloyl chloride, 0.05 g of 2,6-di-t-butyl-4-methylphenol and 60 ml of 1,4-dioxane was heated at 60° C. under a nitrogen atmosphere. After 2 hours heating at 60° C. the mixture was filtered and dropped under stirring into a mixture of 1000 ml of water, 400 g of ice and 10 ml of 2.4 N hydrochloric acid. The solid precipitate was filtered off and recrystallized from 350 ml of ethanol. The solid was dried in a desiccator over silica gel. Yield 19.7 g (77.3%).
Reaction SMILES: Cl.[Cl:2][C:3]1[NH:8][C:7](=[O:9])[CH:6]=[C:5]([OH:10])[C:4]=1[CH3:11].[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[Cl:2][C:3]1[NH:8][C:7](=[O:9])[C:6]([N+:12]([O-:14])=[O:13])=[C:5]([OH:10])[C:4]=1[CH3:11]
Reactant: Cc1c(O)cc(=O)[nH]c1Cl
Reactant: O=[N+]([O-])O
Agent: Cl
Agent: O=S(=O)(O)O
Product: Cc1c(Cl)[nH]c(=O)c([N+](=O)[O-])c1O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
6-Chloro-4-hydroxy-5-methyl-1H-pyridin-2-one hydrochloride (64 g) was dissolved in sulfuric acid (325 mL) while cooling in an ice bath. Nitric acid was added drop wise over a period of 90 minutes. The reaction mixture was allowed to stir for an additional 30 minutes and then it was poured into ice water (2 L). The resulting precipitate was isolated by filtration, washed with water and then dried to provide 42.5 g of 6-chloro-4-hydroxy-5-methyl-3-nitro-1H-pyridin-2-one as a light yellow solid.
Reaction SMILES: [Na].C[O-].[Na+].[CH3:5][C@@H:6]([CH2:9][CH3:10])[CH2:7]Br.[C:11]([O:19][CH2:20][CH3:21])(=[O:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>C(O)C>[CH3:5][C@@H:6]([CH2:9][CH3:10])[CH2:7][CH:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:11]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC[C@H](C)CBr
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(C[C@@H](C)CC)C(=O)OCC

Procedure:
Sodium (57.5 g, 2.5 mols) was added to ethanol (1 l) to prepare sodium methoxide, followed by adding (S)-2-methylbutyl bromide (317 g, 2.1 mols) and diethyl malonate 400 g, 2.5 mols), refluxing the mixture for 5 hours and distilling off ethanol to obtain oily diethyl (S)-2-methylbutylmalonate.
Reaction SMILES: I.[Cl:2][C:3]1[N:4]=[CH:5][N:6]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](SC)=[NH:16])=[CH:10][C:9]=2[O:19][CH3:20])[CH:7]=1.[Cl:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]([C:30]1[CH:35]=[CH:34][C:33]([F:36])=[C:32]([F:37])[CH:31]=1)[C:27](O)=O.[NH2:38][NH2:39]>>[Cl:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]([C:27]1[NH:39][N:38]=[C:15]([NH:14][C:11]2[CH:12]=[CH:13][C:8]([N:6]3[CH:7]=[C:3]([Cl:2])[N:4]=[CH:5]3)=[C:9]([O:19][CH3:20])[CH:10]=2)[N:16]=1)[C:30]1[CH:35]=[CH:34][C:33]([F:36])=[C:32]([F:37])[CH:31]=1
Reactant: O=C(O)C(CCCCCl)c1ccc(F)c(F)c1
Reactant: COc1cc(NC(=N)SC)ccc1-n1cnc(Cl)c1
Reactant: NN
Agent: I
Product: COc1cc(Nc2n[nH]c(C(CCCCCl)c3ccc(F)c(F)c3)n2)ccc1-n1cnc(Cl)c1
Yield: 12 %

Procedure:
Methyl 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylcarbamimidothioate, hydroiodide (500 mg, 1.69 mmol, from preparation A) and 6-chloro-2-(3,4-difluorophenyl)hexanoic acid (443 mg, 1.69 mmol, from preparation AG) were coupled and then reacted with hydrazine (0.211 mL, 6.74 mmol) using a procedure analogous to Step A of Example 13. The crude products were purified using silica gel chromatography (40-100% ethyl acetate/chloroform) to afford 5-(5-chloro-1-(3,4-difluorophenyl)pentyl)-N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-1H-1,2,4-triazol-3-amine (100 mg, 0.197 mmol, 12% yield) as a yellow residue. LC-MS (M+H)+ 507.1.