Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].Cl[C:4]1[N:9]=[C:8](Cl)[N:7]=[C:6](Cl)[N:5]=1.[CH2:12]([NH2:15])[CH2:13][CH3:14]>CC(C)=O.O>[CH2:12]([NH:15][C:4]1[N:9]=[C:8]([NH:15][CH2:12][CH2:13][CH3:14])[N:7]=[CH:6][N:5]=1)[CH2:13][CH3:14]
Reactant: CCCN
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CCCNc1ncnc(NCCC)n1
Temperature: 50 °C
Yield: 100 %

Procedure:
A 2 M NaOH solution (82 mL, 162.68 mmol) was added in a dropwise manner to a suspension of 2,4,6-trichloro-1,3,5-triazine (XVIII) (15.00 g, 81.34 mmol) and n-propylamine (13.4 mL, 162.68 mmol) in acetone (300 mL) and water (15 mL) at 0° C. The reaction mixture was heated at 50° C. for 3 h and then cooled. Water (100 mL) was added to the reaction mixture; the resultant precipitate was filtered, washed with water, ethyl ether and dried to yield 2-chloro-N-(4,6-bis-(n-propylamino)-[1,3,5]triazine (XXXIV) (15.88 g, 85% yield).
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.[C:11]([OH:19])(=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(Cl)CCl.Cl.[NH2:25][C@H:26]([CH:42]([CH3:45])[CH2:43][CH3:44])[C:27]([N:29]1[CH2:34][CH2:33][CH:32]([C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=2)[CH2:31][CH2:30]1)=[O:28]>CN(C=O)C.CCN(C(C)C)C(C)C.CO>[Cl:41][C:38]1[CH:39]=[CH:40][C:35]([CH:32]2[CH2:31][CH2:30][N:29]([C:27](=[O:28])[C@H:26]([NH:25][C:11](=[O:19])[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C@H:42]([CH3:45])[CH2:43][CH3:44])[CH2:34][CH2:33]2)=[CH:36][CH:37]=1
Reactant: CCC(C)[C@@H](N)C(=O)N1CCC(c2ccc(Cl)cc2)CC1
Reactant: O=C(O)c1ccccc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CO
Product: CC[C@@H](C)[C@@H](NC(=O)c1ccccc1)C(=O)N1CCC(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A reaction tube was charged with HOBt (8 mg), benzoic acid (7 mg) and EDC (11 mg) in DMF (0.6 mL) and then agitated at rt. for 15 min. After this time, a solution of (2R)-2-amino-1-(4-(4-chlorophenyl)piperidin-1-yl)-3-methylpentan-1-one hydrochloride (16 mg) in DIEA (38 μL) and DMF (187 μL) was added. Upon completion of addition, the reaction mixture was shaken overnight at rt. At the conclusion of this period, the resulting solution was diluted with MeOH and purified by preparative LC-MS to provide Example 150. MS found: (M+H)+=414.
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][C:11]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:12][CH:13]=3)[CH2:8][C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([Li:26])CCC>CCOCC>[C:1]([C:5]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][C:11]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:12][CH:13]=3)[CH2:8][C:7]=2[C:6]=1[Li:26])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc2c(c1)Cc1cc(C(C)(C)C)ccc1-2
Reactant: [Li]CCCC
Solvent: CCOCC
Product: [Li]c1c(C(C)(C)C)ccc2c1Cc1cc(C(C)(C)C)ccc1-2
Temperature: -78 °C
Reaction time: 12 h

Procedure:
A one-liter flask is charged with 2,7-di-tert-butylfluorene (50 g, 179.6 mmol) and a stir bar, capped with a rubber septum, and placed under a nitrogen atmosphere. Diethyl ether (about 300 mL) is added via a cannula, and the resulting mixture is cooled to −78° C. in a dry-ice bath. This mixture is stirred at this temperature as n-butyllithium (21.5 mL of 10 M in hexanes, 215 mmol) is added slowly via syringe. After the addition of n-butyllithium is complete, the reddish solution is slowly warmed to room temperature and stirred overnight (at least about 12 hours), to provide an ether solution of 2,7-di-tert-butylfluorenyl lithium.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([N:28]=[C:29]=[O:30])[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]>>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([NH:28][C:29](=[O:30])[O:17][C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]3)[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]
Reactant: COc1ccc(N=C=O)cc1OC
Reactant: Oc1ccc2c(c1)CCN2Cc1ccccc1
Product: COc1ccc(NC(=O)Oc2ccc3c(c2)CCN3Cc2ccccc2)cc1OC

Procedure:
The title compound was synthesized from 1-benzylindolin-5-ol (30.0 mg, 0.133 mmol) using the same procedure employed for Example 2 (2), but with 3,4-dimethoxyphenylisocyanate instead of 4-isopropylphenylisocyanate. The product was obtained as a white solid (26.9 mg, 50%) having the following characteristics.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[C:9]1(=O)[O:14][C:12](=[O:13])[C:11]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:10]12>C(O)(=O)C>[Br:8][C:6]1[CH:7]=[C:2]([N:1]2[C:12](=[O:13])[C:11]3[C:10](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:9]2=[O:14])[CH:3]=[N:4][CH:5]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Nc1cncc(Br)c1
Solvent: CC(=O)O
Product: O=C1c2ccccc2C(=O)N1c1cncc(Br)c1
Temperature: 25 °C

Procedure:
A flask is charged with 3-amino-5-bromo pyridine (1.00 g, 5.78 mmol), phthalic anhydride (0.856 g, 5.78 mmol) and acetic acid (20 mL). The reaction is refluxed overnight. The reaction is then cooled to room temperature and concentrated in vacuo. The crude is dissolved in ethyl acetate and washed with water once. The organic layer is dried over sodium sulfate and concentrated in vacuo to afford 2-(5-bromo-pyridin-3-yl)-isoindole-1,3-dione. MS (ESI) m/z 305.1 (M+H)+
Reaction SMILES: [O:1]1[C:5]([NH:6][C:7](=[O:14])OCC(Cl)(Cl)Cl)=[CH:4][CH:3]=[N:2]1.[C:15]1([C:21]2[N:22]=[C:23]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[S:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[O:1]1[C:5]([NH:6][C:7]([N:29]2[CH2:30][CH2:31][N:26]([C:23]3[S:24][CH:25]=[C:21]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:22]=3)[CH2:27][CH2:28]2)=[O:14])=[CH:4][CH:3]=[N:2]1
Reactant: c1ccc(-c2csc(N3CCNCC3)n2)cc1
Reactant: O=C(Nc1ccno1)OCC(Cl)(Cl)Cl
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccno1)N1CCN(c2nc(-c3ccccc3)cs2)CC1

Procedure:
A solution of 2,2,2-trichloroethyl isoxazol-5-ylcarbamate (200 mg, 0.771 mmol), 1-(4-phenyl-1,3-thiazol-2-yl)piperazine (189 mg, 0.771 mmol), diisopropylethylamine (0.134 ml, 0.771 mmol) and dimethylsulfoxide (7 ml) was stirred at 70° C. for 12 hours, 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 distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain the desired product as a solid. This was recrystallized from a mixed solvent of ethyl acetate and hexane to obtain the desired product (98.8 mg, 36.1%) as a solid.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:16])=[C:4]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[NH:14][CH3:15])[CH:5]=[CH:6][CH:7]=1.[CH3:17][S:18]([C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:24]([OH:26])=O)(=[O:20])=[O:19]>>[F:1][C:2]1[C:3]([CH3:16])=[C:4]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH3:15])[C:24](=[O:26])[C:23]2[CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=[C:21]([S:18]([CH3:17])(=[O:19])=[O:20])[CH:22]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CNc1cnccc1-c1cccc(F)c1C
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Product: Cc1c(F)cccc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1

Procedure:
The title compound was prepared in analogy to example 90, from [4-(3-fluoro-2-methyl-phenyl)-pyridin-3-yl]-methyl-amine and 3-(methylsulfonyl)-5-(trifluoromethyl)benzoic acid (example 114, intermediate a) after a reaction time of 23 hours at room temperature. The compound was purified by silica gel chromatography on a 20 g column using an MPLC (Flashmaster) system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). The Product was purified by preparative HPLC (Gemini NX column) with a gradient of MeOH:water (containing 0.05% formic acid) (80:20 to 98:2). Colorless solid (42%). MS (ESI): m/z=467.104 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:21]([C:22]([OH:24])=[O:23])[CH2:20][C:19]2[CH:18]=[C:17]3[C:12]([O:13][C@@H:14]([C:26]4[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]5[CH:39]=[CH:38][C:37]([Cl:40])=[C:36]([Cl:41])[CH:35]=5)=[CH:28][CH:27]=4)[C:15](=[O:25])[NH:16]3)=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:42](Cl)[CH2:43]Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH:10]([C@@H:19]1[CH2:20][CH2:21][C@@H:42]([CH3:43])[CH2:17][C@H:18]1[O:23][C:22]([C@@H:21]1[CH2:20][C:19]2[CH:18]=[C:17]3[C:12]([O:13][C@@H:14]([C:26]4[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]5[CH:39]=[CH:38][C:37]([Cl:40])=[C:36]([Cl:41])[CH:35]=5)=[CH:28][CH:27]=4)[C:15](=[O:25])[NH:16]3)=[CH:11][C:10]=2[CH2:9][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[O:24])([CH3:11])[CH3:9]
Reactant: ClCCCl
Reactant: CC(C)(C)OC(=O)N1Cc2cc3c(cc2CC1C(=O)O)NC(=O)[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OC(=O)[C@@H]1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)C(=O)N3
Temperature: 25 °C
Reaction time: 6 h

Procedure:
(S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylic acid 6-tert-butyl ester (8.0 g, 13.3 mmol) was suspended in 30 mL DCM and 1R-2S-5R (−)-menthol (26.6 mmol), EDC (26.6 mmol) and DMAP (cat.) added. The mixture was stirred at r.t. for 6 h and the mixture diluted with DCM. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The residue purified over silica with hexanes-EtOAc gradient (0% EtOAc to 30%) to provide (3S,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylic acid 6-tert-butyl ester 7-((1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl) ester (2.4 g, 1H NMR (400 MHz, CDCl3): 8.2 (m, 1H), 7.5 (m, 1H), 7.42 (d, 1H), 7.35 (m, 2H), 7.25 (m, 1H), 6.9 (m, 2H), 6.7 (m, 1H), 6.6 (s, 1H), 5.55 (m, 1H), 4.8-5.1 (m, 1H), 5.0 (s, 2H), 4.3-4.6 (m, 3H), 3.1 (m, 2H), 1.8 (m, 1H), 1.6 (m, 3H), 1.5 (d, 9H), 1.3 (m, 2H), 0.7-1.0 (m, 9H), 0.4 (m, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([CH3:12])[CH2:10][OH:11])[C:5]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:32])(=[N:27][CH2:28][CH2:29][O:30][CH3:31])=[O:26])=[CH:21][CH:20]=1>>[CH3:31][O:30][CH2:29][CH2:28][N:27]=[S:25]([C:22]1[CH:21]=[CH:20][C:19]([NH:18][C:2]2[N:7]=[C:6]([NH:8][C@H:9]([CH3:12])[CH2:10][OH:11])[C:5]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[CH:4][N:3]=2)=[CH:24][CH:23]=1)([CH3:32])=[O:26]
Reactant: C[C@H](CO)Nc1nc(Cl)ncc1-c1cccs1
Reactant: COCCN=S(C)(=O)c1ccc(N)cc1
Product: COCCN=S(C)(=O)c1ccc(Nc2ncc(-c3cccs3)c(N[C@H](C)CO)n2)cc1
Yield: 3 %

Procedure:
In the reaction of (R)-2-(2-chloro-5-(2-thienyl)pyrimidine-4-ylamino)propan-1-ol (248.2 mg, 0.92 mmol) with (RS)—S-(4-aminophenyl)-N-(2-methoxy-ethyl)-S-methylsulphoximide (191 mg, 0.84 mmol) according to procedure 5c, the desired product is obtained in 3% yield (10 mg) after chromatographic purification (silica gel, dichloromethane/ethanol (0%-20% ethanol) and HPLC).
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([O:17][CH3:18])[C:11]([CH2:19][C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1)=[C:10]2[Cl:28].[CH:29]([C:31]1[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=1)=[O:30]>C1COCC1>[Cl:28][C:10]1[C:9]2[C:14](=[CH:15][CH:16]=[C:7]([CH:29]([OH:30])[C:31]3[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=3)[CH:8]=2)[N:13]=[C:12]([O:17][CH3:18])[C:11]=1[CH2:19][C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1
Reactant: N#Cc1ccc(C=O)cc1
Reactant: COc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(C#N)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)c3ccc(C#N)cc3)cc2c(Cl)c1Cc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
A solution of n-BuLi (2.5 M in hexanes, 1.25 mL. 3.12 mmol) was added dropwise by syringe to a solution of 4-((6-bromo-4-chloro-2-methoxyquinolin-3-yl)methyl)benzonitrile (1.211 g, 3.125 mmol, Intermediate 8: step d) in dry THF (15 mL) in a dry ice-acetone bath. After 1-2 minutes, a solution of 4-formylbenzonitrile (498.8 mg, 3.804 mmol) in dry THF (2 mL) was added dropwise. The reaction was stirred for 5 minutes and then removed from the cold bath and allowed to warm to room temperature. The reaction was quenched with saturated aqueous ammonium chloride. The mixture was partitioned between water and dichloromethane. The separated aqueous phase was further extracted with dichloromethane. The combined organic phase was dried (Na2SO4), filtered, and concentrated. Crude product was purified by flash column chromatography (silica gel, 100% EtOAc, followed by 0-5% MeOH-DCM), to provide the title compound. 1H NMR (500 MHz, CDCl3) δ 8.13-8.11 (m, 1H), 7.79 (d, J=8.6 Hz, 1H), 7.63-7.59 (m, 2H), 7.56-7.51 (m, 5H), 7.38-7.34 (m, 2H), 6.03 (d, J=3.2 Hz, 1H), 4.33 (s, 2H), 4.05 (s, 3H); MS m/e 440.0 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:27]2[C:28]([C:33]#[N:34])=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:10](=[O:26])[N:11]([C@H:21]2[CH2:24][C@@H:23]([OH:25])[CH2:22]2)[C:12]2[N:13]([N:18]=[CH:19][N:20]=2)[C:14]=1[CH2:15][CH2:16][CH3:17].[N+](=[CH:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[N-]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Rh+2].C([O-])(=O)C>[CH2:41]([O:40][C:38](=[O:39])[CH2:37][O:25][C@H:23]1[CH2:22][C@@H:21]([N:11]2[C:10](=[O:26])[C:9]([CH2:8][C:7]3[CH:6]=[CH:5][C:4]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:33]#[N:34])=[CH:3][C:2]=3[F:1])=[C:14]([CH2:15][CH2:16][CH3:17])[N:13]3[N:18]=[CH:19][N:20]=[C:12]23)[CH2:24]1)[CH3:42]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2C[C@@H](O)C2)c2ncnn12
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2C[C@@H](OCC(=O)OCC)C2)c2ncnn12
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 36.4 %

Procedure:
A mixture of 3′-fluoro-4′-{[4-(cis-3-hydroxycyclobutyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.67 g), rhodium(II) acetate (dimer) (0.0066 g) and toluene (10 mL) was heated to 80° C. under an argon atmosphere, a solution of ethyl diazoacetate (1.5 g) in toluene (10 mL) was added dropwise, and the mixture was stirred at 80° C. for 10 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.29 g, 37%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[N:3]1.[Li]CCCC.[O:12]=[CH:13][CH2:14][C@@:15]1([C:28]([N:30]2[CH2:39][CH2:38][C:37]3[N:36]=[CH:35][C:34]([C:40]([F:43])([F:42])[F:41])=[CH:33][C:32]=3[CH2:31]2)=[O:29])[CH2:19][C@H:18]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:17]=[CH:16]1.[NH4+].[Cl-]>C1COCC1.CCCCCC>[OH:12][CH:13]([C:6]1[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=1)[CH2:14][C@@:15]1([C:28]([N:30]2[CH2:39][CH2:38][C:37]3[N:36]=[CH:35][C:34]([C:40]([F:43])([F:42])[F:41])=[CH:33][C:32]=3[CH2:31]2)=[O:29])[CH2:19][C@H:18]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:17]=[CH:16]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C=C[C@](CC=O)(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)C1
Reactant: Cn1cccn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cn1nccc1C(O)C[C@]1(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)C=C[C@@H](NC(=O)OC(C)(C)C)C1
Reaction time: 1 h

Procedure:
To a solution of 1-methylpyrazole (0.165 mmol, 1.98 mmol, 3 eq) in THF (8 mL) at −78° C. under Ar was added n-BuLi (0.77 mL of a 2.5 M solution in hexane, 1.92 mmol, 2.9 eq) and the solution stirred 1 hr. Then a solution of the product of Example 10, Step A (300 mg, 0.66 mmol, 1 eq) in THF (8 mL) was added over 5 min. After 1 hr, saturated NH4Cl was added, the solution extracted with ethyl acetate, the organics combined, dried over MgSO4 and concentrated. Purification by chromatography (12 g column) eluting with 50 to 100% EtOAc/heptane to 5 to 10% methanol/DCM afforded the title compound of Step A as a mix of diastereomers. 1H NMR (CHLOROFORM-d) δ: 8.70 (s, 1H), 7.62-7.80 (m, 1H), 7.33 (d, J=8.8 Hz, 1H), 6.19-6.49 (m, 1H), 6.09 (br. s., 1H), 5.87 (dd, J=17.9, 5.6 Hz, 1H), 4.54-5.03 (m, 5H), 3.74-3.96 (m, 4H), 3.48 (s, 1H), 2.90-3.23 (m, 2H), 2.46-2.87 (m, 2H), 2.06-2.39 (m, 2H), 1.73-1.98 (m, 1H), 1.43 (br. s., 9H). Calculated for C27H34F3N5O4: 558.2 (M+23). found: 558.2.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:16]([CH:17]([CH3:19])[CH3:18])=[CH:15][CH:14]=[CH:13][C:5]=1[CH2:6][N:7]([CH3:12])[C:8](=[O:11])[CH:9]=[CH2:10])[CH3:2].C(N(C(C)C)CC)(C)C.Br[C:30]1[CH:50]=[N:49][C:33]2[NH:34][C:35](=[O:48])[CH2:36][N:37]([CH2:39][C:40]3[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=3)[CH2:38][C:32]=2[CH:31]=1.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:1]([O:3][C:4]1[C:16]([CH:17]([CH3:18])[CH3:19])=[CH:15][CH:14]=[CH:13][C:5]=1[CH2:6][N:7]([CH3:12])[C:8](=[O:11])/[CH:9]=[CH:10]/[C:30]1[CH:50]=[N:49][C:33]2[NH:34][C:35](=[O:48])[CH2:36][N:37]([CH2:39][C:40]3[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=3)[CH2:38][C:32]=2[CH:31]=1)[CH3:2]
Reactant: COc1ccc(CN2CC(=O)Nc3ncc(Br)cc3C2)cc1
Reactant: C=CC(=O)N(C)Cc1cccc(C(C)C)c1OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: CCOc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)CN(Cc2ccc(OC)cc2)CC(=O)N3)cccc1C(C)C
Yield: 44.5 %

Procedure:
A solution of N-(2-ethoxy-3-isopropylbenzyl)-N-methylacrylamide (0.281 g, 1.07 mmol) in propionitrile (4 mL) and DMF (0.8 mL) was deoxygenated with Ar for 20 min. The solution was treated with diisopropylethylamine (0.30 mL, 1.73 mmol) and 7-bromo-4-(4-methoxy-benzyl)-1,3,4,5-tetrahydro-pyrido[2,3-e][1,4]diazepin-2-one (0.300 g, 0.828 mmol). The solution was deoxygenated with Ar for 20 min. Pd(OAc)2 (0.018 g, 0.082 mmol) and P(o-tol)3 (0.050 g, 0.16 mmol) were then added and the solution was deoxygenated again with Ar for 10 min. The mixture was heated to reflux for 1.5 h, then allowed to cool. The mixture was diluted with H2O (100 mL) and then was washed with EtOAc (3×50 mL). The organic layer was washed with brine (2×100 mL), dried (Na2SO4) and concentrated to an orange oil. Purification by column chromatography (silica gel, CH2Cl2 to CH2Cl2/MeOH, 100 to 99.5:0.5) gave the title compound (0.20 g, 44%) as a light yellow solid and as a mixture of amide rotamers: 1H NMR (300 MHz, DMSO-d6) δ 10.43-10.41 (m, 1H), 8.55-8.49 (m, 1H), 8.10-8.01 (m, 1H), 7.55-7.50 (m, 1H), 7.35-7.17 (m, 4H), 7.12-7.04 (m, 1H), 6.91-6.85 (m, 3H), 4.80-4.66 (m, 2H), 3.83-3.70 (m, 7H), 3.65-3.62 (m, 2H), 3.41-3.38 (m, 2H), 3.29-3.90 (m, 1H), 2.56-2.51 (m, 3H), 1.39-1.37 (m, 3H), 1.25-1.11 (m, 6H); MS (ESI) m/e 543 (M+H)+.
Reaction SMILES: O.O.[Sn](Cl)Cl.[N+:6]([C:9]1[CH:14]=[CH:13][C:12]([S:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)([O-])=O>C(O)C.C(OCC)(=O)C>[CH2:16]([S:15][C:12]1[CH:11]=[CH:10][C:9]([NH2:6])=[CH:14][CH:13]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=[N+]([O-])c1ccc(SCc2ccccc2)cc1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1ccc(SCc2ccccc2)cc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
Tin (II) chloride dihydrate (444 mg) was added to a stirred solution of benzyl 4-nitrophenyl sulfide (A, 704 mg) in ethanol (20 mL). The mixture was stirred at 70° C. for 2 hr under nitrogen, allowed to cool down and then poured into ice. The pH was made slightly basic (pH 7-8). The mixture was diluted with ethyl acetate and washed with saturated sodium hydrogen carbonate and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound (565 mg) as a brown oil: 1H NMR (400 MHz, CDCl3) δ 3.59 (br s, 2H), 3.93 (s, 2H), 6.54-6.57 (m, 2H), and 7.11-7.26 (m, 7H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[NH:10][CH:9]=[N:8][C:7]2=O)[CH3:2].O=P(Cl)(Cl)[Cl:19]>CN(C=O)C>[Cl:19][C:7]1[C:6]2[C:11](=[CH:12][C:13]([O:14][CH3:15])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=2)[N:10]=[CH:9][N:8]=1
Reactant: CCOc1cc2c(=O)nc[nH]c2cc1OC
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CCOc1cc2c(Cl)ncnc2cc1OC
Temperature: 100 °C
Yield: 68.5 %

Procedure:
A mixture of 6-(ethyloxy)-7-(methyloxy)-4(1H)-quinazolinone (560 mg, 2.54 mmol) in POCl3 (5 mL, 53.6 mmol) was treated with 1 drop of DMF and heated at 100° C. for 2 hours before being concentrated. The residue was treated with saturated aqueous NaHCO3 and extracted with CH2Cl2. The organic extracts were dried (sodium sulfate) and concentrated to give 4-chloro-6-(ethyloxy)-7-(methyloxy)quinazoline (416 mg, 1.74 mmol, 69%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.88 (s, 1 H), 7.46 (s, 1 H), 7.39 (s, 1 H), 4.26 (q, J=6.94 Hz, 2 H), 4.02 (s, 3 H), 1.44 (t, J=7.03 Hz, 3 H). MS (m/z) 239.0 (M+H+).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH3:50])[C:35]([NH:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[F:51][C:52]([F:57])([F:56])[C:53]([OH:55])=[O:54].C(Cl)Cl>>[F:51][C:52]([F:57])([F:56])[C:53]([OH:55])=[O:54].[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH3:50])[C:35]([NH:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCCCCCCCNC(=O)N(C)c1ccc2nc(CCCC)n(Cc3ccc(-c4ccccc4C(=O)OC(C)(C)C)cc3)c2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCCCCCNC(=O)N(C)c1ccc2nc(CCCC)n(Cc3ccc(-c4ccccc4C(=O)O)cc3)c2c1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-(N-(n-dodecylaminocarbonyl)-methylamino)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate in trifluoroacetic acid/methylene chloride.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH3:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH3:11][O:12][C:13](=[O:21])[CH2:14][CH2:15][CH2:16][CH2:17][C:18](Cl)=[O:19]>C(Cl)Cl>[CH2:1]([N:8]([CH2:9][CH3:10])[C:18](=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][C:13]([O:12][CH3:11])=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: COC(=O)CCCCC(=O)Cl
Reactant: CCCCCCCNCC
Solvent: ClCCl
Product: CCCCCCCN(CC)C(=O)CCCCC(=O)OC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3.2 gms of the N-heptyl-N-ethylamine in 96 ml of CH2Cl2 are added 5.7 ml of Et3 followed by 3.63 ml of hexanedioic acid monochloride monomethyl ester. This mixture is stirred at room temperature for 18 hours; and after concentrating under vacuum, the residue obtained is partitioned between ethyl acetate and an aqueous 2N HCl solution. The organic layer is separated and washed with aqueous saturated NaHCO3, then brine, and dried over MgSO4. Following filtration and concentration under vacuum, the residue is flash chromatographed on normal phase silica gel using a 3/1 ratio of hexane and ethyl acetate to yield N-heptyl-N-ethyladipamic acid, methyl ester.