Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[C:2]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]([C:17]3[CH:18]=[CH:19][C:20]4[N:24]=[C:23]([C@@H:25]5[CH2:29][CH2:28][CH2:27][N:26]5[C:30](=[O:40])[C@@H:31]([NH:35][C:36]([O:38][CH3:39])=[O:37])[CH:32]([CH3:34])[CH3:33])[NH:22][C:21]=4[CH:41]=3)[CH2:15][CH2:14][CH:13]2[C:42]2[CH:47]=[CH:46][C:45]([C:48]3[NH:52][C:51]([C@@H:53]4[CH2:57][CH2:56][CH2:55][NH2+:54]4)=[N:50][CH:49]=3)=[CH:44][CH:43]=2)=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[CH3:58][O:59][C:60]([NH:62][C@@H:63]([CH:67]([CH3:69])[CH3:68])[C:64](O)=[O:65])=[O:61].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CN1CCOCC1>CN(C=O)C.CCOC(C)=O.C(Cl)Cl>[C:2]([C:6]1[CH:7]=[CH:8][C:9]([N:12]2[C@@H:16]([C:17]3[CH:18]=[CH:19][C:20]4[N:24]=[C:23]([C@@H:25]5[CH2:29][CH2:28][CH2:27][N:26]5[C:30](=[O:40])[C@@H:31]([NH:35][C:36]([O:38][CH3:39])=[O:37])[CH:32]([CH3:34])[CH3:33])[NH:22][C:21]=4[CH:41]=3)[CH2:15][CH2:14][C@@H:13]2[C:42]2[CH:47]=[CH:46][C:45]([C:48]3[NH:52][C:51]([C@@H:53]4[CH2:57][CH2:56][CH2:55][N:54]4[C:64](=[O:65])[C@@H:63]([NH:62][C:60](=[O:61])[O:59][CH3:58])[CH:67]([CH3:69])[CH3:68])=[N:50][CH:49]=3)=[CH:44][CH:43]=2)=[CH:10][CH:11]=1)([CH3:4])([CH3:5])[CH3:3]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc(C3CCC(c4ccc(-c5cnc([C@@H]6CCC[NH2+]6)[nH]5)cc4)N3c3ccc(C(C)(C)C)cc3)cc2[nH]1)C(C)C
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc([C@H]3CC[C@H](c4ccc5nc([C@@H]6CCCN6C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]c5c4)N3c3ccc(C(C)(C)C)cc3)cc2)[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 9 h

Procedure:
The product from example 191L (0.092 g, 0.116 mmole), (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (0.020 g, 0.116 mmole) and HOBt (000.018 g, 0.116 mmole) were combined in a 25 mL RB flask and dissolved in DMF (1 mL). The reaction mixture was placed in an ice bath and treated with EDAC (0.022 g, 0.116 mmole) and N-methylmorpholine (0.12 mL, 1.091 mmole. The light yellow reaction mixture was stirred in the ice bath for 1 hr, then stirred at room temperature for 9 hr. The reaction mixture was diluted with EtOAc (100 mL) washed with water (20 mL) and 10% NaCl (20 mL), dried over anhydrous Na2SO4(s), filtered and solvent removed in vacuo leaving an oily residue. The residue was dissolved in 5 mL CH2Cl2 and applied to a 12 g silica gel column. The column was eluted with a gradient of CH2Cl2/MeOH, 99/1 to 95/5 over 22 minutes. The title compound was isolated from the first fraction eluted from the column as a white solid consisting of a mixture of trans-pyrrolidine isomers, 21 mg, 19%. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.71-0.95 (m, 12H) 1.11 (s, 9H) 1.99 (m, 6H) 2.13 (m, 4H) 3.53 (s, 6H) 3.81 (m, 4H) 4.04 (m, 4H) 5.06 (m, 2H) 5.11-5.15 (m, 1H) 5.18-5.26 (m, 1H) 5.32 (m, 1H) 6.25 (m, 2H) 6.86-6.96 (m, 1H) 7.05 (m, 2H) 7.33 (m, 6H) 7.61 (m, 2H) 11.53 (s, 1H) 11.68 (s, 1H) 12.00 (m, 2H); ESI+: 914.5.
Reaction SMILES: C(O)CC(C)C.[NH2:7][C:8]1[C:17]2[C:12](=[C:13]([O:21][CH3:22])[C:14]([O:19][CH3:20])=[C:15]([Cl:18])[CH:16]=2)[N:11]=[C:10](Cl)[N:9]=1.[O:24]1[CH2:28][CH2:27][CH2:26][CH:25]1[C:29]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)=[O:30]>C(OCC)C>[O:24]1[CH2:28][CH2:27][CH2:26][CH:25]1[C:29]([N:31]1[CH2:32][CH2:33][N:34]([C:10]2[N:9]=[C:8]([NH2:7])[C:17]3[C:12](=[C:13]([O:21][CH3:22])[C:14]([O:19][CH3:20])=[C:15]([Cl:18])[CH:16]=3)[N:11]=2)[CH2:35][CH2:36]1)=[O:30]
Reactant: COc1c(Cl)cc2c(N)nc(Cl)nc2c1OC
Reactant: O=C(C1CCCO1)N1CCNCC1
Solvent: CC(C)CCO
Solvent: CCOCC
Product: COc1c(Cl)cc2c(N)nc(N3CCN(C(=O)C4CCCO4)CC3)nc2c1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 35 ml. of isoamyl alcohol were added 1.50 g. (5.47 mmole) of 4-amino-2,6-dichloro-7,8-dimethoxyquinazoline and 1.11 g. (6.02 mmole) of 1-(2-tetrahydrofuroyl)piperazine and the mixture was heated at reflux under a nitrogen atmosphere for 1.5 hours. The mixture was cooled, 20 ml. of ethyl ether was added and the resulting mixture stirred at room temperature overnight. It was then cooled in ice and the precipitated solid collected by filtration. The crude material was recrystallized once from a mixture of isopropanol, methanol and ethyl ether. The recrystallized material was dissolved in water made strongly alkaline with sodium hydroxide solution while stirring, the precipitated brownish solid collected by filtration, dried, decolorized with activated carbon and recrystallized from isopropanol/ethyl ether to obtain 0.38 g. of yellow solid, M.P. 192°-193° C.
Reaction SMILES: [C:1]([N:4]1[CH2:7][CH:6]([N:8]2[CH2:14][C:13]3[C:15]([F:26])=[C:16]([Cl:25])[CH:17]=[C:18]([C:19]4([CH3:24])OCC[O:20]4)[C:12]=3[O:11][CH:10]([CH3:27])[C:9]2=[O:28])[CH2:5]1)(=[O:3])[CH3:2].Cl>CO.C(OCC)(=O)C.O>[C:19]([C:18]1[C:12]2[O:11][CH:10]([CH3:27])[C:9](=[O:28])[N:8]([CH:6]3[CH2:5][N:4]([C:1](=[O:3])[CH3:2])[CH2:7]3)[CH2:14][C:13]=2[C:15]([F:26])=[C:16]([Cl:25])[CH:17]=1)(=[O:20])[CH3:24]
Reactant: CC(=O)N1CC(N2Cc3c(F)c(Cl)cc(C4(C)OCCO4)c3OC(C)C2=O)C1
Agent: Cl
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(=O)c1cc(Cl)c(F)c2c1OC(C)C(=O)N(C1CN(C(C)=O)C1)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.8 %

Procedure:
A solution of 4-(1-acetylazetidin-3-yl)-7-chloro-6-fluoro-2-methyl-9-(2-methyl-1,3-dioxolan-2-yl)-4,5-dihydro-1,4-benzoxazepin-3(2H)-one (190 mg, 0.460 mmol) in methanol (20 mL) and was treated with 6.0 M hydrogen chloride in water (1.15 mL, 6.90 mmol) and stirred at room temperature for 3 h. The reaction mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered, and concentrated to give the desired product (132 mg, 78%) as a mixture of enantiomers that was used without further purification. LCMS calculated for C17H19ClFN2O4(M+H)+: m/z=369.1; found: 369.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C[Si](C)(C)[N:14]1[CH2:18][CH2:17][CH2:16][C:15]1=[O:19].CN(C)C.CCCCCC.C(OCC)(=O)C>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:14]2[CH2:18][CH2:17][CH2:16][C:15]2=[O:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: C[Si](C)(C)N1CCCC1=O
Agent: CN(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C1CCCN1S(=O)(=O)c1ccc(Cl)cc1
Reaction time: 30.5 h
Yield: 56.1 %

Procedure:
To a solution of 8.4 g of 4-chlorobenzenesulfonyl chloride (0.04 mole) and 6.9 g of N-trimethylsilyl-2-pyrrolidone (0.044 mole) in 50 ml of anhydrous tetrahydrofuran was added 0.2 ml of trimethylamine, and the mixture was stirred at the reflux temperature for 30.5 hours. The solvent was removed from the reaction under reduced pressure, and the residue was dissolved in 50 ml of chloroform. After addition of 15 g of silica gel (Wako Gel C-200) to the solution, chloroform was again removed under reduced pressure. The powdery residue thus obtained was supended in a mixed solvent of hexane-ethyl acetate (7:3). The suspension was subjected to chromatography on a column (D 40 mm×L 500 mm) of 300 g of silica gel (Wako Gel C-200). Elution with a mixed solvent of hexane-ethyl acetate (7:3) followed by a mixed solvent of hexane-ethyl acetate (3:2) gave a crystalline product, which was recrystallized from a mixed solvent of chloroform-ether to give 5.83 g of N-(4'-chlorobenzenesulfonyl)-2-pyrrolidone as crystals.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].[F:5][C:6]1[CH:7]=[C:8](I)[CH:9]=[CH:10][CH:11]=1>[Cu](I)I.C(NCC)C>[F:5][C:6]1[CH:11]=[C:10]([C:3]#[C:2][CH2:1][OH:4])[CH:9]=[CH:8][CH:7]=1
Reactant: Fc1cccc(I)c1
Reactant: C#CCO
Agent: I[Cu]I
Solvent: CCNCC
Product: OCC#Cc1cccc(F)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 92.5 %

Procedure:
A mixture of propargyl alcohol (0.200 g, 5.4 mmol), 3-fluoro iodobenzene (0.63 ml, 5.4 mmol), copper iodide (0.103 g, 0.54 mol), dichlorobis (triphenylphosphine) palladium (II) (0.190 g, 0.3 mmol), diethylamine (10 ml) was degassed for 10 min. and stirred for 20 hrs at 25-25° C. Excess of diethyl amine was distilled off under vacuum. The residue was diluted with water (10 ml) and extracted with ethyl acetate. The organic layer was washed with brine solution and dried over Na2SO4. The solvent was evaporated and the crude product was purified by column chromatography (10% Ethyl acetate in hexane) to obtain pure 3-(3-fluoro-phenyl)-prop-2-yn-1-ol (0.750 g, 93%).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][C:9]2[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][C:8]=2[O:7]1)=O)C.C(=O)=O.CC(C)=O.[H-].C([Al+]CC(C)C)C(C)C.Cl>C1(C)C=CC=CC=1.CO>[C:18]1([CH2:17][O:16][C:14]2[CH:13]=[CH:12][C:9]3[CH2:10][CH2:11][CH:6]([CH:4]=[O:3])[O:7][C:8]=3[CH:15]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(=O)C1CCc2ccc(OCc3ccccc3)cc2O1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: O=C=O
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Solvent: CO
Product: O=CC1CCc2ccc(OCc3ccccc3)cc2O1
Yield: 94.9 %

Procedure:
The ether ester product from example 82 (6.9 g, 22 mmoles) was dissolved in 70 ml of toluene and the solution was cooled to -78° C. (dry-ice-acetone bath). With stirring, 15.6 ml of a 25% solution of diisobutylaluminum hydride in toluene was added dropwise. The reaction mixture was stirred at -78° C. for 2 hours whereupon 2.5 ml of methanol was cautiously added followed by 2N HCl and ice. The mixture was extracted with ethyl acetate and the organic extracts were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue (7.6 g) was chromatographed on silica gel. Elution with 9:1 toluene-ethyl acetate gave 5.6 g (70%) of racemic-3,4-dihydro-7-(phenylmethoxy)-2H-1-benzopyran-2-carboxaldehyde as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:12])[CH3:11])[N:7]([C:13]3[CH:14]=[N:15][CH:16]=[C:17]([F:19])[CH:18]=3)[C:6]=2[CH:20]=1.Cl[C:22]1[N:30]=[CH:29][N:28]=[C:27]2[C:23]=1[N:24]=[CH:25][N:26]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC.CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH:12][C:22]3[N:30]=[CH:29][N:28]=[C:27]4[C:23]=3[N:24]=[CH:25][NH:26]4)[CH3:11])[N:7]([C:13]3[CH:14]=[N:15][CH:16]=[C:17]([F:19])[CH:18]=3)[C:6]=2[CH:20]=1
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1-c1cncc(F)c1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Solvent: CO
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)cc2n1-c1cncc(F)c1
Temperature: 90 °C
Yield: 72 %

Procedure:
A mixture of (S)-1-[6-fluoro-1-(5-fluoropyridin-3-yl)-1H-benzoimidazol-2-yl]ethylamine (46 mg, 0.17 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (44 mg, 0.18 mmol) and DIPEA (86 μL, 0.50 mmol) in n-butanol (1 mL) was heated at 90° C. in a sealed vial for 60 h. After cooling to RT, the resulting mixture was diluted with MeOH and loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-10% MeOH in DCM) to afford 260 as a pale yellow solid (48 mg, 73%). LCMS (Method K): RT 3.04 min [M+H]+ 393.02. 1H NMR (DMSO-d6, 400 MHz): δ 8.63 (1H, s), 8.56 (1H, s), 8.14-8.05 (2H, m), 8.03-7.93 (2H, m), 7.72 (1H, dd, J=8.80, 4.85 Hz), 7.12 (1H, ddd, J=9.86, 8.79, 2.51 Hz), 7.05 (1H, dd, J=8.96, 2.48 Hz), 5.60 (1H, s), 1.65 (3H, d, J=6.80 Hz)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C@H:9]1[CH2:21][OH:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N+]1([O-])CCOCC1>CC#N.C(Cl)Cl.CCCCCC.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C@H:9]1[CH:21]=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O[Si](C)(C)C(C)(C)C)[C@H]1CO
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CCCCCC
Solvent: CC#N
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@H](O[Si](C)(C)C(C)(C)C)[C@H]1C=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.5 %

Procedure:
To a solution of compound 1I (3.3 g, 9.97 mmol) in 10% CH3CN in CH2Cl2 (50 mL) at rt was added NMO (3.0 g, 25.6 mmol) followed by tetrapropyl ammonium perruthenate (300 mg, 0.85 mmol). After a mild exotherm, the reaction was stirred at rt for 4 h. The reaction was diluted with hexane (50 mL), mixed well and filtered through a plug of silica gel (˜50 g). The silica plug was washed liberally with 30% EtOAc in hexane (500 mL). Solvents were removed under vacuum. Purification by flash chromatography (silica gel, 0-15% EtOAc in hexanes) provided the title compound (2.94 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:13][NH:14][C@H:15]1[CH2:34][N:19]2[C:20]3[C:25]([C:26]([CH2:27][C:28]([O:30]CCC)=[O:29])=[C:18]2[CH2:17][CH2:16]1)=[CH:24][CH:23]=[CH:22][CH:21]=3>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:14]([CH3:13])[C@H:15]2[CH2:34][N:19]3[C:20]4[C:25]([C:26]([CH2:27][C:28]([OH:30])=[O:29])=[C:18]3[CH2:17][CH2:16]2)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:12])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(O)Cc1ccc(F)c(Cl)c1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NC)CC2
Product: CN(C(=O)Cc1ccc(F)c(Cl)c1)[C@@H]1CCc2c(CC(=O)O)c3ccccc3n2C1

Procedure:
The title compound was prepared using analogous procedures described in Example 1 (Method A) from (3-chloro-4-fluorophenyl)acetic acid and propyl [(7R)-7-(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate. MS (+ESI) m/z: 429.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][CH3:16])[N:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=1[N:25]=[C:26]=[O:27].C(N(CC)CC)C>CN(C)C=O>[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=1[NH:25][C:26](=[O:27])[N:15]([C:13]1[CH:14]=[C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[N:10]=[CH:11][N:12]=1)[CH3:16]
Reactant: O=C=Nc1c(Cl)cccc1Cl
Reactant: CNc1cc(Nc2ccc(F)cc2)ncn1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C(=O)Nc1c(Cl)cccc1Cl)c1cc(Nc2ccc(F)cc2)ncn1
Temperature: 90 °C
Reaction time: 14 h

Procedure:
A mixture of N-(4-fluoro-phenyl)-N′-methyl-pyrimidine-4,6-diamine (218.2 mg, 1 mmol), 2,6-dichlorophenyl isocyanate (188 mg, 1 mmol) and triethylamine (1.11 mL, 8 mmol) in dry dimethylformamide (2.5 mL) is shaken for 14 h at 90° C. The reaction mixture is evaporated in vacuo and the residue is distributed between ethyl acetate and half-saturated Na2CO3 solution. The organic layer is dried over Na2SO4, evaporated, and the residue purified by flash chromatography (CH2Cl2/CH3OH). The combined pure fractions are evaporated, the residue triturated with CH2Cl2 and the solid filtered off and dried in vacuo to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([F:13])[CH:12]=1)[C@H:5]([OH:9])[C:6]([OH:8])=O.Cl.[NH2:15][C@H:16]([C:18]([NH:20][N:21]1[C:27](=[O:28])[CH:26]([CH3:29])[C:25]2[CH:30]=[CH:31][C:32]([F:34])=[CH:33][C:24]=2[C:23]2[CH:35]=[CH:36][CH:37]=[CH:38][C:22]1=2)=[O:19])[CH3:17]>CO.C(Cl)(Cl)Cl>[F:13][C:11]1[CH:10]=[C:4]([CH:3]=[C:2]([F:1])[CH:12]=1)[C@H:5]([OH:9])[C:6]([NH:15][C@H:16]([C:18]([NH:20][N:21]1[C:27](=[O:28])[CH:26]([CH3:29])[C:25]2[CH:30]=[CH:31][C:32]([F:34])=[CH:33][C:24]=2[C:23]2[CH:35]=[CH:36][CH:37]=[CH:38][C:22]1=2)=[O:19])[CH3:17])=[O:8]
Reactant: CC1C(=O)N(NC(=O)[C@H](C)N)c2ccccc2-c2cc(F)ccc21
Reactant: O=C(O)[C@@H](O)c1cc(F)cc(F)c1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC1C(=O)N(NC(=O)[C@H](C)NC(=O)[C@@H](O)c2cc(F)cc(F)c2)c2ccccc2-c2cc(F)ccc21

Procedure:
Following General Procedure D and using (S)-3,5-difluoromandelic acid (Example L) and 5-(L-alaninyl)-amino-10-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one hydrochloride (Example 7-Q), the title compound was prepared. The reaction was monitored by tlc (Rf=0.4, 10% MeOH/CHCl3) and product was purified by chromatography (silica, 2.5% MeOH/CHCl3).
Reaction SMILES: [C:1]([N:4]1[C:11]2[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:10]=2[CH:9]=[CH:8][C:7]2[N:17]=[C:18](Cl)[C:19]([F:21])=[CH:20][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][N:26]=1.C(N1C2C=CC=CC=2C=CC2N=C(C3C=NC(OC)=CC=3)C(F)=CC=2C1)(=O)C>>[C:1]([N:4]1[C:11]2[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:10]=2[CH:9]=[CH:8][C:7]2[N:17]=[C:18]([C:28]3[CH:27]=[N:26][C:25]([O:24][CH3:23])=[CH:30][CH:29]=3)[C:19]([F:21])=[CH:20][C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(=O)N1Cc2cc(F)c(Cl)nc2C=Cc2cc(Cl)ccc21
Agent: COc1ccc(-c2nc3c(cc2F)CN(C(C)=O)c2ccccc2C=C3)cn1
Product: COc1ccc(-c2nc3c(cc2F)CN(C(C)=O)c2ccc(Cl)cc2C=C3)cn1

Procedure:
The title compound was prepared from 9C and 2A by a route analogous to that used for the preparation of 2B. HPLC Rt=3.496 min; LCMS Found: (M+H)+=410.
Reaction SMILES: Cl.C(C1C=CC(C(N)=N)=CC=1)CCC.C(OC(=O)C(=COCC)C#N)C.CC[O-].[Na+].[OH-].[Na+].[C:33]([C:35]1[C:36](O)=[N:37][C:38]([C:41]2[CH:46]=[CH:45][C:44]([CH2:47][CH2:48][CH2:49][CH3:50])=[CH:43][CH:42]=2)=[N:39][CH:40]=1)#[N:34].P(Cl)(Cl)([Cl:54])=O>C(O)C>[Cl:54][C:36]1[C:35]([C:33]#[N:34])=[CH:40][N:39]=[C:38]([C:41]2[CH:46]=[CH:45][C:44]([CH2:47][CH2:48][CH2:49][CH3:50])=[CH:43][CH:42]=2)[N:37]=1
Reactant: CCCCc1ccc(-c2ncc(C#N)c(O)n2)cc1
Reactant: O=P(Cl)(Cl)Cl
Agent: CCCCc1ccc(C(=N)N)cc1
Agent: CCOC=C(C#N)C(=O)OCC
Agent: CC[O-]
Solvent: CCO
Product: CCCCc1ccc(-c2ncc(C#N)c(Cl)n2)cc1

Procedure:
The starting material can be obtained according to the procedure of A. R. Todd and F. Bergel, J. Chem. Soc. 1937, 365 by reaction of p-n-butylbenzamidine hydrochloride with α-ethoxymethylene-α-cyanoacetic acid ethyl ester and sodium ethylate in ethanol and then with sodium hydroxide solution. The resulting 5-cyano-4-hydroxy-2-(4-n-butylphenyl)-pyrimidine (melting point 230.3°-231.3° C.) is treated with phosphorus oxychloride to give 4-chloro-5-cyano-2-(4-n-butylphenyl)-pyrimidine having a melting point of 106.8°-107.0° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH2:13][CH3:14])=[C:4]([CH:9]=[C:10]([Cl:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[O:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.O>[Cl:12][C:10]1[CH:11]=[C:2]([NH:1][CH:18]2[CH2:19][CH2:20][O:15][CH2:16][CH2:17]2)[C:3]([CH2:13][CH3:14])=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: CCc1c(N)cc(Cl)cc1C(=O)OC
Reactant: O=C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCc1c(NC2CCOCC2)cc(Cl)cc1C(=O)OC
Reaction time: 20 h

Procedure:
To a solution of methyl 3-amino-5-chloro-2-ethylbenzoate (1.5 g, 7.02 mmol) in 1,2-dichloroethane (28 ml) at room temperature under nitrogen was added oxan-4-one (1.3 ml, 14. mmol) followed by acetic acid (2.41 ml, 42 mmol). This solution was stirred for 5 minutes before the addition of sodium triacetoxyborohydride (4.46 g, 21 mmol) at room temperature. After stirring for 20 hours, deionized water (28 ml) was added and the mixture was neutralized with solid NaHCO3. The phases were separated and the aqueous layer was extracted with EtOAc (2×28 ml). The combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by FCC (50 g silica, Isolute cartridge, gradient of eluents; 95:5 Heptane:EtOAc to 8:2 Heptane:EtOAc) to give 1.76 g of crude methyl 5-chloro-2-ethyl-3-[(oxan-4-yl)amino]benzoate as a white solid. The material was taken through the next step without further purification. LC-MS 60%, m/z=298.0/300.0, 1H NMR (500 MHz, Chloroform-d) δ ppm 7.07 (d, J=2.0 Hz, 1H), 6.71 (d, J=1.9 Hz, 1H), 4.01 (dt, J=11.8, 3.4 Hz, 2H), 3.87 (s, 3H), 3.82-3.76 (m, 1H), 3.64-3.47 (m, 3H), 2.79-2.63 (m, 2H), 2.06 (d, J=13.2 Hz, 2H), 1.55-1.46 (m, 2H), 1.18 (t, J=7.5 Hz, 3H).
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](F)=[CH:5][CH:4]=1)#[N:2].[CH3:14][O:15][C:16](=[O:22])[C@@H:17]1[CH2:21][CH2:20][CH2:19][NH:18]1>>[CH3:14][O:15][C:16]([C@@H:17]1[CH2:21][CH2:20][CH2:19][N:18]1[C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)=[O:22]
Reactant: N#Cc1ccc(F)c2ccccc12
Reactant: COC(=O)[C@@H]1CCCN1
Product: COC(=O)[C@@H]1CCCN1c1ccc(C#N)c2ccccc12
Yield: 1.6 %

Procedure:
1-Cyano-4-fluoronaphthalene (109 mg, 0.64 mmol) and L-proline methyl ester (380 mg, 2.95 mmol) were heated to 60° C. for 2 days in a sealed vial. The crude product was concentrated in vacuo and purified by preparative TLC (ethyl acetate/n-heptane 1:3, 3× eluted) to afford the title compound (2.9 mg, 1.7%) as an off-white solid.
Reaction SMILES: [Cl-:1].[Cl-].[CH-:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1.[CH-:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1.[Ti+2:13]>C1COCC1.[Zn]>[Cl-:1].[CH:3]1([Ti+:13][CH:8]2[CH:12]=[CH:11][CH:10]=[CH:9]2)[CH:7]=[CH:6][CH:5]=[CH:4]1
Reactant: c1cc[cH-]c1
Reactant: [Ti+2]
Agent: [Cl-]
Agent: [Zn]
Solvent: C1CCOC1
Product: C1=CC([Ti+]C2C=CC=C2)C=C1
Reaction time: 1 h

Procedure:
To a red solution of titanocene dichloride (0.500 g, 2.00 mmol) in anhydrous THF (4.0 mL) was added zinc dust (0.392 g, 6.00 mmol). The resulting suspension was vigorously stirred for 1 h under an argon atmosphere to give a green suspension. Excess zinc was removed by filtration through a 0.45 μm microfilter to give a green solution of dicyclopentadienyl titanium (III) chloride. To a solution of compound 505A (0.207 g, 0.399 mmol) and 1,4-cyclohexadiene (0.380 mL, 4.02 mmol) in anhydrous THF (1 mL) was added dropwise a 0.5 M solution of the above described dicyclopentadienyl titanium (III) chloride (0.9 mL, 0.45 mmol). After 1 h, an additional aliquot of the 0.5 M solution of dicyclopentadienyl titanium (III) chloride (0.9 mL, 0.45 mmol) was added and stirring was continued for 1 h. The reaction was then quenched with water (2 mL) and diluted with ethyl acetate (10 mL). The layers were separated and the organic layer was washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give a yellow gum. The crude material was dissolved in a minimum amount of methylene chloride and loaded on a 35 g silica gel ISCO column. Gradient elution with 0–80% ethyl acetate in hexane gave 0.043 g (21%) of compound 505Bi as a white solid and 0.023 g (11%) of compound 505Bii as a white solid. Compound 505Bi: HPLC: 3.92 min (retention time) (YMC CombiSreen ODS-A column, 4.6×50 mm, eluting with 10–90% aqueous methanol containing 0.2% phosphoric acid over 4 min, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 521,36 [M+H]+. Compound 505Bii:HPLC: 91% at 3.97 min (retention time) (YMC CombiScreen ODS-A column, 4.6×50 mm, eluting with 10–90% aqueous methanol containing 0.2% phosphoric acid over 4 min, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 521,34 [M+H]+.