Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([N:24]2[CH2:29][CH2:28][CH2:27][C@@H:26]([NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:25]2)=[C:4]2[C:10]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])=[CH:9][N:8]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:5]2=[N:6][CH:7]=1.[C:38](=O)([O-])[O-].[K+].[K+].CB1OB(C)OB(C)O1.CC#N.O>O1CCOCC1.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>[C:34]([O:33][C:31]([NH:30][C@@H:26]1[CH2:27][CH2:28][CH2:29][N:24]([C:3]2[C:2]([CH3:38])=[CH:7][N:6]=[C:5]3[N:8]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH:9]=[C:10]([NH:11][C:12]([CH:14]4[CH2:16][CH2:15]4)=[O:13])[C:4]=23)[CH2:25]1)=[O:32])([CH3:36])([CH3:37])[CH3:35]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3c2c(NC(=O)C2CC2)cn3C(=O)OC(C)(C)C)C1
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: CC#N
Product: Cc1cnc2c(c(NC(=O)C3CC3)cn2C(=O)OC(C)(C)C)c1N1CCC[C@@H](NC(=O)OC(C)(C)C)C1
Yield: 55.3 %

Procedure:
A solution of (R)-tert-butyl 5-bromo-4-(3-(tert-butoxycarbonylamino) piperidin-1-yl)-3-(cyclopropanecarboxamido)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (175 mg, 0.303 mmol) in dioxane (5 mL) at room temperature was treated with potassium carbonate (107 mg, 0.771 mmol), Pd(PPh3)4 (31.5 mg, 0.0272 mmol), and 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (34.2 mg, 0.272 mmol). N2 was bubbled through the mixture for 5 minutes, and the mixture was heated at reflux for 24 hours under N2 atmosphere. The mixture was then diluted with EtOAc (20 mL) and washed with water (1×5 mL). The organic layer was separated, dried (MgSO4), filtered, and concentrated in vacuo. The residue obtained was purified by reverse phase chromatography (Biotage SP4, C-18 25M+, 40-95% CH3CN/water, 24 CV) to provide (R)-tert-butyl 4-(3-(tert-butoxycarbonylamino)piperidin-1-yl)-3-(cyclopropanecarboxamido)-5-methyl-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (86 mg, 55% yield) as a solid. LCMS (APCI+) m/z 514.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14][CH:13]2[CH:25]=O)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH:27]1[CH2:31][CH2:30][CH:29]([OH:32])[CH2:28]1.Cl.[Na].C([BH3-])#N>CO>[NH3:12].[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:14][CH:13]2[CH2:25][N:27]2[CH2:31][CH2:30][CH:29]([OH:32])[CH2:28]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=CC1CN(Cc2ccccc2)CCN1C(=O)Cc1ccc(Cl)c(Cl)c1
Reactant: OC1CCNC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na]
Solvent: CO
Product: N
Product: O=C(Cc1ccc(Cl)c(Cl)c1)N1CCN(Cc2ccccc2)CC1CN1CCC(O)C1
Reaction time: 19 h
Yield: 109.8 %

Procedure:
A solution of the product of stage (ii) (3.67 g) in methanol (60 ml) was added to a stirred suspension of 3-pyrrolidinol (982 mg) and 3 Å molecular sieves (3.68 g) in methanol (35 ml), followed by adjustment of the pH to 6 using methanolic hydrogen chloride solution. Sodium-cyanoborohydride (1.30 g) was added portionwise and the resulting suspension was stirred under nitrogen for 19 h. The suspension was filtered and the filtrate evaporated to dryness. The residue was partitioned between aqueous 2N sodium carbonate solution (150 ml) and dichloromethane (100 ml) and the aqueous layer was further extracted with dichloromethane (2×50 ml)). The combined organic extracts were dried and evaporated to give an oil, which was purified by dry flash column chromatography on silica gel eluting with a mixture of dichloromethane:methanol:0.880 NH3 (200:8:1) to give the title compound as a foam (2.38 g).
Reaction SMILES: O[C:2]1[CH2:7][CH2:6][C:5]([CH3:9])([CH3:8])[CH2:4][C:3]=1[C:10]([O:12]C)=O.[NH2:14][C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][C:24]=1[Br:25])[C:18]([O:20][CH3:21])=[O:19].O1CCOCC1>O>[Br:25][C:24]1[C:15]2[NH:14][C:2]3[CH2:7][CH2:6][C:5]([CH3:8])([CH3:9])[CH2:4][C:3]=3[C:10](=[O:12])[C:16]=2[C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:22][CH:23]=1
Reactant: COC(=O)C1=C(O)CCC(C)(C)C1
Reactant: COC(=O)c1ccc(Br)c(N)c1
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(Br)c2[nH]c3c(c(=O)c12)CC(C)(C)CC3
Temperature: 130 °C
Yield: 26.7 %

Procedure:
A mixture of methyl 2-hydroxy-5,5-dimethylcyclohex-1-enecarboxylate (26 g, 0.141 mol), methyl 3-amino-4-bromobenzoate (25 g, 0.109 mol), polyphosphoric acid (220 g) and dioxane (220 mL) was heated at 130° C. for 5 hours. After cooling, the mixture was diluted with water. The resulting precipitate was collected by filtration and dried. The solid was suspended in methanol (400 mL), and TMSCl (90 mL) was added. The mixture was stirred at reflux for 5 hours, concentrated and treated with water (80 mL), extracted with ethyl acetate (250 mL). The organic layer was separated, concentrated and recrystallized with methanol to afford desired compound (10.6 g, 27%). 1H NMR (DMSO-d6) δ 10.32 (s, 1H), 7.98 (d, 1H, J=7.2 Hz), 7.10 (d, 1H, J=7.2 Hz), 3.80 (s, 3H), 2.90 (t, 2H, J=6.6 Hz), 2.22 (s, 2H), 1.56 (t, 2H, J=6.6 Hz), and 0.97 (s, 6H). MS (ESI) m/e [M+1]+364.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C@H:5]([O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=12)[C:6]1[S:10][CH:9]=[CH:8][CH:7]=1.[C:22](O)(=O)[C@H](C1C=CC=CC=1)O.CC1(C)O[C@H]2[C@@H]3OC(C)(C)O[C@]3(C(O)=O)O[C@H]2CO1.CN(C)CCC(C1SC=CC=1)O.FC1C2C(=CC=CC=2)C=CC=1>>[CH3:1][N:2]([CH3:22])[CH2:3][CH2:4][CH:5]([O:11][C:12]1[C:17]2[C:16](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=1)[C:6]1[S:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(O)[C@@H](O)c1ccccc1
Reactant: CNCC[C@H](Oc1cccc2ccccc12)c1cccs1
Agent: CC1(C)OC[C@@H]2O[C@@]3(C(=O)O)OC(C)(C)O[C@H]3[C@@H]2O1
Agent: CN(C)CCC(O)c1cccs1
Agent: Fc1cccc2ccccc12
Product: CN(C)CCC(Oc1cccc2ccccc12)c1cccs1

Procedure:
The preparation of the enantiomerically pure duloxetine intermediate (S)-AT-OL by its chiral resolution is exemplified in U.S. Pat. No. 5,362,886 (U.S. '886) and in WO 2004/031168, by the use of (S)-(+)-mandelic acid and (−)-2,3:4,6-Di-O-isopropylidene-2-keto-L-gulonic acid, respectively. The U.S. '886 patent describes the preparation of duloxetine by the chiral resolution of N,N-Dimethyl-3-(2-thienyl)-3-hydroxypropanamine (rac-AT-OL) with (S)-mandelic acid (Stage a), its reaction with fluoronaphtalene (Stage b) to give N,N-Dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine (DNT), demethylation with phenyl chloroformate (Stage c), basic hydrolysis in the presence of (Stage d), and acidification (Stage e) in accordance with the following Scheme 1.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][C@H:10]([CH3:14])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:15]([O:22][C:23](ON1C(=O)CCC1=O)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])(O)=O.[Na+]>O1CCOCC1.O.C(OCC)(=O)C>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:23]([O:22][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:24])[C@H:10]([CH3:14])[CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1ccccc1
Reaction time: 12 h

Procedure:
A mixture of 2.4 g (R)-4-N-Boc-2-methyl-piperazine, 3.5 g N-(Benzyloxycarbonyl-oxy)succinimide and 2.0 g NaHCO3 in 10 ml dioxane/water 1/1 was stirred for 12 h. The mixture was diluted with ethyl acetate, the phases separated and the organic phase washed with water, saturated aqueous NaHCO3, 0.1 M HCl and brine. The crude product obtained after drying over MgSO4 and evaporation of the solvents was used in the subsequent reaction. Yield: 4.3 g.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[CH3:16][O:17][CH:18](O)[CH3:19].[OH-:21].[K+].Cl>O>[CH3:16][O:17][CH2:18][CH2:19][O:21][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14]
Reactant: CS(=O)(=O)c1cc([N+](=O)[O-])c(Cl)cc1Cl
Reactant: COC(C)O
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: COCCOc1cc(Cl)c(S(C)(=O)=O)cc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
To a mixture consisting of 50 g of 2,4-dichloro-5-methanesulfonylnitrobenzene and 150 ml of methoxyethanol was added dropwise a methoxyethanol solution of potassium hydroxide (potassium hydroxide 14.6 g/methoxyethanol 150 ml) while keeping the temperature at -5° C. or below. The reaction was carried out at -2° C. for 30 minutes and the reaction mixture was neutralized by adding 4 ml of concentrated hydrochloric acid. The neutralized mixture was heated to 90° C, whereby a uniform solution was formed. After the solution was cooled to 70° C., 220 ml of warm water was added dropwise thereto. The resulting precipitated crystal was recovered by filtration and dried to obtain 2-methoxyethoxy-4-chloro-5-methanesulfonylnitrobenzene. Yield: 50 g (87%).
Reaction SMILES: C(OC([NH:8][C@@H:9]([C:23]([OH:25])=[O:24])[C:10]([S:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)([CH3:12])[CH3:11])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:22][O:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][S:13][C:10]([CH3:12])([CH3:11])[C@H:9]([C:23]([OH:25])=[O:24])[NH2:8])=[CH:20][CH:19]=1
Reactant: COc1ccc(CSC(C)(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(CSC(C)(C)[C@@H](N)C(=O)O)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The N-t-butoxycarbonyl-S-(4-methoxybenzyl)-D-penicillamine (5.0 g, 13.5 mmol) is dissolved in 40 mL of methylene chloride and cooled to 0° C. in an ice bath. Trifluoroacetic acid (18.5 g, 162 mmol) is added next, and the resulting mixture is stirred at 0° C. for 1 hour. The reaction mixture is warmed to room temperature and stirred until the starting material disappeared by TLC and mass spec (3 h.). The trifluoroacetic acid and methylene chloride are evaporated under reduced pressure to give the desired product.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:25][C:24]([CH3:27])([CH3:26])[CH2:23]2)=[C:4]([C@H:10]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8].[F:28][C:29]1[CH:46]=[CH:45][C:32]([CH2:33][CH2:34][O:35][C:36]2[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=2)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.CCOC(C)=O.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>[C:18]([O:17][C@@H:10]([C:4]1[C:5]([CH3:9])=[N:6][C:7]([CH3:8])=[C:2]([C:39]2[CH:38]=[CH:37][C:36]([O:35][CH2:34][CH2:33][C:32]3[CH:31]=[CH:30][C:29]([F:28])=[CH:46][CH:45]=3)=[CH:41][CH:40]=2)[C:3]=1[N:22]1[CH2:25][C:24]([CH3:27])([CH3:26])[CH2:23]1)[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])([CH3:21])([CH3:20])[CH3:19]
Reactant: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)OC(C)C)c(N2CC(C)(C)C2)c1Br
Reactant: OB(O)c1ccc(OCCc2ccc(F)cc2)cc1
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: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)OC(C)C)c(N2CC(C)(C)C2)c1-c1ccc(OCCc2ccc(F)cc2)cc1
Temperature: 90 °C
Reaction time: 4 h
Yield: 67.3 %

Procedure:
The Pd(Ph3P)4 (57.6 mg, 0.05 mmol) was added to a nitrogen purged and degassed solution of (S)-isopropyl 2-(5-bromo-4-(3,3-dimethylazetidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate (110 mg, 0.25 mmol), (4-(4-fluorophenethoxy)phenyl)boronic acid (71.3 mg, 0.27 mmol), and sodium carbonate (185 mg, 1.74 mmol) in dioxane (3 mL) and water (0.6 mL) and stirred in a screw-capped pressure vessel for 4 h at 90° C. The reaction was allowed to cool, diluted with EtOAc, and the organic layer was washed with brine and dried (Na2SO4). The crude product was charged (DCM) to a 24 g ISCO silica gel cartridge and gradient elution (5-65% EtOAc/hexanes) using an Isolera chromatography station gave (S)-isopropyl 2-(tert-butoxy)-2-(4-(3,3-dimethylazetidin-1-yl)-5-(4-(4-fluorophenethoxy)phenyl)-2,6-dimethylpyridin-3-yl)acetate 97 mg (67.5%). 1H NMR (500 MHz, DMSO-d6) δ 7.40-7.37 (m, 2H), 7.32 (br. s, 1H), 7.14 (t, J=8.4 Hz, 2H), 6.99 (d, J=8.1 Hz, 1H), 6.93 (d, J=8.1 Hz, 1H), 6.78 (br. s, 1H), 5.20 (s, 1H), 5.02-4.97 (m, 1H), 4.20 (t, J=6.2 Hz, 2H), 3.44 (s, 4H), 3.05 (t, J=6.6 Hz, 2H), 1.99 (s, 3H), 1.89 (s, 3H), 1.21-1.18 (m, 6H), 1.11 (s, 9H), 1.02 (s, 6H). UPLC (M+H)=577.5.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([OH:9])=[C:4]([F:10])[CH:3]=1.[C:11](Cl)(Cl)=[S:12].[OH-].[Na+]>C(Cl)(Cl)Cl.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([F:10])[C:5]2[O:9][C:11](=[S:12])[O:8][C:6]=2[CH:7]=1
Reactant: Oc1cc(Br)cc(F)c1O
Reactant: S=C(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: Fc1cc(Br)cc2oc(=S)oc12
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 62.1 %

Procedure:
5-Bromo-3-fluorobenzene-1,2-diol (2.0 g, 9.7 mmol, prepared according to Lu, Hejun; Tang, Peng Cho; Chen, Yiqian; Wang, Shenglan; Wang, Hua; Zhang, Lei; Li, Jun, WO 2011140936 A1) was dissolved in chloroform (25 mL), treated with thiophosgene (1.2 g, 11 mmol) and cooled to 0-5° C. Sodium hydroxide (10% aqueous, 8.9 g, 22 mmol) was added dropwise with vigorous stirring over 30 min. After 1 h, the chloroform was removed under vacuum and the pH was adjusted to 2 by addition of 6 M HCl. The solid that was formed was taken up in ethyl acetate (120 mL), washed with saturated NaCl (30 mL), dried (Na2SO4) and evaporated. The material was purified by flash chromatography using a 0-30% ethyl acetate-hexane gradient to give the title compound as a tan solid (1.5 g, 62%): mp 41-42° C.; 1H NMR (400 MHz, CDCl3) δ 7.35-7.30 (m, 1H), 7.29 (d, J=1.6 Hz, 1H); 19F NMR (376 MHz, CDCl3) δ −128.93; EIMS m/z 248/250.
Reaction SMILES: [C:1]1([CH:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH2:11][CH2:10][N:9]([CH2:18][CH2:19][CH2:20][CH2:21][N:22]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.NN>C(O)C>[C:1]1([CH:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH2:11][CH2:10][N:9]([CH2:18][CH2:19][CH2:20][CH2:21][NH2:22])[CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCN1CCc2ccccc2C(c2ccccc2)C1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCCCN1CCc2ccccc2C(c2ccccc2)C1

Procedure:
Batch size: 38.0 g (<89.5 mmol) 2-[4-(1-phenyl-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-butyl]-isoindol-1,3-dione and 8.7 ml (179 mmol) hydrazine hydrate in 200 ml ethanol. The reaction mixture is filtered and the filtrate is concentrated under vacuum. The residue is taken up in 400 ml dichloromethane and washed twice each with 50 ml 10% NaCH solution. The organic phase is dried over sodium sulfate and, subsequently, the solvent is removed under vacuum. The purification occurs chromatographically over silica gel with CHCl3/CH3OH/TEA (95/5/0 to 90/9/1): Yield 15.6 g (59%).
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][NH:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17](F)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7].[C:22](N1C=CN=C1)([N:24]1C=CN=C1)=[O:23].CN(CCN)C.N1(C2C=CC(C(N)=O)=CC=2)CCNCC1>O1CCCC1>[NH2:24][C:22]([C:17]1[CH:18]=[CH:19][C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:6]([NH:5][CH2:4][CH2:3][N:2]([CH3:21])[CH3:1])=[O:7])[CH2:9][CH2:10]2)=[CH:15][CH:16]=1)=[O:23]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CN(C)CCNC(=O)N1CCN(c2ccc(F)cc2)CC1
Agent: CN(C)CCN
Agent: NC(=O)c1ccc(N2CCNCC2)cc1
Solvent: C1CCOC1
Product: CN(C)CCNC(=O)N1CCN(c2ccc(C(N)=O)cc2)CC1
Yield: 20 %

Procedure:
This compound was prepared according to the procedure used to synthesize the compound of Example 11. A mixture of 3.1 g (0.019 mole) of 1,1'-carbonyldiimidazole, 1.7 g (0.019 mole) of unsym-dimethylethylenediamine and 3.9 g (0.019 mole) of 4-(1-piperazinyl)benzamide in a total volume of 150 ml of tetrahydrofuran gave a suspended white solid. The collected solid was recrystallized from ethanol-benzene to give 1.2 g (20%) of the title compound as a white solid, m.p. 193°-195° C.
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]1[CH2:7][CH:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([O:16][CH3:17])[CH:10]=2)[CH2:5]1.[CH3:18][C:19]1[C:28]2[CH:27]=[N:26][C:25](S(C)=O)=[N:24][C:23]=2[N:22]([C:32]2[CH:33]=[C:34]([NH:38][C:39](=[O:42])[CH:40]=[CH2:41])[CH:35]=[CH:36][CH:37]=2)[C:21](=[O:43])[CH:20]=1.CCN(C(C)C)C(C)C>C(O)(C)(C)C>[F:1][CH2:2][CH2:3][N:4]1[CH2:7][CH:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:25]3[N:26]=[CH:27][C:28]4[C:19]([CH3:18])=[CH:20][C:21](=[O:43])[N:22]([C:32]5[CH:33]=[C:34]([NH:38][C:39](=[O:42])[CH:40]=[CH2:41])[CH:35]=[CH:36][CH:37]=5)[C:23]=4[N:24]=3)=[C:11]([O:16][CH3:17])[CH:10]=2)[CH2:5]1
Reactant: COc1cc(NC2CN(CCF)C2)ccc1N
Reactant: C=CC(=O)Nc1cccc(-n2c(=O)cc(C)c3cnc(S(C)=O)nc32)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Product: C=CC(=O)Nc1cccc(-n2c(=O)cc(C)c3cnc(Nc4ccc(NC5CN(CCF)C5)cc4OC)nc32)c1
Temperature: 80 °C
Yield: 48.6 %

Procedure:
To a suspension of N1-(1-(2-fluoroethyl)azetidin-3-yl)-3-methoxybenzene-1,4-diamine (11c; 373 mg, 1.56 mmol) and N-(3-(5-methyl-2-(methylsulfinyl)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (5b; 440 mg, 1.194 mmol) in tert-butanol (10 mL) was added DIEA (0.62 mL, 3.58 mmol). The mixture was heated in an oil bath at 80° C. for 1 h. The reaction mixture was concentrated to dryness under reduced pressure (rotary evaporator) and the crude residue was purified on silica gel on an ISCO Combiflash RF (40 g Redisep column, using a gradient of 5-10% 2M NH3/MeOH in DCM) affording enriched product. It was then repurified on a Gilson preparatory HPLC (Gemini Phenomenex; 30×150 mm, 5μ, 10-95% 0.1% TFA/CH3CN in 0.1% TFA/water). The desired fractions were collected, and concentrated to dryness in a genevac overnight. The resulting solid was dissolved in 9:1=DCM:MeOH and was then passed through a Silicycle SPE-R66030B-20× SiliaSep OT, 5 g/25 mL carbonate column using 10% MeOH/DCM then concentrated and dried under vacuum affording N-(3-(2-((4-((1-(2-fluoroethyl)azetidin-3-yl)amino)-2-methoxyphenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (317 mg, 0.58 mmol, 49% yield) as a yellow solid. m/z (ESI, +ve ion) 544.0 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.37 (1H, s), 8.78 (1H, br. s.), 8.05 (1H, br. s.), 7.84 (1H, d, J=7.0 Hz), 7.60 (1H, s), 7.50 (1H, t, J=8.0 Hz), 7.15 (1H, d, J=9.0 Hz), 6.99 (1H, d, J=9.0 Hz), 6.41-6.51 (1H, m), 6.23-6.34 (2H, m), 6.16 (1H, d, J=2.2 Hz), 5.85 (1H, br. s.), 5.73-5.81 (1H, m), 5.57 (1H, br. s.), 4.49 (1H, t, J=4.8 Hz), 4.37 (1H, t, 1=4.8 Hz), 3.90 (1H, br. s.), 3.73 (5H, br. s.), 2.76-2.88 (2H, m), 2.74 (1H, t, J=4.9 Hz), 2.63-2.71 (1H, m), 2.46 (3H, s).
Reaction SMILES: [CH2:1]([NH:8][C:9]([NH:11][CH:12]1[CH:17]2[CH2:18][CH2:19][N:14]([CH2:15][CH2:16]2)[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:23][CH2:24]Br>CN(C=O)C>[CH2:1]([N:8]1[CH2:24][CH2:23][N:11]([CH:12]2[CH:17]3[CH2:16][CH2:15][N:14]([CH2:19][CH2:18]3)[CH2:13]2)[C:9]1=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NCc1ccccc1)NC1CN2CCC1CC2
Reactant: BrCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1N(Cc2ccccc2)CCN1C1CN2CCC1CC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 28.4 %

Procedure:
To a solution of 1-benzyl-3-(quinuclidin-3-yl)urea (260 mg, 1.00 mmol) in DMF (30 ml) was added NaH [60% dispersion in mineral oil] (96 mg, 2.4 mmol) with ice bath cooling. The resultant mixture was stirred for 2 h before BrCH2CH2Br (0.75 g, 4.0 mmol) was added carefully. The reaction was stirred for an additional 18 h at about 25° C. After HPLC separation, the aqueous layer was lyophilized and purified by prep-TLC (CHCl3 to 5% MeOH in CHCl3 to 5% 2N NH3(MeOH) in CHCl3) to give the title compound (81 mg, 28%). 1H NMR (400 MHz, CDCl3) δ 7.19-7.22 (m, 4H), 7.11-7.14 (m, 1H), 6.09 (dd, J=15.2, 8.4 Hz, 1H), 5.45 (dd, J=15.6, 4.0 Hz, 1H), 5.30 (dd, J=8.0, 3.6 Hz, 1H), 4.17-4.29 (m, 4H), 3.66-3.75 (m, 2H), 3.47 (d, J=12.4 Hz, 1H), 3.19-3.27 (m, 3H), 2.34 (br s, 1H), 2.22 (d, J=2.4 Hz, 1H), 1.92 (br s, 2H), 1.75 (br s, 1H) ppm. 13C NMR (400 MHz, CDCl3) δ 158.9, 141.1, 140.4, 128.7, 127.4, 127.3, 113.6, 63.6, 57.1, 56.0, 45.6, 43.9, 25.2, 23.0, 18.8 ppm. Purity: 93.8% HPLCMS (210 nm); retention time 1.84 min; (M+1) 286.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[C:19]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][C:22](C(Cl)=O)=[CH:21][CH:20]=1.[NH2:34][CH2:35][CH:36]([C:38]1[CH:39]=[C:40]([OH:45])[C:41]([OH:44])=[CH:42][CH:43]=1)[OH:37]>>[C:28]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:29]=[CH:30][C:31]([C:6]([N:8]2[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][CH:9]2[C:16]([NH:34][CH2:35][CH:36]([C:38]2[CH:43]=[CH:42][C:41]([OH:44])=[C:40]([OH:45])[CH:39]=2)[OH:37])=[O:18])=[O:7])=[CH:32][CH:33]=1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: NCC(O)c1ccc(O)c(O)c1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: CON=C1CC(C(=O)NCC(O)c2ccc(O)c(O)c2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, [1,1′-biphenyl]-4-carbonyl chloride, and 4-[(1RS)-2-amino-1-hydroxyethyl]-1,2-benzenediol, the title compound was obtained in 66% purity by HPLC. MS(ESI+): m/z=490.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:25])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]2[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:24])=[O:16])=[CH:10][CH:9]=1)[NH2:6].[Cl:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[C:28]=1[C:29](O)=[O:30].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[CH3:2][O:3][C:4](=[O:25])[C@H:5]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15]([C:17]2[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:24])=[O:16])=[CH:12][CH:13]=1)[NH:6][C:29]([C:28]1[C:32]([CH3:36])=[CH:33][CH:34]=[CH:35][C:27]=1[Cl:26])=[O:30]
Reactant: COC(=O)[C@@H](N)Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1
Reactant: Cc1cccc(Cl)c1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=O)c1c(C)cccc1Cl
Temperature: 25 °C
Reaction time: 48 h
Yield: 105.9 %

Procedure:
To a solution of 4-[[(2,6-dichlorophenyl)carbonyl]amino]-L-phenylalanine methyl ester hydrochloride salt (272.5 mmol, 110 g) and 2-chloro-6-methyl benzoic acid (276 mmol, 47.15 g) in DMF (600 mL) were added HBTU (276 mmol, 105 g) and diisopropylethylamine (1.24 mol, 119 mL) at room temperature. The clear solution was stirred 48 h at room temperature at which time TLC analysis of the reaction mixture indicated the absence of the starting material. The reaction mixture was poured slowly into 5 L of water which contained some ice to lower the temperature. The white precipitated solid was allowed settle and the solid was collected by filtration. The solid cake was washed with water (1 L) and hexane (1 L) and air dried to obtain 150 g of a crude product. This solid product was dissolved in hot acetonitrile (1 L) and cooled in the refrigerator. The solid was collected by filtration and washed with hexane (500 mL) and air dried to obtain 101.1 g. The mother liquor was concentrated and the residue was purified by silica gel column chromatography eluting with dichloromethane and ethyl acetate (15:1) to obtain another 17.07 g (total=118.17 g, 83%). mp 244-245° C. 1H NMR, DMSO-d6 (400 MHz) δ10.66 (s, 1H), 8.83 (d, 1H, J=19 Hz), 7.47-7.6 (m, 5H), 7.15-7.29 (m, 5H), 4.58-4.68 (m, 1H), 3.65 (s, 3H), 3.12 (dd, 1H, J=17, 13 Hz), 2.87 (dd, 1H, J=17, 11 Hz), 2.09 (s, 3H). HR MS: Obs. mass. 518.0652. Calcd. mass, 518.0641.