Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)=[CH2:2].Cl[C:13]1[CH:14]=[C:15]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[CH:16]=[CH:17][CH:18]=1.F[K].C(P)(C)(C)C>C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.[Pd].O1CCOCC1>[CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:17]2[CH:18]=[CH:13][CH:14]=[C:15]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[CH:16]=2)=[CH:5][CH:4]=1)=[CH2:2]
Reactant: Clc1cccc(-c2cccnc2)c1
Reactant: C=Cc1ccc(B(O)O)cc1
Agent: [Pd]
Agent: CC(C)(C)P
Agent: F[K]
Solvent: C1COCCO1
Product: C=Cc1ccc(-c2cccc(-c3cccnc3)c2)cc1
Temperature: 80 °C
Yield: 45 %

Procedure:
This Example was carried out in the same manner as Example 10, except that 23.42 g (0.158 mol) of 4-vinyl-phenyl boronic acid, 20.0 g (0.1055 mol) of 3-(3-chloro-phenyl)pyridine, 500□ of 1,4-dioxane, 27.54 g (0.474 mol, 3.3 equivalent) of fluoro-potassium, 1.69 g (0.0084 mol, 5.3 mol %) of t-butylphosphine [P( t-Bu)3)], and 2.6 g (0.0028 mol, 1.8 mol %) of palladium tris(dibenzylidene acetone) [Pd2(dba)3] were used. Finally, after the resulting solution was heated to reflux at 80° C. for 24 hours, the 3-(4′-vinyl-biphenyl-3-yl)pyridine was isolated. The yield was 45%.
Reaction SMILES: [C:1]([N:4]([CH2:38][C@@H:39]1[O:43][C:42](=[O:44])[N:41]([C:45]2[CH:50]=[CH:49][C:48]([N:51]3[CH2:58][C:57]4[C:53](=[N:54][N:55]([CH3:59])[CH:56]=4)[CH2:52]3)=[C:47]([F:60])[CH:46]=2)[CH2:40]1)[C:5]([O:7][CH2:8][O:9][C:10](=[O:37])[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][O:18][P:19]([O:29]CC2C=CC=CC=2)([O:21]CC2C=CC=CC=2)=[O:20])=[CH:13][CH:12]=1)=[O:6])(=[O:3])[CH3:2]>CO.[Pd]>[C:1]([N:4]([CH2:38][C@@H:39]1[O:43][C:42](=[O:44])[N:41]([C:45]2[CH:50]=[CH:49][C:48]([N:51]3[CH2:58][C:57]4[C:53](=[N:54][N:55]([CH3:59])[CH:56]=4)[CH2:52]3)=[C:47]([F:60])[CH:46]=2)[CH2:40]1)[C:5]([O:7][CH2:8][O:9][C:10](=[O:37])[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][O:18][P:19]([OH:29])([OH:21])=[O:20])=[CH:13][CH:12]=1)=[O:6])(=[O:3])[CH3:2]
Reactant: CC(=O)N(C[C@H]1CN(c2ccc(N3Cc4cn(C)nc4C3)c(F)c2)C(=O)O1)C(=O)OCOC(=O)c1ccc(COP(=O)(OCc2ccccc2)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: CC(=O)N(C[C@H]1CN(c2ccc(N3Cc4cn(C)nc4C3)c(F)c2)C(=O)O1)C(=O)OCOC(=O)c1ccc(COP(=O)(O)O)cc1
Reaction time: 6 h

Procedure:
A suspension of 13 (1 equiv) and 10% Pd/C (1 weight equiv of 13) in methanol is hydrogenated in a Parr shaker at 30 psi for 6 h. The reaction mixture is filtered, concentrated in vacuo, purified directly by HPLC (C-18 column, 0-100% gradient elution, MeCN:H2O), and fractions containing product are lyophilized to give the title compound. Theoretical MS 662 (M+1)+
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH:7]2[CH2:10][NH:9][CH2:8]2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[Cl:22][C:23]1[CH:28]=[C:27](Cl)[CH:26]=[CH:25][N:24]=1>C(O)(C)C>[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N:9]2[CH2:8][CH:7]([O:6][C:5]3[CH:11]=[CH:12][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:10]2)[N:24]=1
Reactant: Fc1ccc(OC2CNC2)cc1
Reactant: Clc1ccnc(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Fc1ccc(OC2CN(c3cccc(Cl)n3)C2)cc1
Temperature: 80 °C
Yield: 53.2 %

Procedure:
To a solution of 3-(4-fluorophenoxy)azetidine (557 mg, 3.37 mmol) [prepared as described in Example AAA] in isopropanol (10 mL, 3 mL/mmol) was added DIPEA (1.5 mL, 8.42 mmol) and 2,4-dichloropyridine (500 mg, 3.37 mmol) and the mixture was heated at 80° C. for 7 h. The reaction mixture was concentrated under reduced pressure and extracted with EtOAc (2×20 mL). The organic extracts were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. Purification by silica gel column chromatography provided 2-chloro-6-(3-(4-fluorophenoxy)azetidin-1-yl)pyridine (500 mg, 55%) as a solid. Observed mass (M+1): 279.1.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH:7]([OH:8])[C:5](=[O:6])[O:4][CH2:3]1.C(=O)([O-])[O-:11].[Li+:14].[Li+].C(=O)=O>O>[OH2:4].[C:5]([O-:11])(=[O:6])[C@@H:7]([C:2]([CH2:3][OH:4])([CH3:9])[CH3:1])[OH:8].[Li+:14]
Reactant: CC1(C)COC(=O)C1O
Reactant: O=C([O-])[O-]
Agent: O=C=O
Agent: [Li+]
Solvent: O
Product: CC(C)(CO)[C@@H](O)C(=O)[O-]

Procedure:
A slurry of 1.00 kilogram of racemic DL-pantolactone and 300 grams of lithium carbonate in 1.5 liters of water was continuously stirred and heated at boiling temperature in a flask provided with a stirrer and reflux condenser for 1.5 hours. After all the evolved carbon dioxide had been expelled, the reaction mixture was filtered while hot and 25 grams of lithium carbonate was thus recovered therefrom. When the filtrate was cooled and stirred, 700 grams of crystals of racemic DL-lithium pantoate monohydrate having a melting point of 107°-110° C. amounting to 53.0% of the theoretical yield, separated and was collected. By evaporation of the mother liquor a further amount of DL-lithium pantoate, equivalent to 42% of the original DL-pantolactone, was recovered.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[O:14][CH3:15].[NH:16]1[CH2:21][CH2:20][CH:19]([C:22]([NH2:24])=[O:23])[CH2:18][CH2:17]1.ClCCl.CO.N>>[CH3:15][O:14][C:6]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:5]=1[O:4][CH2:3][CH2:2][N:16]1[CH2:21][CH2:20][CH:19]([C:22]([NH2:24])=[O:23])[CH2:18][CH2:17]1
Reactant: COc1cc([N+](=O)[O-])ccc1OCCBr
Reactant: NC(=O)C1CCNCC1
Agent: N
Solvent: CO
Solvent: ClCCl
Product: COc1cc([N+](=O)[O-])ccc1OCCN1CCC(C(N)=O)CC1

Procedure:
Prepared analogously to Example 1.1.c. from 1 g (3.622 mmol) of 1-(2-bromoethoxy)-2-methoxy-4-nitrobenzene and 1.4 g (10.87 mmol) of piperidine-4-carboxylic acid amide. Yield: 1.05 g (90% of theory); C15H21N3O5 (M=323.34); calc.: molecular ion peak (M+H)+: 324; found: molecular ion peak (M+H)+: 324; Rf value: 0.4 (silica gel, dichloromethane/methanol/ammonia (9:1:0.1)).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:10])=[O:9])=[CH:6][CH:7]=1.[Br:11]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:11][CH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:9])[CH3:10])=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)c1ccc(C)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)c1ccc(CBr)cc1
Yield: 71.7 %

Procedure:
To a solution of 1-p-tolylethanone (600 mg, 4.47 mmol) in carbon tetrachloride (15 mL) was added N-bromosuccinimide (955 mg, 5.37 mmol) and BPO (31 mg, 0.13 mmol). The mixture was refluxed for 3 h; then it was cooled, and filtered. The filtrate was concentrated to give 1-(4-(bromomethyl)phenyl)ethanone (683 mg, 71%) as a brown oil. LCMS MH+ 213.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([OH:11])[CH:6]=[C:7]([CH2:9][CH3:10])[CH:8]=1)[CH3:2].[Br-:12].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>CO>[Br:12][C:8]1[C:7]([CH2:9][CH3:10])=[CH:6][C:5]([OH:11])=[CH:4][C:3]=1[CH2:1][CH3:2]
Reactant: CCc1cc(O)cc(CC)c1
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CO
Product: CCc1cc(O)cc(CC)c1Br
Temperature: 25 °C
Reaction time: 15 h
Yield: 13 %

Procedure:
To a solution of 3,5-diethylphenol (9.30 g, 61.9 mmol) in methanol (100 mL) was added tetrabutylammonium tribromide (29.8 g, 61.9 mmol), and the mixture was stirred at room temperature for 15 hr. The solvent was evaporated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=0:100-25:75), and the obtained crystals were recrystallized from heptane to give the title compound (1.85 g) as colorless crystals. The mother liquor was concentrated under reduced pressure to give the title compound (8.68 g) as dark-brown crystals (total 10.5 g, total yield 74%).
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]1.[Br:9]Br>CC(O)=O>[Br:9][CH:2]1[C:3](=[O:7])[CH2:4][CH2:5][CH2:6][C:1]1=[O:8]
Reactant: O=C1CCCC(=O)C1
Reactant: BrBr
Solvent: CC(=O)O
Product: O=C1CCCC(=O)C1Br
Reaction time: 2 h

Procedure:
To a stirred solution of cyclohexane-1,3-dione (1.12 g, 10 mmol) in AcOH (20 mL) at r.t. was added bromine (1.6 g, 0.51 mL, 10 mmol) dropwise. The reaction mixture was stirred for 2 h and then the product was isolated by filtration. The precipitate was washed twice with Et2O (100 mL) and then dried in vacuo to give the title compound in quantitative yield as a buff solid, which was used without further purification. LCMS (ES+) 190.9 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH2:6][CH:5]([CH3:7])[N:4]([CH2:8][C:9]([OH:11])=O)[N:3]=1.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=1[CH:20]1[O:24][N:23]=[C:22]([C:25]2[N:26]=[C:27]([CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[S:28][CH:29]=2)[CH2:21]1.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=1[CH:20]1[O:24][N:23]=[C:22]([C:25]2[N:26]=[C:27]([CH:30]3[CH2:35][CH2:34][N:33]([C:9](=[O:11])[CH2:8][N:4]4[CH:5]([CH3:7])[CH2:6][C:2]([CH3:1])=[N:3]4)[CH2:32][CH2:31]3)[S:28][CH:29]=2)[CH2:21]1
Reactant: Fc1cccc(F)c1C1CC(c2csc(C3CCNCC3)n2)=NO1
Reactant: CC1=NN(CC(=O)O)C(C)C1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1=NN(CC(=O)N2CCC(c3nc(C4=NOC(c5c(F)cccc5F)C4)cs3)CC2)C(C)C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 4,5-dihydro-3,5-dimethyl-1H-pyrazole-1-acetic acid (i.e. the product of Step B) (0.10 g, 0.64 mmol), 4-[4-[5-(2,6-difluorophenyl)-4,5-dihydro-3-isoxazolyl]-2-thiazolyl]piperidine (i.e. the product of Example 1, Step D) (175 mg, 0.5 mmol), N3-(ethylcarbodimidoyl)-N1,N1-dimethyl-1,3-propanediamine hydrochloride (191 mg, 1.0 mmol), 1-hydroxybenzotriazole (5 mg, 0.037 mmol) and triethylamine (0.14 mL, 1.0 mmol) in dichloromethane (4 mL) was stirred at room temperature. After 6 h, more N3-(ethylcarbodimidoyl)-N1,N1-dimethyl-1,3-propanediamine hydrochloride (191 mg, 1.0 mmol) and triethylamine (0.14 mL, 1.0 mmol) were added to the reaction mixture. After 3 days, the reaction mixture was diluted with dichloromethane, washed with saturated aqueous ammonium chloride solution and concentrated under reduced pressure. The resulting residue was purified by medium pressure liquid chromatography on silica gel (0 to 100% gradient of ethyl acetate in hexanes, and then 20% methanol in ethyl acetate as eluant) to provide the title compound, a compound of the present invention, as a tan solid (124 mg).
Reaction SMILES: [C:1]1(C)[CH:6]=[CH:5][C:4]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[N:21]=[CH:20][N:19]=3)=[CH:13][CH:12]=2)=[O:9])=[CH:3][CH:2]=1.[F:29][C:30]([F:41])([F:40])C1C=CC=C(N=C=O)C=1>>[F:29][C:30]([F:41])([F:40])[C:6]1[CH:5]=[C:4]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[C:22]([C:24]([F:27])([F:25])[F:26])[N:21]=[CH:20][N:19]=3)=[CH:13][CH:12]=2)=[O:9])[CH:3]=[CH:2][CH:1]=1
Reactant: Cc1ccc(NC(=O)Nc2ccc(Oc3cc(C(F)(F)F)ncn3)cc2)cc1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Product: O=C(Nc1ccc(Oc2cc(C(F)(F)F)ncn2)cc1)Nc1cccc(C(F)(F)F)c1
Reaction time: 2.5 h

Procedure:
The title compound is prepared as described in Example 102 but using 4-(6-trifluoromethyl-pyrimidin-4-yloxy)-phenylamine (Example 114) and α,α,α-trifluoro-m-tolyl-isocyanate. The reaction mixture is stirred for 2.5 h. The title compound is obtained as a white solid: ES-MS: 442.9 [M+H]+; single peak at tR=9.83 min (System 2).
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([CH2:9][NH:10]C(=O)OC(C)(C)C)=[C:4]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:3]=1.[ClH:25]>>[NH2:10][CH2:9][C:5]1[C:6](=[O:8])[NH:7][C:2]([CH3:1])=[CH:3][C:4]=1[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[ClH:25]
Reactant: Cc1cc(Cc2ccccc2)c(CNC(=O)OC(C)(C)C)c(=O)[nH]1
Agent: Cl
Product: Cc1cc(Cc2ccccc2)c(CN)c(=O)[nH]1
Temperature: 25 °C

Procedure:
A solution of 1,1-dimethylethyl {[6-methyl-2-oxo-4-(phenylmethyl)-1,2-dihydro-3-pyridinyl]methyl}carbamate (1.0 g, 3.0 mmol) in 4N HCl (in 15 mL 1,4 dioxane) was heated to 60° C. for 1 h. The mixture was cooled to room temperature. The mixture was filtered and dried to give 3-(aminomethyl)-6-methyl-4-(phenylmethyl)-2(1H)-pyridinone as an HCl salt (0.600 g, 86%). LCMS MH+=229.1 1H NMR (400 MHz, DMSO-d6) δ 11.9-12.0 (br s, 1H), 8.03 (br s, 3H), 7.16-7.30 (m, 5H), 5.84 (s, 1H), 3.91 (s, 2H), 3.81 (s, 2H), 2.10 (s, 3H).
Reaction SMILES: C(OC([NH:8][CH:9]1[C:11]2([CH2:16][CH2:15][N:14]([C:17]3[CH:26]=[C:25]4[C:20]([C:21](=[O:33])[C:22]([C:30]([OH:32])=[O:31])=[CH:23][N:24]4[CH:27]4[CH2:29][CH2:28]4)=[CH:19][C:18]=3[F:34])[CH2:13][CH2:12]2)[CH2:10]1)=O)(C)(C)C.[ClH:35]>>[ClH:35].[NH2:8][CH:9]1[C:11]2([CH2:16][CH2:15][N:14]([C:17]3[CH:26]=[C:25]4[C:20]([C:21](=[O:33])[C:22]([C:30]([OH:32])=[O:31])=[CH:23][N:24]4[CH:27]4[CH2:28][CH2:29]4)=[CH:19][C:18]=3[F:34])[CH2:13][CH2:12]2)[CH2:10]1
Reactant: CC(C)(C)OC(=O)NC1CC12CCN(c1cc3c(cc1F)c(=O)c(C(=O)O)cn3C1CC1)CC2
Agent: Cl
Product: NC1CC12CCN(c1cc3c(cc1F)c(=O)c(C(=O)O)cn3C1CC1)CC2
Yield: 60 %

Procedure:
According to the procedure of example 1B, the compound of step A (420 mg, 0.89 mmol) was hydrolyzed with hydrochloric acid to provide the title product, mp 218° C. (decomp.), 197 mg (0.53 mmol, 60% yield).
Reaction SMILES: C(O[C:4]1[C:5](=[O:16])[C:6](=[O:15])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)C.[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][NH2:30])[CH:18]=1>>[N:12]1[CH:11]=[CH:10][C:9]([NH:8][C:7]2[C:6](=[O:15])[C:5](=[O:16])[C:4]=2[NH:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][O:23][C:19]2[CH:18]=[N:17][CH:22]=[CH:21][CH:20]=2)=[CH:14][CH:13]=1
Reactant: NCCCCCCOc1cccnc1
Reactant: CCOc1c(Nc2ccncc2)c(=O)c1=O
Product: O=c1c(NCCCCCCOc2cccnc2)c(Nc2ccncc2)c1=O

Procedure:
The title compound was prepared according to the procedure described in example 1B starting from 3-ethoxy-4-(pyridin-4-yl-amino)-3-cyclobutene-1,2-dione prepared according to example 7A and 6-(pyridin-3-yloxy)-hexylamine.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[Br:13][C:14]1[C:15]([O:22][CH:23]([CH3:25])[CH3:24])=[C:16]([C:19](O)=[O:20])[S:17][CH:18]=1.[NH2:26][C:27]1[NH:31][N:30]=[N:29][N:28]=1.Cl>O1CCCC1>[Br:13][C:14]1[C:15]([O:22][CH:23]([CH3:25])[CH3:24])=[C:16]([C:19]([NH:26][C:27]2[NH:31][N:30]=[N:29][N:28]=2)=[O:20])[S:17][CH:18]=1
Reactant: Nc1nnn[nH]1
Reactant: CC(C)Oc1c(Br)csc1C(=O)O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)Oc1c(Br)csc1C(=O)Nc1nnn[nH]1
Temperature: 0 °C
Yield: 94.9 %

Procedure:
1,1'-Carbonyldiimidazole (2.2 g, 14 mmoles) is added to a solution of 4-bromo-3-(1-methylethoxy)-2-thiophenecarboxylic acid (3.5 g, 13 mmoles) in tetrahydrofuran (50 mL) under argon. The mixture is stirred and heated under reflux for 1.5 hours. 5-Aminotetrazole (1.1 g, 13 mmoles) is added, and heating under reflux continued for 2.5 additional hours. The mixture is then stirred into ice water (200 mL) and acidified with concentrated HCl. After 1 hour the precipitate is filtered off, rinsed with water and dried to afford the product (4.1 g); mp 193°-194° C.
Reaction SMILES: Cl.[NH2:2][C:3]12[CH2:11][CH2:10][CH:7]([CH2:8][CH2:9]1)[CH2:6][N:5]1[C:12](=[O:30])[C:13]([O:21][C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:23])=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:15]=[C:4]21.[CH3:31][N:32]([CH3:38])[C:33](=[O:37])[C:34](O)=[O:35].C(N(C(C)C)CC)(C)C.O>CN(C=O)C>[CH3:31][N:32]([C:33](=[O:37])[C:34]([NH:2][C:3]12[CH2:11][CH2:10][CH:7]([CH2:8][CH2:9]1)[CH2:6][N:5]1[C:12](=[O:30])[C:13]([O:21][C:22]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[O:23])=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:15]=[C:4]21)=[O:35])[CH3:38]
Reactant: CN(C)C(=O)C(=O)O
Reactant: CCOC(=O)c1nc2n(c(=O)c1OC(=O)c1ccccc1)CC1CCC2(N)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1nc2n(c(=O)c1OC(=O)c1ccccc1)CC1CCC2(NC(=O)C(=O)N(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.1 %

Procedure:
To a stirred solution of ethyl 10-amino-4-oxo-3-((phenylcarbonyl)oxy)-4,6,7,8,9,10-hexahydro-7,10-ethanopyrimido[1,2-a]azepine-2-carboxylate hydrochloride (2.4 g, 5.53 mmol) in DMF (50 mL) as added 2-(dimethylamino)-2-oxoacetic acid (1.295 g, 11.06 mmol), diisopropyl-ethylamine (5.80 mL, 33.2 mmol) and the resulting mixture was stirred at room temperature for 3 h. Water was then added and the mixture extracted with ethyl acetate (2×200 mL). The organic solution was washed with 1N HCl (50 mL), dried (Na2SO4), filtered and concentrated. The crude material was triturated with ethyl acetate/hexane to afford the title compound (2.5 g, 5.04 mmol, 91% yield) as a light yellow solid. 1H NMR (500 MHz, CDCl3) δ: 9.33 (1 H, brs), 8.18 (2 H, d, J=7.02 Hz), 7.64 (1 H, t, J=7.48 Hz), 7.50 (2 H, t, J=7.93 Hz), 4.29 (2 H, q, J=7.02 Hz), 4.17 (2 H, d, J=3.66 Hz), 3.34 (3 H, s), 3.03 (3 H, s), 2.88-3.00 (2 H, m), 2.50 (1 H, brs), 1.93-2.10 (4 H, m), 1.73-1.82 (2 H, m), 1.18 (3 H, t, J=7.17 Hz). LCMS (M+H)=497.79.
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[NH:7][C@H:8]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:9][N:10]1[C:15](=[O:16])[C:14]([N:17]2[CH2:22][CH2:21][NH:20][C:19](=[O:23])[CH2:18]2)=[C:13]([CH3:24])[N:12]([CH2:25][C:26]2[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=2[F:33])[C:11]1=[O:34])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[N+:44]([C:47]1[CH:48]=[C:49]([CH:52]=[CH:53][CH:54]=1)[CH2:50]Br)([O-:46])=[O:45].[Cl-].[NH4+]>C1COCC1.ClCCl>[C:1]([O:5][C:6](=[O:41])[NH:7][C@H:8]([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[CH2:9][N:10]1[C:15](=[O:16])[C:14]([N:17]2[CH2:22][CH2:21][N:20]([CH2:50][C:49]3[CH:52]=[CH:53][CH:54]=[C:47]([N+:44]([O-:46])=[O:45])[CH:48]=3)[C:19](=[O:23])[CH2:18]2)=[C:13]([CH3:24])[N:12]([CH2:25][C:26]2[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=2[F:33])[C:11]1=[O:34])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Reactant: Cc1c(N2CCNC(=O)C2)c(=O)n(C[C@H](NC(=O)OC(C)(C)C)c2ccccc2)c(=O)n1Cc1c(F)cccc1F
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1c(N2CCN(Cc3cccc([N+](=O)[O-])c3)C(=O)C2)c(=O)n(C[C@H](NC(=O)OC(C)(C)C)c2ccccc2)c(=O)n1Cc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 45.3 %

Procedure:
{(R)-2-[3-(2,6-difluoro-benzyl)-4-methyl-2,6-dioxo-5-(3-oxo-piperazin-1-yl)-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethyl}-carbamic acid tert-butyl ester (50 mg, 0.0878 mmol) was dissolved in 1 mL of THF, with nitrogen purge. While on ice, 60% NaH (10 mg, 0.263 mmol) was added to the solution which was then stirred at room temperature for 10 min. Again, while being cooled on ice, 3-nitrobenzyl bromide (23 mg, 0.105 mmol) was added, followed by stirring at room temperature for 1 hr. A little amount of a saturated ammonium chloride solution was added before extraction with dichloromethane. After concentration, the resulting residue was purified by column chromatography eluting with an EtOAc/hexane/dichloromethane (2/1/0.5) eluent to afford 28 mg of the compound (42%).
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([NH:44][CH3:45])=[O:43])[CH:37]=2)=[CH:32][CH:31]=1)([C:6]1[N:7]=[CH:8][N:9](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].Cl.N1C=CC=CC=1>>[OH:1][C:2]([C:30]1[CH:31]=[CH:32][C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([NH:44][CH3:45])=[O:43])[CH:37]=2)=[CH:34][CH:35]=1)([C:6]1[N:7]=[CH:8][NH:9][CH:10]=1)[CH:3]([CH3:5])[CH3:4]
Reactant: CNC(=O)c1cccc(-c2ccc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)cc2)c1
Agent: Cl
Solvent: c1ccncc1
Product: CNC(=O)c1cccc(-c2ccc(C(O)(c3c[nH]cn3)C(C)C)cc2)c1
Yield: 41.8 %

Procedure:
By the reaction in the same manner as in Example 4-(iii) using 4′-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]-N-methyl[1,1′-biphenyl]-3-carboxamide (850 mg) and pyridine hydrochloride (270 mg), the title compound (210 mg) was obtained as a colorless amorphous powder.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:30]([C:32]2[S:36][C:35]3[CH:37]=[CH:38][CH:39]=[C:40]([F:41])[C:34]=3[C:33]=2[Cl:42])=[O:31])[CH2:15][C:16]2[CH:21]=[C:20]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)[CH:19]=[CH:18][C:17]=2[O:28][CH3:29])[CH2:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:7][CH:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:15][C:16]2[CH:21]=[C:20]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)[CH:19]=[CH:18][C:17]=2[O:28][CH3:29])[C:30]([C:32]2[S:36][C:35]3[CH:37]=[CH:38][CH:39]=[C:40]([F:41])[C:34]=3[C:33]=2[Cl:42])=[O:31])[CH2:10][CH2:9]1
Reactant: COc1ccc(-c2cccnc2)cc1CN(C(=O)c1sc2cccc(F)c2c1Cl)C1CCC(NC(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(-c2cccnc2)cc1CN(C(=O)c1sc2cccc(F)c2c1Cl)C1CCC(N)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 48 %

Procedure:
410 is prepared according to a method similar to Method G. {4-[(3-Chloro-4-fluoro-benzo-[b]thiophene-2-carbonyl)-(2-methoxy-5-pyridin-3-yl-benzyl)-amino]-cyclohexyl}-carbamic acid tert-butyl ester (N3) (0.93 g, 1.48 mmol) is dissolved in 10 mL methylene chloride. Trifluoroacetic acid is added (0.35 mL) and the mixture is stirred at room temperature for 20 minutes. The reaction mixture is evaporated and pumped dry. The residue is partitioned between 5% methanol/methylene chloride and half-saturated aqueous sodium bicarbonate. The aqueous layer is extracted with 5% methanol/methylene chloride, and the combined organic extracts are dried (MgSO4), filtered and evaporated to yield an ivory solid (0.375 g, 0.717 mmol; 48% yield) that was pure by LCMS analysis.
Reaction SMILES: S(=O)(=O)(O)N.Cl([O-])=[O:7].[Na+].[C:10]1([C:16]2([CH2:21][CH:22]=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)(C)(C)C>[C:10]1([C:16]2([CH2:21][C:22]([OH:7])=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: [O-][Cl+][O-]
Reactant: O=CCC1(c2ccccc2)CCCC1
Agent: NS(=O)(=O)O
Agent: [Na+]
Solvent: CC(C)(C)O
Product: O=C(O)CC1(c2ccccc2)CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
1 ml of an aqueous solution of 39 mg (0.402 mmol) of sulfamic acid and then 1 ml of an aqueous solution of 37.6 mg (0.416 mmol) of sodium chlorite were added dropwise to a solution of 58.4 mg (0.310 mmol) of 2-(1-phenylcyclopentyl)acetaldehyde [prepared as described in step (v) above] in 1 ml of t-butanol at room temperature, and the resulting mixture was stirred for 1 hour at room temperature, after which it was extracted with methylene chloride. The extract was washed with water and then dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, to give colorless crystals. These were recrystallized from a mixture of ethyl acetate and hexane, to give 57 mg (yield 90%) of the title compound as plate-like crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH:5]2[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1.[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[CH2:20]([C:5]1([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=2)[NH:7][C:6]1=[O:11])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1ccc(C2C(=O)Nc3ccc(Cl)cc32)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COc1ccc(C2(Cc3ccccc3)C(=O)Nc3ccc(Cl)cc32)cc1
Temperature: 60 °C

Procedure:
A mixture of rac-5-chloro-3-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one (0.15 g, 0.55 mmol) (from Example 1b supra), benzyl bromide (113 mg, 0.65 mmol), potassium iodide (108 mg, 0.65 mmol) and potassium carbonate (163 mg, 1.18 mmol) in acetone (5 mL) was heated at 60° C. for 20 hours. After cooling, mixture was diluted with ethyl acetate (50 mL) and extracted with water (50 mL) and brine (50 mL). Aqueous layers were back washed with ethyl acetate (50 mL). Organic layers were combined, dried (MgSO4), filtered and concentrated. Residue was purified by flash chromatography (Biotage 40S, dichloro-methane as solvent) to give two products. Lower Rf sample was recrystallized from ethyl acetate-hexanes to give rac-3-benzyl-5-chloro-3-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one as white crystals. (Yield 58 mg, 29.1%).