Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[OH:13])([CH3:3])[CH3:2].C[O-].[Na+].[C:17](=[O:19])=[O:18]>CN(C)C(=O)C>[CH:10]([C:6]1[CH:7]=[C:8]([CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]=1[OH:13])[C:17]([OH:19])=[O:18])([CH3:12])[CH3:11]
Reactant: CC(C)c1cccc(C(C)C)c1O
Reactant: O=C=O
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(C)c1cc(C(=O)O)cc(C(C)C)c1O
Temperature: 90 °C
Yield: 23 %

Procedure:
This acid was prepared according to the procedure of W. H. Meek et al. J. Chemical and Engineering Data, 14(3), 388, (1969). To a solution of 2,6-diisopropylphenol (Aldrich cat. #D12660-8) (37.0 ml, 0.20 mol) in anhydrous N,N-dimethylacetamide (150 ml) was added sodium methoxide (16.2 g, 0.30 mol). Carbon dioxide was passed through the mixture throughout the subsequent reaction period. The mixture was heated with stirring and the solvent was slowly distilled out during 2 hours of the period until the pot temperature reached to 180° C. The mixture was allowed to continue stirring at 180° C. for another 1.5 hours and then cooled to 90° C. The flow of carbon dioxide was discontinued and water (400 ml) was added. The mixture, after further cooled to room temperature, was washed with toluene (4×60 ml) and then treated with conc. hydrochloric acid in an ice-water bath to pH 3. The resulting-mixture was extracted with diethyl ether (2×150 ml); the ether extract was washed with brine (100 ml) and dried over anhydrous magnesium sulfate. Removal of the solvent under reduced pressure gave 3,5-diisopropyl-4-hydroxybenzoic acid (10.4 g, 23%). Rf 0.5 (silica gel, 50% diethyl ether/hexane). MS (CI, CH4): m/z 223 (M+1).
Reaction SMILES: N.[Li].[CH3:3][C@@:4]12[CH2:17][CH2:16][C:15](=[O:18])[CH:14]=[C:13]1[CH2:12][CH2:11][C@H:10]1[C@H:5]2[CH2:6][C@@H:7]2[CH2:21][CH2:20][C@H:19]([OH:22])[C@@:8]2([CH3:23])[CH2:9]1.[NH4+].[Cl-]>C1COCC1>[CH3:3][C@@:4]12[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][C@H:13]1[CH2:12][CH2:11][C@H:10]1[C@H:5]2[CH2:6][C@@H:7]2[CH2:21][CH2:20][C@H:19]([OH:22])[C@@:8]2([CH3:23])[CH2:9]1
Reactant: C[C@]12C[C@H]3CCC4=CC(=O)CC[C@@]4(C)[C@@H]3C[C@@H]1CC[C@@H]2O
Agent: N
Agent: [Cl-]
Agent: [Li]
Solvent: C1CCOC1
Product: C[C@]12C[C@H]3CC[C@@H]4CC(=O)CC[C@@]4(C)[C@@H]3C[C@@H]1CC[C@@H]2O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 86.5 %

Procedure:
A three-neck flask equipped with a dry ice condenser was cooled to −78° C. and anhydrous ammonia (100 mL) was condensed into the flask. Lithium (134 mg, 19 mmol, 10 equiv) was added, and the resulting blue solution was stirred for 0.5 h. To this was added a solution of compound 19 (550 g, 1.91 mmol) in dry THF (50 mL). After 3 h of stirring, solid NH4Cl was added until the blue color disappeared, and the reaction mixture was allowed to warm to room temperature overnight and aqueous NH4Cl was added. The product was extracted into EtOAc (100 mL×3), and the combined organic extracts were washed with brine, dried and the solvent evaporated. Column chromatography (silica gel eluted with 10% EtOAc in hexanes) gave compound (480 mg, 87%) as a colorless oil: 1H NMR (CDCl3) δ 3.63 (t, J=7.8 Hz, 1H), 0.98 (s, 3H), 0.72 (s, 3H); 13C NMR (CDCl3) δ 212.0, 81.5, 54.0, 46.6, 45.0, 44.5, 43.0, 38.2, 37.9, 35.8, 34.6, 31.8, 30.3, 29.1, 25.5, 24.7, 11.4, 11.1; IR νmax 3416, 1709 cm−1.
Reaction SMILES: C(Cl)(Cl)(Cl)Cl.[Cl:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][C:12]([CH3:32])([CH3:31])[C:13](=[O:30])[N:14]2[CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)=[N:9][CH:8]=1.[Br:33]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(OCC)C>[Br:33][CH:11]1[C:10]2[C:15](=[CH:16][C:7]([Cl:6])=[CH:8][N:9]=2)[N:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:19][CH2:18]2)[C:13](=[O:30])[C:12]1([CH3:32])[CH3:31]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCC(N2C(=O)C(C)(C)Cc3ncc(Cl)cc32)CC1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(N2C(=O)C(C)(C)C(Br)c3ncc(Cl)cc32)CC1
Temperature: 0 °C
Yield: 41 %

Procedure:
A carbon tetrachloride solution (25 ml) of tert-butyl 4-(7-chloro-3,3-dimethyl-2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)piperidine-1-carboxylate (Reference Example 10-2) (1.0 g), N-bromosuccinimide (903 mg) and 2,2′-azobisisobutyronitrile (43.2 mg) was heated at reflux for 40 minutes. After the reaction solution was cooled to 0° C., diethylether was added, and filtered through Celite. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to afford tert-butyl 4-(4-bromo-7-chloro-3,3-dimethyl-2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)piperidine-1-carboxylate (492 mg).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].Cl.[F:8][C:9]1[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[C:14]2[C:10]=1[C:11](=O)[N:12]([NH:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)[C:13]2=O.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[F:8][C:9]1[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[C:14]2[C:10]=1[CH2:11][N:12]([NH:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)[CH2:13]2
Reactant: COc1ccc2c(c1F)C(=O)N(Nc1ccncc1)C2=O
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2c(c1F)CN(Nc1ccncc1)C2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(3-fluoro-4-methoxyphenyl)-4,4-dimethyl-4,5-dihydrooxazole (34.0 g) in dry tetrahydrofuran (300 ml) sec-butyllithium (140 ml of a 1.3 M solution in cyclohexane) was added dropwise at -78° C. with stirring, under nitrogen. The reaction mixture was stirred 15 mins, and carbon dioxide was bubbled below the surface. The reaction was stirred for 1 hr and water added dropwise. The mixture was basified with 10% sodium hydroxide solution and extracted with ethyl acetate. The aqueous extract was cooled to 0° C. and an equal volume of concentrated hydrochloric acid was added dropwise. The solution was stirred, under reflux overnight, cooled and the solid collected. The solid was washed with cold water and dried in vacuo to give 26.6 g of 3-fluoro-4-methoxyphthalic acid. A mixture of 3-fluoro-4-methoxyphthalic acid (26.6 g ) in acetic anhydride (100 ml) was stirred, under reflux, under nitrogen, for 4 hrs. The reaction mixture was cooled to -60° C. and filtered. The solid was collected, washed with ether and dried in vacuo to give 19.9 g (67%) of 3-fluoro-4-methoxyphthalic anhydride, mp 128-130° C. A mixture of 3-fluoro-4-methoxyphthalic anhydride (10.0 g) and 4-hydrazinopyridine hydrochloride (7.42 g) in glacial acetic acid (50 ml) was stirred, under reflux, under nitrogen, for 4 hrs and stirred at ambient temperature overnight. The solid was collected, washed with ether and dried in vacuo at 80° C. overnight to give 10.6 g (64%) of 4-fluoro-5-methoxy-2-(4-pyridinylamino)isoindol-1,3-dione. To a mixture of lithium aluminum hydride (3.72 g) and dry tetrahydrofuran (100 ml), 4-fluoro-5-methoxy-2-(4-pyridinylamino)isoindole-1,3-dione hydrochloride (10.60 g) was added in portions with rapid stirring, under nitrogen, at ambient temperature. The reaction mixture was stirred at ambient temperature, under nitrogen, for 3 hrs, and sodium sulfate decahydrate was added in portions. The mixture was filtered through a bed of celite, the filter pad was washed with ethyl acetate, and the filtrate was concentrated in vacuo. The residue was chromatographed over silica gel, eluting with 7% methanol-dichloromethane followed by 185:14:1 dichloromethane:methanol:ammonium hydroxide. The residue was crystallized from absolute ethanol to give 3.2 g (8%) of product, (dried under vacuum at 80° C. overnight) mp 206-210° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH2:14]([NH2:16])[CH3:15]>ClCCl>[CH2:14]([NH:16][C:4](=[O:5])[C:3]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:2]=1[Cl:1])[CH3:15]
Reactant: CCN
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1Cl
Solvent: ClCCl
Product: CCNC(=O)c1cc([N+](=O)[O-])ccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
Alternatively, 2-chloro-5-nitrobenzoyl chloride (10 g, 45.5 mmol) in anhydrous dichloromethane (250 mL) with Amberlyst A-21 ion-exchange resin (17 g) was treated with a 2M ThF solution of ethylamine (45 mL). The mixture was stirred at rt under nitrogen overnight. After filtration, the filtrate was concentrated to give N-ethyl-2-chloro-5-nitrobenzamide (9.0 g, 39 mmol, 86% yield) as a yellow solid.
Reaction SMILES: BrC1C=CC(S(O[CH2:12][C@@H:13]2[O:27][C:17]3=[C:18]4[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14]2)[N:22]=[C:21]([CH3:26])[CH:20]=[CH:19]4)(=O)=O)=CC=1.[CH3:28][O:29][C:30]1[CH:31]=[C:32]([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH:33]=[CH:34][CH:35]=1>CS(C)=O.C(=O)(O)[O-].[Na+]>[CH3:28][O:29][C:30]1[CH:31]=[C:32]([N:36]2[CH2:41][CH2:40][N:39]([CH2:12][C@@H:13]3[O:27][C:17]4=[C:18]5[C:23](=[CH:24][CH:25]=[C:16]4[O:15][CH2:14]3)[N:22]=[C:21]([CH3:26])[CH:20]=[CH:19]5)[CH2:38][CH2:37]2)[CH:33]=[CH:34][CH:35]=1
Reactant: COc1cccc(N2CCNCC2)c1
Reactant: Cc1ccc2c3c(ccc2n1)OC[C@H](COS(=O)(=O)c1ccc(Br)cc1)O3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cccc(N2CCN(C[C@H]3COc4ccc5nc(C)ccc5c4O3)CC2)c1
Temperature: 65 °C
Yield: 88.5 %

Procedure:
A mixture of [(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl 4-bromobenzenesulfonate (702 mg, 1.56 mmol) and 3-methoxyphenyl piperazine (890 mg, 4.63 mmol) in anhydrous DMSO (10 mL) were heated at 65° C. overnight. The cooled reaction mixture was diluted with saturated aqueous sodium bicarbonate (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. Flash chromatography on silica gel (50% EtOAc/hexanes) afforded 560 mg (88%) of the desired product as a white solid: mp 90–91° C.; MS (ESI) m/z 406 [M+H]+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[C:9]([C@@H:11]([NH:13]S(C(C)(C)C)=O)[CH3:12])[CH:8]=[CH:7][N:6]=1)(=[O:4])=[O:3].[ClH:20].O1CCOCC1>CO>[ClH:20].[CH3:1][S:2]([C:5]1[CH:10]=[C:9]([C@@H:11]([NH2:13])[CH3:12])[CH:8]=[CH:7][N:6]=1)(=[O:4])=[O:3]
Reactant: C[C@H](NS(=O)C(C)(C)C)c1ccnc(S(C)(=O)=O)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: C[C@H](N)c1ccnc(S(C)(=O)=O)c1
Reaction time: 1 h

Procedure:
To a solution of 2-methyl-propane-2-sulfinic acid [(S)-1-(2-methanesulfonyl-pyridin-4-yl)-ethyl]-amide (29.9 g, 98.2 mmol) in methanol (160 mL) was added a solution of 4 N HCl in dioxane (25.8 mL, 103 mmol). After 1 hour, the solution was concentrated to half the original volume and diluted with toluene (100 mL), and concentrated. The crude material was diluted with toluene (3×100 mL) and concentrated in vacuo and dried in vacuo for 18 hours to afford the title compound as an off-white solid which was used without further purification.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=2)[CH2:2]1.C(N(C(C)C)CC)(C)C.[N:20]([C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)=[C:21]=[O:22]>ClCCl>[N:7]1[CH:8]=[CH:9][CH:10]=[C:5]([CH:3]2[CH2:4][N:1]([C:21]([NH:20][C:23]3[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=3)=[O:22])[CH2:2]2)[CH:6]=1
Reactant: c1cncc(C2CNC2)c1
Reactant: COC(=O)c1ccc(N=C=O)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(NC(=O)N2CC(c3cccnc3)C2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 20 mL vial was added 3-(azetidin-3-yl)pyridine, bistrifluoroacetic acid (75 mg, 0.207 mmol) and diisopropylethylamine (0.109 ml, 0.622 mmol) in dichloromethane (2072 μl. Methyl 4-isocyanatobenzoate (47.7 mg, 0.269 mmol) was added, and the mixture was stirred at room temperature for 2 hours and concentrated by rotary evaporation. The residue was purified by regular phase chromatography to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ 8.90 (s, 1H), 8.57 (d, J=2.1 Hz, 1H), 8.48 (dd, J=4.8, 1.6 Hz, 1H), 7.91-7.82 (m, 3H), 7.71-7.64 (m, 2H), 7.41 (ddd, J=7.9, 4.7, 0.8 Hz, 1H), 4.42 (t, J=8.4 Hz, 2H), 4.05-3.96 (m, 2H), 3.89 (dt, J=8.1, 7.0 Hz, 1H), 3.81 (s, 1H); MS (ESI(+)) m/e 312 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:28]=[C:29]([S:33]([NH2:36])(=[O:35])=[O:34])[CH:30]=[N:31][CH:32]=1>>[F:15][C:12]([F:14])([F:13])[C:11]1[N:6]2[N:5]=[CH:4][C:3]([C:1]#[C:2][C:27]3[CH:28]=[C:29]([S:33]([NH2:36])(=[O:35])=[O:34])[CH:30]=[N:31][CH:32]=3)=[C:7]2[N:8]=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:10]=1
Reactant: NS(=O)(=O)c1cncc(Br)c1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: NS(=O)(=O)c1cncc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and 5-bromo-pyridine-3-sulfonic acid amide (example B.1) (356 mg, 1.5 mmol) according to general procedure II. Obtained as a yellow solid (90 mg, 18%). MS (ISP) 512.3 [(M+H)+]; mp 239-240° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:20]2[CH:24]=[C:23]([NH:25][C:26](=[O:40])[CH:27]([NH:29][C:30]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:31])[CH3:28])[N:22]([C:41]([CH3:44])([CH3:43])[CH3:42])[N:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C([O-])(O)=O.[Na+]>FC(F)(F)C(O)=O>[CH2:33]([O:32][C:30](=[O:31])[NH:29][CH:27]([C:26](=[O:40])[NH:25][C:23]1[N:22]([C:41]([CH3:43])([CH3:42])[CH3:44])[N:21]=[C:20]([C:11]2([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH:24]=1)[CH3:28])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC(NC(=O)OCc1ccccc1)C(=O)Nc1cc(C2(c3ccccc3)CCN(C(=O)OC(C)(C)C)CC2)nn1C(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CC(NC(=O)OCc1ccccc1)C(=O)Nc1cc(C2(c3ccccc3)CCNCC2)nn1C(C)(C)C

Procedure:
A solution of 0.54 g (0.9 mmol) of 4-[5-(2-benzyloxycarbonylamino-propionylamino)-1-tert-butyl-1H-pyrazol-3-yl]-4-phenylpiperidine-1-carboxylic acid tert-butyl ester in 4.0 mL of neat trifluoroacetic acid was stirred at rt for 15 min. The reaction mixture was then poured into sat. aq. NaHCO3 and extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated to afford {1-[2-tert-butyl-5-(4-phenylpiperidin-4-yl)-2H-pyrazol-3-ylcarbamoyl]ethyl}-carbamic acid benzyl ester which was used without further purification.
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[C:10](=[O:12])[CH3:11].[C:13]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:16])[CH:14]=[CH2:15]>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:10]([C:3]1[C:2](/[CH:15]=[CH:14]/[C:13]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[C:7]([F:8])[C:6]([Cl:9])=[CH:5][CH:4]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)c1ccc(Cl)c(F)c1Br
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(Cl)c(F)c1/C=C/C(=O)OC(C)(C)C
Temperature: 90 °C
Reaction time: 8 h
Yield: 50.7 %

Procedure:
To a mixture of Intermediate 12C (50 g, 198 mmol), tert-butyl acrylate (50.9 g, 397 mmol) and TEA (55 mL, 397 mmol) in DMF (500 mL) was added Pd(OAc)2 (8.9 g, 39.7 mmol). The resulting mixture was stirred at 90° C. overnight. The reaction was cooled to rt, filtered, and the filtrate was concentrated. Purification by column chromatography gave Intermediate 12D (30 g, 50.8%) as a light yellow solid. MS (ESI) m/z: 242.7 (M+H)+.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][CH:12]=1.[C:20]([O:24][C:25]([NH:27][C:28]([NH:37][C@@H:38]1[CH2:43][CH2:42][CH2:41][CH2:40][C@@H:39]1[NH:44][C:45]1[C:54]2[C:49](=[CH:50][CH:51]=[C:52]([O:55][CH3:56])[CH:53]=2)[N:48]=[C:47]([NH2:57])[N:46]=1)=[N:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:26])([CH3:23])([CH3:22])[CH3:21].O>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:33]([O:32][C:30]([NH:29][C:28]([NH:37][C@@H:38]1[CH2:43][CH2:42][CH2:41][CH2:40][C@@H:39]1[NH:44][C:45]1[C:54]2[C:49](=[CH:50][CH:51]=[C:52]([O:55][CH3:56])[CH:53]=2)[N:48]=[C:47]([NH:57][C:15](=[O:16])[C:14]2[CH:18]=[CH:19][C:11]([Cl:10])=[CH:12][CH:13]=2)[N:46]=1)=[N:27][C:25]([O:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:26])=[O:31])([CH3:34])([CH3:35])[CH3:36]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: COc1ccc2nc(N)nc(N[C@H]3CCCC[C@H]3NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c2c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2nc(NC(=O)c3ccc(Cl)cc3)nc(N[C@H]3CCCC[C@H]3NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 366 mg of N,N-diisopropylethylamine in 10 mL of methylene chloride was combined with 60 mg of 4-dimethylaminopyridine and 0.156 mL of 4-chlorobenzoyl chloride. This was treated dropwise with a solution of 500 mg of (1R,2S)-N-[N,N′-bis(tert-butoxycarbonyl)]amidino-2-(2-amino-6-methoxyquinazolin-4-yl)aminocyclohexylamine in 10 mL of methylene chloride, and stirred at room temperature for 3 hours. The reaction solution was combined with water, extracted with methylene chloride, and dried. After the solvent was distilled off, the residue was purified by column chromatography on silica gel (chloroform:methanol=30:1) to obtain 560 mg of the desirable compound.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[CH:6]=1)[OH:4].O=[C:13]([CH3:27])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:18][CH:17]=1.C1C=CC=CC=1.C([BH3-])#N.[Na+]>CO>[CH3:26][O:25][C:23]([CH2:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][CH2:14][CH:13]([NH:1][CH2:2][CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[CH:6]=2)[OH:4])[CH3:27])=[CH:21][CH:20]=1)=[O:24]
Reactant: COC(=O)Cc1ccc(OCC(C)=O)cc1
Reactant: NCC(O)c1cccc(Br)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)Cc1ccc(OCC(C)NCC(O)c2cccc(Br)c2)cc1
Yield: 56.8 %

Procedure:
Following a procedure similar to that described in Example 3, but using 3.0 g of 2-amino-1-(3-bromophenyl)ethanol (prepared as described in Preparation 41), 3.67 g of methyl 4-(2-oxopropoxy)phenylacetate (prepared as described in Preparation 3), 80 ml of benzene, 60 ml of absolute methanol and 3.1 g of sodium cyanoborohydride, and then purifying the reaction product by column chromatography through silica gel, using ethyl acetate as the eluent, 3.33 g of the title compound were obtained having an Rf=0.25 (thin layer chromatography over silica gel, using ethyl acetate as the developing solvent).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=2[OH:18])=O)=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](O)=[O:28])=[CH:22][CH:21]=1.C([O-])([O-])=O.[K+].[K+].C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C1C=CN=CC=1.CN(C=O)C.O>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[C:27](=[O:28])[O:18][C:11]3[C:10]([C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=2)=[CH:15][CH:14]=[C:13]([O:16][CH3:17])[CH:12]=3)=[CH:22][CH:21]=1
Reactant: COc1ccc(C(=O)c2ccc(O)cc2)c(O)c1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(-c3ccc(O)cc3)c(-c3ccc(Cl)cc3)c(=O)oc2c1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
A suspension of 2-hydroxy-4-methoxyphenyl 4-hydroxyphenyl ketone (2.6 grams, 10.65 mmol), 4-chlorophenylacetic acid (4.0 g, 23.43 mmol), K2CO3 (4.4 g, 31.95 mmol), carbonyldiimidazole (3.8 g, 23.43 mmol), and 4-dimethylaminopyridine (0.1 g,) in 20 mL of DMF was warmed at 90° C. for 5 hours. The reaction mixture was poured into 150 mL of H2O and stirred for 30 minutes. The precipitated product was collected by filtration and the purified desired product was isolated following flash chromatography (2.1 g, 52%, LC/MS=379 (M+H+)).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:6][C:5]2=[O:17].C(OCC)(=O)C.[CH3:24][N:25](C=O)C>[C-]#N.[Zn+2].[C-]#N.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:24]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:6][C:5]2=[O:17])#[N:25]
Reactant: CCOC(=O)c1nc2ccc(I)cc2c(=O)[nH]1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc2ccc(C#N)cc2c(=O)[nH]1
Temperature: 80 °C
Reaction time: 5 h
Yield: 68 %

Procedure:
A suspension of ethyl 6-iodo-4-oxo-3,4-dihydroquinazoline-2-carboxylate (2.00 g, 5.81 mmol), zinc cyanide (375 mg, 3.19 mmol) and tetrakis(triphenylphosphine)palladium (336 mg, 0.29 mmol) in DMF (10 mL) was stirred at 80° C. for 5 hr under argon atmosphere. After cooling to room temperature, ethyl acetate was added to the reaction mixture. The precipitated solid was collected by filtration, washed with ethyl acetate, diisopropyl ether and water, dried over diphosphorus pentaoxide under reduced pressure to give the title compound as a pale-yellow powder (965 mg, 68%).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([NH2:10])=[CH:4][CH:3]=1.[CH3:11][PH:12](=[O:14])[CH3:13].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:11][P:12]([C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([NH2:10])=[CH:4][CH:3]=1)([CH3:13])=[O:14]
Reactant: C[PH](C)=O
Reactant: COc1nc(Br)ccc1N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CN(C)C=O
Product: COc1nc(P(C)(C)=O)ccc1N
Reaction time: 0.33 h
Yield: 38.6 %

Procedure:
To a solution of 6-bromo-2-methoxypyridin-3-ylamine (0.203 g, 1.00 mmol) in 4 mL DMF was added dimethylphosphine oxide (0.171 g, 1.10 mmol), palladium acetate (11.0 mg, 0.0490 mmol), XANTPHOS (35.0 mg, 0.0600 mmol), and potassium phosphate (0.233 g, 1.10 mmol). The mixture was purged with nitrogen, and subjected to microwaves at 150° C. for 20 minutes. The reaction mixture was concentrated and purified by silica gel chromatography (0-10% 7N ammonia in methanol:dichloromethane) to afford the desired product (77.2 mg, 39% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([C:13]#N)[CH2:11][CH2:10][C@H:9]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(O)=[O:24].O>[Ni].O.O>[C:1]([O:5][C:6]([N:8]1[C@H:12]([CH:13]=[O:24])[CH2:11][CH2:10][C@H:9]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)O
Reactant: CC(C)(C)OC(=O)[C@@H]1CC[C@@H](C#N)N1C(=O)OC(C)(C)C
Agent: [Ni]
Solvent: O
Product: CC(C)(C)OC(=O)[C@@H]1CC[C@@H](C=O)N1C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 72 h
Yield: 51 %

Procedure:
90 g Raney-Ni/H2O (50 w % in water, Acros) was added to a solution of 17.905 g (60.42 mmol) of the cyanide 110 in 640 ml Py/AcOH/H2O (2:1:1) and stirred under hydrogen for 72 h at 80° C. 300 ml water was added to the suspension, and the suspension was extracted 3× with 800 ml MTBE each. The combined organic phases were washed twice with water, dried over magnesium sulfate, and the solvent was removed at reduced pressure. The residue was filtered with 1000 ml EtOAc/CyHex (1:1) over silica gel, and, following the removal of the solvent, the raw product was purified by chromatography on silica gel with EtOAc/CyHex 1:4 as eluent. 9.234 g (30.85 mmol, 51%) of the aldehyde 111 was obtained as yellow oil (d.r.: 1.7:1 cis:trans).