Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CON(C)[C:4]([C:6]1[O:10][C:9]([CH3:11])=[N:8][C:7]=1[CH3:12])=[O:5].[C:14]([Li])([CH3:17])([CH3:16])[CH3:15]>>[CH3:11][C:9]1[O:10][C:6]([C:4]([C:14]([CH3:17])([CH3:16])[CH3:15])=[O:5])=[C:7]([CH3:12])[N:8]=1
Reactant: [Li]C(C)(C)C
Reactant: CON(C)C(=O)c1oc(C)nc1C
Product: Cc1nc(C)c(C(=O)C(C)(C)C)o1

Procedure:
Starting with N-methoxy-N-methyl-2,4-dimethyl-5-oxazolecarboxamide and t-butyllithium and following the general method of Preparation 3, the title compound was prepared.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([NH:10][C:11]2[CH:12]=[N:13][C:14]([N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:15][CH:16]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:24]([O:27][CH2:28][C:29]1[C:34]([N:35]2[CH2:47][CH2:46][N:38]3[C:39]4[CH2:40][CH2:41][CH2:42][CH2:43][C:44]=4[CH:45]=[C:37]3[C:36]2=[O:48])=[CH:33][C:32]([F:49])=[CH:31][C:30]=1B1OC(C)(C)C(C)(C)O1)(=[O:26])[CH3:25].CC([O-])=O.[Na+]>CC#N.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:24]([O:27][CH2:28][C:29]1[C:34]([N:35]2[CH2:47][CH2:46][N:38]3[C:39]4[CH2:40][CH2:41][CH2:42][CH2:43][C:44]=4[CH:45]=[C:37]3[C:36]2=[O:48])=[CH:33][C:32]([F:49])=[CH:31][C:30]=1[C:2]1[N:3]=[C:4]([NH:10][C:11]2[CH:12]=[N:13][C:14]([N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:15][CH:16]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:26])[CH3:25]
Reactant: CN1CCN(c2ccc(Nc3nc(Br)cn(C)c3=O)cn2)CC1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Product: CC(=O)OCc1c(-c2cn(C)c(=O)c(Nc3ccc(N4CCN(C)CC4)nc3)n2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Temperature: 110 °C
Yield: 15.3 %

Procedure:
A sealed tube was charged with the mixture of 331a (400 mg, 1 mmol), 4-fluoro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate 210d (578 mg, 1.2 mmol), Pd(dppf)Cl2 (82 mg, 0.1 mmol), K3PO4.3H2O(760 mg, 2 mmol), and NaOAc (164 mg, 2 mmol) in CH3CN (10 mL). The system was evacuated and then refilled with N2 and the reaction mixture was heated at 110° C. for 2 h. The mixture was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by flash column chromatography eluting with 50:1 methylene chloride/methanol to afford 331b as a yellow solid (100 mg, 14%). MS: [M+H]+ 655.
Reaction SMILES: [CH3:1][Mg]Br.[F:4][C:5]1[CH:6]=[C:7]([NH:17][C:18]2[N:35]=[C:21]3[CH:22]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[CH2:23][C:24](=[O:27])[CH2:25][CH2:26][N:20]3[N:19]=2)[CH:8]=[CH:9][C:10]=1[N:11]1[CH:15]=[N:14][C:13]([CH3:16])=[N:12]1>C1COCC1.[Cu]I>[F:4][C:5]1[CH:6]=[C:7]([NH:17][C:18]2[N:35]=[C:21]3[C@@H:22]([C:28]4[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=4)[CH2:23][C@:24]([CH3:1])([OH:27])[CH2:25][CH2:26][N:20]3[N:19]=2)[CH:8]=[CH:9][C:10]=1[N:11]1[CH:15]=[N:14][C:13]([CH3:16])=[N:12]1
Reactant: C[Mg]Br
Reactant: Cc1ncn(-c2ccc(Nc3nc4n(n3)CCC(=O)CC4c3ccc(F)cc3)cc2F)n1
Agent: [Cu]I
Solvent: C1CCOC1
Product: Cc1ncn(-c2ccc(Nc3nc4n(n3)CC[C@@](C)(O)C[C@@H]4c3ccc(F)cc3)cc2F)n1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 7 %

Procedure:
A 25 mL round bottom flask was charged with copper (I) iodide (26.2 mg, 0.138 mmol) in THF (4 mL), and cooled to 0° C. A solution of methyl magnesium bromide (4.92 mL, 6.89 mmol) was added dropwise. The mixture was stirred for 20 min. To the solution of methyl cuprate was added 2-(3-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenylamino)-9-(4-fluorophenyl)-8,9-dihydro-5H-[1,2,4]triazolo[1,5-a]azepin-7(6H)-one (300 mg, 0.689 mmol) in THF (1 mL). The mixture was stirred at 0° C. for 2 h. The reaction mixture was quenched with saturated ammonium chloride and diluted with EtOAc. The organic layer was sequentially washed with H2O (100 mL), aq sat. NaHCO3 solution (100 mL), and brine (100 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo. The crude product was purified using reverse phase preparatory HPLC (MeOH/water/trifluoroacetic acid) to afford (7S,9R)-2-(3-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenylamino)-9-(4-fluorophenyl)-7-methyl-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-7-ol (21 mg, 7% yield, Example 155, first to elute) and (7R,9R)-2-(3-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenylamino)-9-(4-fluorophenyl)-7-methyl-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-7-ol (43.7 mg, 11% yield, Example 154). Data for Example 153: LC-MS (M+H)+ 452.2. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 9.71 (1 H, br. s.), 8.55 (1 H, br. s.), 7.59-7.68 (2 H, m), 7.21-7.28 (2 H, m), 7.06-7.18 (3 H, m), 4.58-4.67 (2 H, m), 4.39 (1 H, ddd, J=14.8, 5.0, 2.4 Hz), 2.50 (3 H, s), 2.17-2.26 (1 H, m), 2.10-2.16 (1 H, m), 1.99-2.07 (1 H, m), 1.89-1.98 (1 H, m), 1.44 (3 H, s). Data for Example 153: LC-MS (M+H)+ 452.2. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.40 (1 H, d, J=2.4 Hz), 7.58-7.69 (2 H, m), 7.21 (2 H, dd, J=8.5, 5.2 Hz), 7.16 (1 H, s), 7.07-7.13 (2 H, m), 7.03 (1 H, dd, J=8.9, 2.1 Hz), 4.54 (1 H, ddd, J=14.8, 8.4, 2.1 Hz), 4.22 (1 H, ddd, J=14.9, 8.8, 1.7 Hz), 4.03-4.11 (1 H, m), 2.51 (3 H, s), 2.42 (1 H, dd, J=14.0, 10.7 Hz), 2.02-2.17 (4 H, m), 1.51 (3 H, s).
Reaction SMILES: C[O-].[Na+].[C:4]([O:11][CH3:12])(=[O:10])[CH2:5][C:6]([O:8][CH3:9])=[O:7].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[CH3:9][O:8][C:6]([CH:5]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:4]([O:11][CH3:12])=[O:10])=[O:7]
Reactant: BrCCCCCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)CC(=O)OC
Agent: C[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(CCCCCCOC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.2 %

Procedure:
Sodium methoxide (1.42 g, 26.2 mmol) was dissolved in dry MeOH (90 mL). Dimethyl malonate (3.0 mL, 26.2 mmol) was added and the mixture was stirred at r.t. for one hour. (6-Bromohexyloxy)triphenylmethane (3.7 g, 8 7 mmol) was added and the mixture was refluxed overnight. The mixture was cooled to r.t. and 50 mL 10% citric acid was added. The mixture was then stirred at r.t. for 5 min. The product was extracted with CH2Cl2 (3×100 mL) and evaporated to dryness. The residue was dissolved in CH2Cl2 and dried with Na2SO4. Purification on silica gel (petroleum ether, by 40-60° C./ethyl acetate 10:1) yielded 2.3 g (56%) of the title compound. ESI-TOF-MS [M+Na]+: calc. for C30H34NaO5+ 497.23. found 497.17.
Reaction SMILES: C(N(CC)CC)C.Cl[CH:9]([NH:14][C:15](=[O:22])[C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)[C:10]([Cl:13])([Cl:12])[Cl:11].C(#N)C.[CH2:26]([NH2:34])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O>[CH2:26]([NH:34][CH:9]([NH:14][C:15](=[O:22])[C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)[C:10]([Cl:13])([Cl:12])[Cl:11])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(NC(Cl)C(Cl)(Cl)Cl)c1ccncc1
Reactant: NCCc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: O=C(NC(NCCc1ccccc1)C(Cl)(Cl)Cl)c1ccncc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.3 %

Procedure:
3.7 g of triethylamine was added dropwise to a liquid mixture of 6.0 g of N-(1,2,2,2-tetrachloroethyl)isonicotinamide. 100 ml of acetonitrile and 2.2 g of phenethylamine at a temperature of up to 5° C. The mixture was stirred at room temperature for 2 h and the obtained reaction solution was heated to 50° to 60° C. to carry out the reaction for 3 h, cooled to room temperature and poured in water to precipitate crystals. The crystals were filtered, washed with water, dried and recrystallized from a solvent mixture of n-hexane and ethyl acetate to obtain 3.2 g of N-[1-(phenethylamino)-2,2,2-trichloroethyl]isonicotinamide. m.p. 115° to 117° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]2([CH2:17][O:16][C:15]3[CH:18]=[C:19]4[C:23](=[CH:24][C:14]2=3)[CH2:22][CH2:21][O:20]4)[C:6]1=[O:25].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl.C(OCC)(=O)C>[O:25]=[C:6]1[C:7]2([CH2:17][O:16][C:15]3[CH:18]=[C:19]4[C:23](=[CH:24][C:14]2=3)[CH2:22][CH2:21][O:20]4)[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]1[CH2:4][CH2:3][CH:2]=[O:1]
Reactant: O=C1N(CCCO)c2ccccc2C12COc1cc3c(cc12)CCO3
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=CCCN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21
Temperature: 0 °C
Reaction time: 17 h
Yield: 87.6 %

Procedure:
To a solution of 1′-(3-hydroxypropyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one (2.00 g, 5.92 mmol) in dichloromethane (100 mL) was added Dess-Martin periodinane (3.70 g, 8.46 mmol). The reaction mixture was stirred at 0° C. for 17 h, diluted with ethyl acetate, washed with 10% sodium thiosulfate solution and saturated sodium bicarbonate solution and brine. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo, the residue was subjected to column chromatography with ethyl acetate in hexanes (20% to 50% gradient) to afford 3-(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)propanal (1.74 g, 87%): MS (ES+) m/z 336.1 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[C:3]=1[OH:9].CC(O[CH2:14][C:15]1[CH2:24][S:23][C@@H:18]2[C@H:19]([NH2:22])[C:20](=[O:21])[N:17]2[C:16]=1[C:25]([OH:27])=[O:26])=O>C(#N)C.B(F)(F)F>[NH2:22][CH:19]1[C:20](=[O:21])[N:17]2[C:16]([C:25]([OH:27])=[O:26])=[C:15]([CH2:14][C:7]3[CH:6]=[C:4]([OH:5])[C:3]([OH:9])=[C:2]([F:1])[CH:8]=3)[CH2:24][S:23][C@H:18]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: Oc1cccc(F)c1O
Agent: FB(F)F
Solvent: CC#N
Product: NC1C(=O)N2C(C(=O)O)=C(Cc3cc(O)c(O)c(F)c3)CS[C@H]12
Reaction time: 40 h

Procedure:
3-fluorocatechol 1.0 g was dissolved in 15% borontrifluoride acetonitrile solution. To the solution was added 7-aminocephalosporanic acid at 5° C. After the stirring for 40 hours at room temperature, the reaction mixture was concentrated to dryness and dissolved in water with the addition of sodium bicarbonate pH 7.0). The solution was washed with ethyl acetate and acidified with 6N-hydrochloric acid to pH The resulting crude crystals were collected by filtration and washed with water to give a mixture of the title compounds (1.74 g). The isolation and purification by high performance liquid chromatography (eluent; 3% acetonitrile in potassium phosphate buffer pH 6.0, column; ODS) gave the fractions of A and B as the order of elution. Each fraction was concentrated to dryness and the resulting solids were slurried in N,N-dimethylacetamide and filtered, respectively. Each DMAc solutions of title compounds A and B were submitted to the next step (Exp. 9 and Exp. 10) without further purification.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[Cl:37]>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([N:24]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[Cl:37])[CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[Cl:37])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ccccc1CBr
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: FC(F)(F)c1cccc2c(-c3cccc(N(Cc4ccccc4Cl)Cc4ccccc4Cl)c3)c(Cc3ccccc3)cnc12

Procedure:
This compound was prepared according to the procedure of example 41, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 1-bromomethyl-2-chloro-benzene MS (ESI) m/z 627.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].C([N:14]1[CH2:19][CH2:18][CH2:17][CH:16]([C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27](=[O:29])[CH3:28])=[C:22]([O:30][C:31](=[O:33])[CH3:32])[CH:21]=2)[CH2:15]1)C1C=CC=CC=1>C(O)C.[H][H]>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[C:31]([O:30][C:22]1[CH:21]=[C:20]([CH:16]2[CH2:17][CH2:18][CH2:19][NH:14][CH2:15]2)[CH:25]=[CH:24][C:23]=1[O:26][C:27](=[O:29])[CH3:28])(=[O:33])[CH3:32]
Reactant: CC(=O)Oc1ccc(C2CCCN(Cc3ccccc3)C2)cc1OC(C)=O
Reactant: [H][H]
Agent: O=C(O)C(=O)O
Solvent: CCO
Product: CC(=O)Oc1ccc(C2CCCNC2)cc1OC(C)=O
Yield: 40.5 %

Procedure:
5 g of 10% palladized activated carbon were added to a solution of 10 g of the product of Step C in 600 ml of ethanol and hydrogen was introduced until hydrogen absorption ceased. The mixture was filtered and the filtrate was evaporated to dryness. The residue was dissolved in ethanol and the solution was cooled and vacuum filtered. The mother liquors were concentrated while progressively adding ethanol to a volume of 50 ml and was cooled and vacuum filtered. The recovered crystals were dried to obtain 3.25 g of 3-(3',4'-diacetoxyphenyl)-piperidine oxalate melting at 160° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:9]=2)=[O:4].CC1C=C(C)[N:28]=[C:27](C)C=1.CC1C([IH+])=C(C)N=C(C)C=1.F[P-](F)(F)(F)(F)F.C([Cu])#N.Cl>C(Cl)Cl.O.CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([C:27]#[N:28])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:9]=2)=[O:4]
Reactant: Cc1cc(C)nc(C)c1
Reactant: COC(=O)c1ncc2cc(CCc3ccccc3)ccc2c1O
Agent: N#C[Cu]
Agent: Cc1cc(C)c([IH+])c(C)n1
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1nc(C#N)c2cc(CCc3ccccc3)ccc2c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.3 %

Procedure:
A mixture of 4-hydroxy-7-phenethyl-isoquinoline-3-carboxylic acid methyl ester (250 mg, 0.81 mmol) and bis(2,4,6-trimethylpyridine)iodine(I) hexafluorophosphate (1.05 g, 2.04 mmol) in CH2Cl2 (10 mL) was stirred at r.t. for 16 h, then diluted with CH2Cl2. The resulting mixture was washed with 5% sodium thiosulfate and 1 M HCl. The organic layer was dried over MgSO4 and concentrated. To the residue were added CuCN (150 mg, 1.62 mmol) and anhydrous DMF (8 mL), and the resulting mixture was refluxed for 20 min. After cooling to r.t., the reaction mixture was poured into a mixture of CH2Cl2 (50 mL) and water (50 mL). 4 M HCl was added with vigorous stirring until no solid was observed. The aqueous layer was extracted with additional CH2Cl2, and the organic layers were combined, dried over MgSO4 and concentrated. The crude product was purified by column chromatography (20-100% CH2Cl2/hexanes) to give 200 mg of the title compound as a light yellow solid. MS: (+) m/z 333.28 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:13](=[O:14])[C:12]2[S:15][CH:16]=[CH:17][C:11]=2[N:10]=[C:9]1[CH:18]=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1.C(O)=O>[Pd].C(O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:13](=[O:14])[C:12]2[S:15][CH:16]=[CH:17][C:11]=2[N:10]=[C:9]1[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1
Reactant: O=c1c2sccc2nc(C=Cc2ccccn2)n1-c1ccccc1Cl
Agent: [Pd]
Solvent: O
Solvent: CCO
Solvent: O=CO
Product: O=c1c2sccc2nc(CCc2ccccn2)n1-c1ccccc1Cl
Yield: 77.4 %

Procedure:
A mixture of 3-(2-chloro-phenyl)-2-[2-pyrid-2-yl-vinyl]-3H-thieno[3,2-d]pyrimidin-4-one (0.12 g, 0.33 mmol), ethanol, 10 mL), formic acid (0.55 mL, 14.8 mmol) and 10% palladium on carbon (0.12 g) was refluxed 4 hours, cooled and diluted with ethanol and water. The mixture was filtered through Celite® (trademark) and the pad was rinsed with ethyl acetate and water. The filtrate was treated with saturated aqueous sodium bicarbonate and the phases were separated. The aqueous layer was extracted with ethyl acetate and the combined organic phase was washed with water and brine, dried over sodium sulfate, and concentrated to afford 0.094 g of 3-(2-chloro-phenyl)-2-(2-pyridin-2-yl-ethyl)-3H-thieno[3,2-d]pyrimidin-4-one as a tan film. The material was dissolved in dioxane (3 mL) and treated with ether saturated with hydrogen chloride. The solid was collected and weighed 0.094 g. The solid was taken up in water, concentrated, and azeotropically dried by suspending the product in chloroform and concentrating three times to yield 3-(2-chloro-phenyl)-2-(2-pyridin-2-yl-ethyl)-3H-thieno[3,2-d]pyrimidin-4-one hydrochloride (0.038 g, 31%) as a yellow solid.
Reaction SMILES: C([O-])=O.[NH4+].[F:5][C:6]([F:49])([F:48])[C:7]1[CH:8]=[C:9]([CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=1)[CH2:10][N:11]([C:35]1[N:36]=[N:37][N:38]([CH3:40])[N:39]=1)[C@H:12]1[CH2:18][CH2:17][CH2:16][N:15](C(OCC2C=CC=CC=2)=O)[C:14]2[C:29]([CH3:34])=[CH:30][C:31]([CH3:33])=[CH:32][C:13]1=2.CO>[Pd]>[F:48][C:6]([F:5])([F:49])[C:7]1[CH:8]=[C:9]([CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=1)[CH2:10][N:11]([C:35]1[N:36]=[N:37][N:38]([CH3:40])[N:39]=1)[C@H:12]1[CH2:18][CH2:17][CH2:16][NH:15][C:14]2[C:29]([CH3:34])=[CH:30][C:31]([CH3:33])=[CH:32][C:13]1=2
Reactant: Cc1cc(C)c2c(c1)[C@@H](N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1)CCCN2C(=O)OCc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Cc1cc(C)c2c(c1)[C@@H](N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1)CCCN2
Temperature: 25 °C
Yield: 45.5 %

Procedure:
Charge a 1 L flask with ammonium formate salt (39.0 g, 618.0 mmoles) and 10% Pd/C (3.91 g) and (S)-benzyl 5-((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)-7,9-dimethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine-1-carboxylate (39.1 g, 61.8 mmoles) dissolved in MeOH (391 mL, 966 moles). Stir the resulting slurry at RT and monitor by HPLC. After the reaction is complete, filter to collect the solid. Rinse the solid with MeOH (100 mL). Combine the filtrate solutions and organic washes and then dry over Na2SO4. Filter and concentrate to dryness. Dissolve in MeOH (92 mL) and seed with seed crystals of the titled compound. Cool and store over night to yield 14.03 g, 45.5% of the titled compound, 99.92% ee by HPLC.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:5]([OH:12])=[CH:4][CH:3]=1.[CH3:13][C:14](OC(C)=O)=[O:15].CCN(CC)CC>CN(C1C=CN=CC=1)C.O>[C:14]([O:12][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:15])[CH3:13]
Reactant: COC(=O)c1cc(Br)ccc1O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(Br)ccc1OC(C)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 99.8 %

Procedure:
In a 50 mL round-bottomed flask fitted with condenser and magnetic stirrer were placed methyl 5-bromosalicylate (5.0 g, 21.64 mmol), Ac2O (2.65 g, 25.97 mmol), Et3N (2.63 g, 25.97 mmol) and catalytic amount of DMAP. The reaction mixture was stirred for 24 h at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated to give methyl 2-acetoxy-5-bromobenzoate (5.9 g, 98%). To a stirred solution of methyl 2-acetoxy-5-bromobenzoate (5.9 g, 21.61 mmol) in acetonitrile (80 mL) were added 4-acetoxystyrene (3.68 g, 22.69 mmol), N,N-diisopropylethylamine (8.38 g, 64.82 mmol), biphenyl-2-yl-di-t-butyl phosphine (368 mg, 1.29 mmol) and palladium acetate (291 mg, 1.29 mmol) under N2. The reaction mixture was heated to 80° C. for 48 h and then cooled to room temperature. Water was added and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water, brine, dried and concentrated to give crude product, which was purified by column chromatography, using 20% ethyl acetate in hexane to give (3.19 g, 42%) of the di-acetoxy stillbene. To a solution of the di-acetoxy stillbene (500 mg, 1.41 mmol) in acetonitrile: THF (10 mL: 10 mL), NaOH (388 mg, 8.47 mmol) was added and stirred for 24 h at room temperature. The reaction mixture was neutralized by dilute HCl and extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried and concentrated to give a crude product, which was purified by crystallization in ethyl acetate and hexane to give 2-hydroxy-5-[(E)-2-(4-hydroxyphenyl)vinyl]benzoic acid (250 mg, 69%). MS (ES) m/z: 256.06 (M), 255.05 (M−1); 13C-NMR (CD3OD): δ 172.3, 161.1, 157.1, 132.7, 129.6, 129.3, 128.0, 127.5, 127.1, 124.3, 117.4, 115.3, 112.7. Mp. 241-243° C.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30](O)=[O:31])[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:69]=[CH:68][C:67]([C:70](=[O:80])[CH2:71][O:72][Si:73]([C:76]([CH3:79])([CH3:78])[CH3:77])([CH3:75])[CH3:74])=[CH:66][CH:65]=1>>[C:76]([Si:73]([CH3:75])([CH3:74])[O:72][CH2:71][C:70]([C:67]1[CH:68]=[CH:69][C:64]([NH:63][C:30]([CH:20]2[NH:19][CH:18]([CH2:33][C:34]([CH3:37])([CH3:35])[CH3:36])[C:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[CH:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:31])=[CH:65][CH:66]=1)=[O:80])([CH3:79])([CH3:78])[CH3:77]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Reactant: CC(C)(C)[Si](C)(C)OCC(=O)c1ccc(N)cc1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(C(=O)CO[Si](C)(C)C(C)(C)C)cc2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Yield: 26.5 %

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.3 g, 0.53 mmol), was reacted with diisopropylethylamine (0.28 g, 2.1 mmol), diphenylphosphinic chloride (0.38 g, 1.6 mmol), then reacted with 1-(4-amino-phenyl)-2-(tert-butyl-dimethyl-silanyloxy)-ethanone (0.21 g, 0.8 mmol) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid {4-[2-(tert-butyl-dimethyl-silanyloxy)-acetyl]-phenyl}-amide as a yellow foam (Yield 0.1 g, 26%).
Reaction SMILES: Br[CH:2]([CH3:4])[CH3:3].[Cl:5][C:6]1[C:15]2[C:10](=[C:11]([OH:16])[CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([CH3:17])[N:7]=1.C([O-])([O-])=O.[K+].[K+].[NH4+].[Cl-]>CS(C)=O>[Cl:5][C:6]1[C:15]2[C:10](=[C:11]([O:16][CH:2]([CH3:4])[CH3:3])[CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([CH3:17])[N:7]=1
Reactant: Cc1nc(Cl)c2cccc(O)c2n1
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1nc(Cl)c2cccc(OC(C)C)c2n1
Reaction time: 16 h

Procedure:
2-Bromopropane (9 mmol) was added to a stirred mixture of 4-chloro-8-hydroxy-2-methyl-quinazoline (A2) (6 mmol), K2CO3 (24 mmol) and DMSO (20 mL). After 16 h at RT, saturated NH4Cl (20 mL) was added and the mixture extracted with dichloromethane (20 mL×3). The extracts were combined and concentrated. Diethyl ether (100 mL) was added to the residue and the resulting mixture washed successively with 2 N NaOH, H2O and brine, and dried (Na2SO4). Solvent removal afforded 4-chloro-8-isopropoxy-2-methyl-quinazoline (35) as a solid.