Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]=[C:11]([C:13]1[N:18]=[C:17]([C:19](=O)[CH3:20])[CH:16]=[CH:15][CH:14]=1)[CH3:12].[CH3:22][C:23]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:24]=1[NH2:25]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]=[C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([C:19](=[N:25][C:24]2[C:26]([CH3:30])=[CH:27][CH:28]=[CH:29][C:23]=2[CH3:22])[CH3:20])[N:18]=1)[CH3:12]
Reactant: Cc1cccc(C)c1N
Reactant: CC(=O)c1cccc(C(C)=Nc2c(C)cc(C)cc2Cl)n1
Solvent: C1CCOC1
Product: CC(=Nc1c(C)cccc1C)c1cccc(C(C)=Nc2c(C)cc(C)cc2Cl)n1
Temperature: 25 °C
Yield: 67 %

Procedure:
18.80 g of 1-{6-[1-(2-chloro-4,6-dimethylphenylimino)-ethyl]pyridin-2-yl}ethanone (0.0625 mol), 15.13 g of 2,6-dimethylaniline (0.125 mol) and 20.0 g of Sicapent were heated under reflux under argon in 300 ml of tetrahydrofuran for 17 h. A further portion of Sicapent (10.0 g) was added and the mixture was heated under argon for a further 4 h and then cooled to room temperature. It was filtered and the residue on the filter was washed with 50 ml of tetrahydrofuran. The solvent was distilled off completely from the combined filtrates and the residue was stirred with 50 ml of methanol. The precipitate formed was filtered off, washed twice with methanol, stirred with 100 ml of hot methanol and then filtered. 16.92 g (0.0419 mol) of 2-[1-(2-chloro-4,6-dimethylphenylimino)ethyl]-6-[1-(2,6-dimethylphenylimino)ethyl]pyridine were obtained in a yield of 67%.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[NH:4][CH:5]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:7]=1.[CH3:15][Si:16]([CH2:19][CH2:20][O:21][CH2:22]Cl)([CH3:18])[CH3:17]>>[F:14][C:2]([F:1])([F:13])[C:3]1[N:4]([CH2:22][O:21][CH2:20][CH2:19][Si:16]([CH3:18])([CH3:17])[CH3:15])[CH:5]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:7]=1
Reactant: CCOC(=O)c1c[nH]c(C(F)(F)F)n1
Reactant: C[Si](C)(C)CCOCCl
Product: CCOC(=O)c1cn(COCC[Si](C)(C)C)c(C(F)(F)F)n1

Procedure:
The title compound was prepared using the procedure described in Example 52(b) starting from ethyl 2-(trifluoromethyl)-1H-imidazole-4-carboxylate (9.5 mmol, 2 g) and SEM-Cl (11.5 mmol, 2.1 ml). Yield 1.9 g. 1H-NMR (400 MHz; CDCl3): δ −0.01 (s, 9H), 0.91 (t, 2H), 1.40 (t, 3H), 3.54 (t, 2H), 4.40 (q, 2H), 5.43 (s, 2H), 7.85 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:13]=2)=[N:5][C:4]([NH2:25])=[N:3]1.[CH3:26][N:27]=[C:28]=[O:29]>C(#N)C>[CH3:26][NH:27][C:28]([NH:25][C:4]1[N:5]=[C:6]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:13]=2)[N:2]([CH3:1])[N:3]=1)=[O:29]
Reactant: Cn1nc(N)nc1NCCCOc1cccc(CN2CCCCC2)c1
Reactant: CN=C=O
Solvent: CC#N
Product: CNC(=O)Nc1nc(NCCCOc2cccc(CN3CCCCC3)c2)n(C)n1
Yield: 81.5 %

Procedure:
A mixture of 1-methyl-N5 -[3-[3-(1-piperidinylmethyl)phenoxy]propyl]-1H-1,2,4-triazole-3,5-diamine (2.00 g) and methylisocyanate (1.2 g) in dry acetonitrile (60 ml) was heated at reflux for 2 h. and allowed to cool. The precipitated solid was collected and recrystallised from methanol to give the title compound (1.9 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][OH:30])=[C:22]([Br:31])[CH:21]=1)[C:9]([NH2:18])=[N:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:32](Cl)([C:35]1[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=1)(=[O:34])=[O:33].CCN(CC)CC>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:39][C:38]1[CH:40]=[CH:41][C:35]([S:32]([O:30][CH2:29][CH2:28][CH2:27][O:26][C:23]2[CH:24]=[CH:25][C:20]([CH2:19][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[C:9]([NH2:18])=[N:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:21][C:22]=2[Br:31])(=[O:34])=[O:33])=[CH:36][CH:37]=1
Reactant: CC(C)(C)OC(=O)N=C(N)N(Cc1ccc(OCCCO)c(Br)c1)C(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCCOc2ccc(CN(C(=O)OC(C)(C)C)C(N)=NC(=O)OC(C)(C)C)cc2Br)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 86.6 %

Procedure:
To a solution of the product of Example 1A (339 mg, 0.676 mmol) dissolved in anhydrous CH2Cl2 (6.76 mL) was added TsCl (155 mg, 0.812 mmol), DMAP (99 mg, 0.812 mmol) and Et3N (0.141 mL, 1.01 mmol). The reaction mixture was stirred at room temperature for 1.5 h then concentrated to a yellow oil. The crude material was directly purified using silica gel chromatography (4:1 hexanes:EtOAc) to yield a colorless oil (384.3 mg, 87% yield). 1H NMR (CDCl3, 600 MHz): δ 7.74 (d, J=8.4 Hz, 2H), 7.50 (d, J=1.8 Hz, 1H), 7.21 (m, 3H), 6.70 (d, J=8.4 Hz, 1H), 5.08 (brs, 2H), 4.30 (t, J=6.0 Hz, 2H), 4.00 (t, J=6.0 Hz, 2H), 2.37 (s, 3H), 2.16 (m, 2H), 1.51 (s, 9H), 1.43 (s, 9H); 13C NMR (CDCl3, 150 MHz): δ 160.6, 154.9, 154.0, 145.0, 133.0, 132.9, 132.7, 130.0, 128.0, 112.9, 111.9, 84.7, 79.0, 67.0, 64.1, 46.4, 29.0, 28.5, 28.2, 21.8.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[C:14]2[NH:13][C:12](=[O:15])[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.[CH2:16]([NH:23][CH:24]1[CH2:30][CH2:29][CH2:28][C:27]2[CH:31]=[C:32]([OH:35])[CH:33]=[CH:34][C:26]=2[CH2:25]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)C>[CH2:16]([N:23]([CH2:3][CH:2]([OH:1])[CH2:4][O:5][C:6]1[C:14]2[NH:13][C:12](=[O:15])[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1)[CH:24]1[CH2:30][CH2:29][CH2:28][C:27]2[CH:31]=[C:32]([OH:35])[CH:33]=[CH:34][C:26]=2[CH2:25]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Oc1ccc2c(c1)CCCC(NCc1ccccc1)C2
Reactant: O=c1[nH]c2cccc(OCC3CO3)c2[nH]1
Solvent: CCO
Product: O=c1[nH]c2cccc(OCC(O)CN(Cc3ccccc3)C3CCCc4cc(O)ccc4C3)c2[nH]1
Temperature: 25 °C
Yield: 64.9 %

Procedure:
A mixture of 4-oxiranylmethoxy-1,3-dihydro-2-benzimidazolone (82.5 mg) and N-benzyl-(6,7,8,9-tetrahydro-2-hydroxy-5H-benzocyclohepten-6-yl)amine (107 mg) in ethanol (1.5 ml) was stirred under reflux for 13 hours, cooled to room temperature and evaporated in vacuo. The residue was chromatographed (dichloromethane-methanol)by silica gel (4.2 g) to afford 1-[N-benzyl-N-(6,7,8,9-tetrahydro-2-hydroxy-5H-benzocyclohepten-6-yl) amino]-3-(1,3-dihydro-2-benzoimidazolon-4-yloxy)-2-propanol (123 mg) as a colorless powder.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]2[C:23]([C:24]#[C:25][C:26]3[CH:27]=[N:28][C:29]([NH2:32])=[CH:30][CH:31]=3)=[C:22]([CH3:33])[N:21]=[C:20]([NH2:34])[N:19]=2)[CH:9]=1)(C)(C)C.Cl>O1CCOCC1>[NH2:32][C:29]1[N:28]=[CH:27][C:26]([C:25]#[C:24][C:23]2[C:18]([C:10]3[CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=[C:8]([NH2:7])[CH:9]=3)=[N:19][C:20]([NH2:34])=[N:21][C:22]=2[CH3:33])=[CH:31][CH:30]=1
Reactant: Cc1nc(N)nc(-c2cc(NC(=O)OC(C)(C)C)cc(C(F)(F)F)c2)c1C#Cc1ccc(N)nc1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1nc(N)nc(-c2cc(N)cc(C(F)(F)F)c2)c1C#Cc1ccc(N)nc1

Procedure:
The title compound is synthesized starting from 632 mg (1.3 mmol) {3-[2-amino-5-(6-amino-pyridin-3-ylethynyl)-6-methyl-pyrimidin-4-yl]-5-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (A-42) by treatment with a 4 M solution of HCl in dioxane. After completion of the reaction the solvent is removed in vacuo followed by extraction with DCM and a saturated aqueous solution of NaHCO3. Yield: 310 mg (62%).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:30])[C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH:16]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1.Cl>C1COCC1.CO.CCOC(C)=O>[CH:24]1([C:17]2[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:15]([S:12]([C:9]3[CH:10]=[CH:11][C:6]([C:5]([OH:30])=[O:4])=[CH:7][CH:8]=3)(=[O:14])=[O:13])[CH:16]=2)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: COC(=O)c1ccc(S(=O)(=O)n2cc(C3CCCCC3)c3ccccc32)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(S(=O)(=O)n2cc(C3CCCCC3)c3ccccc32)cc1
Reaction time: 1.5 h
Yield: 86.4 %

Procedure:
Add 5N sodium hydroxide (1.17 ml, 3 eq) to a solution of 4-(3-Cyclohexyl-indole-1-sulfonyl)-benzoic acid methyl ester (775 mg, 1.95 mmol, 1 eq) dissolve in a mixture of 10 ml THF and 5 ml MeOH. Stir for 1.5 hours. Remove solvent on rotovap and add 1 N HCl. Dissolve the solid that crashes out of solution in EtOAc. Extract product into organics, separate organics, dry over MgSO4, and concentrate on rotovap to give 4-(3-Cyclohexyl-indole-1-sulfonyl)-benzoic acid (646 mg, 86% yield) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([NH:6][CH3:7])=[CH:4][CH:3]=1.Br[CH:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([N:6]([CH:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH3:7])=[CH:4][CH:3]=1
Reactant: CNc1ccc(Cl)cc1
Reactant: CCOC(=O)C(Br)C(=O)OCC
Solvent: c1ccccc1
Product: CCOC(=O)C(C(=O)OCC)N(C)c1ccc(Cl)cc1
Yield: 32.8 %

Procedure:
p-Chloro-N-methylaniline (10.1 g), diethyl bromomalonate (8.5 g) and dry benzene (60 ml) were mixed, and heated under reflux for 7 hours with stirring. The reaction mixture was washed, dried and concentrated by the same procedure as in Example 2, (1). The residue was chromatographed on a silica gel column using benzene/hexane (1:1) as an eluent to give 3.5 g (yield 33%) of diethyl p-chloro-N-methylanilinomalonate having the following NMR data.
Reaction SMILES: CO.[F:3][C:4]1[CH:5]=[C:6]([C:27]2[C:28]([CH3:42])=[CH:29][C:30]([O:33][CH2:34][C:35]([CH3:41])([CH3:40])[C:36]([O:38]C)=[O:37])=[N:31][CH:32]=2)[CH:7]=[CH:8][C:9]=1[C:10]1[N:11]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:14]=1.[OH-].[Na+].Cl>C(OCC)(=O)C.O1CCCC1>[F:3][C:4]1[CH:5]=[C:6]([C:27]2[C:28]([CH3:42])=[CH:29][C:30]([O:33][CH2:34][C:35]([CH3:40])([CH3:41])[C:36]([OH:38])=[O:37])=[N:31][CH:32]=2)[CH:7]=[CH:8][C:9]=1[C:10]1[N:11]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:24])([CH3:26])[CH3:25])[CH:12]=[C:13]([C:15]([F:18])([F:16])[F:17])[N:14]=1
Reactant: COC(=O)C(C)(C)COc1cc(C)c(-c2ccc(-c3nc(C(F)(F)F)cn3COCC[Si](C)(C)C)c(F)c2)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cc(OCC(C)(C)C(=O)O)ncc1-c1ccc(-c2nc(C(F)(F)F)cn2COCC[Si](C)(C)C)c(F)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 111.9 %

Procedure:
Methanol (3.0 mL) and tetrahydrofuran (3.0 mL) were added to methyl 3-[(5-{3-fluoro-4-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]-2,2-dimethylpropanoate (660 mg), and after adding 2N aqueous sodium hydroxide solution (4.0 mL) to the mixture, the resulting mixture was stirred at 50° C. for 2 hours. Ethyl acetate was added to the reaction mixture, and the mixture was neutralized by 2N hydrochloric acid. The organic layer was separated, washed with a saturated brine, and concentrated under reduced pressure to obtain 3-[(5-{3-fluoro-4-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]-2,2-dimethylpropanoic acid (721 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15](C1CCCCO1)[N:14]=[C:13]2[C:25]1[CH:30]=[C:29]([O:31]CC2C=CC(OC)=CC=2)[N:28]=[C:27]([N:41]([CH3:43])[CH3:42])[N:26]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[NH:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][N:14]=[C:13]2[C:25]1[N:26]=[C:27]([N:41]([CH3:42])[CH3:43])[NH:28][C:29](=[O:31])[CH:30]=1
Reactant: COc1ccc(COc2cc(-c3nn(C4CCCCO4)c4ccc(Nc5c(F)cccc5F)cc34)nc(N(C)C)n2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)c1nc(-c2n[nH]c3ccc(Nc4c(F)cccc4F)cc23)cc(=O)[nH]1
Temperature: 25 °C
Reaction time: 26 h
Yield: 50.1 %

Procedure:
N-(2,6-Difluorophenyl)-3-(2-(dimethylamino)-6-((4-methoxybenzyl)oxy)pyrimidin-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (260 mg, 0.443 mmol) in DCM (2.0 mL) was treated with TFA, 99% (2.0 mL, 26.9 mmol) at RT and stirred at 50° for 26 h. The mixture was cooled to RT and evaporated to dryness. The residue was diluted with DCM and extracted with sat'd NaHCO3 solution. The aqueous layer was extracted with DCM 3 times, and the combined organics were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude material was purified with silica gel chromatography (eluting with 0-8% MeOH in DCM with 2 M NH3) to give 6-(5-((2,6-difluorophenyl)amino)-1H-indazol-3-yl)-2-(dimethylamino) pyrimidin-4(3H)-one (85 mg, 0.222 mmol, 50.2% yield) as a yellow solid. MS (ESI, pos. ion) m/z: 383 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.90 (s, 6 H), 6.28 (br. s., 1 H), 7.05-7.25 (m, 4 H), 7.45 (d, J=8.80 Hz, 1H), 7.51 (br. s., 1 H), 7.74 (s, 1 H), 10.86 (br. s., 1 H), 13.21 (br. s., 1 H).
Reaction SMILES: [CH3:1][C:2]1([C:17]([O:19][CH3:20])=[O:18])[C@H:7]([NH:8][C@@H](C2C=CC=CC=2)C)[CH2:6][CH2:5][O:4][CH2:3]1.[ClH:21]>CO.[OH-].[OH-].[Pd+2]>[ClH:21].[NH2:8][CH:7]1[CH2:6][CH2:5][O:4][CH2:3][C:2]1([CH3:1])[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)C1(C)COCC[C@H]1N[C@H](C)c1ccccc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: COC(=O)C1(C)COCCC1N
Reaction time: 72 h

Procedure:
(4R)-Methyl 3-methyl-4-((R)-1-phenylethylamino)-tetrahydro-2H-pyran-3-carboxylate (1.37 g, 4.94 mmol) in methanol (70 mL) was treated with 10% palladium hydroxide on carbon (0.42 g, 3.5% mol) and aqueous 1N HCl (7 mL, 1.4 eq) and stirred under a hydrogen balloon for 72 h. The catalyst was removed by filtration. Removal of solvent provided crude methyl 4-amino-3-methyl-tetrahydro-2H-pyran-3-carboxylate hydrochloride that was used in the next step without further purification. MS: (M+H)+=174.1.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH:7]([OH:17])[CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH2:18]([O:20][C:21]([C:23]1([C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][C:35](B4OC(C)(C)C(C)(C)O4)=[CH:34][CH:33]=3)=[CH:28][CH:27]=2)[CH2:25][CH2:24]1)=[O:22])[CH3:19]>>[CH2:18]([O:20][C:21]([C:23]1([C:26]2[CH:27]=[CH:28][C:29]([C:32]3[CH:33]=[CH:34][C:35]([C:2]4[S:3][CH:4]=[CH:5][C:6]=4[CH:7]([OH:17])[CH2:8][CH2:9][CH2:10][C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[CH:36][CH:37]=3)=[CH:30][CH:31]=2)[CH2:25][CH2:24]1)=[O:22])[CH3:19]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(B4OC(C)(C)C(C)(C)O4)cc3)cc2)CC1
Reactant: OC(CCCc1ccccc1)c1ccsc1Br
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4sccc4C(O)CCCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 5, Step 2, using the following starting materials: 1-(2-bromo-thiophen-3-yl)-4-phenyl-butan-1-ol (Enantiomer A) and 1-[4′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[C:12]([OH:17])[CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH2:18][CH2:19][CH3:20].Br[CH2:28][C:29]([O:31][CH3:32])=[O:30].[H-].[Na+]>CN(C=O)C>[CH3:32][O:31][C:29](=[O:30])[CH2:28][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[CH:10]=[C:9]([CH2:18][CH2:19][CH3:20])[N:8]2[CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCCc1cc2c(O)cccc2n1Cc1ccccc1-c1ccccc1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1cc2c(OCC(=O)OC)cccc2n1Cc1ccccc1-c1ccccc1
Yield: 56 %

Procedure:
1-([1,1'-Biphenyl]-2-ylmethyl)-4-hydroxy-2-propyl-1H-indole (794 mg, 2.8 mmol) was alkylated by treating with 0.22 mL (2.3 mmol) of methyl bromoacetate and 93 mg (2.3 mmol) of 60% NaH/mineral oil in DMF as described in Example 1, Part E. The product was purified by chromatography over silica gel eluting with 20% EtOAc/hexane, to give 533 mg (56% yield) of [[1-([1,1'-biphenyl]-2-ylmethyl)-2-propyl-1H-indol-4-yl]oxy]acetic acid methyl ester.
Reaction SMILES: [OH:1][CH:2]([CH:4]1[C:10](=[O:11])[N:9]2[CH:5]1[CH2:6][C:7]([N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)=[C:8]2[C:12]([O:14]CC1C=CC=CC=1)=[O:13])[CH3:3].C(=O)(O)[O-].[Na+:32]>O1CCOCC1.O>[OH:1][CH:2]([CH:4]1[C:10](=[O:11])[N:9]2[CH:5]1[CH2:6][C:7]([N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)=[C:8]2[C:12]([O-:14])=[O:13])[CH3:3].[Na+:32]
Reactant: CC(O)C1C(=O)N2C(C(=O)OCc3ccccc3)=C(N3CCOCC3)CC12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(O)C1C(=O)N2C(C(=O)[O-])=C(N3CCOCC3)CC12
Reaction time: 0.5 h

Procedure:
A solution of benzyl 6-(1-hydroxyethyl)-3-morpholino-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate (30 mg) in dioxane (3 ml) is diluted with water (1 ml) containing sodium bicarbonate (7 mg). 10% palladium on powdered charcoal (30 mg) is also dried and the resulting mixture is hydrogenated at 40 psi for 30 mins. The catalyst is filtered off and washed with water (3×3 ml). The combined filtrate is extracted with ethyl acetate (3×2 ml), concentrated in vacuo to ca. 2 ml, and lyophilized to give sodium 6-(1-hydroxyethyl)-3-morpholino-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate.
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[O:16][N:15]=[C:14]4[C:17]5[C:22]([CH2:23][CH2:24][C:13]=34)=[CH:21][C:20]([CH:25]=[O:26])=[CH:19][CH:18]=5)[C:8]=2[C:27]([F:30])([F:29])[F:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([C:35]#[N:36])(C)C.Cl.C(OCC)(=O)C>C(#N)C.[I-].[Zn+2].[I-]>[OH:26][CH:25]([C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[C:14]1=[N:15][O:16][C:12]([C:9]3[C:8]([C:27]([F:28])([F:29])[F:30])=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[O:11][N:10]=3)=[C:13]1[CH2:24][CH2:23]2)[C:35]#[N:36]
Reactant: O=Cc1ccc2c(c1)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Reactant: C[Si](C)(C)C#N
Agent: Cl
Agent: [I-]
Agent: [Zn+2]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: N#CC(O)c1ccc2c(c1)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 100 %

Procedure:
To 3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazole-7-carbaldehyde (Preparation 88A, 1 g, 2.4 mmol) in acetonitrile (75 mL) was added trimethylsilyl cyanide (0.49 mL, 3.7 mmol) and zinc iodide (0.79 g, 2.4 mmol). The reaction mixture was stirred for 70 min. at room temperature. After being cooled in ice-water bath, the mixture was acidified by addition of aqueous hydrochloric acid (1N, 4.4 mL, 4.4 mmol). Ethyl acetate (100 mL) was added and the layers were separated. The organic phase was washed with saturated sodium thiosulfate solution (5 mL×2). The organic phase was then dried, filtered, and concentrated to provide the product (±)-2-hydroxy-2-(3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)acetonitrile (1.1 g, 2.4 mmol, 99% yield); LC/MS M+1=438.00; 1H NMR (400 MHz, CDCl3) δ ppm 8.09 (1H, d, J=7.92 Hz), 7.76 (2H, d, J=7.26 Hz), 7.50-7.68 (5H, m), 5.62 (1H, s), 3.11 (4H, s).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:28][CH2:27][N:26]([C:29](=[O:31])[CH3:30])[CH2:25][CH2:24]3)=[CH:19][N:18]=2)=[O:15])=[CH:9][C:8]=1[Cl:32])(=O)=O.[CH3:35][N:36](C=O)C>[C-]#N.[C-]#N.[Zn+2].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:29]([N:26]1[CH2:25][CH2:24][N:23]([C:20]2[CH:21]=[CH:22][C:17]([NH:16][C:14](=[O:15])[CH2:13][C:10]3[CH:11]=[CH:12][C:7]([C:35]#[N:36])=[C:8]([Cl:32])[CH:9]=3)=[N:18][CH:19]=2)[CH2:28][CH2:27]1)(=[O:31])[CH3:30]
Reactant: CN(C)C=O
Reactant: CC(=O)N1CCN(c2ccc(NC(=O)Cc3ccc(OS(=O)(=O)C(F)(F)F)c(Cl)c3)nc2)CC1
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]
Product: CC(=O)N1CCN(c2ccc(NC(=O)Cc3ccc(C#N)c(Cl)c3)nc2)CC1
Temperature: 80 °C
Reaction time: 96 h

Procedure:
A mixture of 4-(2-(5-(4-acetylpiperazin-1-yl)pyridin-2-ylamino)-2-oxoethyl)-2-chlorophenyl trifluoromethanesulfonate 237-2 (65 mg, 0.125 mmol), Zn(CN)2 (30 mg, 0.255 mmol), Pd(PPh3)4 (14 mg, 0.012 mmol) in DMF (0.6 ml) was stirred at 80° C. under argon for 96 hours. After cooled to room temperature, it was filtered through celite, washed with ethyl acetate, and concentrated by evaporation of solvents. The residue was subjected to reverse phase HPLC purification to give N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(3-chloro-4-cyanophenyl)acetamide as solid 237-3.
Reaction SMILES: [CH:1]1[N:5]2[C:6]3[C:11]([CH:12]=[CH:13][C:4]2=[N:3][C:2]=1[CH2:14][OH:15])=[CH:10][CH:9]=[CH:8][CH:7]=3>[O-2].[O-2].[Mn+4].C(Cl)(Cl)Cl>[CH:1]1[N:5]2[C:6]3[C:11]([CH:12]=[CH:13][C:4]2=[N:3][C:2]=1[CH:14]=[O:15])=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: OCc1cn2c(ccc3ccccc32)n1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: O=Cc1cn2c(ccc3ccccc32)n1
Yield: 81.8 %

Procedure:
A mixture of 4.2 g of imidazo-[1,2-a]-quinoline-2-methanol, 16.0 g of manganese dioxide and 11 ml of chloroform was refluxed for 4 hours and was then cooled overnight. The mixture was filtered through cellulose powder and the filter was washed with chloroform. The filtrate was evaporated to dryness under reduced pressure and the residue was triturated with diethyl ether to obtain 3.4 g of imidazo-[1,2-a]-quinoline-2-carboxaldehyde in the form of needles melting at 184°-185° C. after crystallization from an etherchloroform mixture.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[C:8]([C:9]([O:11]CC)=[O:10])=[C:7]([OH:14])[C:6]([CH3:15])=[C:5]([C:16]([F:19])([F:18])[F:17])[N:4]=1.[OH-].[K+].CO.Cl>O>[F:20][C:2]([F:1])([F:21])[C:3]1[C:8]([C:9]([OH:11])=[O:10])=[C:7]([OH:14])[C:6]([CH3:15])=[C:5]([C:16]([F:19])([F:18])[F:17])[N:4]=1
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)F)c(C)c1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1c(C(F)(F)F)nc(C(F)(F)F)c(C(=O)O)c1O
Temperature: 0 °C
Yield: 39.5 %

Procedure:
A mixture of 13 g (0.041 mol) of product of Example 35, 10 g of KOH, 100 ml of methanol, 100 ml of water was held at reflux for 20 hours, cooled, and poured into ice water (500 ml) containing 20 ml of concentrated HCl. The mixture was extracted with ether. The ether solution was dried and concentrated to give a solid which was recrystallized from hexane to give 4.68 g (39%) of product; mp 161°-162° C. A second crop, 4.74 g (40%), mp 155°-159° C., was obtained from mother liquor. Total yield was 79%.
Reaction SMILES: [NH:1]([CH2:3][C:4]([OH:6])=[O:5])[CH3:2].[CH3:7][CH:8]([CH3:26])[CH2:9][C:10]([O:12][CH2:13][CH2:14][O:15][C:16](ON1C(=O)CCC1=O)=[O:17])=[O:11]>>[CH3:2][N:1]([C:16]([O:15][CH2:14][CH2:13][O:12][C:10](=[O:11])[CH2:9][CH:8]([CH3:7])[CH3:26])=[O:17])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: CNCC(=O)O
Reactant: CC(C)CC(=O)OCCOC(=O)ON1C(=O)CCC1=O
Product: CC(C)CC(=O)OCCOC(=O)N(C)CC(=O)O
Yield: 27.6 %

Procedure:
Following the general procedure for the synthesis of acyloxyalkyl carbamates, sarcosine (0.104 g, 1.1 mmol) and (2,5-dioxoazolidinyloxycarbonyloxy)ethyl 3-methylbutanoate (0.28 g, 0.97 mmol) were reacted to provide 0.070 g (27.5% yield) of the title compound (45) as a colorless, waxy material after work-up and mass-guided preparative HPLC purification. 1H NMR (CD3OD, 400 MHz): δ=6.78 (q, 1H), 4.12 (m, 2H), 2.99 (2s, 3H), 2.23 (m, 2H), 2.12 (m, 1H), 1.52 (2d, 3H), 0.99 (t, 3H). MS (ESI) m/z 284.08 (M+Na)+, 260.13 (M−H)−.