Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[CH:14]=[O:15])[CH3:2].[Li+].[BH4-]>C1COCC1>[CH2:1]([O:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[CH2:14][OH:15])[CH3:2]
Reactant: CCOc1ccc(C(=O)OC)cc1C=O
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOc1ccc(C(=O)OC)cc1CO
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.4 %

Procedure:
A suspension of methyl 3-formyl-4-hydroxy-benzoate (3.0 g, 16.7 mmol), bromoethane (2.7 g, 1.85 mL, 24.9 mmol) and powdered K2CO3 (6.9 g, 49.9 mmol) in DMF (15 mL) was heated at 40° C. for 16 hours. After 16 hours, a further aliquot of bromoethane (1 mL) was added and the reaction mixture was heated for a further 2 hours. The reaction mixture was diluted with DCM (50 mL), filtered and concentrated in vacuo to give a yellow solid, which was diluted with ether (200 mL), washed sequentially with water (50 mL), sat. aq. NaHCO3 (50 mL) and brine solution (50 mL). The organics were separated, dried over MgSO4 and concentrated in vacuo to give methyl 4-ethoxy-3-formylbenzoate (3.52 g, 100%) as a white solid. ESI-MS m/z calc. 208.0. Found 209.3 (M+1)+; Retention time: 1.34 minutes (3 min run). Methyl 4-ethoxy-3-formylbenzoate (1.73 g, 8.91 mmol) was dissolved in THF (20 mL) and cooled to 0° C. LiBH4 (100 mg, 4.59 mmol) was added and the reaction mixture was stirred for 1 hour, then slowly quenched with dropwise addition of acetic acid. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate (50 mL), washed sequentially with sat. aq. NaHCO3 (20 mL) and brine (20 mL). The organics were separated, dried over MgSO4 and purified by silica gel column chromatography using 0-100% EtOAc/DCM as eluent to give methyl 4-ethoxy-3-(hydroxymethyl)benzoate (1.6 g, 46%) as a white solid. ESI-MS m/z calc. 210.0. Found 211.3 (M+1)+; Retention time: 1.11 minutes (3 min run); 1H NMR (400 MHz, CDCl3) δ 8.05-7.86 (m, 2H), 6.99-6.79 (m, 1H), 4.72 (s, 2H), 4.16 (q, J=7.0 Hz, 2H), 3.89 (s, 3H), 1.64 (d, J=7.0 Hz, 2H), 1.47 (t, J=7.0 Hz, 3H).
Reaction SMILES: [Si:1](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:19][C:20]1[S:24][C:23]([CH2:25][OH:26])=[CH:22][CH:21]=1.CN(C)C=O.N1C=CN=C1>CCOCC>[Si:1]([O:26][CH2:25][C:23]1[S:24][C:20]([Br:19])=[CH:21][CH:22]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccc(Br)s1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)[Si](OCc1ccc(Br)s1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Tert-butyldiphenylsilyl chloride (7.8 mL, 30.1 mmol) was added to a solution of 5-bromo(thiophen-2-yl)methyl alcohol (4.9 g, 25.1 mmol) and 9.7 mL of dimethylformamide. The solution was treated with imidazole (4.29 g, 62.8 mmol) and stirred overnight at room temperature. The solution was diluted with ether and washed with 2% aqueous HCl. The layers were separated and the aqueous layer was extracted with ether. The combined organic extracts were washed with brine, and dried (MgSO4), and filtered, and the solvents were removed in vacuo. The residue was purified by silica gel chromatography (hexane) to produce the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=2[O:17][CH3:18])=[CH:5][CH:4]=1.[C:19]([N:23]1[C:27](=[O:28])[CH2:26][CH:25]([C:29]2[CH:34]=[CH:33][C:32]([CH2:35][SH:36])=[CH:31][CH:30]=2)[S:24]1(=[O:38])=[O:37])([CH3:22])([CH3:21])[CH3:20]>>[C:19]([N:23]1[C:27](=[O:28])[CH2:26][CH:25]([C:29]2[CH:34]=[CH:33][C:32]([CH2:35][S:36][CH2:2][C:3]3[CH:8]=[CH:7][C:6]([C:9]4[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=4[O:17][CH3:18])=[CH:5][CH:4]=3)=[CH:31][CH:30]=2)[S:24]1(=[O:37])=[O:38])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)N1C(=O)CC(c2ccc(CS)cc2)S1(=O)=O
Reactant: COc1ccc(-c2ccc(CBr)cc2)c(OC)c1
Product: COc1ccc(-c2ccc(CSCc3ccc(C4CC(=O)N(C(C)(C)C)S4(=O)=O)cc3)cc2)c(OC)c1

Procedure:
This compound was prepared according to the procedure of Example 1.35, Step 4, using 4.18-B of Step 2 and 4.15-F of Example 4.15, Step 6 as the starting materials. LCMS found for C29H34NO5S2 (M+H)+: m/z=539.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.Br[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CCOC(C)=O>CN(C=O)C>[CH2:13]([O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: O=C1CCc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1CCc2cc(OCc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 17 h
Yield: 75 %

Procedure:
A mixture of 5-hydroxy-1-indanone 5.1 (available from Aldrich) (5 g, 34 mmol), 1-(bromomethyl)benzene (available from Aldrich) (4 mL, 37 mmol) and cesium carbonate (16 g, 51 mmol) in DMF (40 mL) was stirred at room temperature for 17 hours. EtOAc (400 mL) was added, and the mixture was washed with water and brine, and dried over anhydrous sodium sulfate. After removing solvent, the residue was purified by chromatography (silica gel, 1:4 EtOAc/hexane) to give 5.2 in 75% yield.
Reaction SMILES: C([O:4][C:5]1[N:6]=[C:7]([CH2:35][NH:36][C:37](=[O:39])[CH3:38])[C:8]2[C:13]([C:14]=1[CH2:15][C:16]1[C:17]([NH:28][CH2:29][CH3:30])=[N:18][C:19]3[C:24]([CH:25]=1)=[CH:23][C:22]([O:26][CH3:27])=[CH:21][CH:20]=3)=[CH:12][C:11]([O:31][CH3:32])=[C:10]([O:33][CH3:34])[CH:9]=2)(=O)C.N>C(Cl)Cl.CO>[CH2:29]([NH:28][C:17]1[C:16]([CH2:15][C:14]2[C:13]3[C:8](=[CH:9][C:10]([O:33][CH3:34])=[C:11]([O:31][CH3:32])[CH:12]=3)[C:7]([CH2:35][NH:36][C:37](=[O:39])[CH3:38])=[N:6][C:5]=2[OH:4])=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:26][CH3:27])[CH:23]=2)[N:18]=1)[CH3:30]
Reactant: CCNc1nc2ccc(OC)cc2cc1Cc1c(OC(C)=O)nc(CNC(C)=O)c2cc(OC)c(OC)cc12
Agent: N
Solvent: CO
Solvent: ClCCl
Product: CCNc1nc2ccc(OC)cc2cc1Cc1c(O)nc(CNC(C)=O)c2cc(OC)c(OC)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(acetamidomethyl)-4-((2-(ethylamino)-6-methoxyquinolin-3-yl)methyl)-6,7-dimethoxyisoquinolin-3-yl acetate 56 (20 mg, 38 μmol) in CH2Cl2 (9 mL) in a 25 mL round-bottomed flask equipped with a magnetic stirrer was added a 7 N NH3 solution in MeOH (1 mL) and the reaction mixture was stirred overnight at RT then diluted with CH2Cl2:MeOH=9:1 (50 mL) and the organic solution was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 90:10) gave N-((4-((2-(ethylamino)-6-methoxyquinolin-3-yl)methyl)-3-hydroxy-6,7-dimethoxyisoquinolin-1-yl)methyl)acetamide. The free base was dissolved in MeOH (3 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.4 M HCl solution in MeOH (1 mL). The reaction mixture was stirred for 5 min at RT and concentrated at 40° C. under vacuum to afford N-((4-((2-(ethylamino)-6-methoxyquinolin-3-yl)methyl)-3-hydroxy-6,7-dimethoxyisoquinolin-1-yl)methyl)acetamide dihydrochloride 57 as a pale yellow solid (17 mg, 79% yield).
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26]([OH:28])=O)[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O[N:30]=[C:31]([NH2:39])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH2:32]([C:31]1[N:39]=[C:26]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:23])([F:25])[F:24])=[CH:17][CH:16]=3)[CH2:14][N:9]([C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:8])[CH2:10]2)[O:28][N:30]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: NC(Cc1ccccc1)=NO
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Product: O=C(N1CCOCC1)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(Cc3ccccc3)no2)C1

Procedure:
80 mg (0.20 mmol) of 1-(morpholin-4-ylcarbonyl)-5-[4-(trifluoromethoxy)phenyl]piperidine-3-carboxylic acid (Example 44A) and 33 mg (0.22 mmol, 1.1 eq.) of N′-hydroxy-2-phenylethanimidamide were reacted according to the General Method 1. Yield: 46 mg (44% of theory)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[C:5]([OH:8])=[CH:6][CH:7]=1.[Na].[C:11]1([S:17]([OH:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[Br:1][C:2]1[CH:3]=[C:4]([OH:9])[C:5]([OH:8])=[CH:6][C:7]=1[S:17]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:19])=[O:18]
Reactant: O=S(O)c1ccccc1
Reactant: Oc1ccc(Br)cc1O
Agent: [Na]
Product: O=S(=O)(c1ccccc1)c1cc(O)c(O)cc1Br

Procedure:
48.0 g of 4-bromo-1,2-benzenediol [cf. W. Rosermund, Ber. 62, 1262 and so forth (1923)] are oxidatively condensed with 33.4 g of the sodium salt of benzenesulphinic acid in a manner analogous to that described in Example 5a). Crystallisation from 1,2-dichloroethane yields 4-bromo-5-(phenylsulphonyl)-1,2-benzenediol in the form of colourless crystals having a melting point of 166°-168°.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[C:11]([OH:17])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N12CCN(CC1)CC2.[C:26](#[N:29])[CH:27]=[CH2:28]>>[C:2]1([CH2:1][O:8][C:9]2[CH:16]=[CH:15][C:12]3[CH:13]=[C:27]([C:26]#[N:29])[CH2:28][O:17][C:11]=3[CH:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC#N
Reactant: O=Cc1ccc(OCc2ccccc2)cc1O
Agent: C1CN2CCN1CC2
Product: N#CC1=Cc2ccc(OCc3ccccc3)cc2OC1
Yield: 45.6 %

Procedure:
A mixture of 1.14 g of 4-benzyloxy-2-hydroxybenzaldehyde, 0.125 g of 1,4-diazabicyclo[2,2,2]octane and 0.65 g of acrylonitrile was stirred and heated at 80°-85° C., under argon, for 2 hours. After removal of the solvent, the residual product was dissolved in tetrahydrofuran-ether (1:1), washed with 1N-sodium hydroxide, water, dried, and the solvents evaporated in vacuo. The crude material (1.10 g) was purified by column chromatography on silica gel to afford 0.6 g (45.7%) of 7-(phenylmethoxy)-2H-1-benzopyran-3-carbonitrile, as a colorless solid mp 95°-98° C. (from ethyl acetate-hexane).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:8]2Cl.[OH:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[C:22]([CH3:27])[CH:21]=1>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:8]2[NH:24][C:23]1[CH:25]=[CH:26][C:20]([OH:19])=[CH:21][C:22]=1[CH3:27]
Reactant: Cc1cc(O)ccc1N
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1Cl
Solvent: CCO
Product: CCOC(=O)c1cnc2c(OC)cccc2c1Nc1ccc(O)cc1C

Procedure:
Ethyl 8-methoxy-4-chloroquinoline-3-carboxylate (2.6 g, 0.0098 mol) and 4-hydroxy-2-methylaniline (2.4 g, 0.0196 mol) in ethanol (150 ml) were heated under refulx for 30 minutes. The solvent was evaporated under reduced pressure. The residue was dissolved in chloroform and extracted with 2N hydrochloric acid (3×100 ml). On basification of the chloroform extracts, a solid precipitated out, this was collected by filtration and dried. Recrystallisation from dimethylformamide gave the title compound. Yield=2.52 g, m.p. 277°-279° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7](=O)[C:8]([OH:10])=O.[CH2:12]([C:19]1[C:20]([NH2:31])=[N:21][CH:22]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:24]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([C:19]1[NH:24][C:23]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:22][N:21]2[C:8](=[O:10])[C:7]([CH2:6][C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)=[N:31][C:20]=12)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Nc1ncc(-c2ccccc2)nc1Cc1ccccc1
Reactant: O=C(O)C(=O)Cc1ccco1
Product: O=c1c(Cc2ccco2)nc2c(Cc3ccccc3)[nH]c(-c3ccccc3)cn1-2

Procedure:
Synthesized from method C using 3-(furan-2-yl)-2-oxopropanoic acid and 3-benzyl-5-phenylpyrazin-2-amine as starting materials. 1H NMR (300 MHz, dmso) δ 8.88 (s, 1H), 8.02 (d, J=7.9, 2H), 7.61-7.38 (m, 6H), 7.37-7.14 (m, 3H), 6.38 (s, 1H), 6.26 (d, J=3.2, 1H), 4.64 (s, 3H), 4.40 (s, 3H); exact mass calculated for C24H20N3O2+ m/z+ 382.16, found m/z+ 382.
Reaction SMILES: [C:1]([C:3]1[CH:51]=[CH:50][C:6]2[N:7]([CH2:36][C:37]3[C:46]4[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=4)[N:40]=[CH:39][C:38]=3[CH:47]3[CH2:49][CH2:48]3)[C:8](=[O:35])[C@@H:9]([NH:21][C:22](=[O:34])[C@@H:23]([N:25](C)[C:26](=O)OC(C)(C)C)[CH3:24])[C@H:10]([CH3:20])[N:11]([C:12]([CH:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[O:13])[C:5]=2[CH:4]=1)#[N:2].[ClH:52]>O1CCOCC1.CCOCC>[ClH:52].[ClH:52].[C:1]([C:3]1[CH:51]=[CH:50][C:6]2[N:7]([CH2:36][C:37]3[C:46]4[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=4)[N:40]=[CH:39][C:38]=3[CH:47]3[CH2:49][CH2:48]3)[C:8](=[O:35])[C@@H:9]([NH:21][C:22](=[O:34])[C@@H:23]([NH:25][CH3:26])[CH3:24])[C@H:10]([CH3:20])[N:11]([C:12]([CH:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[O:13])[C:5]=2[CH:4]=1)#[N:2]
Reactant: C[C@@H](C(=O)N[C@@H]1C(=O)N(Cc2c(C3CC3)cnc3ccccc23)c2ccc(C#N)cc2N(C(=O)C2CCOCC2)[C@H]1C)N(C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CN[C@@H](C)C(=O)N[C@@H]1C(=O)N(Cc2c(C3CC3)cnc3ccccc23)c2ccc(C#N)cc2N(C(=O)C2CCOCC2)[C@H]1C
Yield: 81 %

Procedure:
A rt solution of tert-butyl(S)-1-((3S,4S)-7-cyano-1-((3-cyclopropylquinolin-4-yl)methyl)-4-methyl-2-oxo-5-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (53 mg, 76.3 μmol) in 4 M HCl in dioxane (381 μl) was stirred for 2 h. The reaction was diluted with Et2O and the solids were collected by vacuum filtration to provide (S)-N-((3S,4S)-7-cyano-1-((3-cyclopropylquinolin-4-yl)methyl)-4-methyl-2-oxo-5-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-2-(methylamino)propanamide dihydrochloride (41.4 mg, 81%) as a white solid. MS m/z 595 (MH)+.
Reaction SMILES: Cl.[O:2]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22].C(N(CC)CC)C>C(Cl)Cl>[O:2]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21](=[O:23])[CH3:22])[CH2:17][CH2:16]2)=[CH:11][CH:10]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(=O)OC(C)=O
Reactant: c1ccc(Oc2ccc(N3CCNCC3)cc2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCN(c2ccc(Oc3ccccc3)cc2)CC1
Reaction time: 1 h
Yield: 64 %

Procedure:
To a solution of the compound from Example 8, step 2 (100 mg 0.3 mmol) in CH2Cl2 was added acetic anhydride (0.1 mL) and triethylamine (0.4 mL) sequentially at rt. The reaction mixture was stirred at it for 1 h and poured onto water (100 mL). The precipitate was collected by filtration and washed with water to give the title compound (58 mg, 64%) as an off-white solid: MS (ESI) m/z 297 (M+H); 1H NMR (400 MHz, CDCl3) δ 2.15 (s, 3H), 3.12 (m, 4H), 3.63 (t, J=5.2 Hz, 2H), 3.78 (t, J=5.2 Hz, 2H), 6.91-6.99 (m, 6H), 7.05 (m, 1H), 7.28-7.32 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][C:7]1=O)=[O:5])[CH3:2].[CH3:12][N:13]([CH3:17])[CH2:14][CH2:15][NH2:16]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[CH2:10][CH2:9][CH2:8][C:7]=1[NH:16][CH2:15][CH2:14][N:13]([CH3:17])[CH3:12])=[O:5])[CH3:2]
Reactant: CN(C)CCN
Reactant: CCOC(=O)C1CCCC1=O
Solvent: CCO
Product: CCOC(=O)C1=C(NCCN(C)C)CCC1
Temperature: 80 °C
Yield: 92.5 %

Procedure:
A solution of 2-oxo-cyclopentanecarboxylic acid ethyl ester (5.00 g, 32.0 mmol) in ethanol (50 mL) was treated with N,N-dimethylethylenediamine (3.85 mL, 35.2 mmol). The solution was heated at reflux at 80° C. for 16 h. After cooling to 25° C. the solvent was removed in vacuo, and the residue was purified by flash column chromatography (Teledyne Isco RediSep Flash Column 40 g; 0-100% ethyl acetate in hexanes) to afford the desired product, 2-(2-dimethylamino-ethylamino)-cyclopent-1-enecarboxylic acid ethyl ester (6.7 g, 29.6 mmol, 92.5%), as a light yellow oil. The product was used immediately in the following step without characterization.
Reaction SMILES: [C:1]([C:3]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)([C:5]#[N:6])[CH3:4])#[N:2].C(C1(C2C=CC(OC)=C(C=2)[CH:25]=[O:26])CC1)#N>>[C:5]([C:3]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([CH:8]=1)[CH:25]=[O:26])([C:1]#[N:2])[CH3:4])#[N:6]
Reactant: COc1ccc(C2(C#N)CC2)cc1C=O
Reactant: COc1ccc(C(C)(C#N)C#N)cc1
Product: COc1ccc(C(C)(C#N)C#N)cc1C=O

Procedure:
This compound was prepared from Compound 36 in the same manner of Compound 2.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14]2[C:19]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][CH3:28])=[C:18]([O:29][CH2:30][CH2:31][NH2:32])[N:17]=[C:16]([C:33]3[N:38]=[CH:37][CH:36]=[CH:35][N:34]=3)[N:15]=2)(=[O:12])=[O:11])=[N:8][CH:9]=1)([CH3:3])[CH3:2].[CH3:39][C:40]1[CH:45]=[CH:44][C:43]([S:46](Cl)(=[O:48])=[O:47])=[CH:42][CH:41]=1>>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14]2[C:19]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][CH3:28])=[C:18]([O:29][CH2:30][CH2:31][NH:32][S:46]([C:43]3[CH:44]=[CH:45][C:40]([CH3:39])=[CH:41][CH:42]=3)(=[O:48])=[O:47])[N:17]=[C:16]([C:33]3[N:34]=[CH:35][CH:36]=[CH:37][N:38]=3)[N:15]=2)(=[O:11])=[O:12])=[N:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)C)cn2)nc(-c2ncccn2)nc1OCCN
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)C)cn2)nc(-c2ncccn2)nc1OCCNS(=O)(=O)c1ccc(C)cc1

Procedure:
According to the procedure described in Example 4a) 129 mg 5-isopropyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-pyridine sulfonamide was reacted with 4-methylbenzenesulfonylchloride to give 104 mg 5-isopropyl-N-[6-(2-(4-methylbenzenesulfonylamino)-ethoxy)-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-pyridine sulfonamide. LC-MS: tR=5.04 min, [M+1]+=692.65, [M−1]−=690.76.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:38])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]([O:30]CC3C=CC=CC=3)=[O:29])=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:14]=[N:15][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][CH:18]=2)[CH:11]=1>C(OCC)(=O)C.[C].[Pd]>[CH3:1][O:2][CH2:3][C@H:4]([CH3:38])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]([OH:30])=[O:29])=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:14]=[N:15][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][CH:18]=2)[CH:11]=1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc(-c2ccc(C(=O)OCc3ccccc3)[nH]2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc(-c2ccc(C(=O)O)[nH]2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 101.7 %

Procedure:
Benzyl 5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenyl)-1H-pyrrole-2-carboxylate (5.08 g, 9.47 mmol) synthesized in Example (78j) was dissolved in ethyl acetate (30 mL), and a 10% palladium carbon catalyst (1.10 g) was added, followed by stirring at room temperature for 3 hours under hydrogen atmosphere. After Celite filtration, the solvent was distilled off under reduced pressure to afford the desired compound (4.30 g, yield ˜100%) as a white solid.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:13]([O:15][C:16](=[O:37])[CH2:17][O:18][CH2:19]/[CH:20]=[CH:21]\[CH2:22][N:23]1[C:28](=[O:29])[CH2:27][CH2:26][CH2:25][C@@H:24]1[CH2:30][O:31]C(OCC)C)C>CO>[CH3:13][O:15][C:16](=[O:37])[CH2:17][O:18][CH2:19]/[CH:20]=[CH:21]\[CH2:22][N:23]1[C:28](=[O:29])[CH2:27][CH2:26][CH2:25][C@@H:24]1[CH2:30][OH:31]
Reactant: CCOC(=O)COC/C=C\CN1C(=O)CCC[C@@H]1COC(C)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: COC(=O)COC/C=C\CN1C(=O)CCC[C@@H]1CO
Reaction time: 17 h
Yield: 64.4 %

Procedure:
p-Toluenesulfonic acid hydrate (620 mg, 3.26 mmol) was added to a solution of {(Z)-4-[(R)-2-(1-ethoxyethoxymethyl)-6-oxo-piperidin-1-yl]-but-2-enyloxy}-acetic acid ethyl ester (1.10 g, 3.08 mmol) in MeOH (10 mL). After 17 h at rt, the reaction was quenched with saturated aqueous NaHCO3 (20 mL) and the mixture was extracted with CH2Cl2 (3×30 mL). The combined organic phase was dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (40% EtOAc/CH2Cl2→60% EtOAc/CH2Cl2, gradient, then 7% MeOH/CH2Cl2) afforded 538 mg (64%) of [(Z)-4((R)-2-hydroxymethyl-6-oxo-piperidin-1-yl)-but-2-enyloxy]-acetic acid methyl ester.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:12][C:11]2=[O:22])[S:5][C:6]=1[C:7](O)=[O:8].ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.[CH2:53]([NH2:60])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1>CN(C)C=O>[CH2:53]([NH:60][C:7]([C:6]1[S:5][C:4]([N:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][C:11]2=[O:22])=[N:3][C:2]=1[CH3:1])=[O:8])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1
Reactant: Cc1nc(-n2ccc(-c3ccccc3)cc2=O)sc1C(=O)O
Reactant: NCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(-n2ccc(-c3ccccc3)cc2=O)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 46.7 %

Procedure:
To a solution of 4-methyl-2-(2-oxo-4-phenylpyridin-1(2H)-yl)thiazole-5-carboxylic acid (0.20 g, 0.64 mmol) in anhydrous N,N-dimethylformamide (3 mL) was added 1-hydroxybenzotriazole (0.23 g, 1.67 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (0.15 g, 0.77 mmol), N,N-diisopropylethylamine (0.11 g, 0.83 mmol), and benzylamine (0.084 mL, 0.77 mmol). The reaction mixture was stirred at ambient temperature for 5 hours and N,N-dimethylformamide was removed in vacuo. The residue was dissolved in ethyl acetate (15 mL) and washed with saturated aqueous sodium bicarbonate (2×5 mL) and brine (5 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford the title compound as a white solid (0.12 g, 47%): mp 235-237° C. (ethyl acetate); 1H NMR (300 MHz, DMSO-d6) δ 8.83 (t, J=5.8 Hz, 1H), 8.77 (d, J=7.6 Hz, 1H), 7.87-7.77 (m, 2H), 7.52-7.49 (m, 3H), 7.34-7.18 (m, 5H), 7.08-7.00 (m, 2H), 4.40 (d, J=5.8 Hz, 2H), 2.59 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 161.9, 160.4, 153.7, 151.4, 150.6, 139.9, 135.9, 131.6, 130.9, 129.7, 128.8, 127.8, 127.5, 127.3, 124.5, 43.2, 17.6; MS (ES+) m/z 402.5 (M+1).
Reaction SMILES: C([O:3][C:4](=[O:19])[C@@H:5]([O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][CH2:15]Cl)=[CH:9][CH:8]=1)C.[OH:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[O:27][C:26]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[CH:25][C:24]2=[O:37]>>[CH3:18][O:17][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]#[C:14][CH2:15][O:20][C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][C:26]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:25][C:24]3=[O:37])=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:19]
Reactant: CCOC(=O)[C@H](Cc1ccc(C#CCCl)cc1)OC
Reactant: O=c1cc(-c2ccccc2)oc2ccc(O)cc12
Product: CO[C@@H](Cc1ccc(C#CCOc2ccc3oc(-c4ccccc4)cc(=O)c3c2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(3-Chloro-prop-1-ynyl)-phenyl]-2-methoxy-propionic acid ethyl ester from Example 5, Step A and 6-hydroxyflavone in a manner analogous to that described for Example 5, Step B. MS(ES) for C28H22O6[M+H]+: 455.2.