Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:7]2[C:16]3[C:11](=[CH:12][C:13]([F:19])=[C:14](F)[C:15]=3[F:17])[C:10](=[O:20])[C:9]([C:21]([OH:23])=[O:22])=[CH:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:24]([NH:26][CH2:27][CH:28]1[CH2:32][CH2:31][NH:30][CH2:29]1)[CH3:25]>C(#N)C>[CH:1]1([N:7]2[C:16]3[C:11](=[CH:12][C:13]([F:19])=[C:14]([N:30]4[CH2:31][CH2:32][CH:28]([CH2:27][NH:26][CH2:24][CH3:25])[CH2:29]4)[C:15]=3[F:17])[C:10](=[O:20])[C:9]([C:21]([OH:23])=[O:22])=[CH:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1cn(C2CCCCC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: CCNCC1CCNC1
Solvent: CC#N
Product: CCNCC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CCCCC4)c3c2F)C1
Yield: 80.6 %

Procedure:
To 0.80 g (2.46 mmol) of 1-cyclohexyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in 15 ml of acetonitrile was added 0.37 g (2.46 mmol) of 1,8-diazobicyclo[5.4.0]undec7-ene and 0.33 g (2.58 mmol) of 3-[(ethylamino)methyl]pyrrolidine. The mixture was refluxed for one hour, cooled, filtered, and the solids washed with ether to give 0.86 g of 1-cyclohexyl-7-[3-[(ethylamino)methyl]-1-pyrrolidinyl]-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, mp 194°-196° C.
Reaction SMILES: C[O:2][C:3](=[O:25])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:15]([C:17]1[CH:22]=[C:21]([CH2:23][CH3:24])[CH:20]=[CH:19][N:18]=1)=[O:16].Cl>[OH-].[Na+].C(O)C>[Cl:14][C:10]1[CH:9]=[C:8]2[C:13]([C:5]([CH2:4][C:3]([OH:25])=[O:2])=[C:6]([C:15]([C:17]3[CH:22]=[C:21]([CH2:23][CH3:24])[CH:20]=[CH:19][N:18]=3)=[O:16])[NH:7]2)=[CH:12][CH:11]=1
Reactant: CCc1ccnc(C(=O)c2[nH]c3cc(Cl)ccc3c2CC(=O)OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCc1ccnc(C(=O)c2[nH]c3cc(Cl)ccc3c2CC(=O)O)c1
Temperature: 25 °C
Yield: 88.2 %

Procedure:
A yellow suspension of methyl[6-chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate (Example 57, 297 mg, 0.83 mmol) in 2N aqueous sodium hydroxide (2.5 ml) and ethanol (20 ml) was heated at reflux temperature for 3 h. After cooling to room temperature, the mixture was neutralized with 2N aqueous hydrochloric acid (2.5 ml) and concentrated. The residue was diluted with THF (150 ml), dried (MgSO4) and concentrated. The residual solids were recrystallization from ethyl acetate to give 251 mg (88%) of the title compound as yellow solids.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[O:17][CH2:16][CH2:15][CH:14]2[C:19]([OH:21])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:22]([C:25]1[CH:30]=[CH:29][C:28]([NH:31][CH2:32][C:33]2[CH:34]=[N:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=2)=[CH:27][CH:26]=1)([CH3:24])[CH3:23]>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[O:17][CH2:16][CH2:15][CH:14]2[C:19]([N:31]([C:28]1[CH:29]=[CH:30][C:25]([CH:22]([CH3:24])[CH3:23])=[CH:26][CH:27]=1)[CH2:32][C:33]1[CH:34]=[N:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=1)=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CNc2ccc(C(C)C)cc2)cn1
Reactant: O=C(O)C1CCOc2c(OCc3ccccc3)cccc21
Product: COc1ccc(CN(C(=O)C2CCOc3c(OCc4ccccc4)cccc32)c2ccc(C(C)C)cc2)cn1
Yield: 70.6 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 8-(benzyloxy)chroman-4-carboxylic acid (0.47 g) and (4-isopropylphenyl)[(6-methoxypyridin-3-yl)methyl]amine 0.43 g) as starting materials, 8-benzyloxy-N-(4-isopropylphenyl)-N-[(6-methoxypyridin-3-yl)methyl]chroman-4-carboxamide (0.61 g) was obtained.
Reaction SMILES: [C:1]([C:3]1[C:4](=[C:18]([C:21]#[N:22])[C:19]#[N:20])[O:5][C:6]([CH3:17])([CH3:16])[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]#[CH:15])=[CH:10][CH:9]=1)#[N:2].[N:23]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[N+:24]=[N-:25].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+].O>C(O)C.S([O-])([O-])(=O)=O.[Cu+2]>[C:1]([C:3]1[C:4](=[C:18]([C:19]#[N:20])[C:21]#[N:22])[O:5][C:6]([CH3:17])([CH3:16])[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:25]=[N:24][N:23]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:15]=2)=[CH:10][CH:9]=1)#[N:2]
Reactant: CCCCCCCCN=[N+]=[N-]
Reactant: C#Cc1ccc(C2=C(C#N)C(=C(C#N)C#N)OC2(C)C)cc1
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Solvent: O
Product: CCCCCCCCn1cc(-c2ccc(C3=C(C#N)C(=C(C#N)C#N)OC3(C)C)cc2)nn1
Temperature: 50 °C

Procedure:
A mixture of 2-[3-cyano-4-(4-ethynyl-phenyl)-5,5-dimethyl-5H-furan-2-ylidene]malononitrile (90 mg, 0.34 mmol) and 1-azidooctane (80 mg, 0.51 mmol) in 15 mL ethanol was stirred at 50° C. under nitrogen and a solution of sodium ascorbate (25 mg, 0.12 mmol in 1 mL water) was added, followed by copper sulfate (15 mg, 0.06 mmol in 1 mL water) solution. The resulting mixture was stirred at the same temperature for 24 h, cooled and the reaction mixture was poured into cold water (100 mL). The mixture was stirred overnight at room temperature, the precipitate formed was filtered off and air dried. The crude product was recrystallized from dichloromethane/1-propanol, Yield: 70 mg (46%) Mp (DSc): 203° C.; IR (neat) 2933, 2974, 2266, 1574, 1565 cm−1, 1H NMR (400 MHz, CDCl3) δ 8.02 (d, J=8.4 Hz 2H), 7.87 (s, 1H), 7.85 (d, J=8.4 Hz, 2H), 4.39 (t, J=7.2 Hz, 2H), 1.94-1.96 (m, 2H), 1.82 (s, 6H), 1.20-1.31 (m, 10H), 0.82 (t, 3H); 13C NMR (CDCl3) δ 176.69, 175.14, 145.30, 136.33, 129.01, 126.40, 125.91, 121.03, 111.20, 110.47, 110.38, 100.79, 99.08, 59.85, 50.44, 31.41, 30.01, 29.41, 28.76, 28.66, 26.20, 22.31, 13.78; Anal. Calcd for C26H28N6O: C, 70.89; H, 6.41, N, 19.08. Found: C, 70.59, H, 6.18; N, 19.37. UV-Vis (CH2Cl2): λmax=384 nm ε=3.01×104 L.mol−1cm−1.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[S:19][CH:18]=[CH:17][N:5]2[C:6](=[O:16])[C:7]=1[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1.[CH3:20][O:21][C:22]1[C:23]([O:30][CH2:31][CH2:32][O:33][CH3:34])=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH:25]=O.[O-]CC.[Na+]>>[CH3:20][O:21][C:22]1[C:23]([O:30][CH2:31][CH2:32][O:33][CH3:34])=[C:24](/[CH:25]=[CH:1]/[C:2]2[N:3]=[C:4]3[S:19][CH:18]=[CH:17][N:5]3[C:6](=[O:16])[C:7]=2[C:8]2[CH:9]=[CH:10][C:11]([C:12]#[N:13])=[CH:14][CH:15]=2)[CH:27]=[CH:28][CH:29]=1
Reactant: COCCOc1c(C=O)cccc1OC
Reactant: Cc1nc2sccn2c(=O)c1-c1ccc(C#N)cc1
Agent: CC[O-]
Agent: [Na+]
Product: COCCOc1c(/C=C/c2nc3sccn3c(=O)c2-c2ccc(C#N)cc2)cccc1OC
Yield: 40.3 %

Procedure:
The title compound was prepared by condensation of Intermediate 4 (350 mg, 1.312 mmol) with 3-methoxy-2-(2-methoxyethoxy)benzaldehyde (385 mg, 1.833 mmol) in presence of sodium ethoxide (178 mg, 2.624 mmol) according to the procedure outlined in Example 9 to afford 243 mg of the desired product as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 3.47-3.53 (m, 2H), 3.70 (s, 3H), 3.78 (s, 3H), 3.99-4.05 (m, 2H), 6.79 (d, J=15.6 Hz, 1H), 6.93-7.01 (m, 3H), 7.50-7.58 (m, 3H), 7.92 (d, J=8.1 Hz, 2H), 8.01 (d, J=4.8 Hz, 1H), 8.22 (d, J=15.9 Hz, 1H); ESI-MS (m/z) 460.50 (M+H)+.
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].C([O:8][C:9]([C:11]1[S:12][C:13]([N:16]2[CH2:21][CH2:20][N:19]([C:22](=[O:33])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]([F:32])([F:31])[F:30])[CH2:18][CH2:17]2)=[N:14][N:15]=1)=O)C>>[CH2:1]([NH:5][C:9]([C:11]1[S:12][C:13]([N:16]2[CH2:17][CH2:18][N:19]([C:22](=[O:33])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]([F:32])([F:31])[F:30])[CH2:20][CH2:21]2)=[N:14][N:15]=1)=[O:8])[CH2:2][CH2:3][CH3:4]
Reactant: CCOC(=O)c1nnc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)s1
Reactant: CCCCN
Product: CCCCNC(=O)c1nnc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)s1

Procedure:
Following the procedure as described in Example 3, making variations only as required to use n-butylamine in place of isoamylamine to react with 5-[4-(2-trifluoromethylbenzoyl)piperazin-1-yl][1,3,4]thiadiazole-2-carboxylic acid ethyl ester, the title compound was obtained as a white solid (0.042 g, yield 79%). 1H NMR (300 MHz, CDCl3) δ 7.72-7.69 (m, 1H), 7.63-7.49 (m, 2H), 7.33-7.3 (m, 1H), 7.03 (m, 1H), 4.08-3.8 (m, 1H), 3.9-3.8 (m, 1H), 3.68-3.62 (m, 2H), 3.54-3.47 (m, 2H), 3.42-3.35 (m, 2H), 3.33-3.28 (m, 2H), 1.6-1.5 (m, 2H), 1.42-1.3 (m, 2H), 0.9 (t, J=7.5 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 174.5, 167.5, 158.2, 155.9, 133.9, 132.4, 129.6, 127.1, 126.9, 126.8, 126.3, 125.4, 121.7, 49.5, 48.9, 45.9, 40.7, 39.4, 31.5, 19.9, 13.6. MS (ES+) m/z 442 (M+1).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:12][C:13]1[NH:14][C:15]([NH2:24])=[C:16]2[C:20]([N:21]=1)=[N:19][C:18]([O:22][CH3:23])=[N:17]2)[CH2:9][CH2:10][CH3:11].Br[CH2:26][CH2:27][CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][O:30]1>>[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:26][CH2:27][CH2:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][O:30]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCOc1nc2nc(OC)nc-2c(N)[nH]1
Reactant: BrCCCC1CCCCO1
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCCO3)c2n1

Procedure:
Prepared similarly to Intermediate 216 from 2-(butyloxy)-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 2-(3-bromopropyl)tetrahydro-2H-pyran.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:36])=[C:11]([C:15]#[C:16][C:17]4[CH:22]=[C:21]([CH2:23][C:24]5[C:25]([NH2:31])=[N:26][C:27]([NH2:30])=[N:28][CH:29]=5)[CH:20]=[C:19]([O:32][CH3:33])[C:18]=4[O:34][CH3:35])[C:12]=3[F:14])[C:7](=[O:37])[C:6]([C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:5]2)[CH2:3][CH2:2]1.[H][H]>CO.[Pd]>[NH2:30][C:27]1[N:26]=[C:25]([NH2:31])[C:24]([CH2:23][C:21]2[CH:20]=[C:19]([O:32][CH3:33])[C:18]([O:34][CH3:35])=[C:17](/[CH:16]=[CH:15]\[C:11]3[C:12]([F:14])=[C:13]4[C:8]([C:7](=[O:37])[C:6]([C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:5][N:4]4[CH:1]4[CH2:3][CH2:2]4)=[CH:9][C:10]=3[F:36])[CH:22]=2)=[CH:29][N:28]=1
Reactant: [H][H]
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(C#Cc3cc(Cc4cnc(N)nc4N)cc(OC)c3OC)c(F)cc2c1=O
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)c1cn(C2CC2)c2c(F)c(/C=C\c3cc(Cc4cnc(N)nc4N)cc(OC)c3OC)c(F)cc2c1=O
Yield: 53 %

Procedure:
A suspension of 250 mg of ethyl 1-cyclopropyl-7-[5-(2,4-diamino-pyrimidin-5-ylmethyl)-2,3-dimethoxy-phenylethynyl]-6,8-difluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylate (Example 12a)) and 50 mg of 5% palladium-on-charcoal in 50 ml of methanol is hydrogenated at normal hydrogen pressure. The reaction mixture is filtered after 6 hrs. The filtrate is concentrated and the crude product is triturated in succession with 20 ml and 10 ml of ethyl acetate and filtered off under suction. 133 mg (53%) of ethyl (Z)-7-[2-[5-(2,4-diamino-pyrimidin-5-ylmethyl)-2,3-dimethoxy-phenyl]-vinyl]-1-cyclopropyl-6,8-difluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylate are obtained as a colourless solid. M.p.>220°. Mass spectrum: peaks: inter alia at 577 (M+, 100%), 562 (35%), 530 (28%), 516 (68%), 474 (45%).
Reaction SMILES: [Br:1][C:2]1[C:3](=O)[O:4][C:5](=[O:7])[CH:6]=1.[CH3:9][NH2:10].C(OC(=O)C)(=O)C>O.C(O)(=O)C>[Br:1][C:2]1[C:3](=[O:4])[N:10]([CH3:9])[C:5](=[O:7])[CH:6]=1
Reactant: O=C1C=C(Br)C(=O)O1
Reactant: CN
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: CN1C(=O)C=C(Br)C1=O
Reaction time: 4 h

Procedure:
A 15 mmol solution of 3-bromo-2,5-furanedione and 15 mmol of methylamine at 40% in water, in 300 ml of glacial acetic acid is carried under reflux for 16 hours. After having allowed the reaction mixture to return to ambient temperature, 20 ml of acetic anhydride are added. The reaction medium is again brought to reflux under stirring for 4 hours before evaporating the solvents under reduced pressure. The expected product is obtained after purification by silica gel chromatography (heptane/ethyl acetate: 1/1) and recrystallization in ethanol.
Reaction SMILES: N[C:2]1[N:11]=[CH:10][C:9]2[CH2:8][CH2:7][C:6]3[C:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:13][N:14]([CH3:15])[C:5]=3[C:4]=2[N:3]=1.[I-:21].[Cs+].II.N(OCCC(C)C)=O>C(COC)OC.[Cu](I)I>[I:21][C:2]1[N:11]=[CH:10][C:9]2[CH2:8][CH2:7][C:6]3[C:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:13][N:14]([CH3:15])[C:5]=3[C:4]=2[N:3]=1
Reactant: [I-]
Reactant: CCOC(=O)c1nn(C)c2c1CCc1cnc(N)nc1-2
Agent: I[Cu]I
Agent: CC(C)CCON=O
Agent: II
Solvent: COCCOC
Product: CCOC(=O)c1nn(C)c2c1CCc1cnc(I)nc1-2
Yield: 44.9 %

Procedure:
To a well stirred suspension of ethyl 8-amino-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate (9.0 g, 33 mmol) in dimethoxyethane (0.7 L) under N2, cesium iodide (8.6 g, 33 mmol), bisublimated iodine (4.19 g, 16.5 mmol), copper iodide (2.0 g, 10 mmol) and isopentyl nitrite (6.62 mL, 49.5 mmol) were added in sequence. The reaction mixture was stirred vigorously at 65-70° C. for 3 hours. After cooling in an ice-water bath, the solid was filtered off. The filtrate was diluted with dichloromethane (2.0 L), washed with 30% ammonium hydroxide (150 mL), sodium thiosulphate (300 mL), brine, dried over anhydrous Na2SO4 and concentrated to give 5.69 g of the title compound (46% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][N:3]=1.CCN(CC)CC.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([S:23]([CH3:22])(=[O:25])=[O:24])[CH2:11][CH2:10]2)=[CH:4][N:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: Clc1ccc(OC2CCNCC2)cn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCC(Oc2ccc(Cl)nc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.3 %

Procedure:
A solution of 2-chloro-5-(piperidin-4-yloxy)-pyridine (4.55 g, 21.39 mmol) and Et3N (5.92 mL, 42.8 mmol) in DCM (50 mL) was treated with methanesulfonyl chloride (2.48 mL, 32.09 mmol) and stirred at room temperature for 2 hours. The mixture was diluted with DCM, washed with 1 N aqueous HCl, saturated aqueous NaHCO3, water and brine, dried over Na2SO4 and concentrated under vacuum. Purification by silica gel column chromatography (0-70% EtOAc in cyclohexane) gave 2-chloro-5-(1-methanesulfonyl-piperidin-4-yloxy)-pyridine (3.19 g, 51%). 1H NMR (300 MHz, CDCl3) δ 8.07 (d, J=2.9 Hz, 1H), 7.28-7.16 (m, 2H), 4.58-4.49 (m, 1H), 3.44-3.28 (m, 4H), 2.83 (s, 3H), 2.13-1.92 (m, 4H). LCMS (m/z, Method A) ES+ 290.9 [M+1]+.
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][C:10]#[N:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:13][CH2:14][CH2:15]Br.O.C1(C)C=CC=CC=1>CN(C=O)C>[C:3]1([C:9]2([C:10]#[N:11])[CH2:15][CH2:14][CH2:13]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: BrCCCBr
Reactant: N#CCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: Cc1ccccc1
Product: N#CC1(c2ccccc2)CCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 64.9 %

Procedure:
Sodium hydride (1.54 g, 64.1 mmol) dissolved in DMF (15 ml) and cooled to 0° C. Phenyl acetonitrile (3 g, 25.6 mmol) and 1,3-dibromopropane (5.2 g, 25.6 mmol) were dissolved in DMF (15 ml) and added to above mixture drop-wise at 0° C. This mixture was heated to rt and continued stirring for 2 h. Work up (H2O/Toluene) afforded the title compound (2.61 g) as crude, which was used in the next without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:23]=[CH:22][C:6]2[NH:7][C:8](=[O:21])[C@@H:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C@H:10]([CH3:12])[NH:11][C:5]=2[CH:4]=1)#[N:2].Cl[CH2:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][C:27]=1[O:36][CH3:37].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[C:1]([C:3]1[CH:23]=[CH:22][C:6]2[N:7]([CH2:25][C:26]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH:29]=[CH:28][C:27]=3[O:36][CH3:37])[C:8](=[O:21])[C@@H:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:19])[CH3:17])[C@H:10]([CH3:12])[NH:11][C:5]=2[CH:4]=1)#[N:2]
Reactant: C[C@@H]1Nc2cc(C#N)ccc2NC(=O)[C@H]1NC(=O)OC(C)(C)C
Reactant: COc1ccc2ccccc2c1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc2ccccc2c1CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H](C)Nc2cc(C#N)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.9 %

Procedure:
To a rt solution of tert-butyl(3S,4S)-7-cyano-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamate (406 mg, 1.28 mmol) in DMF (3.21 ml) was added 1-(chloromethyl)-2-methoxynaphthalene (318 mg, 1.54 mmol) and cesium carbonate (1.25 g, 3.85 mmol). The reaction was stirred at rt for 16 h, then diluted with EtOAc, washed with H2O and sat. aq. NaCl, dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash chromatography to provide tert-butyl(3S,4S)-7-cyano-1-((2-methoxynaphthalen-1-yl)methyl)-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamate (448 mg, 72%) as an off-white solid. MS m/z 509 (MNa)+.
Reaction SMILES: [F:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9]C2CCCCO2)[CH:5]=[CH:4][C:3]=1[C:16]1[CH:21]=[CH:20][N:19]([CH2:22][CH2:23][C@@:24]([CH3:39])([S:35]([CH3:38])(=[O:37])=[O:36])[C:25]([NH:27][O:28]C2CCCCO2)=[O:26])[C:18](=[O:40])[CH:17]=1.Cl.O>O1CCOCC1.CO>[F:1][C:2]1[C:7]([CH3:8])=[C:6]([OH:9])[CH:5]=[CH:4][C:3]=1[C:16]1[CH:21]=[CH:20][N:19]([CH2:22][CH2:23][C@@:24]([CH3:39])([S:35]([CH3:38])(=[O:36])=[O:37])[C:25]([NH:27][OH:28])=[O:26])[C:18](=[O:40])[CH:17]=1
Reactant: Cc1c(OC2CCCCO2)ccc(-c2ccn(CC[C@](C)(C(=O)NOC3CCCCO3)S(C)(=O)=O)c(=O)c2)c1F
Agent: Cl
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: Cc1c(O)ccc(-c2ccn(CC[C@](C)(C(=O)NO)S(C)(=O)=O)c(=O)c2)c1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 5.6 %

Procedure:
(2R)-4-{4-[2-fluoro-3-methyl-4-(tetrahydro-2H-pyran-2-yloxy)phenyl]-2-oxopyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (335 mg, 0.58 mmol) was dissolved in 3 mL of dioxane. To this solution was added 1 mL of 4M HCl in dioxane 1 mL of water. The resulting solution was stirred at RT for 10 minutes. The material was diluted up with methanol and concentrated (3×). Dichloromethane was added and the mixture was stirred for 18 h. The solution retained color and a fine particulate was suspended. The mixture was filtered leaving 13.3 mg (6%) of white solid. LCMS m/z 413.6 (M+1) 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.71 (s, 3H) 2.14 (d, J=1.56 Hz, 3H) 2.33-2.46 (m, 1H) 2.54-2.68 (m, 1H) 3.10 (s, 3H) 3.91-4.05 (m, 1H) 4.24-4.40 (m, 1H) 6.70 (d, J=8.59 Hz, 1H) 6.75-6.86 (m, 2H) 7.23 (t, J=8.68 Hz, 1H) 7.75 (d, J=6.83 Hz, 1H)
Reaction SMILES: CI.[Cl:3][C:4]1[N:9]=[C:8]([NH:10][C:11]2[C:12]3[CH:13]=[N:14][N:15]([CH2:20][C:21]4[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=4)[C:16]=3[CH:17]=[CH:18][CH:19]=2)[CH:7]=[CH:6][N:5]=1.[C:29](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:3][C:4]1[N:9]=[C:8]([N:10]([CH3:29])[C:11]2[C:12]3[CH:13]=[N:14][N:15]([CH2:20][C:21]4[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=4)[C:16]=3[CH:17]=[CH:18][CH:19]=2)[CH:7]=[CH:6][N:5]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(Cn2ncc3c(Nc4ccnc(Cl)n4)cccc32)cc1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc(Cn2ncc3c(N(C)c4ccnc(Cl)n4)cccc32)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 81.9 %

Procedure:
Methyl iodide (1.021 mL, 16.40 mmol) was added dropwise to a stirred suspension of N-(2-chloropyrimidin-4-yl)-1-(4-methoxybenzyl)-1H-indazol-4-amine (4 g, 10.93 mmol, Example 3 starting material) and potassium carbonate (2.267 g, 16.40 mmol) in DMF (40 mL) at 0° C. under nitrogen. The resulting suspension was stirred at 0° C. for 15 minutes and was allowed to warm to room temperature. The reaction mixture was stirred at room temperature overnight, filtered off and washed with ethyl acetate. The filtrate was concentrated to dryness, diluted with dichloromethane (40 ml), washed with water (40 ml), brine (40 ml), dried over magnesium sulfate and concentrated. The residue was purified by flash chromatography on silica gel eluting with 0 to 45% ethyl acetate in petroleum ether to afford N-(2-chloropyrimidin-4-yl)-1-(4-methoxybenzyl)-N-methyl-1H-indazol-4-amine (3.4 g, 82%) as a pale orange solid. NMR Spectrum: (DMSOd6) 3.50 (s, 3H), 3.71 (s, 3H), 5.63 (s, 2H), 6.19 (d, 1H), 6.89 (d, 2H), 7.16 (d, 1H), 7.29 (d, 2H), 7.49 (dd, 1H), 7.81 (d, 1H), 7.96 (d, 1H), 8.00 (s, 1H); Mass spectrum: MH+ 380.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[CH:10]=[C:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:8]=[CH:7][C:6]=1[OH:25])[CH3:4].S([O-])(=O)(=O)C.[CH3:31][C:32]1([CH3:39])[O:36][CH:35]([CH2:37]O)[CH2:34][O:33]1>CN(C)C=O>[CH2:3]([C:5]1[CH:10]=[C:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:8]=[CH:7][C:6]=1[O:25][CH2:37][CH:35]1[CH2:34][O:33][C:32]([CH3:39])([CH3:31])[O:36]1)[CH3:4]
Reactant: CC1(C)OCC(CO)O1
Reactant: CCCCCCCCCCCCCCc1ccc(O)c(CC)c1
Agent: CS(=O)(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCc1ccc(OCC2COC(C)(C)O2)c(CC)c1
Temperature: 80 °C

Procedure:
To a suspension of 2.53 g of prewashed 50% sodium hydride in 130 ml of dimethylformamide was added dropwise a solution of 11.99 g of 2-ethyl-4-tetradecylphenol in dimethylformamide. The resulting suspension was heated at 80° C. for 1/2 hour, then allowed to cool and 10.29 g the mesylate of solketal was added. The mixture was heated at reflux for 3 hours, then cooled quenched slowly with water and extracted several times with ether. The ether extracts were combined, washed with brine, dried and the solvents evaporated, giving 16.1 g of the desired compound, mp 34°-38° C.
Reaction SMILES: [NH:1]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C@H:2]([C:11]([OH:13])=O)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Cl.C(O[C:32](=[O:43])[C@H:33]([CH2:35][C:36]1[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][CH:37]=1)[NH2:34])CCCCC.N=C=N>>[NH:1]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C@H:2]([C:11]([NH:34][C@H:33]([C:32]([CH2:11][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[O:43])[CH2:35][C:36]1[CH:37]=[CH:38][C:39]([OH:42])=[CH:40][CH:41]=1)=[O:13])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1
Reactant: O=C(N[C@@H](Cc1ccc(O)cc1)C(=O)O)OCc1ccccc1
Reactant: CCCCCCOC(=O)[C@@H](N)Cc1ccc(O)cc1
Agent: Cl
Agent: N=C=N
Product: CCCCCCC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1

Procedure:
Z-Tyr-Tyr-Hex was prepared from Z-Tyr and Tyr-Hex.HCl by the carbodiimide coupling technique. Yield of crude product: 89%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][CH2:6]2.[OH:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]=O.Cl>C(O)C.[Cl-].[Na+].O>[OH:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]=[C:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9]1=[O:13]
Reactant: O=Cc1ccccc1O
Reactant: COc1ccc2c(c1)CCCC2=O
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc2c(c1)CCC(=Cc1ccccc1O)C2=O
Yield: 62.9 %

Procedure:
To a solution of 6-methoxy-1-tetralone (30 g) and 2-hydroxybenzaldehyde (25 g) in ethanol (200 ml) was added concentrated hydrochloric acid (10 ml), and the solution was refluxed for one day and one night. To the reaction solution was added brine, the solution was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to provide 2-(2-hydroxybenzylidene)-6-methoxy-3,4-dihydro-2H-naphthalen-1-one(30 g). To a solution of a portion thereof (15 g) in ethanol (200 ml) was added platinum(IV) oxide (0.1 g), and the solution was stirred overnight under a hydrogen atmosphere at ambient pressure. The reaction solution was filtered, and the solvent was evaporated in vacuo. To a solution of a portion of the resulting 2-(2-hydroxybenzyl)-6-methoxy-3,4-dihydro-2H-naphthalen-1-one crude product (1.0 g) in ethylene glycol (15 ml) was added potassium hydroxide (1.2 g) and hydrazine hydrate (2 ml), and the solution was refluxed overnight. To the reaction solution was added 5N hydrochloric acid, the solution was extracted with ethyl acetate, then washed with brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. Obtained by purifying the residue by silica gel column chromatography (hexane-ethyl acetate system), 2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-ylmethyl)phenol (810 mg) was used according to an analogous synthetic method to Preparation Example 80 to provide the title compound (1.1 g).