Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[C:31]([NH:35][CH3:36])([CH3:34])([CH3:33])[CH3:32]>>[C:31]([N:35]([CH3:36])[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:18]=[CH:19][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:21][CH:22]=3)=[CH:13][C:11]=2[CH:12]=1)([CH3:34])([CH3:33])[CH3:32]
Reactant: CNC(C)(C)C
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cc3)ccc2o1
Product: CN(CCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cc3)ccc2o1)C(C)(C)C

Procedure:
The product from Example 23D and tert-butyl(methyl)amine were processed as described in Example 1D to provide the titled compound. 1H NMR (300 MHz, CD3OD) δ 7.83 (m, 1H), 7.74 (d, J=8.1, 2H), 7.55 (m, 2H), 7.51 (d, J=8.1 Hz, 2H), 6.81 (s, 1H), 3.3-3.8 (m, 12H), 2.93 (s, 3H), 1.48 (s, 9H); MS (DCI) m/z 421 (M+H)+;
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:11]=[C:12]([CH2:16]O)[CH:13]=[CH:14][CH:15]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.N1C=CC=CC=1.S(=O)(=O)=O.[CH2:36]([O:38][C:39](=[O:60])[CH:40]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:37]>CS(C)=O.ClCCl.C(OCC)(=O)C.O>[CH2:36]([O:38][C:39](=[O:60])/[CH:40]=[CH:16]/[C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([S:9][C:6]2[CH:7]=[CH:8][C:3]([N:2]([CH3:18])[CH3:1])=[CH:4][CH:5]=2)[CH:11]=1)[CH3:37]
Reactant: CN(C)c1ccc(Sc2cccc(CO)c2)cc1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)/C=C/c1cccc(Sc2ccc(N(C)C)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.8 %

Procedure:
To a solution of (3-(4-dimethylamino-phenylsulfanyl)-phenyl)-methanol (255 mg, 0.98 mmol) and triethylamine (1.3 mL, 9.2 mmol) in dimethyl sulfoxide (5 mL) was added a solution of pyridine-sulphur trioxide (469 mg, 2.95 mmol) in dimethyl sulfoxide (5 mL). The mixture was stirred for 1 hour at room temperature and water (20 mL) and ethyl acetate (40 mL) were added. The organic layer was washed with water (3×10 mL) and brine (20 mL), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give a colourless oil. This oil was dissolved in dichloromethane (10 mL) and (triphenylphosphoranylidene)-acetic acid ethyl ester (700 mg, 2.0 mmol) was added. The mixture was stirred at reflux for 3 hours and concentrated under reduced pressure. The residue was purified by flash chromatography (20:80:1 ethyl acetate:40-60° C. petroleum ether:triethylamine) to give the title compound as a colourless oil (240 mg, 74%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[CH3:21][S:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30]O)=[CH:25][CH:24]=1>>[CH3:1][O:2][C:3](=[O:20])[CH:4]([O:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:30][CH2:29][C:26]2[CH:27]=[CH:28][C:23]([S:22][CH3:21])=[CH:24][CH:25]=2)=[CH:8][CH:7]=1
Reactant: CSc1ccc(CCO)cc1
Reactant: COC(=O)C(Cc1ccc(O)cc1)Oc1ccccc1
Product: COC(=O)C(Cc1ccc(OCCc2ccc(SC)cc2)cc1)Oc1ccccc1

Procedure:
3-(4-Hydroxyphenyl)-2-phenoxypropanoic acid methyl ester was reacted with 2-(4-methylsulfanylphenyl)ethanol using the same methods as in Example 38(c) to give 3-{4-[2-(4-methylsulfanylphenyl)ethoxy]phenyl}-2-phenoxy-propanoic acid methyl ester.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:36])[C:10]3([CH:15](C4C=CC=C(Cl)C=4)[CH2:14][C:13](=[O:23])[N:12](CC(F)=O)[CH:11]3C3C=C(F)C=CC=3C)[C:5]2=[CH:4][CH:3]=1.CN1CCC(N)CC1.CN1CCOCC1>CN(C)C1C=CN=CC=1.O1CCCC1>[NH:12]1[C:13](=[O:23])[CH2:14][CH2:15][C:10]2([C:5]3[C:6](=[CH:7][CH:2]=[CH:3][CH:4]=3)[NH:8][C:9]2=[O:36])[CH2:11]1
Reactant: Cc1ccc(F)cc1C1N(CC(=O)F)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Agent: CN(C)c1ccncc1
Agent: CN1CCC(N)CC1
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: O=C1CCC2(CN1)C(=O)Nc1ccccc12
Yield: 105.3 %

Procedure:
In a manner similar to the method described in example 34b, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-[(fluorocarbonyl)-methyl]-2′-(5-fluoro-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.1 g, 0.18 mmol) prepared in example 57a was reacted with 1-methyl-piperidin-4-ylamine (0.1 g, 0.88 mmol), N-methylmorpholine (0.1 g, 0.99 mmol) and 4-dimethylaminopyridine (1 mg, 0.008 mmol) in tetrahydrofuran to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-1′-[(1-methyl-piperidin-4-yl)aminocarbonyl)-methyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as an off-white solid (Yield 0.041 g, 36.7%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:11]Br>ClCCl>[Br:11][CH:8]([CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH:9]=[O:10]
Reactant: BrBr
Reactant: O=CCCc1ccccc1
Solvent: ClCCl
Product: O=CC(Br)Cc1ccccc1
Yield: 143.6 %

Procedure:
To a solution of 3-phenylpropionaldehyde (13.4 g, purity 90%, 0.09 mol) in dichloromethane at 0° C. was slowly added bromine (13.7 g, 0.085 mol). After 12 h at rt the solvent was evaporated to yield crude title compound (26.0 g (purity about 60%), 81%).
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].[CH3:11][C:12]([CH3:26])([CH2:23][CH2:24]C)[CH2:13][NH:14][C:15]1[N:16]([CH3:22])[N:17]=[C:18]([CH3:21])[C:19]=1[NH2:20].[K+].[Br-]>>[CH3:26][C:12]([CH3:11])([CH2:23][CH3:24])[CH2:13][NH:14][C:15]1[N:16]([CH3:22])[N:17]=[C:18]([CH3:21])[C:19]=1[NH:20][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: CCCC(C)(C)CNc1c(N)c(C)nn1C
Reactant: N#Cc1ccc(C=O)cc1
Agent: [Br-]
Agent: [K+]
Product: CCC(C)(C)CNc1c(NCc2ccc(C#N)cc2)c(C)nn1C
Yield: 19 %

Procedure:
The title compound was prepared according to the procedure of Example 1, Step 5 except that 4-cyanobenzaldehyde was used in place of 4-pyridinecarboxaldehyde and N(3)-(2,2-dimethyl-pentyl)-2,5-dimethyl-2H-pyrazole-3,4-diamine was used in place of N(3)-(2,2-dimethyl-propyl)-2,5-dimethyl-2H-pyrazole-3,4-diamine. Yellow oil, yield: 19%, 1H NMR (300 MHz, CDCl3): δ0.83 (t, 3H), 0.89 (s, 6H), 1.28 (q, 2H), 2.10 (s, 3H), 2.61 (s, 2H), 3.59 (s, 3H), 4.04 (s, 2H), 7.42 (d, 2H), 7.61 (d, 2H), IR (KBr, cm−1): 3340m, 2961s, 2877m, 2226s, 1588m, 1565m, 1537m, 1462m, 1378m, 1365m, 1296w, 821w, MS (ES) m/z (relative intensity): 326 (M+H+, 100). Anal. Calcd. for C19H27N5: C, 70.12; H. 8.36; N, 21.52. Found: C, 68.87; H, 8.49; N, 20.92.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.[CH3:25][N:26]([CH3:41])[CH2:27][CH2:28][NH:29][C:30]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)=[O:31]>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:35]4[CH:36]=[CH:37][C:32]([C:30]([NH:29][CH2:28][CH2:27][N:26]([CH3:25])[CH3:41])=[O:31])=[CH:33][CH:34]=4)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1
Reactant: CN(C)CCNC(=O)c1ccc(B(O)O)cc1
Reactant: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(Br)cc32)N=C1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN(C)CCNC(=O)c1ccc(-c2ccc3c(c2)C2(CC(c4ccccc4)O3)N=C(N)N(C)C2=O)cc1
Yield: 18.1 %

Procedure:
Pd(PPh3)2Cl2 (10 mg, 0.01 mmol) in a 10 mL of flask under Ar2 was treated sequentially with 2′-amino-6-bromo-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 4-(2-(dimethylamino)ethylcarbamoyl)phenylboronic acid (25 mg, 0.104 mmol). The mixture was heated under 120 at Ar2 under microwave for 30 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified preparative TLC and HPLC to give 4-(2′-amino-1′-methyl-5′-oxo-2-phenyl-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)-N-(2-(dimethylamino)ethyl)benzamide (4.68 mg, 18%). 1H-NMR (MeOD): 2.47 (m, 1H), 2.63 (m, 1H), 3.01 (s, 6H), 3.30 (s, 3H), 3.42 (m, 2H), 3.79 (m, 2H), 5.88 (m, 1H), 7.17 (m, 1H), 7.39 (m, 1H), 7.46 (m, 2H), 7.52 (m, 2H), 7.58 (m, 1H), 7.71 (m, 1H), 7.76 (m, 2H), 7.96 (m, 2H).
Reaction SMILES: Cl.[CH3:2][N:3]([C:12]([S:14][CH3:15])=[NH:13])[N:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.[CH3:23][S:24]([CH2:27][C:28](Cl)=[O:29])(=[O:26])=[O:25].O>ClCCl>[CH3:2][N:3]([C:12]([S:14][CH3:15])=[N:13][C:28](=[O:29])[CH2:27][S:24]([CH3:23])(=[O:26])=[O:25])[N:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CS(=O)(=O)CC(=O)Cl
Reactant: CSC(=N)N(C)N=Cc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CSC(=NC(=O)CS(C)(=O)=O)N(C)N=Cc1ccccc1
Reaction time: 18 h
Yield: 35.2 %

Procedure:
To a stirred solution of methyl 1-methyl-2-(phenylmethylene)hydrazinecarboximidothioate hydrochloride (5.71 g) and triethylamine (5.2 g) in dichloromethane (100 ml) was added methylsulphonylacetyl chloride (4.9 g) in dichloromethane (20 ml) dropwise during 0.5 h at 20°. The mixture was stirred at 20° during 18 h, water (100 ml) added and the phase separated. The dichloromethane layer was washed with water, dried, and evaporated. The residue was crystallised from ethanol to give the title compound (2.7 g) as off white needles. m.p. 149.5°-150.5°.
Reaction SMILES: Br[CH2:2][C:3]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:5]Br.[Na+].[I-]>CC(C)=O>[C:7]1([C:4]([C:3]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH2:2])=[CH2:5])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: BrCC(=C(CBr)c1ccccc1)c1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: C=C(C(=C)c1ccccc1)c1ccccc1

Procedure:
The process of this invention for synthesis of 2,3-diphenyl-1,3-butadiene is comprised of a four step procedure wherein the starting compound acetophenone is dimerized under an ultra violet reaction process to yield acetophenone pinacol which is subsequently converted to 2,3-diphenyl-2-butene in the step 2 procedure. The 2,3-diphenyl-2-butene is then reacted with N-bromosuccinimide (NBS) in an ultra violet reactor in a CCl4 reaction solvent to form 1,4-dibromo-2,3-diphenyl-2-butene in the step 3 procedure. The 1,4-dibromo-2,3-diphenyl-2-butene is reacted with NaI in a hot acetone solution to yield 2,3-diphenyl-1,3-butadiene in the step 4 procedure.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][C@H:27]4[CH2:32][CH2:31][NH:30][CH2:29][C@H:28]4[OH:33])=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1.C([O:37][CH2:38][C:39](Cl)=[O:40])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][C@H:27]4[CH2:32][CH2:31][N:30]([C:38](=[O:37])[CH2:39][OH:40])[CH2:29][C@@H:28]4[OH:33])=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1
Reactant: CC(=O)OCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CCNC[C@H]1O
Agent: Cl
Product: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CCN(C(=O)CO)C[C@@H]1O

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluorophenyl]-N-[(3R*,4S*)-3-hydroxypiperidin-4-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f11) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: C(=O)(O)[O-].[Na+].[C:6]([O:10][C:11](=[O:31])[NH:12][CH2:13][CH2:14][N:15]1[CH2:22][CH:21]2[O:23][CH:17]([CH2:18][N:19](CC3C=CC=CC=3)[CH2:20]2)[CH2:16]1)([CH3:9])([CH3:8])[CH3:7]>C(O)C.ClCCl.[Pd]>[C:6]([O:10][C:11](=[O:31])[NH:12][CH2:13][CH2:14][N:15]1[CH2:16][CH:17]2[O:23][CH:21]([CH2:20][NH:19][CH2:18]2)[CH2:22]1)([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)NCCN1CC2CN(Cc3ccccc3)CC(C1)O2
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCN1CC2CNCC(C1)O2
Reaction time: 18 h
Yield: 89.1 %

Procedure:
Sodium bicarbonate (0.058 g, 0.069 mmol) and 5% Pd/C (0.250 g, Johnson Matthey Type 440 paste) were added to a solution of [2-(7-benzyl-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)ethyl]carbamic acid tert-butyl ester (see Example I (Alternative I) above; 1 g, 2.77 mmol) in ethanol (10 mL). The mixture was then hydrogenated at 500 kPa (5 bar) for 18 hours. The reaction mixture was filtered through Celite® and then washed with ethanol (20 mL). The solution was concentrated under reduced pressure to give an oil. This was dissolved in dichloromethane (20 mL) and washed with sodium hydroxide (1 M, 10 mL). The organic phase was separated, dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure to give the title compound as a yellow solid (0.67 g, 87%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[Cl:13][C:14]1[C:32]([C:33]([F:36])([F:35])[F:34])=[CH:31][CH:30]=[CH:29][C:15]=1[CH2:16][NH:17]C(=O)C(C1C=CC=CC=1Cl)C>>[Cl:13][C:14]1[C:32]([C:33]([F:34])([F:35])[F:36])=[CH:31][CH:30]=[CH:29][C:15]=1[CH2:16][NH:17][C:9](=[O:11])[CH:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[CH3:12]
Reactant: CC(C(=O)O)c1ccc(Cl)cc1
Reactant: CC(C(=O)NCc1cccc(C(F)(F)F)c1Cl)c1ccccc1Cl
Product: CC(C(=O)NCc1cccc(C(F)(F)F)c1Cl)c1ccc(Cl)cc1
Yield: 32 %

Procedure:
The titled compound was prepared from 2-(4-Chlorophenyl)propionic acid in 32% yield in the same manner as the preparation of N-(2-Chloro-3-trifluoromethylbenzyl)-2-(2-chlorophenyl)propionamide in Example 184b. MS (ESI) 376 (MH+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:17])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=1>CCO.CCOC(C)=O.[Pd]>[NH2:14][C:11]1[CH:10]=[CH:9][C:8]([CH2:7][C:6]([NH:5][CH2:4][CH2:3][CH2:2][OH:1])=[O:17])=[CH:13][CH:12]=1
Reactant: O=C(Cc1ccc([N+](=O)[O-])cc1)NCCCO
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1ccc(CC(=O)NCCCO)cc1
Reaction time: 2 h
Yield: 95 %

Procedure:
A slurry of N-(3-hydroxy-propyl)-2-(4-nitro-phenyl)-acetamide (as prepared in the previous step, 183 mg, 0.768 mmol) and 5% Pd—C (130 mg) in EtOH-EtOAc (5 mL, 4:1 v/v) was stirred under 1 atm H2 for 2 h. The reaction was filtered and concentrated to afford 152 mg (95%) of the title compound. 1H-NMR (DMSO-d6; 400 MHz): δ 7.78 (br s, 1H), 6.88 (d, 2H, J=8.3 Hz), 6.47 (d, 2H, J=8.3 Hz), 4.88 (br s, 2H), 4.39 (t, 1H, J=5.2 Hz), 3.43-3.34 (m, 2H), 3.16 (s, 2H), 3.08-3.03 (m, 2H), 1.55-1.48 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([NH:11][NH2:12])[N:3]=1.[CH:13](=O)[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1>C(O)(=O)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([NH:11][N:12]=[CH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:3]=1
Reactant: COc1ccc(C=O)cc1
Reactant: NNc1nc(N)nc2[nH]cnc12
Solvent: CC(=O)O
Product: COc1ccc(C=NNc2nc(N)nc3[nH]cnc23)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 65.4 %

Procedure:
2-Amino-6-hydrazino-9H-purine (1.0 g, 6.1 mmol) and p-anisaldehyde (1.24 g, 9.1 mmol) were added to acetic acid (40 ml), and the mixture was stirred for 4 hours at room temperature. After completion of reaction, the solvent was evaporated under reduced pressure so as to precipitate solid crystals. The crystals were recrystallized from DMF to obtain 1.13 g (yield 66%) of colorless powdery crystals (m.p.=174° C. (decomposed)).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]([OH:13])=[C:8]([CH2:11][CH3:12])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:17]([O:16][C:14]([C:3]1[O:4][C:5]2[CH:10]=[CH:9][C:8]([CH2:11][CH3:12])=[C:7]([O:13][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:6]=2[C:2]=1[CH3:1])=[O:15])[CH3:18]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1oc2ccc(CC)c(O)c2c1C
Product: CCOC(=O)c1oc2ccc(CC)c(OCc3ccccc3)c2c1C
Yield: 99.8 %

Procedure:
According to the procedure of Example 86, Step 3, 0.250 g (1.01 mmol) of 3-methyl-4-hydroxy-5-ethylbenzofuran carboxylic acid ethyl ester (Example 86, Step 2) and 0.599 mL (5.04 mmol) of benzyl bromide gave 0.341 g of 5-ethyl-4-benzyloxy-3-methylbenzofuran-2-carboxylic acid ethyl ester after chromatography on silica gel eluting with ethyl acetate/hexanes (1:20).
Reaction SMILES: NC1C=CC=CC=1.Br[C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[OH:19])=[CH:16][CH:15]=[CH:14][CH:13]=2>>[OH:19][C:18]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][CH:9]=1
Reactant: Oc1c(Br)cnc2ccccc12
Solvent: Nc1ccccc1
Product: Oc1ccnc2ccccc12

Procedure:
4-Hydroxyquinoline 8(4) was prepared from aniline 8(1) according to the method described in J. Org. Chem. 2000, 23, 8005, 3-bromo-4-hydroxyquinoline 8(5)—according to the procedure given in J. Am. Chem. Soc. 1946, 1229-1231.
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:30]([C:33]([NH:35][C:36]2[CH:41]=[C:40]([CH3:42])[CH:39]=[CH:38][C:37]=2[F:43])=[O:34])=[CH:29][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[NH:15][CH:14]=[C:13]([C:16]([NH:18][CH2:19][CH2:20][NH:21]C(=O)OC(C)(C)C)=[O:17])[CH:12]=2)[CH:6]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:21][CH2:20][CH2:19][NH:18][C:16]([C:13]1[CH:12]=[C:11]([C:7]2[CH:6]=[C:5]([O:4][C:3]3[CH:29]=[C:30]([C:33]([NH:35][C:36]4[CH:41]=[C:40]([CH3:42])[CH:39]=[CH:38][C:37]=4[F:43])=[O:34])[CH:31]=[CH:32][C:2]=3[F:1])[CH:10]=[CH:9][N:8]=2)[NH:15][CH:14]=1)=[O:17]
Reactant: Cc1ccc(F)c(NC(=O)c2ccc(F)c(Oc3ccnc(-c4cc(C(=O)NCCNC(=O)OC(C)(C)C)c[nH]4)c3)c2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(F)c(NC(=O)c2ccc(F)c(Oc3ccnc(-c4cc(C(=O)NCCN)c[nH]4)c3)c2)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirred suspension of tert-butyl {2-[({5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrol-3-yl}carbonyl)amino]ethyl}carbamate (360 mg, 0.61 mmol) in 5 ml of methylene chloride was added 3 ml of trifluoroacetic acid. The mixture was stirred at room temperature for 20 minutes and evaporated to dryness under reduced pressure. The residue was re-dissolved in MeOH (5 ml) and poured into 100 ml of water with vigorous stirring. Saturated NaHCO3 solution was added until pH=8-9. The precipitates were filtered, washed with water and dried in vacuo to give N-(2-aminoethyl)-5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxamide as beige solid. Yield: 280 mg, 94%.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:20])[N:8]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH2:9][CH2:10][CH2:11][C:5]=2[NH:4][C:3]=1[CH:21]=O.[F:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][C:32]=1[NH:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=1)[NH:29][C:28](=[O:42])[CH2:27]2>>[F:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][C:32]=1[NH:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=1)[NH:29][C:28](=[O:42])/[C:27]/2=[CH:21]\[C:3]1[NH:4][C:5]2[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[C:7](=[O:20])[C:6]=2[C:2]=1[CH3:1]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCOCC1)CCC2
Reactant: O=C1Cc2cc(F)c(NCc3ccc(F)cc3)cc2N1
Product: Cc1c(/C=C2\C(=O)Nc3cc(NCc4ccc(F)cc4)c(F)cc32)[nH]c2c1C(=O)N(CCN1CCOCC1)CCC2
Yield: 69 %

Procedure:
The title compound was prepared under the same conditions as described in step 4 of Example 10 with 3-methyl-5-(2-morpholin-4-yl-ethyl)-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 10c obtained from step 3 of Example 10 and 5-fluoro-6-(4-fluoro-benzylamino)-1,3-dihydro-indol-2-one 3e obtained from step 4 of Example 3 as starting materials to obtain (Z)-2-[5-fluoro-6-(4-fluoro-benzylamino)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-3-methyl-5-(2-morpholin-4-yl-ethyl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 19 (57 mg, yield 69%) as a carmine solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([OH:19])=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:20](N(CC)CC)C.ClCOC=O>ClCCl.CN(C)C1C=CN=CC=1>[CH3:20][O:18][C:17](=[O:19])[C@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CCN(CC)CC
Agent: CN(C)c1ccncc1
Agent: O=COCCl
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C

Procedure:
To a solution of 8.8 g(0.0344 mol) of N-t-butoxycarbonylphenylalanine in 50 ml of dichloromethane were successively added 5.25 ml of triethylamine solution, and 3 ml of chloromethylformate at 0° C. 50 mg of 4-dimethylaminopyridine was added to catalyze the reaction. After the reaction was completed the reaction mixture was extracted with dichloromethane and distilled under a reduced pressure to give the title compound quantitatively.
Reaction SMILES: [CH2:1]([N:3]([CH2:25][CH3:26])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:14]2[CH:19]=[CH:18][C:17]([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:15]=2)=[CH:11][CH:12]=O)=[CH:6][CH:5]=1)[CH3:2].[CH3:27][C:28]([CH3:31])([O-])[CH3:29].[K+]>CN(C=O)C>[CH2:1]([N:3]([CH2:25][CH3:26])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:14]2[CH:19]=[CH:18][C:17]([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:15]=2)=[CH:11][CH:12]=[CH:27][C:28]2[CH:31]=[CH:31][C:28]([CH:27]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[CH:16][C:17]([N:20]([CH2:21][CH3:22])[CH2:23][CH3:24])=[CH:18][CH:19]=3)[C:7]3[CH:8]=[CH:9][C:4]([N:3]([CH2:25][CH3:26])[CH2:1][CH3:2])=[CH:5][CH:6]=3)=[CH:29][CH:29]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CC(C)(C)[O-]
Reactant: CCN(CC)c1ccc(C(=CC=O)c2ccc(N(CC)CC)cc2)cc1
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(CC)c1ccc(C(=CC=Cc2ccc(C=CC=C(c3ccc(N(CC)CC)cc3)c3ccc(N(CC)CC)cc3)cc2)c2ccc(N(CC)CC)cc2)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 63.3 %

Procedure:
In 100 ml of DMF were dissolved 2.5 g of 3,3-bis(p-diethylaminophenyl)acrolein and 1.5 g of p-xylene-α,α'-diylbis(diethyl phosphonate), and then 0.9 g of potassium tert-butoxide was added to the solution at room temperature. Thereafter, the reaction was carried out for 4 hours at room temperature with stirring and the reaction mixture was poured into 100 ml of ice-water with stirring. Then, precipitates thus deposited were collected by filtration, dissolved in benzene, and separated and purified by silica gel column chromatography (eluent:benzene). After distilling off benzene from the effluent, the residue was recrystallized from ethyl acetate to provide 1.74 g (yield 63.0%) of red crystals having a melting point of 201.5° C. to 204.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:33][O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[N:41]=[C:42]=[O:43]>ClCCl>[CH3:33][O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[NH:41][C:42]([N:14]1[CH2:15][CH2:16][CH2:17][CH:12]([C:6]2([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)[C:5]3[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=3)[NH:8][C:7]2=[O:11])[CH2:13]1)=[O:43]
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCNC1
Reactant: COc1ccccc1N=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1NC(=O)N1CCCC(C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of rac-6-chloro-3-(3-chloro-benzyl)-3-piperidin-3-yl-1,3-dihydro-indol-2-one (50 mg, 0.13 mmol) (from Example 25a supra) in dichloromethane (3 mL) was added triethylamine (20 mg, 0.19 mmol) (Aldrich), followed by the addition of 2-methoxyphenyl isocyanate (24 mg, 0.16 mmol) (Aldrich). The mixture was stirred at room temperature for 30 mins. The mixture was partitioned between dichlormethane and water. The aqueous layer was extracted with dichlormethane. The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated. The residue was purified by chromatography to give rac-3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carboxylic acid (2-methoxy-phenyl)-amide as a white solid. (Yield 45 mg, 64%).