Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[F:55][C:56]1[CH:64]=[CH:63][C:59]([C:60](Cl)=[O:61])=[CH:58][CH:57]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:60](=[O:61])[C:59]2[CH:63]=[CH:64][C:56]([F:55])=[CH:57][CH:58]=2)[CH2:49][CH2:48]1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC1CCN(C(=O)c2ccc(F)cc2)CC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 26 %

Procedure:
The desired compound was prepared according to the procedure of Example A20 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 4-fluorobenzoyl chloride as starting materials in 26% yield. LCMS for C31H30ClFNγO2 (M+H)+: m/z=586.2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[CH2:4][CH2:5][N:6]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][NH:25][CH2:26][C:27]2[NH:28][CH:29]=[CH:30][N:31]=2)=[CH:20][CH:19]=1)[CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.[CH3:33][N:34]1[CH:38]=[CH:37][N:36]=[C:35]1[CH:39]=O.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH3:1][O:2][C:3](=[O:32])[CH2:4][CH2:5][N:6]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][N:25]([CH2:26][C:27]2[NH:28][CH:29]=[CH:30][N:31]=2)[CH2:39][C:35]2[N:34]([CH3:33])[CH:38]=[CH:37][N:36]=2)=[CH:20][CH:19]=1)[CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: Cn1ccnc1C=O
Reactant: COC(=O)CCN(CCCCN1CCCCC1)Cc1ccc(CNCc2ncc[nH]2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)CCN(CCCCN1CCCCC1)Cc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 68.1 %

Procedure:
The compound (403 mg) obtained in Example 62-2 was dissolved in anhydrous methanol (16 ml) and added with 1-methyl-2-imidazole carboxaldehyde (151 mg) and sodium cyanoborohydride (172 mg). After the solution was adjusted to pH 5 with acetic acid, the whole was stirred at room temperature for 18 hours. After completion of the reaction, the solvent was distilled off. The resultant was added with a 1 mol/l sodium hydroxide aqueous solution and the whole was subjected to extraction with chloroform. The resultant was dried with magnesium sulfate and the solvent was distilled off. The resultant was purified through silica gel column chromatography (chloroform/ethyl acetate), thereby obtaining the subject compound (333 mg) as a colorless oily substance.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1[C:10]([NH2:11])=[CH:9][S:8][CH:7]=1)=[O:5].C(N(CC)CC)C.[Cl:19][C:20]1[CH:32]=[CH:31][CH:30]=[CH:29][C:21]=1[O:22][CH2:23][CH2:24][CH2:25][C:26](Cl)=[O:27]>ClCCl>[CH3:2][O:3][C:4]([C:6]1[C:10]([NH:11][C:26](=[O:27])[CH2:25][CH2:24][CH2:23][O:22][C:21]2[CH:29]=[CH:30][CH:31]=[CH:32][C:20]=2[Cl:19])=[CH:9][S:8][CH:7]=1)=[O:5]
Reactant: COC(=O)c1cscc1N
Reactant: O=C(Cl)CCCOc1ccccc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cscc1NC(=O)CCCOc1ccccc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.9 %

Procedure:
To 4-amino-thiophene-3-carboxylic acid methyl ester hydrochloride (199 mg, 0.994 mmol) in dichloromethane (1.9 mL) and triethylamine (0.29 mL, 2.08 mmol), was slowly added a crude solution of 4-(2-chloro-phenoxy)-butyryl chloride (271 mg, approximately 1.16 mmol) in dichloromethane (1.9 mL). The reaction mixture was stirred for 3 hours at room temperature. The reaction mixture was then further diluted with dichloromethane (50 mL) and washed with water. The aqueous phase was then extracted with dichloromethane and the combined organic phases were dried with sodium sulfate, and concentrated in vacuo. The residue was then purified by column chromatography (SiO2, Heptane/EtOAc: 0-80%) to yield the title compound as a white solid (281 mg, 80%).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][OH:13])[CH2:7][CH2:6]2)OCC1.C1COCC1.Cl.C([O-])(O)=O.[Na+]>CC(C)=O>[OH:13][CH2:12][CH2:11][CH:8]1[CH2:9][CH2:10][C:5](=[O:1])[CH2:6][CH2:7]1
Reactant: OCCC1CCC2(CC1)OCCO2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: O=C1CCC(CCO)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-(1,4-Dioxaspiro[4.5]dec-8-yl)ethanol (2.70 g, 0.0145 mol) was dissolved in acetone (10.00 mL) and THF (10.00 mL) and 6.00 M HCl (6.00 mL) was added. The reaction was stirred at 25° C. for 16 hours, neutralized with NaHCO3 solution and was then extracted with ethyl acetate. The organic extracts were washed with water, and with saturated NaCl, then dried (MgSO4) and concentrated in vacuo. The crude product was used in the next reaction without further purification. 1H NMR(CDCl3): 3.75 (m, 2H), 2.36 (m, 4H), 1.20-2.13 (m, 7H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([C:12]2[C:16]([Cl:17])=[C:15]([O:18][CH:19]([F:21])[F:20])[N:14]([CH3:22])[N:13]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:26])=O>C1(C)C=CC=CC=1.CN(C)C=O>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([C:12]2[C:16]([Cl:17])=[C:15]([O:18][CH:19]([F:21])[F:20])[N:14]([CH3:22])[N:13]=2)=[CH:7][C:3]=1[C:4]([Cl:26])=[O:5]
Reactant: Cn1nc(-c2cc(C(=O)O)c(Cl)cc2F)c(Cl)c1OC(F)F
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Cn1nc(-c2cc(C(=O)Cl)c(Cl)cc2F)c(Cl)c1OC(F)F
Reaction time: 0.5 h

Procedure:
A solution of 8 g (22 mmol) of 2-chloro-5-(4-chloro-5-difluoromethoxy-1-methyl-1H-pyrazol-3-yl)-4-fluorobenzoic acid in 100 ml of toluene was treated with 1 drop of dimethylformamide and 8.6 g (67 mmol) of oxalyl chloride. After the mixture had been stirred for 30 minutes at reflux temperature, it was cooled and concentrated. Yield: quantitative.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]([CH2:18][OH:19])([CH2:8][O:9][CH2:10][C:11]([CH2:16][OH:17])([CH2:14][OH:15])[CH2:12][OH:13])[CH2:6][OH:7].[CH3:20][C:21]([CH2:37][CH2:38][CH2:39][CH:40]([CH3:52])[CH2:41][CH2:42][CH2:43][CH:44]([CH3:51])[CH2:45][CH2:46][CH2:47][CH:48]([CH3:50])[CH3:49])=[CH:22][CH2:23][CH2:24][CH2:25]OS(C1C=CC(C)=CC=1)(=O)=O.O>CN(C)C=O>[CH3:20][C:21]([CH2:37][CH2:38][CH2:39][CH:40]([CH3:52])[CH2:41][CH2:42][CH2:43][CH:44]([CH3:51])[CH2:45][CH2:46][CH2:47][CH:48]([CH3:50])[CH3:49])=[CH:22][CH2:23][CH2:24][CH2:25][O:13][CH2:12][C:11]([CH2:16][OH:17])([CH2:10][O:9][CH2:8][C:5]([CH2:18][OH:19])([CH2:6][OH:7])[CH2:4][OH:3])[CH2:14][OH:15]
Reactant: OCC(CO)(CO)COCC(CO)(CO)CO
Reactant: CC(=CCCCOS(=O)(=O)c1ccc(C)cc1)CCCC(C)CCCC(C)CCCC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=CCCCOCC(CO)(CO)COCC(CO)(CO)CO)CCCC(C)CCCC(C)CCCC(C)C
Temperature: 50 °C
Reaction time: 1 h
Yield: 19 %

Procedure:
0.37 g (60%, 9.2 mmol) of sodium hydride was added to a solution of 2.35 g (9.24 mmol) of dipentaerythritol in dry N,N-dimethylformamide (6 mL) with cooling on ice. After the mixture was stirred for 1 hour at 50° C., the above (5,9,13,17-tetramethyloctadec-4-enyl)tosylate was added dropwise thereto, with additional stirring for 20 hours at 60° C. After addition of water at 0° C., the reaction mixture was extracted with ethyl acetate. The extract was washed with water, 1M hydrochloric acid, saturated sodium bicarbonate aqueous solution, and saturated brine, successively, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (methanol/methylene chloride mixture) to obtain 494 mg of the title compound (19% yield in 2 steps) as a white solid. The results of NMR analysis of the thus obtained compound are as shown below.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:12]([O:14][CH3:15])=[O:13])[C:5](S(C)(=O)=O)=[N:4][C:3]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[F:33].[CH2:34]([NH2:37])[CH:35]=[CH2:36].C(OCC)(=O)C>CN(C1C=CN=CC=1)C.O1CCOCC1>[CH2:34]([NH:37][C:5]1[N:6]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:12]([O:14][CH3:15])=[O:13])[C:7](=[O:8])[C:2]([Cl:1])=[C:3]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=2[F:33])[N:4]=1)[CH:35]=[CH2:36]
Reactant: C=CCN
Reactant: COC(=O)c1ccc(C)c(-n2c(S(C)(=O)=O)nc(OCc3ccc(F)cc3F)c(Cl)c2=O)c1
Agent: CN(C)c1ccncc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C=CCNc1nc(OCc2ccc(F)cc2F)c(Cl)c(=O)n1-c1cc(C(=O)OC)ccc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.6 %

Procedure:
A mixture of methyl 3-[5-chloro-4-[(2,4-difluorobenzyl)oxy]-2-(methylsulfonyl)-6-oxopyrimidin-1(6H)-yl]-4-methylbenzoate (from Step 1) (3.02 g, 6.05 mmol), allyl amine (0.55 mL, 7.26 mmol), and DMAP (0.07 g, 0.61 mmol) in dioxane (8 mL) was stirred at ambient temperature overnight. Observed product and impurity (1:1 ratio). Added ethyl acetate (4 mL), cooled (0° C.) the reaction mixture, filtered the precipitate, and dried in vacuo to give the product as a white solid (1.17 g, 41%). 1H NMR (CD3OD/400 MHz) δ8.08 (m, 1H) , 7.82 (s, 1H), 7.57 (m, 2H), 7.00 (t, 2H, J=8.8 Hz), 5.80 (m, 1H), 5.51 (m, 2H), 5.07 (m, 2H), 4.56 (s, 1H), 3.93 (m, 1H), 3.89 (s, 3H), 3.65 (s, 3H). ESHRMS m/z 476.1184 (M+H calculated for C23H21ClF2N3O4 requires 476.1183).
Reaction SMILES: CO[C:3]([C:5]1[S:6][C:7]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[CH:8][C:9]=1[N:10]=[CH:11][N:12]([CH3:14])C)=[O:4].[CH3:22][N:23]1[CH2:28][CH2:27][CH2:26][C:25]([CH2:30][O:31][C:32]2[CH:33]=[C:34](CN)[CH:35]=[CH:36][CH:37]=2)([CH3:29])[CH2:24]1>CO>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([C:7]2[S:6][C:5]3[C:3](=[O:4])[N:12]([CH2:14][C:36]4[CH:35]=[CH:34][CH:33]=[C:32]([O:31][CH2:30][C:25]5([CH3:29])[CH2:26][CH2:27][CH2:28][N:23]([CH3:22])[CH2:24]5)[CH:37]=4)[CH:11]=[N:10][C:9]=3[CH:8]=2)=[CH:20][CH:19]=1
Reactant: CN1CCCC(C)(COc2cccc(CN)c2)C1
Reactant: COC(=O)c1sc(-c2ccc(Cl)cc2)cc1N=CN(C)C
Solvent: CO
Product: CN1CCCC(C)(COc2cccc(Cn3cnc4cc(-c5ccc(Cl)cc5)sc4c3=O)c2)C1
Temperature: 25 °C

Procedure:
5-(4-Chloro-phenyl)-3-(dimethylamino-methyleneamino)-thiophene-2-carboxylic acid methyl ester (0.16 g, 0.5 mmol), 1-{3-[(1,3-dimethylpiperidin-3-yl)methoxy]phenyl}methanamine (0.10 g, 0.4 mmol) in MeOH (2 mL) were heated by microwave at 120° C. for 20 minutes. The reaction mixture was allowed to cool to room temperature and the precipitate was filtered off and washed with MeOH to give the title compound as a solid. Yield: 0.12 g (49%). 1H NMR (400 MHz, CDCl3) δ 8.09 (s, 1H), 7.61 (d, 2H, J=8.91 Hz), 7.45 (s, 1H), 7.43 (d, 2H, J=8.91 Hz), 7.21-7.25 (m, 1H), 6.84-6.92 (m, 3H), 5.17 (s, 2H), 3.72-3.83 (m, 2H), 2.34 (m, 2H), 2.18 (s, 3H), 2.06 (m, 1H), 1.49-1.64 (m, 4H), 1.18 (m, 1H), 1.04 (s, 3H). MS (ESI+) 494.06 (M+1H+).
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH3:6][N+:7]1[C:12](Cl)=[CH:11][C:10]([NH2:14])=[CH:9][N:8]=1.C(#N)C.[CH2:18]([SH:20])[CH3:19]>C(N(CC)CC)C>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH3:6][N+:7]1[C:12]([S:20][CH2:18][CH3:19])=[CH:11][C:10]([NH2:14])=[CH:9][N:8]=1
Reactant: CCS
Reactant: C[n+]1ncc(N)cc1Cl
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCSc1cc(N)cn[n+]1C

Procedure:
24.4 parts of 1-methyl-4-amino-6-chloropyridazinium perchlorate in 250 parts of acetonitrile is stirred with 10 parts of ethylmercaptan and 10 parts of triethylamine for four hours at 50° to 60°C. After the solvent has been distilled off the residue is washed with 100 parts of water. 18.3 parts (67.9% of theory) of 1-methyl-4-amino-6-ethylmercaptopyridazinium perchlorate is obtained; C7H12O4N3SCl, melting point 136° to 137°C after having been recrystallized from alcohol.
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.CCN(C(C)C)C(C)C>C(#N)C>[F:13][C:9]1[CH:8]=[C:7]([CH:2]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:3]([O:5][CH3:6])=[O:4])[CH:12]=[CH:11][CH:10]=1
Reactant: COC(=O)C(Br)c1cccc(F)c1
Reactant: C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)C(c1cccc(F)c1)N1CCCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.3 %

Procedure:
Methyl 2-bromo-2-(3-fluorophenyl)acetate (310 mg, 1.25 mmol), piperidine (0.15 ml, 1.51 mmol), and DIPEA (0.26 ml, 1.51 mmol) were dissolved in acetonitrile (15 ml) and stirred at room temperature for 16 hours. The solvent was evaporated and the crude was purified by flash chromatography (petroleum ether/EtOAc=9/1) to afford methyl 2-(3-fluorophenyl)-2-(piperidin-1-yl)acetate (224 mg, 71% yield) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([S:8](Cl)(=[O:10])=[O:9])=[C:5]([CH3:7])[N:6]=1.Cl.[NH:13]1[CH2:16][CH2:15][CH2:14]1.C(N(CC)CC)C>C(Cl)Cl>[N:13]1([S:8]([C:4]2[S:3][C:2]([Cl:1])=[N:6][C:5]=2[CH3:7])(=[O:10])=[O:9])[CH2:16][CH2:15][CH2:14]1
Reactant: C1CNC1
Reactant: Cc1nc(Cl)sc1S(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc(Cl)sc1S(=O)(=O)N1CCC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-chloro-4-methylthiazole-5-sulphonylchloride (462 mg; 2.0 mmol) in DCM (5 mL) was added to an ice-cold solution of azetidine hydrochloride (196 mg; 2.1 mmol) and triethylamine (1.0 mL; 7.2 mmol) in DCM (15 mL) and the mixture stirred at 0° C. for 30 minutes. The DCM was removed in vacuo to give a residue which was partitioned between water (50 mL) and ethyl acetate (75 mL). The organic layer was washed with brine, dried (MgSO4) and evaporated to a residue which was chromatographed on silica, eluting with 10% ethyl acetate in isohexane, to give the desired material as a solid which was crystallised from ethyl acetate and isohexane (100 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([C:16]([NH:18][C:19]3[CH:51]=[CH:50][C:22]([C:23]([N:25]([CH3:49])[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[O:32][CH2:33][C:34]4[CH:39]=[CH:38][C:37]([C:40]([N:42]5[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]5)=[O:41])=[CH:36][N:35]=4)=[O:24])=[CH:21][CH:20]=3)=[O:17])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:5]=1)([O-])=O>C(O)C.C(O)(=O)C.[Fe]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([C:16]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([C:23]([N:25]([CH3:49])[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[O:32][CH2:33][C:34]4[CH:39]=[CH:38][C:37]([C:40]([N:42]5[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]5)=[O:41])=[CH:36][N:35]=4)=[O:24])=[CH:50][CH:51]=3)=[O:17])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:5]=1
Reactant: CN1CCN(C(=O)c2ccc(COc3ccccc3N(C)C(=O)c3ccc(NC(=O)c4ccccc4-c4ccc([N+](=O)[O-])cc4)cc3)nc2)CC1
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: CN1CCN(C(=O)c2ccc(COc3ccccc3N(C)C(=O)c3ccc(NC(=O)c4ccccc4-c4ccc(N)cc4)cc3)nc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.7 %

Procedure:
A mixture of 4-(4′-nitrobiphenyl-2-carboxamido)-N-methyl-N-[2-[5-(4-methylpiperazin-1-ylcarbonyl)pyrid-2-ylmethoxy]phenyl]benzamide (300 mg) and iron powder (122 mg) in a mixture of ethanol (10 ml) and acetic acid (1 ml) was refluxed for 3 hours and the mixture was evaporated in vacuo. The residue was stirred in a mixture of chloroform (20 ml) and saturated aqueous sodium hydrogen carbonate (20 ml) at ambient temperature for 30 minutes and the mixture was filtered through a bed of Celite. The organic phase of the filtrate was separated and washed with brine. The organic solution was dried over magnesium sulfate and the solvent was evaporated in vacuo to give a syrup. The crude product was purified by silica gel column (chloroform:methanol:conc. ammonia=10:1:0.1) to give 4-(4′-aminobiphenyl-2-carboxamido)-N-methyl-N-[2-[5-(4-methylpiperazin-1-ylcarbonyl)pyrid-2-ylmethoxy]phenyl]benzamide (157 mg) as a pale yellow amorphous.
Reaction SMILES: [N:1]([C:4]1[C:5]([Cl:11])=[N:6][CH:7]=[CH:8][C:9]=1[I:10])=[N+]=[N-].[C:12]1([P:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1COCC1.[N-]=[N+]=[N-]>O>[Cl:11][C:5]1[C:4]([N:1]=[P:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[C:9]([I:10])[CH:8]=[CH:7][N:6]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: [N-]=[N+]=Nc1c(I)ccnc1Cl
Agent: [N-]=[N+]=[N-]
Solvent: O
Solvent: C1CCOC1
Product: Clc1nccc(I)c1N=P(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 92 %

Procedure:
3-azido-2-chloro-4-iodopyridine (7 g, 25 mmol) and triphenylphosphine (8.5 g, 32 mmol) was stirred in 100 mL 1:1 mixture of THF and water until azide starting material disappears in TLC. After that most of the THF was removed under vacuum. Crude product was partitioned between brine and ethylacetate. Organic layer was isolated, dried over anhd. Na2SO4 and purified by silica gel column chromatography using 5-40% ethyl acetate and hexanes as eluent. 2-chloro-4-iodo-N-(triphenylphosphoranylidene)pyridin-3-amine (12 g, 23 mmol, 93% yield) was isolated as crystalline white solid.
Reaction SMILES: [F:1][CH:2]([C:6]1[CH:15]=[CH:14][C:13]2[C:12]([CH3:17])([CH3:16])[CH2:11][CH2:10][C:9]([CH3:19])([CH3:18])[C:8]=2[CH:7]=1)[C:3](O)=[O:4].[NH2:20][C:21]1[CH:32]=[CH:31][C:24]([C:25]([O:27][CH2:28][CH:29]=[CH2:30])=[O:26])=[CH:23][CH:22]=1>>[F:1][CH:2]([C:6]1[CH:15]=[CH:14][C:13]2[C:12]([CH3:17])([CH3:16])[CH2:11][CH2:10][C:9]([CH3:19])([CH3:18])[C:8]=2[CH:7]=1)[C:3]([NH:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([O:27][CH2:28][CH:29]=[CH2:30])=[O:26])=[CH:31][CH:32]=1)=[O:4]
Reactant: CC1(C)CCC(C)(C)c2cc(C(F)C(=O)O)ccc21
Reactant: C=CCOC(=O)c1ccc(N)cc1
Product: C=CCOC(=O)c1ccc(NC(=O)C(F)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1

Procedure:
In a manner similar to Example 4(c), by reaction of 1.35 g (5.1 mmol) of α-fluoro-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylacetic acid with 920 mg (5.1 mmol) of allyl 4-aminobenzoate, 1.7 g (81%) of ester are obtained in the form of an oil.
Reaction SMILES: [CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH2:13][C:14]2[N:18]([CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[C:17]3[CH:24]=[CH:25][C:26]([C:28]#N)=[CH:27][C:16]=3[N:15]=2)[C:5]1=[O:30])([CH3:3])[CH3:2].[OH-:31].[NH4+].[OH-:33].[Na+]>Cl>[CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH2:13][C:14]2[N:18]([CH2:19][CH2:20][CH:21]([CH3:22])[CH3:23])[C:17]3[CH:24]=[CH:25][C:26]([C:28]([OH:33])=[O:31])=[CH:27][C:16]=3[N:15]=2)[C:5]1=[O:30])([CH3:3])[CH3:2]
Reactant: [OH-]
Reactant: CC(C)CCn1c(Cn2c(=O)n(C(C)C)c3ccccc32)nc2cc(C#N)ccc21
Agent: Cl
Agent: [NH4+]
Agent: [Na+]
Product: CC(C)CCn1c(Cn2c(=O)n(C(C)C)c3ccccc32)nc2cc(C(=O)O)ccc21
Yield: 83 %

Procedure:
A mixture of 2-(3-isopropyl-2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl)-1-(3-methyl-butyl)-1H-benzoimidazole-5-carbonitrile (2.00 g, 5.0 mmol) and 6M HCl (50 mL) was heated to reflux for 12 h. After cooling, the final solution was neutralized by ammonium hydroxide and 1M NaOH to pH 6. The precipitate was collected by filtration and the solid washed with water thoroughly and dried in a vacuum oven to yield 1.74 g (83%) of 2-(3-isopropyl-2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl)-1-(3-methyl-butyl)-1H-benzoimidazole-5 carboxylic acid as a white solid.
Reaction SMILES: Cl.[NH2:2][C:3]1([C:8]([O:10][CH3:11])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4]1.Br[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:15].C([O-])(O)=O.[Na+].O>CN(C=O)C>[O:15]=[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:13][NH:2][C:3]1([C:8]([O:10][CH3:11])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: O=C(CBr)c1ccccc1
Reactant: COC(=O)C1(N)CCCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C1(NCC(=O)c2ccccc2)CCCC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of methyl 1-aminocyclopentanecarboxylate hydrochloride (2.00 g, 11.1 mmol, described in Intermediate 25), 2-bromoacetophenone (2.44 g, 12.2 mmol), and NaHCO3 (2.34 g, 27.9 mmol) in DMF (20 mL) was stirred at ambient temperature for 5 h. H2O (25 mL) was added and the mixture was extracted with EtOAc (2×75 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. The product-containing fractions were combined, adjusted to pH 10 by addition of saturated aqueous Na2CO3 and extracted with EtOAc (2×75 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to provide the title compound. MS: m/z=262 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C:9]([F:14])([F:13])[CH2:8][N:7]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:20]=1.[C:21](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C)C=O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:21])[C:10](=[O:12])[C:9]([F:14])([F:13])[CH2:8][N:7]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:20]=1
Reactant: O=C([O-])[O-]
Reactant: O=C1Nc2cnc(Cl)nc2N(C2CCCC2)CC1(F)F
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Reaction time: 4 h
Yield: 94 %

Procedure:
To a solution of 1.4 g (0.0046 mole) of 2-chloro-9-cyclopentyl-7,7-difluoro-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-100) in 30 mL of dimethylformamide was added 2.27 g (0.0069 mole) of cesium carbonate, followed by 0.87 mL (0.014 mole) of iodomethane. After stirring four hours, the mixture filtered and then concentrated under reduced pressure. Ice water was added to the residue to give a precipitate. The solid was collected by filtration, washed with water and dried under vacuum to give 1.37 g of 2-chloro-9-cyclopentyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-100) as a white solid.
Reaction SMILES: [C:1]([CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][CH2:15][C:16](=[O:18])[CH3:17])([O:3]C)=[O:2].[C:19](OCC)(=[O:25])[C:20](OCC)=[O:21].[Na]>C(O)C>[C:1]([CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][CH:15]1[C:20](=[O:21])[C:19](=[O:25])[CH2:17][C:16]1=[O:18])([OH:3])=[O:2]
Reactant: COC(=O)CCCc1ccccc1CCC(C)=O
Reactant: CCOC(=O)C(=O)OCC
Agent: [Na]
Solvent: CCO
Product: O=C(O)CCCc1ccccc1CC1C(=O)CC(=O)C1=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 55.2 %

Procedure:
A solution of 96 g (0.44 mol) of 4-[2-(3-carbomethoxypropyl)phenyl]-2-butanone, 10, and 129 g (0.88 mol) of diethyl oxalate was added dropwise at room temperature to a solution made by dissolving 20.2 g (0.88 g-atm) sodium in 200 ml absolute ethanol. After the addition was complete, the reaction was stirred 1 hour at room temperature and 1 hour at 50° C. It was then concentrated, the residue taken up in H2O, and acidified with 70 ml concentrated HCl. The precipitated material was extracted into ether and washed twice with H2O. The acidic material was then extracted out of this ether phase with aqueous sodium carbonate solution. Upon acidification of the sodium carbonate solution a red oil separated. This oil was heated overnight in a solution of 200 ml concentrated HCl and 200 ml methanol. The reaction mixture was diluted with 300 ml H2O and extracted with ether. Evaporation of the ether gave 70 g of red oil. This was chromatographed on 400 g silicic acid and eluted with benzene:ethanol. Like fractions were combined and crystallized. Recrystallization from benzene gave 23 g of the trione acid 11, mp 123° C.