Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]2[NH:6][C:7]([C:12]3[C:13](=[O:29])[C@:14]([CH3:28])([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:15]4[C:20]([C:21]=3[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=4)=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.N1C=CC=CC=1.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>ClCCl>[OH:22][C:21]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C@@:14]([CH3:28])([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:13](=[O:29])[C:12]=1[C:7]1[NH:6][C:5]2[CH:30]=[CH:31][C:2]([NH:1][S:39]([CH3:38])(=[O:41])=[O:40])=[CH:3][C:4]=2[S:9](=[O:11])(=[O:10])[N:8]=1
Reactant: CC(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Yield: 64.7 %

Procedure:
To a solution of the product of Example 39-6 (310 g, 0.705 mol) and pyridine (167.6 g, 2.12 mol) in dichloromethane (1645 mL) at 18-20° C. was added methanesulfonyl chloride (121.1 g, 1.06 mol) over 45 minutes. The solution was mixed at RT for 16 h then quenched with 1 M HCl (2000 mL). The layers were separated and the organic layer was concentrated under vacuum. The product was crystallized from ethyl acetate/heptane (1/1, 8 volumes) to give the title compound (236.0 g, 65%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[C:5]([C:7]2[O:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1.Cl.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[N:23][CH:22]=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>CN(C=O)C>[O:8]1[CH:9]=[CH:10][CH:11]=[C:7]1[C:5]1[N:6]=[C:2]([NH:1][C:20]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[O:27])[S:3][C:4]=1[CH2:12][N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1
Reactant: O=C(Cl)c1cccnc1
Reactant: Nc1nc(-c2ccco2)c(CN2CCOCC2)s1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1nc(-c2ccco2)c(CN2CCOCC2)s1)c1cccnc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 23.2 %

Procedure:
2-Amino-4-(2-furyl)-5-(morpholinomethyl)thiazole (225 mg, 0.85 mmol) obtained in Step 1 was dissolved in DMF (4 mL), and nicotinoyl chloride hydrochloride (302 mg, 1.70 mmol) and triethylamine (0.24 mL, 1.70 mmol) were added thereto, followed by stirring at room temperature for 4 hours. A saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (hexane:ethyl acetate=1:1) to afford the entitled Compound 94 (73.0 mg, 23%).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([OH:10])=[CH:4][C:3]=2[O:2]1.[H-].[Na+].F[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1.Cl>CS(C)=O.O>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([O:10][C:14]3[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=3)=[CH:4][C:3]=2[O:2]1
Reactant: O=Cc1ccc(F)cc1
Reactant: Oc1ccc2c(c1)OCO2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=Cc1ccc(Oc2ccc3c(c2)OCO3)cc1
Temperature: 150 °C
Reaction time: 12 h
Yield: 67.7 %

Procedure:
A solution of 3,4-methylenedioxyphenol (7.0 g, 50.7 mmol) in anhydrous DMSO (20 mL) was added dropwise over 30 minutes to a stirred suspension of 60% oil dispersion sodium hydride (2.02 g, 50 mmol) in anhydrous DMSO (40 mL) under a nitrogen atmosphere. Upon completion of addition, a solution of p-fluorobenzaldehyde (6.2 g, 50 mmol) in DMSO (10 mL) was added, and the temperature was slowly raised to 150° C. The reaction mixture was maintained at 130°-160° C. for one hour and then allowed to cool to ambient temperature. After 12 hours at ambient temperature, the reaction mixture was poured onto crushed ice and water, made slightly acidic with concentrated hydrochloric acid and extracted with ether. The combined organic extracts were washed with successively with cold dilute aqueous sodium hydroxide, cold dilute hydrochloric acid, ice-cold water and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and evaporated to give a red liquid which solidified. The solid was triturated with boiling n-pentane, filtered and washed with boiling pentane to give 8.2 g (67%) of the title compound. m.p. 67°-70° C. 1H NMR (CDCl3, 300MHz) δ 6.0 (s, 2H), S.6 (m, 2H), 6.8 (d, 1H), 7.04 (m, 2H), 7.84 (m, 2H), 9.92 (s, 1H). MS (DCl/NH3) m/e 243 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.Cl[CH2:17][C:18]1[N:19]=[C:20]([C:23]2[S:24][C:25]([C:28]#[N:29])=[CH:26][CH:27]=2)[O:21][CH:22]=1>>[C:28]([C:25]1[S:24][C:23]([C:20]2[O:21][CH:22]=[C:18]([CH2:17][O:1][C:2]3[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]4[CH:15]=[CH:14][N:13]=[CH:12]4)=[CH:4][CH:3]=3)[N:19]=2)=[CH:27][CH:26]=1)#[N:29]
Reactant: N#Cc1ccc(-c2nc(CCl)co2)s1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Product: N#Cc1ccc(-c2nc(COc3ccc(CCCn4ccnc4)cc3)co2)s1
Yield: 70 %

Procedure:
In substantially the same manner as in Working Example 72, 1-[3-(4-hydroxyphenyl)propyl]imidazole was reacted with 4-chlorometyl-2-(5-cyano-2-thienyl)oxazole to obtain 2-(5-cyano-2-thienyl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole. The yield was 70%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 73-74° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](O)=[O:8].CN(C=O)C.S(Cl)([Cl:19])=O.C(=O)(O)[O-].[Na+]>ClC(Cl)C>[Cl:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([Cl:19])=[O:8]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(Cl)Cl
Product: O=C(Cl)c1cnc(Cl)c(Cl)c1
Temperature: 75 °C

Procedure:
To a well stirred suspension of 5,6-dichloronicotinic acid 5 (600 g, 3.125 mole, Sigma-Aldrich) and DMF (20.0 mL) in dichloroethane (1.2 L) was added drop wise with stirring thionyl chloride (743.56 g, 6.25 mole). The reaction mixture was set up for heating with reflux, fitted with a gas trap filled with saturated aqueous sodium bicarbonate and heated at a temperature of 75° C. until the reaction mixture formed a clear solution, about 3 h. LC/MS of a sample quenched in methanol showed only the presence of the methyl ester. The reaction mixture was cooled to a temperature of about 25° C. and concentrated under reduced pressure to provide 5,6-dichloronicotinoyl chloride 6 as a thick paste.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:26])[C:8]=2[NH:12][C:13](=[O:25])[CH2:14][CH:15]2[CH2:20][CH2:19][CH:18]([C:21]([F:24])([F:23])[F:22])[CH2:17][CH2:16]2)[N:3]=1.[NH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[Cl:26][C:7]1[C:8]([NH:12][C:13](=[O:25])[CH2:14][CH:15]2[CH2:20][CH2:19][CH:18]([C:21]([F:24])([F:23])[F:22])[CH2:17][CH2:16]2)=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[CH:11]=[CH:10]2
Reactant: C1CNCCN1
Reactant: O=C(CC1CCC(C(F)(F)F)CC1)Nc1c(Cl)ccc2nc(Cl)ccc12
Product: O=C(CC1CCC(C(F)(F)F)CC1)Nc1c(Cl)ccc2nc(N3CCNCC3)ccc12
Yield: 24.5 %

Procedure:
Prepared according to the method of example 2 using N-(2,6-dichloro-5-quinolinyl)-4 (trifluoromethyl)-cyclohexaneacetamide (Example 8 (c)) (200 mg) and piperazine (420 mg). Purification (SiO2, dichloromethane:methanol 95:5 as eluant) afforded the title compound as a solid (55 mg).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:42][C:43]1[N:44]=[CH:45][NH:46][CH:47]=1)[C:3]([NH:5][C@@H:6]([CH2:35][CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1)[C@@H:7]([OH:34])[CH2:8][C@@H:9]([CH:31]([CH3:33])[CH3:32])[CH:10]([OH:30])[CH2:11][N:12]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)[C:13](=[O:22])[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:4].[NH:48](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:49]([C:57](O)=[O:58])[CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.C(N1CCOCC1)C.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C)C=O>[CH:36]1([CH2:35][C@H:6]([NH:5][C:3](=[O:4])[C@H:2]([CH2:42][C:43]2[N:44]=[CH:45][NH:46][CH:47]=2)[NH:1][C:57](=[O:58])[C@H:49]([CH2:50][C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)[NH2:48])[C@@H:7]([OH:34])[CH2:8][C@@H:9]([CH:31]([CH3:33])[CH3:32])[CH:10]([OH:30])[CH2:11][N:12]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[C:13](=[O:22])[O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Reactant: CC(C)[C@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@@H](N)Cc1c[nH]cn1)C(O)CN(Cc1ccccn1)C(=O)OCc1ccccc1
Agent: CCN1CCOCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)[C@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H](N)Cc1ccccc1)C(O)CN(Cc1ccccn1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.6 %

Procedure:
A mixture of 340 mg (0.52 mmol) of benzyl [(2RS,3S, 5S,6S)-6-[(S)-α-amino-4-imidazolepropionamido]-7-cyclohexyl-2,5-dihydroxy-3-isopropylheptyl]-(2-pyridylmethyl)carbamate, 225 mg (0.58 mmol) of Fmoc-Phe-OH, 0.132 ml (1.05 mmol) of 4-ethylmorpholine, 155 mg (1.15 mmol) of HOBT, 121 mg (0.63 mmol) of EDC and 10 ml of dimethylformamide is stirred at room temperature overnight. Thereafter, the reaction mixture is poured into 70 ml of ice-cold 2N sodium bicarbonate solution and extracted three times with 150 ml of ethyl acetate each time. The organic extracts are washed in succession with 70 ml of sodium bicarbonate solution and 70 ml of saturated sodium chloride solution, combined, dried and evaporated. The residue (640 mg) in 30 ml of methylene chloride and 1 ml of piperidine is stirred at room temperature for 2.5 hours. Then, the reaction mixture is evaporated and the residue (500 mg) is chromatographed on 50 mg of silica gel with a 14:1:0.1 mixture of methylene chloride, methanol and ammonia as the eluting agent. Recrystallization of the crude product obtained (320 mg) from methylene chloride/ether/hexane yields 280 mg of benzyl [(2RS,3S,5S,6S)-7-cyclohexyl-2,5-dihydroxy-3-isopropyl-6-[[N-(3-phenyl-L-alanyl)-L-histidyl]amino]heptyl]-(2-pyridylmethyl)carbamate as a white solid, melting point 94°.
Reaction SMILES: [CH:1]1([N:4]=[C:5]=[O:6])[CH2:3][CH2:2]1.[NH:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([NH2:25])[CH:23]=2)[N:18]([CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)[N:17]=1.N1C=CC=CC=1>C(Cl)Cl>[NH:9]1[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:7]=[C:8]1[C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([NH:25][C:5]([NH:4][CH:1]3[CH2:3][CH2:2]3)=[O:6])[CH:23]=2)[N:18]([CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)[N:17]=1
Reactant: Nc1ccc2c(c1)c(-c1nc3ccccc3[nH]1)nn2C1CCCCO1
Reactant: O=C=NC1CC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccc2c(c1)c(-c1nc3ccccc3[nH]1)nn2C1CCCCO1)NC1CC1
Reaction time: 24 h
Yield: 53.4 %

Procedure:
Cyclopropylisocyanate (4 g, 0.048 mmol) was added to a solution of 3-(1H-benzo[d]imidazol-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (15 mg, 0.045 mmol) and pyridine (0.01 mL, 0.126 mmol) in CH2Cl2 (5 mL). The mixture was stirred for 24 h, and then the solvent was removed in vacuo. Purification by flash chromatography (2% CH3OH/CH2Cl2) afforded the title compound (10 mg) as a solid. 1H NMR (400 MHz, CDCl3): δ 8.22 (s, 1H), 7.93 (d, 1H, J=8.8 Hz), 7.83 (m, 1H), 7.49 (d, 1H, J=8.8 Hz), 7.27-7.24 (m, 2H), 7.17 (s, 1H), 5.71 (dd, 1H, J=2.4 and 9.2 Hz), 4.04 (m, 1H), 3785 (m, 1H), 2.59 (m, 2H), 2.17-2.07 (m, 2H), 1.74 (m, 5H), 0.84 (q, 2H, J=5.2 Hz).
Reaction SMILES: C([O:3][C:4](=O)[C:5]([CH3:19])([CH3:18])[CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])C.[CH3:21][NH2:22]>>[CH2:11]([O:10][C:8]([NH:7][CH2:6][C:5]([CH3:19])([CH3:18])[C:4]([NH:22][CH3:21])=[O:3])=[O:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)C(C)(C)CNC(=O)OCc1ccccc1
Reactant: CN
Product: CNC(=O)C(C)(C)CNC(=O)OCc1ccccc1

Procedure:
4.19 g of 3-benzyloxycarbonylamino-2,2-dimethylpropionic acid ethyl ester and 50 ml of 33% methylamine (in ethanol) are stirred for 8 days at 60° C. in a bomb tube. The reaction mixture is concentrated by evaporation and the residue is purified by FC (220 g of silica gel, dichloromethane/methanol=95:5). The title compound is obtained: Rf (dichloromethane/methanol=9:1)=0.51.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8]([N:14]([CH2:28][CH2:29][N:30]([CH3:32])[CH3:31])[C:15](=[O:27])[C:16]3[C:21](OC)=[C:20]([O:24][CH3:25])[CH:19]=[CH:18][C:17]=3I)=[CH:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(Cl)(=O)[C:34](Cl)=[O:35].COC1C=C(C(I)=CC=1OC)C(O)=O.[N+](C1C=C2C(C(NCCN(C)C)=CC=N2)=CC=1)([O-])=O.C(N(CC)CC)C>C(Cl)Cl>[CH3:25][O:24][C:20]1[C:19]([O:35][CH3:34])=[CH:18][C:17]2[C:9]3[C:8](=[C:7]4[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:13][C:12]4=[N:11][CH:10]=3)[N:14]([CH2:28][CH2:29][N:30]([CH3:31])[CH3:32])[C:15](=[O:27])[C:16]=2[CH:21]=1
Reactant: COc1ccc(I)c(C(=O)N(CCN(C)C)c2ccnc3cc([N+](=O)[O-])ccc23)c1OC
Reactant: O=C(Cl)C(=O)Cl
Agent: CN(C)CCNc1ccnc2cc([N+](=O)[O-])ccc12
Agent: COc1cc(I)c(C(=O)O)cc1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2c(=O)n(CCN(C)C)c3c4ccc([N+](=O)[O-])cc4ncc3c2cc1OC
Yield: 53 %

Procedure:
N-(7-Nitroquinolin-4-yl)-N-(N,N-dimethylaminoethyl)-2-iodo-5,6-dimethoxybenzamide (8b). Oxalyl chloride (1.5 mg, 12.0 mmol) was added to a solution of 3,4-dimethoxy-6-iodobenzoic acid (985 mg, 3.2 mmol) in anhydrous methylene chloride (30 mL), and the stirred mixture was refluxed for 3 hours. The mixture was then concentrated to dryness under reduced pressure. The acid chloride was redissolved in 20 mL of anhydrous methylene chloride, and this solution was added to a solution of 7b (680 mg, 2.6 mmol) and triethylamine (2.0 g, 20.0 mmol) in methylene chloride (30 mL), and the resulting mixture was stirred at reflux for 2 hours. The reaction mix was cooled and washed with saturated sodium bicarbonate (3×75 mL), and extracted with 5% aqueous HCl (4×100 mL). The combined aqueous extracts were basified with 30% NaOH and then extracted with chloroform (3×100 mL). Combined organic extracts were then dried (MgSO4) and evaporated to give 760 mg of the amide, in 53% yield; 1H NMR (CDCl3) δ 2.23 (s, 6H), 2.63 (m, 2H), 3.28 (s, 3H), 3.73 (s, 3H), 3.92 (m, 1H), 4.50 (m, 1H), 6.33 (s, 1H), 7.02 (s, 1H), 7.73 (d, 1H, J=4.8), 8.41 (m, 2H), 8.98 (m, 2H); 13C NMR (CDCl3) δ 45.5, 47.5, 55.6, 56.1, 56.8, 82.9, 110.4, 120.6, 121.8, 124.1, 125.4, 126.6, 129.2, 133.3, 147.5, 148.4, 148.8, 149.9, 152.6, 153.1, 169.7; IR (CHCl3) 1345, 1536, 1655.
Reaction SMILES: O[CH2:2][C:3]1[CH:16]=[N:15][C:6]2[C:7]3[N:8]([CH:12]=[CH:13][CH:14]=3)[C:9](=[O:11])[NH:10][C:5]=2[CH:4]=1.[F:17][C:18]1[CH:19]=[C:20]([CH:25]=[CH:26][C:27]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[C:21]([NH:23][CH3:24])=[O:22].[I-].C(C[P+](C)(C)C)#N.C(N(C(C)C)C(C)C)C>C(#N)CC>[F:17][C:18]1[CH:19]=[C:20]([CH:25]=[CH:26][C:27]=1[N:28]1[CH2:29][CH2:30][N:31]([CH2:2][C:3]2[CH:16]=[N:15][C:6]3[C:7]4[N:8]([CH:12]=[CH:13][CH:14]=4)[C:9](=[O:11])[NH:10][C:5]=3[CH:4]=2)[CH2:32][CH2:33]1)[C:21]([NH:23][CH3:24])=[O:22]
Reactant: CNC(=O)c1ccc(N2CCNCC2)c(F)c1
Reactant: O=c1[nH]c2cc(CO)cnc2c2cccn12
Agent: C[P+](C)(C)CC#N
Agent: [I-]
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)[nH]c(=O)n3cccc43)CC2)c(F)c1
Temperature: 95 °C
Reaction time: 15 h
Yield: 80.2 %

Procedure:
To a suspension of 3-(hydroxymethyl)pyrido[2,3-e]pyrrolo[1,2-c]pyrimidin-6(5H)-one (50.00 mg, 0.232 mmol), 3-fluoro-N-methyl-4-(piperazin-1-yl)benzamide (68.9 mg, 0.290 mmol) and (cyanomethyl)trimethylphosphonium iodide (90 mg, 0.372 mmol) in Propiononitrile (Volume: 1.00 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.202 mL, 1.162 mmol) at 23° C. The reaction was stirred at 95° C. for 15 hr. The suspension was cooled to 23° C., concentrated via rotary evaporation, re-constituted in ACN (2.0 mL), stirred for 15 min, filtered, rinsed with ACN (3×1 mL) and dried in vacuo. The crude solid was re-suspended in ACN (2.0 mL), heated to reflux, cooled to 23° C., filtered, rinsed with ACN (3×2.0 mL) to provide 3-fluoro-N-methyl-4-(4-((6-oxo-5,6-dihydropyrido[2,3-e]pyrrolo[1,2-c]pyrimidin-3-yl)methyl)piperazin-1-yl)benzamide (0.081 g, 0.186 mmol, 80.0% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.54-2.63 (m, 4H) 2.75 (d, J=4.55 Hz, 3 H) 3.08-3.17 (m, 4 H) 3.63 (s, 2 H) 6.71-6.75 (m, 1 H) 7.02-7.10 (m, 2 H) 7.53-7.63 (m, 3 H) 7.67 (dd, J=3.03, 1.52 Hz, 1 H) 8.29 (q, J=4.29 Hz, 1 H) 8.33-8.38 (m, 1 H) 11.56 (br. s., 1 H). ESI-MS: m/z 435.4 (M+H)+. mp=288.0-294.5° C.
Reaction SMILES: CC1C=CC(S([O:11][CH2:12][CH2:13][O:14][CH:15]2[CH2:20][CH2:19][N:18](C(OCC3C=CC=CC=3)=O)[CH2:17][CH2:16]2)(=O)=O)=CC=1.[O:31]1[CH2:35][CH2:34][CH:33]([CH2:36]O)[CH2:32]1>>[O:31]1[CH2:35][CH2:34][CH:33]([CH2:36][O:11][CH2:12][CH2:13][O:14][CH:15]2[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]2)[CH2:32]1
Reactant: OCC1CCOC1
Reactant: Cc1ccc(S(=O)(=O)OCCOC2CCN(C(=O)OCc3ccccc3)CC2)cc1
Product: C1CC(OCCOCC2CCOC2)CCN1
Yield: 66.6 %

Procedure:
Using benzyl 4-(2-{[(4-methylphenyl)sulfony]oxy}ethoxy)piperidine-1-carboxylate (4.00 g, 9.23 mmol) produced in Reference Example 1 (1c) and (tetrahydrofuran-3-yl)methanol (1.23 g, 12.0 mmol), the desired title compound (1.41 g, yield 67%) was obtained by the same method as in Examples 1 (1d) and 1 (1e).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:14][CH:13]=1)[C:6]([C:24]([O:26]CC)=[O:25])=[C:5]2[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[C:35]([C:39]1[CH:44]=[CH:43][C:42](B(O)O)=[CH:41][CH:40]=1)([CH3:38])([CH3:37])[CH3:36]>>[C:15]1([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:14]=[CH:13][C:12]([CH2:11][N:7]2[C:8]3[C:4](=[CH:3][C:2]([NH:1][C:42]4[CH:43]=[CH:44][C:39]([C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:40][CH:41]=4)=[CH:10][CH:9]=3)[C:5]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[C:6]2[C:24]([OH:26])=[O:25])=[CH:17][CH:16]=1
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: CCOC(=O)c1c(-c2ccccc2)c2cc(N)ccc2n1Cc1ccc(-c2ccccc2)cc1
Product: CC(C)(C)c1ccc(Nc2ccc3c(c2)c(-c2ccccc2)c(C(=O)O)n3Cc2ccc(-c3ccccc3)cc2)cc1

Procedure:
The title compound was prepared from ethyl 5-amino-1-(1,1′-biphenyl-4-ylmethyl)-3-phenyl-1H-indole-2-carboxylate and 4-tert-butylbenzeneboronic acid according to the procedure of Example 1 Step 3 as a pale green solid: 1H NMR (CDCl3) δ 1.28 (s, 9 H), 5.85 (s, 2 H), 6.86 (d, J=8.6 Hz, 2 H), 7.15-7.55 (m, 19 H); MS (ESI) m/z 551 (MH+); HRMS calcd. for C38H34N2O2 551.2699; found (ESI+): 551.2681; Anal. calcd. for C38H34N2O2.0.5H2O: C, 81.55; H, 6.30; N, 5.01. Found: C, 81.91; H, 6.39; N, 4.65.
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.S(=O)(=O)(O)O.[CH2:19](O)[CH3:20]>>[NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([O:8][CH2:19][CH3:20])=[O:7])=[CH:4][N:3]=1
Reactant: CCO
Reactant: Nc1ncc(C(=O)O)cc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cnc(N)c([N+](=O)[O-])c1
Yield: 73 %

Procedure:
A solution of 6-amino-5-nitronicotinic acid (10 g) and concentrated sulfuric acid (20 ml) in ethanol (250 ml) was heated under reflux for 18 hr. The reaction mixture was concentrated, diluted with water and adjusted with sodium hydrogencarbonate to pH 8. The precipitated crystals were collected by filtration and washed with water to give the title compound (8.5 g, yield 73%) as yellow crystals. purity 84%. M+H: 212.
Reaction SMILES: [CH2:1]([O:6][C:7]1[N:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=O)[CH:2]=[C:3]([CH3:5])[CH3:4].[NH2:16][CH2:17][CH:18]1[CH2:22][CH2:21][CH2:20][N:19]1[CH2:23][CH3:24]>>[CH2:23]([N:19]1[CH2:20][CH2:21][CH2:22][CH:18]1[CH2:17][NH:16][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][CH:14]=[N:15][C:7]=1[O:6][CH2:1][CH:2]=[C:3]([CH3:4])[CH3:5])[CH3:24]
Reactant: CC(C)=CCOc1ncccc1C(=O)O
Reactant: CCN1CCCC1CN
Product: CCN1CCCC1CNC(=O)c1cccnc1OCC=C(C)C
Yield: 92 %

Procedure:
In a manner identical to Example 15, 2-prenyloxynicotinic acid (1.00 g) was subjected to a condensation reaction with 2-aminomethyl-1-ethylpyrrolidine (0.63 g), thereby yielding 1.41 g (92%) of the aimed compound.
Reaction SMILES: [F:1]C1C=C2C(=CC=1)NC=C2C=O.C(O[C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([C:26]([NH2:28])=[O:27])[CH:21]=[C:20]2[N:29]=[C:30]=[O:31])C=C>>[F:1][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([C:26]([NH2:28])=[O:27])[CH:21]=[C:20]2[N:29]=[C:30]=[O:31]
Reactant: C=CCOc1ccc2c(c1)c(N=C=O)cn2C(N)=O
Reactant: O=Cc1c[nH]c2ccc(F)cc12
Product: NC(=O)n1cc(N=C=O)c2cc(F)ccc21

Procedure:
was prepared from 5-fluoro-1H-indole-3-carbaldehyde using the protocol described for steps C, D and E in scheme A4 for the preparation of 5-allyloxy-3-isocyanato-indole-1-carboxylic acid amide.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([NH:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:20][C:21]([F:31])([F:30])[C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=1.O>CC(CC)=O>[CH3:13][NH:12][C:10](=[O:11])[CH:9]=[CH:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:26][C:25]2[CH:24]=[CH:23][C:22]([C:21]([F:20])([F:30])[F:31])=[CH:29][CH:28]=2)=[CH:7][CH:6]=1
Reactant: CNC(=O)C=Cc1ccc(O)cc1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: CNC(=O)C=Cc1ccc(OCc2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.5 %

Procedure:
195 mg (1.1 mmol) 3-(4-hydroxy-phenyl)-N-methyl-acrylamide is dissolved in 25 ml ethyl methyl ketone and 304 mg (2.2 mmol) potassium carbonate is added, followed by 289 mg (1.2 mmol) of 4-(trifluoromethyl)benzyl bromide. The reaction mixture is stirred overnight at RT, heated to 50° C. for 3 hours, treated with water and extracted 3 times with dichloromethane. The extract is dried over magnesium sulfate, concentrated and treated with ether to yield 260 mg (70%) of a colorless solid. MS: m/e=336.1 (M++H).
Reaction SMILES: C[Sn](C)(C)[C:3]1[CH:4]=[C:5]([O:11][CH3:12])[C:6]([O:9][CH3:10])=[CH:7][CH:8]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20](Br)=[CH:19][N:18]=1>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:12][O:11][C:5]1[CH:4]=[C:3]([C:20]2[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[N:18][CH:19]=2)[CH:8]=[CH:7][C:6]=1[O:9][CH3:10]
Reactant: COc1ccc(Br)cn1
Reactant: COc1ccc([Sn](C)(C)C)cc1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COc1ccc(-c2ccc(OC)c(OC)c2)cn1
Temperature: 90 °C

Procedure:
A solution of 2.00 g (6.64 mmol) of 4-trimethylstannylveratrole, 2.49 g (13.2 mmol) of 2-methoxy-5-bromopyridine and 370 mg (0.332 mmol) of Pd (PPh3)4 in 30 mL of dry dimethylformamide is flushed thoroughly with nitrogen and heated to 90° C. for 12 hours. The reaction mixture is partitioned between ethyl acetate (150 mL) and water (100 mL). The aqueous layer is back extracted with ethyl acetate (100 mL) and the combined organics are washed with brine (75 mL), dried (MgSO4) and evaporated to give a crude yellow oil. The oil is chromatographed on silica gel (eluting with 95:5 hexane/ethyl acetate and then with 9:1 hexane/ethyl acetate) which gives 5-(3,4-dimethoxy-phenyl)-2-methoxypyridine m.p 83-84° C.