Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:14][C:15]2[N:19]([CH3:20])[C:18]3[C:21]([N:25]([CH2:29][CH2:30][CH3:31])[CH2:26][CH2:27][CH3:28])=[CH:22][CH:23]=[CH:24][C:17]=3[N:16]=2)=[C:6]([CH:13]=1)[O:7]C(CC)C#N.[OH-:32].[Na+]>CCO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:14][C:15]2[N:19]([CH3:20])[C:18]3[C:21]([N:25]([CH2:26][CH2:27][CH3:28])[CH2:29][CH2:30][CH3:31])=[CH:22][CH:23]=[CH:24][C:17]=3[N:16]=2)=[C:6]([CH:13]=1)[O:7][CH2:3][CH2:4][CH2:5][C:6]([OH:7])=[O:32]
Reactant: CCCN(CCC)c1cccc2nc(Nc3ccc(Cl)cc3OC(C#N)CC)n(C)c12
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCN(CCC)c1cccc2nc(Nc3ccc(Cl)cc3OCCCC(=O)O)n(C)c12
Temperature: 75 °C
Reaction time: 48 h
Yield: 70 %

Procedure:
To a solution of 63 mg (0.14 mmol) of 4-[(5-chloro-2-[[7-(dipropylamino)-1-methyl-1H-benzimidazol-2-yl]amino]phenoxy]butanenitrile in 3 mL of EtOH and 1 mL of water was added 29 mg (0.72 mmol) of sodium hydroxide pellets and the reaction was stirred at 75° C. for 48 h. To the reaction mixture was added 75 mg (1.87 mmol) of sodium hydroxide pellets and the reaction heated at 75° C. for 24 h and concentrated in vacuo to a residue. The thus obtained residue was dissolved in 5 mL of water and the pH was adjusted to 4-5 using hydrochloric acid (1N aqueous solution). The resulting slurry was filtered, and the solids were washed with water and dried under high vacuum to give 46 mg (70%) of the title compound as white solids.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.Cl.Cl.[N:14]1[CH:19]=[CH:18][C:17]([S:20][CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:16][CH:15]=1.[OH-].[Na+]>O>[N:14]1[CH:19]=[CH:18][C:17]([S:20]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[O:9])=[CH:16][CH:15]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: c1cc(SC2CCNCC2)ccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=S(c1ccncc1)C1CCNCC1
Reaction time: 3 h
Yield: 90.8 %

Procedure:
m-Chloroperbenzoic acid (1.20 g) was added to a stirred solution of 4-[(4-pyridyl)thio]piperidine dihydrochloride (1.33 g) in water (30 ml) under ice-cooling, and the mixture was stirred at the same temperature for 3 hours and then at room temperature for 5.5 hours. The resultant mixture was diluted with water and the pH of the mixture was adjusted to about 11 with 5% sodium hydroxide solution. The solution was extracted several times with chloroform. The extracts were combined, dried over magnesium sulfate, and concentrated in vacuo. The oily residue was crystallized from n-hexane and the crystals were recrystallized from a mixture of n-hexane and isopropanol to give 4-[(4-pyridyl)sulfinyl]piperidine (0.95 g).
Reaction SMILES: [CH2:1]1[CH:5]2[CH:6]3[CH:10]=[CH:9][CH:8]([CH:4]2C=C1)[CH2:7]3.C([NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])C=C>>[C:15]([NH:14][CH2:1][CH:5]1[CH2:4][CH:8]2[CH2:7][CH:6]1[CH:10]=[CH:9]2)([CH3:18])([CH3:17])[CH3:16]
Reactant: C=CCNC(C)(C)C
Reactant: C1=CC2C3C=CC(C3)C2C1
Product: CC(C)(C)NCC1CC2C=CC1C2
Temperature: 185 °C
Reaction time: 15 h
Yield: 64.7 %

Procedure:
5-(t-butylanfinomethyl)norbomene. 14 g of dicyclopentadiene and 60 g of the N-allyl-N-t-butylamine were placed neat in a Parr High-Pressure Reactor. The reaction was heated to 185° C. with stirring for 15 h. The reaction was then cooled down and the reaction solution was distilled under vacuum (0.5 torr). The desired product distilled over at 35°-36 ° C. 24.6 g of product was collected in this way (64.7% yield).
Reaction SMILES: F[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([F:9])=[CH:4][N:3]=1.Cl.N.[OH2:12]>>[OH:12][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1ncc(F)c(Cl)n1
Reactant: O
Agent: Cl
Agent: N
Product: Oc1ncc(F)c(Cl)n1
Yield: 92.2 %

Procedure:
15.05 g (0.1 mole) of 2,5-difluoro-4-chloropyrimidine were heated under reflux together with 30 ml of 37% strength aqueous hydrochloric acid for 2 hours. The volatile constituents were then stripped off in vacuo, the residue was taken up in 100 ml of water and this mixture was rendered weakly alkaline (pH 7.5) with 20% strength aqueous ammonia. The mixture was then again concentrated in vacuo down to 20% of the original volume. The solid obtained was filtered off with suction and dried. 13.7 g of product with a melting point of 176° to 177° C. (decomposition) were obtained, corresponding to a yield of 92.2%.
Reaction SMILES: [CH2:1]([O:12][P:13]([OH:16])([OH:15])=[O:14])[C@H:2]1[O:7][C@H:6]([OH:8])[C@H:5]([NH2:9])[C@@H:4]([OH:10])[C@@H:3]1[OH:11].[C:17](N1C(=O)CCC1=O)(=[O:19])[CH3:18]>C1COCC1.O>[CH3:18][C:17]([NH:9][CH:5]1[CH:6]([OH:8])[O:7][CH:2]([CH2:1][O:12][P:13]([OH:16])([OH:15])=[O:14])[CH:3]([OH:11])[CH:4]1[OH:10])=[O:19]
Reactant: CC(=O)N1C(=O)CCC1=O
Reactant: N[C@@H]1[C@@H](O)[C@H](O)[C@@H](COP(=O)(O)O)O[C@@H]1O
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)NC1C(O)OC(COP(=O)(O)O)C(O)C1O

Procedure:
In one process, GlcN-6-P was acetylated in THF/water using N-acetylsuccinimide (NAS) to form GlcNAc-6-P. Acetic anhydride can also be used. That N-acetyl compound was treated with an enzyme preparation from Candida utilis containing N-acetylglucosamine phosphomutase (EC 2.7.5.2) and UDP-GlcNAc pyrophosphorylase (EC 2.7.7.23) to first form GlcNAc-1-P and then UDP-GlcNAc in the presence of UTP and inorganic pyrophosphatase (EC 3.6.1.1) to destroy the inorganic pyrophosphate formed.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:37])[CH:5]([N:20]([CH:34]1[CH2:36][CH2:35]1)[C:21](=O)[C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=1)[C:6]([C:8]1[N:12]=[CH:11][N:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:9]=1)=O)[CH3:2].FC(F)(F)C([O-])=O.[NH4+:45]>>[CH2:1]([O:3][C:4]([C:5]1[N:20]([CH:34]2[CH2:35][CH2:36]2)[C:21]([C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]([F:31])([F:32])[F:30])=[CH:24][CH:23]=2)=[N:45][C:6]=1[C:8]1[N:12]=[CH:11][N:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:9]=1)=[O:37])[CH3:2]
Reactant: [NH4+]
Reactant: CCOC(=O)C(C(=O)c1ncn(Cc2ccccc2)n1)N(C(=O)c1ccc(OC(F)(F)F)cc1)C1CC1
Agent: O=C([O-])C(F)(F)F
Product: CCOC(=O)c1c(-c2ncn(Cc3ccccc3)n2)nc(-c2ccc(OC(F)(F)F)cc2)n1C1CC1

Procedure:
The title compound was prepared from 3-(1-benzyl-1H-[1,2,4]triazol-3-yl)-2-[cyclopropyl-(4-trifluoromethoxy-benzoyl)-amino]-3-oxo-propionic acid ethyl ester in direct analogy to intermediate 8B, by reaction with ammonium trifluoroacetate. MS: 498.2 (MH+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=3[N:16]=[C:15]2[CH:25]([F:27])[F:26])[N:3]=1.[NH2:28][CH:29]1[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]1.CCN(C(C)C)C(C)C>C1COCC1>[F:26][CH:25]([F:27])[C:15]1[N:14]([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=[C:2]([NH:28][CH:29]3[CH2:30][CH2:31][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:33][CH2:34]3)[N:3]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=2[N:16]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCOCC2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(NC2CCN(C(=O)OC(C)(C)C)CC2)nc(N2CCOCC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
A mixture of 0.397 g (1 mmol) of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole (Example 2), 0.24 g (1.2 mmol) of tert-butyl 4-amino-1-piperidinecarboxylate, and 0.194 g (1.5 mmol) of DIPEA in 25 mL of THF was stirred at room temperature overnight. Dilution with water and extraction with CH2Cl2, followed by chromatography on silica eluting with CH2Cl2/EtOAc (4:1) gave 0.51 g (91% yield) of tert-butyl 4-{[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]amino}-1-piperidinecarboxylate: mp (hexanes/CH2Cl2) 142-145° C.; 1H NMR (CDCl3) (rotamer mixture; ratio ca. 3:2) δ 7.96 and 7.95 (2d, J=8.3 and 7.9 Hz, 1H), 7.54 and 7.52 (2t, JHF=53.6 Hz, 1H), 7.34 (br t, J=8.1 Hz, 1H), 6.81 (t, J=6.9 Hz, 1H), 5.22 and 5.17 (2d, J=7.4 and 7.6 Hz, exchangeable with D2O, 1H), 4.10 (m, 3H), 4.05 (s, 3H), 3.87 (m, 4H), 3.78 (m, 4H), 2.93 (t, J=12.1 Hz, 2H) 2.06 (m, 2H), 1.48 (s, 9H), 1.43 (m, 2H); Anal. Calcd. for C26H34F2N8O4: C, 55.7; H, 6.1; N, 20.0. Found: C, 55.6; H, 6.2; N, 20.0%.
Reaction SMILES: CC([NH:4][C@@H:5]1[C:21]2[C:14](=[CH:15][CH:16]=[C:17]([S:22][CH3:23])[C:18]([CH:20]=2)=[O:19])[C:13]2[C:8](=[CH:9][C:10]([O:28][CH3:29])=[C:11]([O:26][CH3:27])[C:12]=2[O:24][CH3:25])[CH2:7][CH2:6]1)=O.Cl>CO>[CH3:29][O:28][C:10]1[CH:9]=[C:8]2[CH2:7][CH2:6][C@H:5]([NH2:4])[C:21]3[C:14]([C:13]2=[C:12]([O:24][CH3:25])[C:11]=1[O:26][CH3:27])=[CH:15][CH:16]=[C:17]([S:22][CH3:23])[C:18](=[O:19])[CH:20]=3
Reactant: COc1cc2c(c(OC)c1OC)-c1ccc(SC)c(=O)cc1[C@@H](NC(C)=O)CC2
Agent: Cl
Solvent: CO
Product: COc1cc2c(c(OC)c1OC)-c1ccc(SC)c(=O)cc1[C@@H](N)CC2
Yield: 81.2 %

Procedure:
A mixture containing 16.3 g of thiocolchicine, 200 ml of methanol and 200 ml of aqueous HCl (2N) is heated under reflux. The hydrolysis reaction which occurs is complete at the end of a period of time of 28 hours. 215 ml of aqueous methanol are then distilled off and the remaining aqueous solution extracted 3 times with 300 ml of chloroform. The chloroform extracts are combined and the mixture thereof washed 4 times with 300 ml of water. The remaining part of the aforesaid aqueous solution and the aqueous washing solutions are combined and alcalinized to pH13 by adding aqueous sodium hydroxide 10N. The desired product passes into the form of the free amine and is extracted using 5 portions of 300 ml of chloroform. The chloroform extracts are combined, washed with water until neutrality and dried. After evaporation of the solvent, the amine is recrystallized from a mixture chloroform (65ml)-ether (390 ml) to give 11.9 g of the product (yield 79 %).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.[C:8]([O:12][N:13]1[C:22](=[O:23])[C:21]2[CH:24]=[C:25]([Cl:28])[C:26](Cl)=[C:19]3[C:20]=2[C:15](=[CH:16][CH:17]=[CH:18]3)[C:14]1=[O:29])([CH3:11])([CH3:10])[CH3:9].O>CC(N(C)C)=O>[C:8]([O:12][N:13]1[C:22](=[O:23])[C:21]2[CH:24]=[C:25]([Cl:28])[C:26]([N:5]3[CH2:6][CH2:7][CH:3]([O:2][CH3:1])[CH2:4]3)=[C:19]3[C:20]=2[C:15](=[CH:16][CH:17]=[CH:18]3)[C:14]1=[O:29])([CH3:11])([CH3:9])[CH3:10]
Reactant: COC1CCNC1
Reactant: CC(C)(C)ON1C(=O)c2cccc3c(Cl)c(Cl)cc(c23)C1=O
Solvent: O
Solvent: CC(=O)N(C)C
Product: COC1CCN(c2c(Cl)cc3c4c(cccc24)C(=O)N(OC(C)(C)C)C3=O)C1
Yield: 91 %

Procedure:
Following the procedure of Example Q2, 3-methoxypyrrolidine (0.2 g, 2.0 mmol) and 2-tert-butyloxy-5,6-dichloro-benzo[de]isoquinoline-1,3-dione (0.4 g, 1.2 mmol, from Example V2) were reacted in DMA (1.0 mL) at 120° C. overnight followed by addition of water (10 mL). The precipitate that formed was filtered to give 0.44 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[OH:9][C@@H:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[NH:15][C:16]1[N:24]=[CH:23][N:22]=[C:21]2[C:17]=1[N:18]=[CH:19][N:20]2[CH:25]1[C@H:29]([OH:30])[C@H:28]([OH:31])[C@@H:27]([CH2:32]Cl)[O:26]1>[OH-].[Na+].CN(C)C=O>[OH:9][C@@H:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[NH:15][C:16]1[N:24]=[CH:23][N:22]=[C:21]2[C:17]=1[N:18]=[CH:19][N:20]2[CH:25]1[C@H:29]([OH:30])[C@H:28]([OH:31])[C@@H:27]([CH2:32][S:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[O:26]1
Reactant: O[C@@H]1[C@@H](CCl)OC(n2cnc3c(N[C@@H]4CCC[C@H]4O)ncnc32)[C@@H]1O
Reactant: Fc1ccccc1S
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O[C@@H]1[C@@H](CSc2ccccc2F)OC(n2cnc3c(N[C@@H]4CCC[C@H]4O)ncnc32)[C@@H]1O
Yield: 85.4 %

Procedure:
To a solution of 2-fluorothiophenol (38 mL, 406 mmol) in 2N sodium hydroxide (100 mL) was added 2-{6-[((1R,2R)-2-hydroxycyclopentyl)amino]purin-9-yl}(4S,5S,3R)-5-(chloromethyl)oxolane-3,4-diol (15.0 g, 40.6 mmol) in N,N-dimethylformamide (120 mL). The mixture was warmed to 100 C for 4 hours, following the progress of the reaction by TLC. The N,N-dimethylformamide was removed under reduced pressure, and the remaining mixture was diluted with water (200 mL), neutralized with acetic acid, extracted with ethyl acetate (3×125 mL), and the combined organic layers were dried over MgSO4. After removing the solvent under reduced pressure the residue was triturated with diethyl ether and filtered, to afford 16 grams of 2-{6-[((1R,2R)-2-hydroxycyclopentyl)amino]purin-9-yl}(4S,5 S,3R)-5-[(2-fluorophenylthio)methyl]oxolane-3,4-diol as a white powder (85% yield).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[C@H:28]([NH2:30])[CH3:29].C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:30][C@@H:28]([C:19]2[CH:20]=[CH:21][C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:18]=2)[CH3:29])[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: C[C@@H](N)c1ccc2ccccc2c1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: C[C@@H](Nc1nc(N)nc(-c2ccco2)c1C#N)c1ccc2ccccc2c1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, (R)-(−)-1-(2-naphthyl)ethylamine and DBU in DME. ES-MS m/e (%): 356 (M+H+, 100).
Reaction SMILES: O[C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:18][S:19](Cl)(=[O:21])=[O:20].CCN(CC)CC>>[CH3:18][S:19]([C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1cccc(-c2ccccc2)c1O
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(-c2ccccc2)c1S(C)(=O)=O

Procedure:
An ethereal solution (1 liter) containing 50.0 g (0.22 mol) of methyl 2-hydroxy-3-phenylbenzoate, 0.25 mole of methanesulfonyl chloride and 0.25 mole of Et3N was allowed to react at room temperature for 18 hours. The reaction mixture was washed with 1 N NaOH (1 × 1 liter) and H2O (1 × 500 ml). After drying with MgSO4 the ether solution was evaporated to give a yellow solid; yield 61.9 g (91.7%), mp. 101°-115°. Recrystallization of the crude product from benzene-hexane gave the analytical sample, mp. 120°-124°.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([O:26][CH3:27])=[C:12]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=3[F:25])[CH:13]=2)[N:8]([C@H:28]([C:32](C)(C)[O:33][SiH2]C(C)(C)C)[CH:29]([CH3:31])[CH3:30])[CH:7]=1)=[O:5])C.C(O)(C)C.[OH-].[Na+]>CCCCCCC>[Cl:24][C:20]1[C:19]([F:25])=[C:18]([CH:23]=[CH:22][CH:21]=1)[CH2:17][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][C:11]=1[O:26][CH3:27])[N:8]([C@H:28]([CH2:32][OH:33])[CH:29]([CH3:31])[CH3:30])[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[C:15]2=[O:16]
Reactant: CCOC(=O)c1cn([C@@H](C(C)C)C(C)(C)O[SiH2]C(C)(C)C)c2cc(OC)c(Cc3cccc(Cl)c3F)cc2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCCC
Solvent: CC(C)O
Product: COc1cc2c(cc1Cc1cccc(Cl)c1F)c(=O)c(C(=O)O)cn2[C@H](CO)C(C)C
Temperature: 70 °C
Reaction time: 3 h
Yield: 99.6 %

Procedure:
1-[(S)-1-(tert-butyldimethyl-silanyloxymethyl)-2-methylpropyl]-6-(3-chloro-2-fluorobenzyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester (900 mg) was added to isopropyl alcohol (3.6 mL), and 1N sodium hydroxide (3.6 mL) was added. After stirring at 70° C. for 3 hr, the completion of the reaction was confirmed by HPLC. The reaction mixture was cooled, and allowed to cool to room temperature. n-Heptane (5 mL) was added and, after stirring, the mixture was partitioned. The aqueous layer was washed with n-heptane (5 mL). 35% Hydrochloric acid (400 mg) was added to the aqueous layer, methylisopropylketone (10 mL) was added and, after stirring, the mixture was partitioned. The organic layer was washed successively with 8.5% aqueous sodium hydrogencarbonate solution (5 mL) (3 times), 0.5N hydrochloric acid (5 mL) containing sodium chloride (250 mg), and 10% brine (5 mL). After the washing, methylisopropylketone was evaporated under reduced pressure to give 6-(3-chloro-2-fluorobenzyl)-1-[(S)-1-hydroxymethyl-2-methylpropyl]-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (680 mg, yield 99.3%) as a yellow-white solid.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3](=[O:11])[CH2:2]1.Br[CH2:13][CH2:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[O:11]=[C:3]1[N:4]([CH2:13][CH2:14][O:15][C:16]2[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=2)[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[O:1][CH2:2]1
Reactant: O=C1COc2ccccc2N1
Reactant: O=Cc1ccc(OCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(OCCN2C(=O)COc3ccccc32)cc1
Temperature: 80 °C
Reaction time: 10 h
Yield: 91.2 %

Procedure:
A mixture of 2H-1,4-benzoxazin-3-(4H)-one (1.6 g, 10.7 mmol), 4-(2-bromoethoxy)benzaldehyde (2.95 g, 12.8 mmol) and potassium carbonate (5.93 g, 42.97 mmol) in dry dimethyl formamide (30 mL) was stirred at 80° C. for 10 h. Water (100 mL) was added and extracted with ethyl acetate (2×75 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried (Na2SO4), filtered and the solvent was evaporated. The residue was chromatographed over silica gel using a mixture of ethyl acetate and pet. ether (2:8) to afford the title compound (2.9 g, 91%) as a colorless solid. mp: 75-78° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH3:4].[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([OH:16])=[C:10]([CH:15]=1)[C:11]([O:13][CH3:14])=[O:12].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([O:16][CH2:2][CH2:3][CH3:4])=[C:10]([CH:15]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: CCCBr
Reactant: COC(=O)c1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCOc1ccc(Cl)cc1C(=O)OC
Temperature: 25 °C
Yield: 97.2 %

Procedure:
A mixture of 1-bromo-propane (1 ml, 11 mmol), methyl 5-chloro-2-hydroxy-benzoate (1.0 g, 5.4 mmol), potassium carbonate (1.5 g, 10.9 mmol), and acetonitrile (20 ml) was heated under reflux for 4 hours. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was partitioned between ethyl acetate (100 ml) and saturated aqueous sodium chloride solution (50 ml). The organic layer was concentrated under reduced pressure to provide methyl 5-chloro-2-propoxy-benzoate (1.2 g, 97% yield).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[C:15](Cl)[N:14]=[N:13][C:12]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][CH:29]=[CH:28]2>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[C:15]([NH:24][C:25]3[CH:26]=[C:27]4[C:31](=[CH:32][CH:33]=3)[NH:30][CH:29]=[CH:28]4)[N:14]=[N:13][C:12]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: CC(C)(C)c1ccc(-c2cc(Cl)nnc2-c2ccccc2)cc1
Product: CC(C)(C)c1ccc(-c2cc(Nc3ccc4[nH]ccc4c3)nnc2-c2ccccc2)cc1

Procedure:
Analogous to the procedure used to prepare Example 5(b), 4-(4-tert-butylphenyl)-6-chloro-3-phenylpyridazine, Example 78(d), (95 mg, 0.3 mmol) and 5-aminoindole (39 mg, 0.3 mmol, Aldrich) afforded the title compound as a light-yellow crystalline solid. MS (ESI, pos. ion) m/z: 419 (M+1). MP: 138–140° C.
Reaction SMILES: Br[C:2]1[CH:34]=[CH:33][C:5]([O:6][C:7]2[N:12]=[C:11]([O:13][C:14]3[CH:15]=[C:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:17]=[CH:18][CH:19]=3)[C:10]([CH2:28][CH3:29])=[N:9][C:8]=2[C:30](=[O:32])[NH2:31])=[CH:4][CH:3]=1.[CH3:35][N:36]1[CH2:41][CH:40]=[C:39](B2OC(C)(C)C(C)(C)O2)[CH2:38][CH2:37]1.CN(C)C=O.C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)(=O)C>[C:30]([C:8]1[N:9]=[C:10]([CH2:28][CH3:29])[C:11]([O:13][C:14]2[CH:15]=[C:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:17]=[CH:18][CH:19]=2)=[N:12][C:7]=1[O:6][C:5]1[CH:33]=[CH:34][C:2]([C:39]2[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH:38]=2)=[CH:3][CH:4]=1)(=[O:32])[NH2:31]
Reactant: CN1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: CCc1nc(C(N)=O)c(Oc2ccc(Br)cc2)nc1Oc1cccc(NC(=O)OC(C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1nc(C(N)=O)c(Oc2ccc(C3=CCN(C)CC3)cc2)nc1Oc1cccc(NC(=O)OC(C)(C)C)c1
Reaction time: 1 h
Yield: 27.5 %

Procedure:
To a mixture of tert-butyl (3-{[6-(4-bromophenoxy)-5-carbamoyl-3-ethylpyrazin-2-yl]oxy}phenyl)carbamate (540 mg), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (273 mg), and N,N-dimethylformamide (10 mL) were added a 1,1′-bis(diphenylphosphino)ferrocene palladium (II) dichloride-dichloromethane complex (83 mg) and cesium carbonate (665 mg), followed by reacting at 80° C. for 1 hour. The reaction mixture was left to be cooled, and then ethyl acetate was added thereto. The mixture was washed with water and saturated brine and dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; chloroform:methanol=1:0-9:1) and silica gel column chromatography (NH2 type, eluent; chloroform:methanol=100:0-98:2) to obtain tert-butyl [3-({5-carbamoyl-3-ethyl-6-[4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenoxy]pyrazin-2-yl}oxy)phenyl]carbamate (153 mg) as a pale yellow oily substance.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][OH:5].[C:10]([OH:23])(=O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].N#N>>[C:10]([O:1][CH2:2][C:3]([CH2:8][O:9][C:10](=[O:23])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])([CH2:6][O:7][C:10](=[O:23])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:4][O:5][C:10](=[O:23])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])(=[O:23])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: OCC(CO)(CO)CO
Reactant: CCCCCCCCCCCC(=O)O
Agent: N#N
Product: CCCCCCCCCCCC(=O)OCC(COC(=O)CCCCCCCCCCC)(COC(=O)CCCCCCCCCCC)COC(=O)CCCCCCCCCCC
Temperature: 215 °C

Procedure:
A 1000 ml round bottomed flask was charged with 619.9 g (0.12 mol) PEG 150 pentaerythritol and 96.0 g (0.48 mol) lauric acid. The mass was heated to 100° C. with a N2 sparge, 1.0 g. phosphoric acid and 0.1 g. hypophosphorus acid were charged. The batch was heated to 215° C. while collecting the water of reaction, and maintained until an acid value of 12.4 was reached. The finished material was a white waxy solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6]>C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C:5](=[O:6])[C:2]2[CH:3]=[CH:4][CH:8]=[CH:9][CH:10]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: O=C(Cl)c1cccc(Br)c1
Solvent: c1ccccc1
Product: O=C(c1ccccc1)c1cccc(Br)c1

Procedure:
reacting m-bromobenzoyl chloride from A) with benzene in the presence of a Friedel-Crafts catalyst to form m-bromobenzophenone;
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].Br[C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1/[C:8](=[CH:16]/[C:17]1[NH:18][CH:19]=[CH:20][C:21]=1[O:22][CH3:23])/[C:9](=[O:15])[NH:10]2>CN(C=O)C.CCN(CC)CC>[OH:4][CH2:1][C:2]#[C:3][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1/[C:8](=[CH:16]/[C:17]1[NH:18][CH:19]=[CH:20][C:21]=1[O:22][CH3:23])/[C:9](=[O:15])[NH:10]2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Reactant: C#CCO
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CCO)c21

Procedure:
Using Method D above, propargyl alcohol (43.9 mg, 0.78 mmol) (Aldrich) was coupled with (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (100 mg, 0.31 mmol) (Starting Material 1 supra) using DPPFPdCl2 (12.8 mg) and Cul (3 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 85° C. for 18 h to yield (Z)-1,3-dihydro-4-(3-hydroxy-1-propynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 42 mg, 46%).