Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)O.[CH:6]([N:19]1[CH2:22][CH2:21][CH:20]1[C:23](=N)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(=O)(O)[O-:32].[Na+]>CO>[CH:6]([N:19]1[CH2:22][CH2:21][CH:20]1[C:23](=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C([O-])O
Reactant: N=C(c1ccccc1)C1CCN1C(c1ccccc1)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: O=C(c1ccccc1)C1CCN1C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Add 68 ml of 3.6N aqueous sulfuric acid to a stirred solution of 40.0 g of 1-benzhydryl-2-benzimidoylazetidine in 800 ml. of methanol. Stir under a nitrogen atmosphere for 1.5 hours at room temperature. Slowly pour the mixture, with continuous stirring, into 234 ml. of 1.1N aqueous sodium bicarbonate. Filter the resultant solid, and extract the filter cake with methylene chloride. Combine the methylene chloride extracts with the methanolic filtrate and remove all solvnt in vacuo. Dissolve the residual solid in ether, wash with water, and dry over anhydrous sodium sulfate. Remove the drying agent, concentrate the solution in vacuo to a volume of 350 ml. and triturate the solid which precipitates. Filter to obtain the analytically pure product, m.p 114°-115° C.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[CH:9]1(B(O)O)[CH2:11][CH2:10]1.C(=O)([O-])[O-].[Na+].[Na+].N1C=CC=CC=1C1C=CC=CN=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClC(Cl)C>[CH:9]1([N:6]2[CH:7]=[CH:8][C:4]([N+:1]([O-:3])=[O:2])=[N:5]2)[CH2:11][CH2:10]1
Reactant: OB(O)C1CC1
Reactant: O=[N+]([O-])c1cc[nH]n1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CC(Cl)Cl
Product: O=[N+]([O-])c1ccn(C2CC2)n1
Temperature: 70 °C
Yield: 84.6 %

Procedure:
A 250-mL three-neck round-bottomed flask equipped with a reflux condenser and magnetic stirrer was purged with nitrogen and charged with 3-nitro-(1H)pyrazole (1.30 g, 11.5 mmol), cyclopropylboronic acid (1.98 g, 23.0 mmol), sodium carbonate (3.66 g, 34.5 mmol), 2,2′-bipyridyl (3.58 g, 23.0 mmol), dichloroethane (60 mL) and copper(II) acetate (2.08 g, 11.5 mmol). The reaction mixture was heated at 70° C. (oil bath temperature) for 3 h. After this time, another portion of cyclopropyl boronic acid (1.98 g, 23.0 mmol) was added, and the mixture was heated for 3 h. After this time, the mixture was cooled to room temperature and filtered. The filtrate was diluted with ethyl acetate (350 mL) and water (40 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3×150 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 0% to 100% ethyl acetate/hexanes) to afford an 85% yield (1.49 g) of 123a as a colorless oil: 1H NMR (500 MHz, CDCl3) d 7.53 (d, 1H, J=2.4 Hz), 6.87 (d, 1H, J=2.5 Hz), 3.71 (m, 1H), 1.25 (m, 2H), 1.12 (m, 2H); MS (APCI+) m/z 154.1 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:18]=[C:17]3[C:13]([CH:14]=[CH:15][N:16]3[C:19]3[N:24]=[CH:23][N:22]=[C:21]([NH2:25])[CH:20]=3)=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O>CO.O1CCOCC1.[Ni]>[NH2:1][C:4]1[CH:5]=[C:6]([C:10]2[CH:18]=[C:17]3[C:13]([CH:14]=[CH:15][N:16]3[C:19]3[N:24]=[CH:23][N:22]=[C:21]([NH2:25])[CH:20]=3)=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: Nc1cc(-n2ccc3ccc(-c4cccc([N+](=O)[O-])c4)cc32)ncn1
Agent: [Ni]
Solvent: C1COCCO1
Solvent: CO
Product: Nc1cccc(-c2ccc3ccn(-c4cc(N)ncn4)c3c2)c1
Reaction time: 1.5 h
Yield: 43.3 %

Procedure:
6-(6-(3-Nitrophenyl)-1H-indol-1-yl)pyrimidin-4-amine (400 mg, 1.21 mmol) was dissolved in methanol/dioxane (1:1, 6 mL) and Raney nickel was added. The mixture solution was stirred under hydrogen gas (1 atm) for 1.5 hours. The mixture solution was filtered through a diatomite pad, and the filtrate was concentrated under reduced pressure. After adding methylene chloride to the residue, thus prepared solid was filtered. 6-(6-(3-Aminophenyl)-1H-indol-1-yl)pyrimidin-4-amine (158 mg) was yielded as white solid. Concentration of the filtrate followed by column chromatography (silica gel, EA:Hx=1:1→MC:MeOH=20:1) further gave the target compound.
Reaction SMILES: [ClH:1].[CH:2]1([NH:5][C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]=[C:17]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][C@H:25]4C)[C:18]4[CH2:23][NH:22][CH2:21][C:19]=4[N:20]=3)=[C:11]([F:31])[CH:10]=2)=[O:7])[CH2:4][CH2:3]1.C1(NC(=O)NC2C=CC(C3N=C(N4CCOCC4)C4CN(C(OC(C)(C)C)=O)CC=4N=3)=C(F)C=2)CC1>>[ClH:1].[CH:2]1([NH:5][C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]=[C:17]([N:24]4[CH2:25][CH2:26][O:27][CH2:28][CH2:29]4)[C:18]4[CH2:23][NH:22][CH2:21][C:19]=4[N:20]=3)=[C:11]([F:31])[CH:10]=2)=[O:7])[CH2:3][CH2:4]1
Reactant: C[C@@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2F)nc2c1CNC2
Agent: CC(C)(C)OC(=O)N1Cc2nc(-c3ccc(NC(=O)NC4CC4)cc3F)nc(N3CCOCC3)c2C1
Agent: Cl
Product: O=C(Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CNC3)c(F)c1)NC1CC1
Yield: 82 %

Procedure:
Method as described for (R)-1-cyclopropyl-3-(3-fluoro-4-(4-(3-methylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea hydrochloride (intermediate 33) step 3 using tert-Butyl 2-(4-(3-(cyclopropylureido)-2-fluorophenyl)-4-morpholino-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (example 143). The resulting solid was triturated from methanol/ether to give a cream solid (82% yield).
Reaction SMILES: [NH2:1][C@H:2]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33](=[O:49])[N:34]([CH2:42][CH2:43][O:44][Si](C)(C)C)[CH2:35][CH2:36][O:37][Si](C)(C)C)=[CH:27][CH:26]=1)[C:3]([NH:5][C@H:6]([C:15]1[NH:19][C:18]2[CH:20]=[C:21]([I:24])[CH:22]=[CH:23][C:17]=2[N:16]=1)[C@H:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:8])=[O:4].[O:50]=[C:51](Cl)OC(Cl)(Cl)Cl>>[OH:37][CH2:36][CH2:35][N:34]([CH2:42][CH2:43][OH:44])[C:33](=[O:49])[CH2:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([C@@H:2]2[C:3](=[O:4])[N:5]([C@H:6]([C:15]3[NH:19][C:18]4[CH:20]=[C:21]([I:24])[CH:22]=[CH:23][C:17]=4[N:16]=3)[C@H:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:8])[C:51](=[O:50])[NH:1]2)=[CH:26][CH:27]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: C[C@@H](c1ccccc1)[C@H](NC(=O)[C@H](N)c1ccc(OCC(=O)N(CCO[Si](C)(C)C)CCO[Si](C)(C)C)cc1)c1nc2ccc(I)cc2[nH]1
Product: C[C@@H](c1ccccc1)[C@@H](c1nc2ccc(I)cc2[nH]1)N1C(=O)N[C@H](c2ccc(OCC(=O)N(CCO)CCO)cc2)C1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 27.7 %

Procedure:
After cyclization of (R)-2-amino-2-(4-{[bis-(2-trimethylsilanyloxy-ethyl)-carbamoyl]-methoxy}-phenyl)-N-[(1S,2S)-1-(6-iodo-1H-benzoimidazol-2-yl)-2-phenyl-propyl]-acetamide with diphosgene was complete and the reaction mixture had been partitioned between ethyl acetate and ice/water (as described in example 1, step 1-G) 1N aqueous hydrochloric acid (20 mL) was added to the ethyl acetate extracts and the mixture was stirred at ambient temperature for 15 minutes. The layers were separated and the aqueous layer was extracted with ethyl acetate (2×50 mL) and washed with brine (50 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by gradient flash chromatography using silica gel eluted with from 0 to 10% v/v methanol in dichloromethane. The product containing fractions were combined and concentrated to give a solid which was triturated with a 1:1 v/v mixture of dichloromethane/ether (1 mL). The suspension was stirred for 1 hour then filtered and dried to give N,N-bis-(2-hydroxy-ethyl)-2-(4-{(R)-1-[(1S,2S)-1-(6-iodo-1H-benzoimidazol-2-yl)-2-phenyl-propyl]-2,5-dioxo-imidazolidin-4-yl}-phenoxy)-acetamide (30 mg, 27.7%).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN1CCCC1=O.C(OCC)(=O)C>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:33]=[CH:34][C:35]([NH:38][C:12]([C:10]3[N:11]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[O:8][C:9]=3[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:36][CH:37]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (2.5 g, 9.76 mmol), 4-(4-amino-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (2.65 g, 10.34 mmol), and triethylamine (4.1 mL, 29.3 mmol) were dissolved in 50 mL of 1-methyl-2-pyrrolidinone. To this solution was added (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP, 4.51 g, 10.34 mmol) in one portion. The mixture was stirred at room temperature overnight and then diluted with 250 mL of ethyl acetate. The organic layer was washed with saturated sodium bicarbonate (2×50 mL), dried over magnesium sulfate, filtered and evaporated to dryness under vacuum. The residue was purified by chromatography over a silica gel plug (eluting with ethyl acetate/methylene chloride) to yield 4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperazine-1-carboxylic acid tert-butyl ester as an amorphous solid. ES-MS calcd for C26H27F3N4O4 (m/e) 516.52, obsd 517 (M+H).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[N:9][C:10]3[C:15]([N:16]=2)=[CH:14][C:13]([C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=2)=[CH:12][CH:11]=3)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>N1C=CC=CC=1>[N:1]1([C:7]2[CH:8]=[N:9][C:10]3[C:15]([N:16]=2)=[CH:14][C:13]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][S:25]([CH3:24])(=[O:27])=[O:26])=[CH:19][CH:18]=2)=[CH:12][CH:11]=3)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: Nc1ccc(-c2ccc3ncc(N4CCOCC4)nc3c2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(-c2ccc3ncc(N4CCOCC4)nc3c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.6 %

Procedure:
A mixture of 4-(3-morpholin-4-yl-quinoxalin-6-yl)-phenylamine [intermediate example 4.1] (100 mg) and pyridine (0.5 mL) was treated with a solution of methane sulfonyl chloride (75 mg, 0.65 mmol) in pyridine (0.6 mL) and stirred at room temperature overnight. The reaction was partitioned between dichloromethane and water, the phases separated and the organic layer concentrated in vacuo. The residue was triturated with dichloromethane and filtered to give the title compound (71 mg). UPLC-MS: RT=0.97 min; m/z (ES+) 385.19 [MH+]; required MW=384.46.
Reaction SMILES: [C:1]1([CH:9]=[C:7]([OH:8])[CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].C([O:12][C:13]([CH:15]1[CH:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:19][CH2:18][CH2:17][C:16]1=O)=O)C.Cl>C(O)C>[OH:2][C:1]1[C:9]2[C:16]3[CH2:17][CH2:18][CH2:19][CH:20]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:15]=3[C:13](=[O:12])[O:8][C:7]=2[CH:6]=[C:4]([OH:5])[CH:3]=1
Reactant: CCOC(=O)C1C(=O)CCCC1c1ccccc1
Reactant: Oc1cc(O)cc(O)c1
Agent: Cl
Solvent: CCO
Product: O=c1oc2cc(O)cc(O)c2c2c1C(c1ccccc1)CCC2

Procedure:
A solution of phloroglucinol (0.7 g) and 2-ethoxycarbonyl-3-phenylcyclohexanone (1.5 g) in ethanol was treated with dry HCl as described in example 1a. The product was first recrystallized from ethanol-water (1:1) and then triturated with ether. Yield 0.61 g.
Reaction SMILES: [Na].[OH:2][N:3]1[C:7](=[O:8])[C:6]2=[CH:9][CH:10]=[CH:11][CH:12]=[C:5]2[C:4]1=[O:13].Cl.Cl[CH2:16][C:17]1[N:18]=[CH:19][NH:20][CH:21]=1>C(O)C>[NH:20]1[CH:21]=[C:17]([CH2:16][O:2][N:3]2[C:4](=[O:13])[C:5]3=[CH:12][CH:11]=[CH:10][CH:9]=[C:6]3[C:7]2=[O:8])[N:18]=[CH:19]1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: ClCc1c[nH]cn1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: O=C1c2ccccc2C(=O)N1OCc1c[nH]cn1
Temperature: 25 °C
Yield: 58.6 %

Procedure:
A mixture of ethanol and 270 mg of sodium was cooled in an ice-bath and 1.91 g of N-hydroxyphthalimide was added to the mixture. 594 mg of 4-(chloromethyl)imidazole hydrochloride was added thereto under stirring at room temperature and the resulting mixture was stirred for 14 hours. The solvent was distilled off and SSB was added to the residue and the mixture was extracted with chloroform. The extract was washed with SSC and dried with sodium sulfate and then concentrated to dryness. The residue was recrystallized from a mixture of diisopropyl ether and ether to give 553 mg of N-((imidazol-4-yl)methoxy)phthalimide with mp 163°-165° C.
Reaction SMILES: [CH2:1]([NH:8][C@@:9]([CH3:15])([CH2:13][OH:14])[C:10]([OH:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:17][C:18](Cl)=[O:19]>>[CH2:1]([N:8]1[C:18](=[O:19])[CH2:17][O:14][CH2:13][C@@:9]1([CH3:15])[C:10]([OH:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@](CO)(NCc1ccccc1)C(=O)O
Reactant: O=C(Cl)CCl
Product: C[C@@]1(C(=O)O)COCC(=O)N1Cc1ccccc1
Yield: 65 %

Procedure:
(S)-2-(benzylamino)-3-hydroxy-2-methylpropanoic acid (2.09 g, 10 mmol) was reacted with chloroacetyl chloride (1.74 g, 15.4 mmol) according to the procedure as described in Example 46, Step B to give the title compound as a gray solid (1.62 g, 65%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [Cl:1][C:2]([F:8])(I)[C:3]([F:6])([F:5])[Cl:4].FC(F)=C(F)F.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.ClC(F)(C(F)(F)Cl)C(F)(F)C(F)(F)[C:37]([F:43])([F:42])[C:38]([F:41])([F:40])[I:39]>>[Cl:1][C:2]([F:8])([C:3]([F:6])([F:5])[Cl:4])[C:37]([F:43])([F:42])[C:38]([F:41])([F:40])[I:39]
Reactant: FC(F)(Cl)C(F)(Cl)C(F)(F)C(F)(F)C(F)(F)C(F)(F)I
Reactant: FC(F)(Cl)C(F)(Cl)I
Agent: FC(F)=C(F)F
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: FC(F)(Cl)C(F)(Cl)C(F)(F)C(F)(F)I
Temperature: 130 °C
Yield: 51 %

Procedure:
A mixture of 400 g of 1,2-dichloro-1-iodotrifluoroethane, 140 g of tetrafluoroethene and 4 g of benzoyl peroxide was heated in 1 L autoclave at 130° C. for 4.5 hours. GC analysis of the reaction mixture (458 g) indicated 37% of starting material, 51% of desired product and 7% of 5,6-dichloro-1-iodoperfluorohexane. The reaction mixture was distilled on a 91 cm spinning band column to give 18.6 g of lower boiler, bp 80°-99° C. (mainly starting material), 138.6 g of starting material, bp 100°-102° C., 50.1 g of mixture of starting material and desired product, bp 103°-140° C. and 211 g of pure desired product, bp 140°-142° C.
Reaction SMILES: [C:1]([N:8]([CH3:20])[C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH2:21][CH2:22][C:23]([O:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:27])=[O:24].ClC(OCC(C)C)=O>>[C:1]([N:8]([CH3:20])[C@H:9]([C:17]([NH:21][CH2:22][C:23]([O:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:27])=[O:24])=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: NCC(=O)OC(=O)c1ccccc1
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](Cc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Product: CN(C(=O)OC(C)(C)C)[C@@H](Cc1ccccc1)C(=O)NCC(=O)OC(=O)c1ccccc1
Yield: 52 %

Procedure:
Condensation of BocMePheOH (5.0 g.) and HGlyOBz (3.75 g.) by the mixed anhydride method using isobutyl chloroformate gave BocMePhe-GlyOBz in 52% yield. De-t-butoxycarbonylation of BocMePhe-GlyOBz (2.0 g.) using hydrogen chloride in ethyl acetate gave HMePhe-GlyOBz in 95% yield.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[CH3:9][NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:9][N:10]([CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: ClCc1ccccn1
Reactant: CNc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(Cc1ccccn1)c1ccccc1
Temperature: 120 °C
Reaction time: 4 h
Yield: 50.2 %

Procedure:
A mixture of 2-chloromethylpyridine (50 g), N-methylaniline (42 g), and potassium carbonate (120 g) in N,N-dimethylformamide (200 ml) was stirred for 4 hours at 120° C. The reaction mixture was cooled to room temperature, added to water (1 l), and extracted with ether. The ether extract was washed with water and then treated with activated carbon. After drying over magnesium sulfate, the ether extract was filtered and concentrated. The residue was crystallized from isopropyl alcohol to give N-methyl-N-(2-pyridylmethyl)aniline (39 g).
Reaction SMILES: [OH-].[Na+].[C:3]1([CH2:9][OH:10])([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4]1.Cl[C:12]1[C:13]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)=[C:19]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[O:18][C:14]=2[N:15]=[CH:16][N:17]=1.Cl>C1(C)C=CC=CC=1.COCCOC.O.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:28][O:27][C:24]1[CH:23]=[CH:22][C:21]([C:20]2[C:13]3[C:12]([O:8][CH2:7][C:3]4([CH2:9][OH:10])[CH2:6][CH2:5][CH2:4]4)=[N:17][CH:16]=[N:15][C:14]=3[O:18][C:19]=2[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:26][CH:25]=1
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Cl)c23)cc1
Reactant: OCC1(CO)CCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=S(=O)([O-])O
Solvent: COCCOC
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(OCC4(CO)CCC4)c23)cc1
Temperature: 70 °C
Reaction time: 17 h

Procedure:
Add 2.6 ml of an 11.25N sodium hydroxide solution at 70° C. to a solution of 1.72 g (14.85 mmol) of cyclobutane-1,1-diyldimethanol [F. X. Tavares, J. Med. Chem. 2004, 47 (21), 5057-5068] in 20 ml of toluene, 8 ml of 1,2-dimethoxyethane and 8 ml of water. After adding 0.10 g (0.30 mmol) of tetra-n-butylammonium hydrogen sulphate and 1.00 g (2.97 mmol) of 4-chloro-5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidine, stir the reaction mixture at 70° C. for 17 h. After cooling to room temperature, adjust to pH 7 with concentrated hydrochloric acid. Extract three times with 50 ml of dichloromethane each time. Wash the combined organic extracts with satd. sodium chloride solution, dry over sodium sulphate and filter. Concentrate the filtrate under reduced pressure. Stir the residue in acetonitrile, filter and purify the filtrate by means of preparative RP-HPLC (gradient: water/acetonitrile). 0.30 g (24% of theory) of the desired product are obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[NH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>>[N:1]1[CH:2]=[CH:3][C:4]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:12]([N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[O:14])=[CH:15][CH:16]=2)=[CH:5][CH:6]=1
Reactant: O=C(O)c1ccc(Nc2ccncc2)cc1
Reactant: C1CCNCC1
Product: O=C(c1ccc(Nc2ccncc2)cc1)N1CCCCC1
Yield: 49.5 %

Procedure:
1-[4-(4-Pyridinylamino)benzoyl]piperidine was prepared from 4-(4-pyridinylamino)benzoic acid and piperidine according to a procedure analogous to that of Example 48(b), and was obtained in 49.5% yield in the form of a buff powder, m.p. 170°-172° C. when recrystallized from acetonitrile.
Reaction SMILES: [CH3:1][C:2](=[O:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH3:13][CH:14]([CH2:21][CH3:22])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>>[CH3:13][CH:14]([CH:15]([C:2]([OH:12])([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:21][CH3:22]
Reactant: CCCCCCCCCC(C)=O
Reactant: CCOC(=O)CC(C)CC
Product: CCCCCCCCCC(C)(O)C(C(=O)OCC)C(C)CC

Procedure:
Pyrolysis of a sample of the prepared hydroxy-ester at about 300° C. for 2 minutes yields a 1:1 mixture of 2-undecanone and ethyl 3-methylvalerate.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12]([C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]=1)=[O:13].[C:21]([O:24][C:25]([CH3:30])([CH3:29])[C:26](Cl)=[O:27])(=[O:23])[CH3:22]>>[C:21]([O:24][C:25]([CH3:30])([CH3:29])[C:26]([NH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12]([C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]=1)=[O:13])=[O:27])(=[O:23])[CH3:22]
Reactant: Cc1ccnc(C(=O)c2[nH]c3cc(Cl)ccc3c2N)c1
Reactant: CC(=O)OC(C)(C)C(=O)Cl
Product: CC(=O)OC(C)(C)C(=O)Nc1c(C(=O)c2cc(C)ccn2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 19 employing 3-amino-6-chloro-2-(4-methylpyridine-2-carbonyl)indole (Example 70) and 2-acetoxyisobutyryl chloride. m.p.: 222-223° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[C:6]([O:8][CH3:9])=[O:7].[Br:15]Br>CC(O)=O>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:12]([O:13][CH3:14])=[CH:11][C:10]=1[Br:15]
Reactant: COC(=O)c1ccc(OC)c(OC)c1
Reactant: BrBr
Solvent: CC(=O)O
Product: COC(=O)c1cc(OC)c(OC)cc1Br
Reaction time: 0.75 h
Yield: 63.6 %

Procedure:
To 10.00 g (51 mmol) of methyl 3,4 dimethoxybenzoate (6) in 50 mL of AcOH at 0° C. was added 8.90 g (56 mmol) of Br2 in 50 mL of AcOH over 1.5 h. The ice bath was removed and the mixture stirred 45 min. The reaction was quenched by pouring into 700 mL of H2O, stirred 30 min, left quiescent for 1 h, and filtered. The collected solid was washed with H2O and washed with sat. aq. Na2S2O3. The solid was partially dried, dissolved in 300 mL hot MeOH, and the resultant solution was cooled. The cool methanolic solution of product was treated with 200 mL of H2O and the white solid filtered to give 8.92 g (64% yield) of methyl-2-bromo-4,5-dimethoxybenzoate (7) as a white powder. The compound matched the physical and spectral properties of the known compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH:18]=O>CC(C)=O>[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH:18]=[CH:12][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[C:2]([OH:1])[CH:3]=[CH:4][CH:5]=2)[N:10]=1
Reactant: O=Cc1ccco1
Reactant: Cc1ccc2cccc(O)c2n1
Solvent: CC(C)=O
Product: Oc1cccc2ccc(C=Cc3ccco3)nc12
Temperature: 25 °C

Procedure:
A mixture of 8-hydroxyquinaldine (5.09 g) and 2-furaldehyde (8.0 mL) are heated at reflux overnight. The reaction is cooled to room temperature. The residue is taken up in acetone and adsorbed onto silica. A silica gel column eluting with 100% CH2Cl2 is run and the product-containing fractions evaporated under reduced pressure to give an orange/yellow oil. The product is crystallized with EtOH/H2O, filtered, washed thoroughly with water, and dried (1.18 g).
Reaction SMILES: CN(C)C=[N:4][C:5]1[S:9][C:8]2[CH:10]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[S:12][C:7]=2[C:6]=1[C:18]#[N:19].Cl>C(O)C>[NH2:4][C:5]1[S:9][C:8]2[CH:10]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[S:12][C:7]=2[C:6]=1[C:18]#[N:19]
Reactant: CCOC(=O)c1cc2sc(N=CN(C)C)c(C#N)c2s1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cc2sc(N)c(C#N)c2s1
Yield: 80 %

Procedure:
A mixture of 319 parts of N,N-dimethyl-N'-(3-cyano-5-ethoxycarbonylthieno[3,2-b]thien-2-yl)formamidine, 2,000 parts of ethanol and 210 parts of concentrated hydrochloric acid was heated at the boil for 1 hour. After cooling down, the precipitate was filtered off with suction, washed with methanol and then with water and dried. This gave 210 parts (80% of theory) of ethyl 2-amino-3-cyanothieno[3,2-b]thiophene-5-carboxylate.