Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[Cl:5][CH:6]([CH3:10])[C:7](Cl)=[O:8].[NH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][C:12]1=[O:21]>C(=S)=S>[Cl:5][CH:6]([CH3:10])[C:7]([C:17]1[CH:16]=[C:15]2[C:20](=[CH:19][CH:18]=1)[NH:11][C:12](=[O:21])[CH2:13][CH2:14]2)=[O:8]
Reactant: O=C1CCc2ccccc2N1
Reactant: CC(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(Cl)C(=O)c1ccc2c(c1)CCC(=O)N2
Yield: 85.7 %

Procedure:
A suspension of 72.5 g (0.544 mol) of AlCl3 in 800 mL of CS2 was stirred under dry N2 while 14.1 mL (20.0 g, 0.177 mol) of 2-chloropropionyl chloride was added followed by 20.0 g (0.136 mol) of 3,4-dihydroquinolin-2(1H)-one. The reaction mixture was refluxed for 4 h at which time a separation of phases was noted. The reaction was quenched by pouring onto ice with vigorous stirring. The pale yellow precipitate which formed was separated by filtration, washed with water and dried overnight over P2O5 to give 27.7 g (91%) of the desired product, m.p. 236.5-238° C.
Reaction SMILES: [C:1]([O:5][C:6]1[C:7]([CH:12]=O)=[N:8][CH:9]=[CH:10][N:11]=1)([CH3:4])([CH3:3])[CH3:2].[C:14]([C:17]1[CH:30]=[CH:29][CH:28]=[CH:27][C:18]=1[O:19][CH2:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)(=[O:16])[NH2:15].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCl.C(OCC)(=O)C>[C:1]([O:5][C:6]1[C:7]([CH2:12][N:24]2[CH2:23][CH2:22][CH:21]([CH2:20][O:19][C:18]3[CH:27]=[CH:28][CH:29]=[CH:30][C:17]=3[C:14]([NH2:15])=[O:16])[CH2:26][CH2:25]2)=[N:8][CH:9]=[CH:10][N:11]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)Oc1nccnc1C=O
Reactant: NC(=O)c1ccccc1OCC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)Oc1nccnc1CN1CCC(COc2ccccc2C(N)=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.8 %

Procedure:
After dissolving 106 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and 105 mg of 4-(2-carbamoylphenoxymethyl)piperidine in 5 ml of dichloromethane, 153 mg of sodium triacetoxyborohydride was added and the mixture was stirred overnight at room temperature. Aqueous sodium bicarbonate solution was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by NH silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (171 mg, 95% yield).
Reaction SMILES: N1([CH2:7][N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)CCCCC1.C(Cl)(=O)C.[C:18]([C:21]1[CH:22]=[C:23]2[N:31]3[C:26](=[CH:27][CH:28]=[C:29]([O:32][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[C:30]=13)[C:25]([CH2:40][CH3:41])=[C:24]2[C:42]1[CH:47]=[CH:46][C:45]([O:48][CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)=[CH:44][CH:43]=1)(=[O:20])[CH3:19]>C(COC)OC>[CH2:33]([O:32][C:29]1[C:30]2[N:31]3[C:26](=[CH:27][CH:28]=1)[C:25]([CH2:40][CH3:41])=[C:24]([C:42]1[CH:47]=[CH:46][C:45]([O:48][CH2:49][C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)=[CH:44][CH:43]=1)[C:23]3=[CH:22][C:21]=2[C:18](=[O:20])[CH2:19][CH2:7][N:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: C1CCN(CN2CCCCC2)CC1
Reactant: CCc1c(-c2ccc(OCc3ccccc3)cc2)c2cc(C(C)=O)c3c(OCc4ccccc4)ccc1n23
Solvent: CC(=O)Cl
Solvent: COCCOC
Product: CCc1c(-c2ccc(OCc3ccccc3)cc2)c2cc(C(=O)CCN3CCCCC3)c3c(OCc4ccccc4)ccc1n23
Temperature: 25 °C
Reaction time: 16 h
Yield: 28.5 %

Procedure:
Dipiperidinomethane (0.3 ml, 1.5 mmol) was dissolved in 20 ml of dimethoxyethane and acetyl chloride (0.11 ml, 1.5 mmol) was added. The mixture was stirred for 30 minutes, while 4-acetyl-5-benzyloxy-2-(4benzyloxyphenyl)-1-ethylpyrrolo[2,1,5-cd]indolizine (0.5 g, 1.0 mmol) was added and HCl-gas was bubbled through the mixture for 15 minutes. The reaction mixture was refluxed for 5 hours and stirred at room temperature for 16 hours. The solvent was evaporated, and the crude HCl-salt was purified by column chromatography over silica gel 60, using 5% of methanol in dichloromethane as the eluent. Fractions containing the HCl-salt were combined and the solvent was evaporated. The salt was dissolved in 20 ml of dry dichloromethane and 2.13 g sodium sulfate and 2.76 g potassium carbonate was added. The mixture was stirred at room temperature for 24 hours. Remaining salts were filtered off, and the solvent was evaporated. The crude product was purified by column chromatography over silica gel 60, using 5% methanol in dichloromethane as the eluent to afford 170 mg (28%) of 5-benzyloxy-2-(4-benzyloxyphenyl)-1-ethyl-4-(1-oxo-3-piperidinopropyl)pyrrolo[2,1,5-cd]indolizine as an oil. 1H--NMR (CDCl3, 200 MHz) δ: 1.35-1.75 (m, 9 H); 2.34-3.75 (m, 10 H); 5.17 (s, 4 H); 7.10-7.78 (m, 17 H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:4][C:5](=[O:18])[N:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.C(N(CC)CC)C.[C:33](Cl)(=[O:38])[O:34][CH:35]([CH3:37])[CH3:36]>ClCCl>[CH3:1][C:2]1[C:3]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([C:33]([O:34][CH:35]([CH3:37])[CH3:36])=[O:38])[CH2:22][CH2:21]2)=[CH:4][C:5](=[O:18])[N:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:15])=[O:16])=[CH:10][CH:9]=2)[CH:7]=1
Reactant: Cc1cn(-c2ccc(S(C)(=O)=O)cc2)c(=O)cc1OC1CCNCC1
Reactant: CC(C)OC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cn(-c2ccc(S(C)(=O)=O)cc2)c(=O)cc1OC1CCN(C(=O)OC(C)C)CC1

Procedure:
The compound obtained in Example 160, Step A (25 mg, 0.069 mmol) was dissolved in dichloromethane (0.5 mL) to which was then added triethylamine (0.029 mL, 0.207 mmol) and isopropyl carbonochloridate (10.1 mg, 0.083 mmol). After 45 minutes the solvent was removed in vacuo and the residue purified by passing through a UCT (United Chemical Technologies) 2.5 g C-18 cartridge (#CEC181(2500)6) and eluting as follows;
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:15]([OH:17])=[O:16])[CH2:13]Cl)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C(=O)([O-])[O-].[Na+].[Na+].[C:24]1([SH:30])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl>O>[C:1]([NH:11][C@H:12]([C:15]([OH:17])=[O:16])[CH2:13][S:30][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: Sc1ccccc1
Reactant: O=C(N[C@@H](CCl)C(=O)O)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(N[C@@H](CSc1ccccc1)C(=O)O)OCc1ccccc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
N-Carbobenzyloxy-β-chloro-L-alanine (0.108 g, 0.42 mmol) was dissolved in 0.5 ml of water and, then, 0.097 g (0.92 mmol) of sodium carbonate was added. Thereafter, 0.054 g (0.50 mmol) of thiophenol was added dropwise at room temperature in a nitrogen gas atmosphere. After 2 hours of stirring at 60° C., the reaction mixture was cooled with ice and acidified with 1 N hydrochloric acid, and then extracted with ethyl acetate. The solvent was distilled off and the residue was purified by column chromatography to give 0.112 g (0.34 mmol, 81%) of N-carbobenzyloxy-S-phenyl-L-cysteine. The compound obtained had an optical purity of not less than 98% e.e. The optical purity was determined by HPLC. The analytical conditions are shown below.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]([O:8][CH3:9])=[O:7].C=O.[C:12]([BH3-])#N.[Na+]>CO>[CH3:12][N:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)C1CCCN1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1CCCN1C
Temperature: 2.5 °C
Reaction time: 2 h

Procedure:
Methyl pyrrolidine-2-carboxylate 10b crude product (5 g) was dissolved in 100 mL of methanol. The solution was cooled to 0-5° C. in an ice-water bath, followed by addition of 13 mL of 40% formaldehyde. The reaction mixture was warmed up to room temperature and stirred for 2 hours, then cooled to 0-5° C. in an ice-water bath, and sodium cyanoborohydride (5.45 g, 87.20 mmol) was added in batches. The reaction mixture was warmed up to room temperature and stirred for 24 hours. The mixture was concentrated under reduced pressure and added with 5 mL of water, extracted with dichloromethane (5 mL×3). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain methyl 1-methylpyrrolidine-2-carboxylate 10c (4.7 g, yield 70.1) crude product as a brown oil.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH2:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](=[O:21])[NH:13][N:12]=1.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C>[O:21]=[C:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:11]([CH2:10][NH:9][C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:12][NH:13]1
Reactant: O=C(Cl)c1ccccc1
Reactant: NCc1n[nH]c(=O)c2ccccc12
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NCc1n[nH]c(=O)c2ccccc12)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.2 %

Procedure:
Triethylamine (5.9 ml, 42 mmol) was added dropwise to a stirred suspension of 4-aminomethyl-2H-phthalazin-1-one hydrochloride (Geterotsikl. Soedin, 1972, (9), 15) (3.00 g, 14.2 mmol) in DMF (150 ml) at room temperature under nitrogen. The mixture was stirred for 1.5 h before the addition of benzoyl chloride (2.5 ml, 22 mmol) and then stirred at room temperature overnight. The reaction mixture was filtered and water added to the filtrate to form a solid. The mixture was cooled and the solid collected by filtration, washed successively with diethyl ether and isohexane, and dried in vacuo to give the title-compound (3.18 g, 80%), 1H NMR (360 MHZ, d6-DMSO) δ 4.81 (2H, d, J=5.6 Hz, CH2), 7.43-7.53 (3H, m, 3 of Ar—H), 7.83-7.96 (4H, m, 4 of Ar—H), 8.08 (1H, d, J=7.9 Hz, Ar—H), 8.28 (1H, dd, J=7.8 and 1.2 Hz, Ar—H), 8.98 (1H, br s, NH), 12.62 (1H, s NH).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH2:16]([C@H:21]1[CH2:26][CH2:25][C@H:24]([C:27]([OH:29])=[O:28])[CH2:23][CH2:22]1)[CH2:17][CH2:18][CH2:19][CH3:20].O[C:31]1[CH:36]=[CH:35][C:34]([S:37]([F:42])([F:41])([F:40])([F:39])[F:38])=[CH:33][CH:32]=1>C(Cl)Cl>[CH2:16]([C@H:21]1[CH2:22][CH2:23][C@H:24]([C:27]([O:29][C:31]2[CH:32]=[CH:33][C:34]([S:37]([F:40])([F:38])([F:42])([F:39])[F:41])=[CH:35][CH:36]=2)=[O:28])[CH2:25][CH2:26]1)[CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: Oc1ccc(S(F)(F)(F)(F)F)cc1
Reactant: CCCCC[C@H]1CC[C@H](C(=O)O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCC[C@H]1CC[C@H](C(=O)Oc2ccc(S(F)(F)(F)(F)F)cc2)CC1

Procedure:
A mixture of 10.6 g of dicyclohexylcarbodiimide and 40 ml of methylene chloride is added to a mixture of 9.1 g of trans-4-pentylcyclohexylcarboxylic acid, 11.2 g of p-hydroxyphenyl-sulfur pentafluoride and 100 ml of methylene chloride, and the combined mixture is heated at the boil for 6 hours. Working up in the customary manner gives 4-(trans-4-pentylcyclohexylcarbonyloxy)-phenyl-sulfur pentafluoride.
Reaction SMILES: CO[C:3]([C:5]1[NH:9][N:8]=[C:7]([N+:10]([O-:12])=[O:11])[N:6]=1)=[O:4].[CH3:13][O:14][CH2:15][CH2:16][NH2:17]>O1CCOCC1>[CH3:13][O:14][CH2:15][CH2:16][NH:17][C:3]([C:5]1[NH:9][N:8]=[C:7]([N+:10]([O-:12])=[O:11])[N:6]=1)=[O:4]
Reactant: COC(=O)c1nc([N+](=O)[O-])n[nH]1
Reactant: COCCN
Solvent: C1COCCO1
Product: COCCNC(=O)c1nc([N+](=O)[O-])n[nH]1

Procedure:
To 1 g of 3-nitro-1,2,4-triazole-5-carboxylic acid methyl ester dissolved in 5 ml of dioxane is added 1 g of methoxy ethylamine. The reaction mixture is warmed at 40°-50° C. for 2 hr with stirring.
Reaction SMILES: Cl.CO.[OH:4][C:5]1[CH:15]=[CH:14][C:8]2[C:9](=[O:13])[CH:10]=[CH:11][O:12][C:7]=2[CH:6]=1.[CH2:16]([O:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH:22]=O)[CH3:17]>O>[CH2:16]([O:18][C:19]1[CH:20]=[C:21]([CH:22]=[C:10]2[C:9](=[O:13])[C:8]3[CH:14]=[CH:15][C:5]([OH:4])=[CH:6][C:7]=3[O:12][CH2:11]2)[CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH3:17]
Reactant: CCOc1cc(C=O)ccc1OC
Reactant: O=c1ccoc2cc(O)ccc12
Agent: Cl
Solvent: CO
Solvent: O
Product: CCOc1cc(C=C2COc3cc(O)ccc3C2=O)ccc1OC
Reaction time: 22.5 h
Yield: 20.6 %

Procedure:
After a saturated hydrogen chloride-methanol solution 15 ml was added to 7-hydroxy-4(4H)-benzopyranone 1.0 g and 3-ethoxy-4-methoxybenzaldehyde 1.30 g, the mixture was srtirred for 22.5 hours, water 100 ml was added, and the precipitated crystals were filtered. The crystals were added to methanol 30 ml of 55° C., and the mixture was filtered. The resulting crystals were dried over phosphorous pentoxide for four hours under reduced pressure to obtain the desired compound 0.415 g.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([NH:28][C:29](=[O:31])[CH3:30])([CH2:23][O:24][C:25](=[O:27])[CH3:26])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:16]=2[F:22])=[CH:11][CH:10]=1)(=[O:3])[CH3:2].[CH3:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.N1C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:25]([O:24][CH2:23][C:6]([NH:28][C:29](=[O:31])[CH3:30])([CH2:5][O:4][C:1](=[O:3])[CH3:2])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:36]3[CH:37]=[CH:38][C:33]([CH3:32])=[CH:34][CH:35]=3)=[CH:17][C:16]=2[F:22])=[CH:11][CH:10]=1)(=[O:27])[CH3:26]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: CC(=O)NC(CCc1ccc(-c2ccc(O)cc2F)cc1)(COC(C)=O)COC(C)=O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)NC(CCc1ccc(-c2ccc(Oc3ccc(C)cc3)cc2F)cc1)(COC(C)=O)COC(C)=O
Yield: 77.4 %

Procedure:
A solution of N-[1,1-bis(acetoxymethyl)-3-(2′-fluoro-4′-hydroxybiphenyl-4-yl)propyl]acetamide (278 mg), 4-methylphenylboronic acid (175 mg), copper(II) acetate (117 mg), pyridine (255 mg) and molecular sieves 4A (500 mg) in methylene chloride (5 mL) was stirred at room temperature for 9 hr. 2% Aqueous citric acid solution (100 mL) was added to the reaction mixture, and the mixture was extracted with chloroform. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (0.26 g) as white crystals.
Reaction SMILES: [OH:1][C:2]1[N:3]=[C:4]2[CH:14]=[C:13]([O:15][CH2:16][C:17]3[S:18][CH:19]=[C:20]([CH:22]([CH3:24])[CH3:23])[N:21]=3)[CH:12]=[CH:11][N:5]2[C:6](=[O:10])[C:7]=1[CH:8]=O.CN(C)C=O.[C:30]([O:34][C:35]([CH:37]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:36])([CH3:33])([CH3:32])[CH3:31]>O1CCCC1>[OH:1][C:2]1[N:3]=[C:4]2[CH:14]=[C:13]([O:15][CH2:16][C:17]3[S:18][CH:19]=[C:20]([CH:22]([CH3:24])[CH3:23])[N:21]=3)[CH:12]=[CH:11][N:5]2[C:6](=[O:10])[C:7]=1/[CH:8]=[CH:37]/[C:35]([O:34][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:36]
Reactant: CC(C)c1csc(COc2ccn3c(=O)c(C=O)c(O)nc3c2)n1
Reactant: CC(C)(C)OC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)c1csc(COc2ccn3c(=O)c(/C=C/C(=O)OC(C)(C)C)c(O)nc3c2)n1
Temperature: 100 °C
Yield: 62.4 %

Procedure:
2-Hydroxy-8-[(4-isopropyl-1,3-thiazol-2-yl)methoxy]-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-carbaldehyde (45 mg, 0.13 mmol) dissolved in tetrahydrofuran (2 ml) and dimethylformamide (1 ml) was added with (tert-butoxycarbonylmethylene)triphenyl-phosphorane (60 mg, 0.16 mmol) and refluxed by heating at 100° C. for 2 hours. The reaction solution was returned to room temperature and concentrated under reduced pressure, and the residue was purified by thin layer silica gel chromatography (chloroform:methanol=20:1) to obtain 36 mg (62%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][N:20]([CH3:35])[C:21]1[CH:22]=[C:23]([C:27]2[O:31][CH:30]=[N:29][C:28]=2[C:32](O)=[O:33])[CH:24]=[CH:25][CH:26]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:32]([C:28]3[N:29]=[CH:30][O:31][C:27]=3[C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([N:20]([CH3:35])[CH3:19])[CH:22]=3)=[O:33])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ncc(N)n3)o2)OCCO1
Reactant: CN(C)c1cccc(-c2ocnc2C(=O)O)c1
Product: CC(=O)c1ccc(Cn2ncc(NC(=O)c3ncoc3-c3cccc(N(C)C)c3)n2)o1

Procedure:
Following general procedure A followed by B, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(3-dimethylamino-phenyl)-oxazole-4-carboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[CH:3]=1.[Br:11][CH:12]([CH:15]=O)[CH:13]=O>>[CH3:10][O:9][C:7]([C:4]1[CH:3]=[C:2]2[N:1]=[CH:13][C:12]([Br:11])=[CH:15][N:6]2[N:5]=1)=[O:8]
Reactant: O=CC(Br)C=O
Reactant: COC(=O)c1cc(N)[nH]n1
Product: COC(=O)c1cc2ncc(Br)cn2n1

Procedure:
The title compound, brown solid, MS: m/e=256.0/254.1 (M+H+), can be prepared in accordance with the general method of example 9, step 1 from methyl 5-amino-1H-pyrazole-3-carboxylate and 2-bromomalonaldehyde.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:7])/[CH:4]=[CH:5]/[CH3:6].CN(C)C(=N)N(C)C.[N+:16]([CH3:19])([O-:18])=[O:17]>C(OC(=O)CC(C)=O)C>[CH3:1][O:2][C:3](=[O:7])[CH2:4][CH:5]([CH3:6])[CH2:19][N+:16]([O-:18])=[O:17]
Reactant: C[N+](=O)[O-]
Reactant: C/C=C/C(=O)OC
Agent: CN(C)C(=N)N(C)C
Solvent: CCOC(=O)CC(C)=O
Product: COC(=O)CC(C)C[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 576 h
Yield: 78.9 %

Procedure:
3 g (29.9 mmol) of trans-2-butenoic acid methyl ester and 0.69 g (5.99 mmol) of tetramethylguanidine and 9.14 g (149 mmol) of nitromethane were mixed. The resulting mixture was stirred at room temperature for 24 days. 100 mL of ethylacetoacetate was added to the solution and the reaction solution was washed with water, then an organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, then the residue was purified by column chromatography to give 5.7 g (23.6 mmol) of the title compound in a yield of 100%.
Reaction SMILES: C(O)C.[F:4][C:5]1[CH:33]=[CH:32][C:8]([C:9]([CH:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:31])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[N+:28]([O-])=O)[CH2:13][CH2:12]2)=[O:10])=[CH:7][CH:6]=1.[H][H]>[Pt].CO>[NH2:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:21]([NH:20][CH2:19][CH2:18][CH2:17][N:14]1[CH2:15][CH2:16][CH:11]([C:9](=[O:10])[C:8]2[CH:7]=[CH:6][C:5]([F:4])=[CH:33][CH:32]=2)[CH2:12][CH2:13]1)=[O:31]
Reactant: [H][H]
Reactant: O=C(NCCCN1CCC(C(=O)c2ccc(F)cc2)CC1)c1ccccc1[N+](=O)[O-]
Agent: [Pt]
Solvent: CCO
Solvent: CO
Product: Nc1ccccc1C(=O)NCCCN1CCC(C(=O)c2ccc(F)cc2)CC1
Yield: 45 %

Procedure:
To 1 part of a solution of 2 parts of thophene in 40 parts of ethanol are added 18 parts of N-[3-[4-(4-fluorobenzoyl)-1-piperidinyl]propyl]-2-nitrobenzamide and 200 parts of methanol. The whole is hydrogenated at normal pressure and at room temperature with 2 parts of platinum-on-charcoal catalyst 5%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The oily residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The oily residue is crystallized from 2-propanol. The product is filtered off and dried, yielding 7.5 parts (45%) of 2-amino-N-[3-[4-(4-fluorobenzoyl)-1-piperidinyl]propyl]benzamide; mp. 113.2° C. The mother liquor is evaporated, yielding a second fraction of 6 parts (36%) of 2-amino-N-[3-[4-(4-fluorobenzoyl)-1-piperidinyl]propyl]benzamide as an oily residue.
Reaction SMILES: COC1C=CC(C[O:8][C:9]2[C:10](=[O:16])[CH:11]=[C:12]([CH3:15])[O:13][CH:14]=2)=CC=1.FC(F)(F)C(O)=O>C1(OC)C=CC=CC=1>[OH:8][C:9]1[C:10](=[O:16])[CH:11]=[C:12]([CH3:15])[O:13][CH:14]=1
Reactant: COc1ccc(COc2coc(C)cc2=O)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(=O)c(O)co1
Reaction time: 3 h

Procedure:
5-p-Methoxybenzyloxy-2-methyl-4-pyrone, 10 g, was dissolved in 10 ml of anisole and 15 ml of trifluoroacetic acid was dropwise added to the solution under ice cooling. After stirring at the same temperature for 3 hours, the mixture was concentrated under reduced pressure. The concentrate was separated and purified by flash column chromatography (eluting solution; chloroform: methanol=20:1) using Wako Gel C-300 (200 g) to give 2.4 g of the title compound.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([NH2:16])[C:5]2[N:6]([N:8]=[C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH:7]=1.[CH2:17]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:18][CH2:19][C:20]#[CH:21].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CN(C=O)C.CCOC(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.[Cu]I>[O:12]1[CH:13]=[CH:14][CH:15]=[C:11]1[C:9]1[N:10]=[C:5]2[C:4]([NH2:16])=[N:3][C:2]([C:21]#[C:20][CH2:19][CH2:18][CH2:17][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:7][N:6]2[N:8]=1
Reactant: C#CCCCc1ccccc1
Reactant: Nc1nc(Br)cn2nc(-c3ccco3)nc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1nc(C#CCCCc2ccccc2)cn2nc(-c3ccco3)nc12
Yield: 40.8 %

Procedure:
A solution of 6-bromo-2-furan-2-yl-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamine (56 mg, 0.2 mmol; see Examples 1 and 2 above), pent-4-ynyl-benzene (44 mg, 0.3 mmol), Pd(PPh3)4 (26 mg, 0.03 mmol), CuI (4 mg, 0.03 mmol), PPh3 (8 mg, 0.03 mmol), and TEA (11 μL, 2.5 mmol) in DMF (5 mL) was heated (at around 105° C.) under N2 for 2 hours. The reaction was diluted with EtOAc (15 mL) and washed with brine (3×10 mL) and dried with MgSO4. The solvent was removed and the reaction purified by HPLC (C18, H2O:MeCN gradient) to afford the product as a brown solid (28 mg,). 1H NMR (400 MHz, DMSO-d6) δ 1.85 (quin, J=7.5 Hz, 2H) 2.44 (t, J 7.1 Hz, 2H), 2.74 (t, J=7.8 Hz, 2H), 6.72 (dd, J=3.4, 1.8 Hz, 1H), 7.14 (dd, J=3.5, 0.8 Hz, 1H), 7.2-7.30 (br m, 5H), 7.92 (dd, J=1.7, 0.8 Hz, 1H), 8.35 (s, 1H). MS: m/z 344 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)=O.C(=O)(O)[O-].[Na+]>C(O)C>[Cl:8][C:7]1[C:2]2[N:3]([CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[N:1]=2)[CH:4]=[CH:5][CH:6]=1
Reactant: O=C(CBr)c1ccc(F)cc1
Reactant: Nc1ncccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Fc1ccc(-c2cn3cccc(Cl)c3n2)cc1
Yield: 80.3 %

Procedure:
To a solution of 2-amino-3-chloropyridine (6.51 g, 51 mmol) and 2-bromo-4′-fluoroacetophenone (13.0 g, 60 mmol) in ethanol (100 mL) was added sodium bicarbonate (4.91 g, 60 mmol) and the reaction mixture was heated at reflux for 6 hours. The resulting mixture was concentrated to a solid in vacuo. This residue was dissolved in ethyl acetate and the organic phase was washed with water and an aqueous sodium chloride solution. The organic phase was dried (magnesium sulfate), filtered through a silica gel pad and concentrated to give a solid. This solid was recrystallized from acetonitrile, to give 10.1 g (80%) 8-chloro-2-(4-fluorophenyl)imidazo[1,2-α]pyridine as a solid. 1H NMR (CDCl3): δ 8.06 (d, 1H), 7.96 (q, 2H), 7.86 (s, 1H), 7.25 (d, 1H), 7.13 (t, 2H), 6.73 (t, 1H); 19F NMR (CDCl3) δ −114.0; MS m/z 247 (M+1).