Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:15])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.[C:16](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:17]>ClCCl>[N:15]([C:5]1[CH:6]=[CH:7][C:8]([N:9]2[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]2)=[C:3]([O:2][CH3:1])[CH:4]=1)=[C:16]=[S:17]
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Solvent: ClCCl
Product: COc1cc(N=C=S)ccc1-n1cnc(C)c1
Yield: 93.8 %

Procedure:
A solution of 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine (203 mg, 1 mmol) and of 1,1′-thiocarbonyldi-2(1H)-pyridone (263 mg, 1.1 mmol) in dichloromethane (10 mL) was stirred at room temperature over night to yield an orange solution. The reaction was concentrated under reduced pressure to ¼ of its volume and directly purified on silica gel using dichloromethane/methanol (95:5 v/v) as eluent to yield the title compound (230 mg, 94%) as a yellow oil, which solidifies on standing. MS ISP (m/e): 246.3 (100) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.67 (s, 1H), 7.21 (d, 1H), 6.91-6.86 (m, 3H), 3.86 (s, 3H), 2.29 (s, 3H).
Reaction SMILES: [CH2:1]([N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[CH:9]=O)[CH2:2][CH3:3].[CH:11](=[N:18]/[C:19]1[CH:27]=[CH:26]C=C2[C:20]=1[CH2:21][O:22]C2=O)\[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C[O-].[Na+].[C:32]([O:36][CH2:37][CH3:38])(=[O:35])[CH2:33][CH3:34]>>[O:22]=[C:21]1[C:20]2[C:33]([C:32]([O:36][CH2:37][CH3:38])=[O:35])=[CH:34][CH:26]=[CH:27][C:19]=2[NH:18][CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:9]1[C:5]1[N:4]([CH2:1][CH2:2][CH3:3])[CH:8]=[CH:7][N:6]=1
Reactant: O=C1OCc2c(/N=C/c3ccccc3)cccc21
Reactant: CCOC(=O)CC
Reactant: CCCn1ccnc1C=O
Agent: C[O-]
Agent: [Na+]
Product: CCCn1ccnc1C1C(=O)c2c(cccc2C(=O)OCC)NC1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
To the mixture of 1-propyl-1H-imidazole-2-carbaldehyde (1.1 g, 8.0 mmol) and (E)-4-(benzylideneamino) isobenzofuran-1(3H)-one (1.7 g, 7.2 mmol) were added in ethyl propionate (50 mL) and then sodium methoxide was added under 0° C. The mixture was stirred overnight at room temperature. The mixture was concentrated and the residue was extracted with ethyl acetate (100 mL×4). The organic layer dried over anhydrous sodium sulfate, purified by chromatography (silica gel, petroleum ether/ethyl acetate=10:1 to 1:1) to give ethyl 4-oxo-2-phenyl-3-(1-propyl-1H-imidazol-2-yl)-1,2,3,4-tetrahydroquinoline-5-carboxylate (770 mg, yield 30%). LC-MS (ESI) m/z: 404 (M+1)+.
Reaction SMILES: I[CH2:2][CH3:3].C([O-])([O-])=O.[K+].[K+].[OH:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[N+:19]([O-:21])=[O:20])[CH:14]=[O:15].O>CN(C=O)C>[CH2:2]([O:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[N+:19]([O-:21])=[O:20])[CH:14]=[O:15])[CH3:3]
Reactant: CCI
Reactant: O=Cc1ccc([N+](=O)[O-])c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cc(C=O)ccc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 18 h

Procedure:
At 20° C. iodoethane (3.78 g) was added to a suspension of K2CO3 (1.09 g) and 3-hydroxy-4-nitro-benzaldehyde (1.0 g) in DMF (5 ml). The reaction mixture was stirred at 70° C. for 18 h, poured into water and then extracted with ethyl acetate. The organic phases were combined, dried (MgSO4) and concentrated in vacuo. The title product was obtained as a yellow solid. Yield: 1.17 g. MS-ESI: [M+H]+=196.
Reaction SMILES: C(C1N=C(N2CCOCC2)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.[C:28]([C:32]1[N:33]=[C:34](Cl)[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29].[CH3:50][C@@H:51]1[O:56][C@H:55]([CH3:57])[CH2:54][NH:53][CH2:52]1>>[C:28]([C:32]1[N:33]=[C:34]([N:53]2[CH2:52][C@H:51]([CH3:50])[O:56][C@H:55]([CH3:57])[CH2:54]2)[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: C[C@@H]1CNC[C@H](C)O1
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Agent: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Product: C[C@@H]1CN(c2nc(C(C)(C)C)nc3c2nnn3Cc2ccccc2Cl)C[C@H](C)O1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and (2S,6R)-2,6-dimethylmorpholine and isolated as white solid (13.1 mg, 67%). MS(m/e): 415.5 (MH+).
Reaction SMILES: [C:1]([Li])([CH3:4])([CH3:3])[CH3:2].[CH3:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[CH3:16])[C:10](Cl)=[O:11].CO.[Cl-].[NH4+]>O1CCCC1.C1(S[Cu])C=CC=CC=1>[CH3:6][C:7]1[CH:8]=[C:9]([C:10](=[O:11])[C:1]([CH3:4])([CH3:3])[CH3:2])[CH:13]=[CH:14][C:15]=1[CH3:16]
Reactant: Cc1ccc(C(=O)Cl)cc1C
Reactant: [Li]C(C)(C)C
Agent: [Cu]Sc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)C(C)(C)C)cc1C
Temperature: -20 °C
Reaction time: 0.08 h

Procedure:
A suspension of 25.9 g. (0.15 mole) of phenyl thio copper in 1 liter dry tetrahydrofuran is cooled to -20° C. and treated by the dropwise addition of 120 ml. t-butyl lithium (0.149 mole, 1.24 M in pentane) for about 20 minutes maintaining the temperature at -20° C. The resulting green solution is stirred at -20° C. for 5 minutes and then cooled to -72° C. and treated by the dropwise addition of 17.8 g. (0.107 mole) 3,4-dimethyl-benzoyl chloride in 50 ml. tetrahydrofuran for about 20 minutes. The mixture is then stirred at -22° C. for 11/2 hours and then treated with 100 ml. methanol and allowed to warm to room temperature and then hydrolyzed by the addition of 250 ml. saturated ammonium chloride. The resulting solids are filtered and washed with tetrahydrofuran. The filtrate is dried over anhydrous magnesium sulfate, filtered and evaporated and the oil distilled to give 3',4' -dimethylpivalophenone; (b.p. 73°-76° C. at 0.1 mm).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[NH:7][N:6]=[N:5][N:4]=1.[C:8]([O-])([O-])=O.[K+].[K+].[CH3:14]I.O>CN(C=O)C>[Cl:1][CH2:2][C:3]1[N:7]([CH3:8])[N:6]=[N:5][N:4]=1.[Cl:1][CH2:2][C:3]1[N:4]=[N:5][N:6]([CH3:14])[N:7]=1
Reactant: O=C([O-])[O-]
Reactant: ClCc1nnn[nH]1
Reactant: CI
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nnc(CCl)n1
Product: Cn1nnnc1CCl
Temperature: 25 °C
Yield: 55 %
Yield: 26 %

Procedure:
5-chloromethyl-1H-tetrazole (300 mg, 2.53 mmol) prepared the above a was dissolved in DMF (10 ml), therein K2CO3 (455 mg, 3.29 mmol) was added. Thereafter, therein MeI (0.16 ml, 2.53 mmol) was slowly added dropwise for 4 hours at room temperature, the reaction mixture was stirred at room temperature. After the said reaction was completed, water (30 ml) was added to the reaction mixture. The reaction mixture was extracted with ether (50 μl), thereafter the organic layer was washed with saturated brine solution, dried over anhydrous MgSO4, and concentrated. The residue was purified by silcagel column chromatography (developing solvent-n-hexane:ethyl acetate=4:1) to give 5-chloromethyl-1-methyl-1H-tetrazole (88.1 mg, 26%) and 5-chloromethyl-2-methyl-2H-tetrazole (184.2 mg, yield: 55%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C(O)C>[Br:8][C:5]1[CH:4]=[N:3][C:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:7][CH:6]=1
Reactant: Brc1ccc(Br)nc1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: c1ccccc1
Product: Brc1ccc(-c2ccccc2)nc1

Procedure:
10 g (42.2 mmol) of 2,5-dibromopyridine, 5.2 g (42.2 mmol) of phenylboronic acid and 30 ml of benzene are placed in a 250 ml three-necked round-bottomed flask, 1.5 g (1.3 mmol) of tetrakis(triphenylphosphine)palladium, 30 ml of benzene and 30 ml of aqueous 2 M sodium carbonate solution and 1.4 ml of ethanol are added and the mixture is refluxed for 17 h.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([N:8]([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O)=[O:7])=[CH:4][CH:3]=1.[CH:22]([NH:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40]([O:42]CC)=[O:41])([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[OH-].[K+]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([N:35]([CH:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:36][CH2:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41])=[O:15])=[O:7])=[CH:20][CH:21]=1
Reactant: CCCCN(CCCCC(=O)O)C(=O)c1ccc(Cl)cc1
Reactant: CCOC(=O)CCCCNC(c1ccccc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCCN(CCCCC(=O)N(CCCCC(=O)O)C(c1ccccc1)c1ccccc1)C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Analogously to Example 1, by using equivalent quantities, reacting N-(p-chlorobenzoyl)-5-(n-butylamino)valeric acid and ethyl 5-benzhydrylaminovalerate and suitable processing, dissolving the evaporation residue in ethanol, adding an ethanolic solution of potassium hydroxide, stirring for 12 hours at room temperature and further processing yields N-[N-(p-chlorobenzoyl)-5-(n-butylamino)pentanoyl]-5-benzhydrylaminovaleric acid.
Reaction SMILES: [C:1]1([CH:7]([NH:14][C:15]2[S:16][CH:17]=[C:18]([CH:20]=[C:21]3[S:25][C:24](=[S:26])[N:23]([CH2:27][C:28]([OH:30])=[O:29])[C:22]3=[O:31])[N:19]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O-].[Na+:34]>C(O)C>[OH2:29].[C:1]1([CH:7]([NH:14][C:15]2[S:16][CH:17]=[C:18]([CH:20]=[C:21]3[S:25][C:24](=[S:26])[N:23]([CH2:27][C:28]([O-:30])=[O:29])[C:22]3=[O:31])[N:19]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+:34]
Reactant: O=C(O)CN1C(=O)C(=Cc2csc(NC(c3ccccc3)c3ccccc3)n2)SC1=S
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: O
Product: O=C([O-])CN1C(=O)C(=Cc2csc(NC(c3ccccc3)c3ccccc3)n2)SC1=S

Procedure:
Following a procedure similar to that described in Example 35, the desired compound was prepared from 200 mg of 5-(2-diphenylmethylaminothiazol-4-ylmethylene)rhodanine-3-acetic acid, 24.5 mg of sodium methoxide and 6 ml of ethanol. The resulting product was a yellow powder having the following physical properties.
Reaction SMILES: Br[C:2]1[C:3]([CH3:21])([CH3:20])[O:4][C:5]2[C:10]([C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)=[CH:9][CH:8]=[C:7]([Cl:19])[CH:6]=2.[CH2:22]([Sn](CCCC)(CCCC)C=C)[CH2:23]CC.[F-].[K+]>O1CCOCC1.C(OCC)(=O)C.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>[Cl:19][C:7]1[CH:6]=[C:5]2[C:10]([C:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[C:2]([CH:22]=[CH2:23])[C:3]([CH3:21])([CH3:20])[O:4]2)=[CH:9][CH:8]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CC1(C)Oc2cc(Cl)ccc2C(c2ccc(F)cc2)=C1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C=CC1=C(c2ccc(F)cc2)c2ccc(Cl)cc2OC1(C)C
Temperature: 25 °C

Procedure:
A mixture of 3-bromo-7-chloro-4-(4-fluorophenyl)-2,2-dimethyl-2H-chromen (a compound obtained in Reference Example 8(1); 220 mg), tributyl(vinyl)tin (350 μL) and tetrakis(triphenylphosphine)palladium(0) (140 mg) in dioxane was heated under reflux for 23 hours. After cooling, the reaction solution was diluted with ethyl acetate, a saturated aqueous solution of potassium fluoride was added thereto, and the mixture was stirred at room temperature for an hour. The reaction solution was filtered through Celite and the filtrate was extracted with ethyl acetate. The organic layer was washed successively with water and brine, filtered through a column of porous diatomite (Chem Elut) and the filtrate was concentrated in vacuo. The resultant residue was purified by column chromatography on silica gel (Solvent: n-hexane/chloroform=100/0 to 95/5) to give the titled compound (157 mg) as a pale yellow viscous oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[Cl:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[C:15](=[O:28])[C:14]([C:29]#[N:30])=[C:13]2[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>N1C=CC=CC=1>[Cl:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH2:20][C:21]1[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=1)[C:15](=[O:28])[C:14]([C:29]#[N:30])=[C:13]2[N:31]1[CH2:36][CH2:35][N:34]([C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[O:7])[CH2:33][CH2:32]1
Reactant: N#Cc1c(N2CCNCC2)c2cc(Cl)ccc2n(Cc2ccc(F)cc2)c1=O
Reactant: O=C(Cl)c1cccs1
Solvent: c1ccncc1
Product: N#Cc1c(N2CCN(C(=O)c3cccs3)CC2)c2cc(Cl)ccc2n(Cc2ccc(F)cc2)c1=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 55.2 %

Procedure:
2-Thiophene carbonyl chloride (160 μL, 1.5 mmol) was added to a stirred solution of Compound 72 (397 mg, 1.0 mmol) in pyridine (5 mL) under argon at 0° C. The solution was allowed to come to room temperature and further stirred overnight. The solution was poured into ice water and the solids formed were filtered. The solids were washed by excess water, dried, and recrystallized by ethyl acetate to yield 280 mg (55%) of white solids. M.P. 253° C. 1H NMR (DMSO-d6): δ 3.70 (m, 4H), 3.93 (m, 4H), 5.46 (s, 2H), 7.13-7.17 (m, 3H), 7.27 (m, 2H), 7.44 (d, J=9.0 Hz, 1H), 7.51 (d, J=4.0 Hz, 1H), 7.68 (dd, J=2.6, 9.0 Hz, 1H), 7.79 (d, J=4.0 Hz, 1H), 7.89 (s, 1H). EIMS m/z 508 (M+1). Anal. (C26H20FClN4O2S) C,H, N.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][CH:11]=[C:12]([C:15]([CH3:17])=O)[C:13]=2[OH:14])[CH:5]=[CH:6][C:7]=1[Cl:8].[N:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][NH:27][C:28]([C:30]2[S:31][C:32]([C:35]([NH:37][NH2:38])=[O:36])=[CH:33][CH:34]=2)=[O:29])=[CH:20][CH:19]=1.O>CN(C)C=O>[N:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][NH:27][C:28]([C:30]2[S:31][C:32]([C:35]([NH:37][N:38]=[C:15]([C:12]3[C:13]([OH:14])=[C:9]([C:4]4[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=4)[S:10][CH:11]=3)[CH3:17])=[O:36])=[CH:33][CH:34]=2)=[O:29])=[CH:20][CH:19]=1
Reactant: NNC(=O)c1ccc(C(=O)NCCCc2ccncc2)s1
Reactant: CC(=O)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Solvent: CN(C)C=O
Solvent: O
Product: CC(=NNC(=O)c1ccc(C(=O)NCCCc2ccncc2)s1)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Reaction time: 16 h
Yield: 95 %

Procedure:
2-(3,4-Dichlorophenyl)-3-hydroxy-4-methylcarbonylthiophene (42 mg, 0.14 mmol) and 5-hydrazinocarbonylthiophene-2-carboxylic acid 3-(pyridin-4-yl)propylamide (40 mg, 0.13 mmol) prepared in Reference Synthetic Example 26 were dissolved in N,N-dimethylformamide (1.0 mL) and left at 70° C. for 16 hours and then at room temperature for 24 hours. Water (0.36 mL) was added with stirring, and the precipitated solid was recovered by filtration to give the desired product, 5-{1-[5-(3,4-dichlorophenyl)-4-hydroxythiophen-3-yl]ethylidenehydrazinocarbonyl}thiophene-2-carboxylic acid 3-(pyridin-4-yl)propylamide (yield 95%).
Reaction SMILES: C[O:2][C:3]([C:5]1[O:6][C:7]2[C:12]([C:13](=[O:23])[C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)=[CH:11][C:10]([Cl:24])=[C:9]([OH:25])[CH:8]=2)=[O:4].C([O-])(O)=O.[Na+]>CO>[Cl:24][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][C:9]=1[OH:25])[O:6][C:5]([C:3]([OH:4])=[O:2])=[C:14]([C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)[C:13]2=[O:23]
Reactant: COC(=O)c1oc2cc(O)c(Cl)cc2c(=O)c1-c1ccc(OC)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COc1ccc(-c2c(C(=O)O)oc3cc(O)c(Cl)cc3c2=O)cc1
Temperature: 25 °C

Procedure:
6-Chloro-7-hydroxy-3-(4-methoxy-phenyl)-4-oxo-4H-chromene-2-carboxylic acid methyl ester was taken up in a 2:1 mixture of sat. NaHCO3 (aq): Methanol and all was heated at 65° C. for 5 hours. The solution was cooled to room temperature and concentrated in vacuo to remove the methanol. The residual aqueous solution was acidified with 1M HCl (aq) and a buff coloured precipitated dropped out of solution. This was collected by vacuum filtration, washed with water and with diethyl ether, to give 6-chloro-7-hydroxy-3-(4-methoxy-phenyl)-4-oxo-4H-chromene-2-carboxylic acid.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH3:11][CH:12]([CH2:15][CH3:16])[CH2:13]O.S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:11][CH:12]([CH3:13])[CH2:15][CH3:16])=[O:7])=[CH:4][CH:3]=1
Reactant: CCC(C)CO
Reactant: O=C(O)c1ccc(O)cc1
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CCC(C)COC(=O)c1ccc(O)cc1
Yield: 82.9 %

Procedure:
4.0 g of p-hydroxybenzoic acid and 12.5 g of 2-methylbutanol were refluxed for 6 hours in toluene in the presence of sulfuric acid while removing water. The resulting reaction solution was then washed with water to remove sulfuric acid. The organic phase was then dried, concentrated, and purified by column chromatography to obtain 5.0 g of the objective ester (liquid, at room temperature, [α]D23 =+4.9° (CHCl3)). (Yield: 83%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1.[Br:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O.[CH2:21]=[C:22]([CH3:24])[CH3:23].FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>C(#N)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:4]1[CH:5]=[C:6]2[C:7](=[CH:8][CH:9]=1)[NH:10][CH:16]([C:15]1[CH:18]=[CH:19][CH:20]=[C:13]([Br:12])[CH:14]=1)[CH2:21][C:22]2([CH3:24])[CH3:23])=[O:11]
Reactant: C=C(C)C
Reactant: O=Cc1cccc(Br)c1
Reactant: COC(=O)c1ccc(N)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(c1)C(C)(C)CC(c1cccc(Br)c1)N2
Temperature: 85 °C
Reaction time: 18 h
Yield: 39.9 %

Procedure:
To a stirred solution of 4-amino-benzoic acid methyl ester (11.3 g, 78.4 mmol) and 3-bromobenzaldehyde (9.2 mL, 78.4 mmol) in acetonitrile (150 mL) were added isobutene (21.0 mL, 313.5 mmol) and ytterbium(III) trifluoromethanesulfonate (Yb(OTf)3) (5.8 g, 9.5 mmol). The resulting mixture was stirred at 85° C. for 18 h in sealed tube. The mixture was diluted with ethyl acetate (300 mL) and washed with water (100 mL×2) and brine (100 mL×2) and then dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by ISCO combi-flash chromatography (gradient elution, 10-50% ethyl acetate in petroleum ether) to afford 2-(3-bromo-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid methyl ester (11.7 g, 40.0%) as a light yellow solid: MS (ESI) M+1=374.0.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.B(O)(O)[C:10]1[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[Cl:8][C:7]1[C:2]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Clc1cccnc1Cl
Reactant: Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc(-c2ncccc2Cl)cc1
Yield: 84 %

Procedure:
{circle around (1)} 100 g (0.676 mol) of 2,3-dichloropyridine, 91.87 g (0.676 mol) of p-tolylboronic acid, and 86 g (0.811 mol) of sodium carbonate were dissolved in 500 mL of 1,2-dimethoxyethane and 500 mL of distilled water, after which 78 g (0.0676 mol) of Pd(PPh3)4 was added. The mixture was heated to reflux for 18 hours so that it was allowed to react. After completion of the reaction, the reaction solution was concentrated under reduced pressure to remove 1,2-dimethoxyethane, and then extracted with ethyl acetate. The extract was treated with magnesium sulfate, filtered, and concentrated under reduced pressure, yielding 3-chloro-2-para-tolylpyridine as represented below in a 84% yield.
Reaction SMILES: [CH3:1][NH:2][CH3:3].Cl[S:5]([C:8]1[CH:9]=[CH:10][C:11]([OH:18])=[C:12]([CH:17]=1)[C:13]([O:15][CH3:16])=[O:14])(=[O:7])=[O:6]>O.ClCCl>[CH3:1][N:2]([CH3:3])[S:5]([C:8]1[CH:9]=[CH:10][C:11]([OH:18])=[C:12]([CH:17]=1)[C:13]([O:15][CH3:16])=[O:14])(=[O:7])=[O:6]
Reactant: COC(=O)c1cc(S(=O)(=O)Cl)ccc1O
Reactant: CNC
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1cc(S(=O)(=O)N(C)C)ccc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 33% solution of dimethylamine (1.53 ml, 9.97 mmol) in water was added dropwise to methyl 5-(chlorosulfonyl)-2-hydroxybenzoate (may be prepared as described in Description 60; 500 mg, 2.00 mmol) in dichloromethane (20 ml) at 25° C., and the mixture was allowed to stir at 25° C. for 2 h. The mixture was then concentrated in vacuo to give the yield the title compound as a crude product. 260 mg.
Reaction SMILES: [CH:1]1([NH:4][CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[O:15][N:14]=[C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[N:12]=3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[N:22]1[CH:27]=[CH:26][C:25]([C:28]2[N:33]=[CH:32][C:31]([C:34](O)=[O:35])=[CH:30][N:29]=2)=[CH:24][CH:23]=1>>[CH:1]1([N:4]([CH:5]2[CH2:6][CH2:7][N:8]([C:11]3[O:15][N:14]=[C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[N:12]=3)[CH2:9][CH2:10]2)[C:34]([C:31]2[CH:32]=[N:33][C:28]([C:25]3[CH:26]=[CH:27][N:22]=[CH:23][CH:24]=3)=[N:29][CH:30]=2)=[O:35])[CH2:3][CH2:2]1
Reactant: O=C(O)c1cnc(-c2ccncc2)nc1
Reactant: c1ccc(-c2noc(N3CCC(NC4CC4)CC3)n2)cc1
Product: O=C(c1cnc(-c2ccncc2)nc1)N(C1CC1)C1CCN(c2nc(-c3ccccc3)no2)CC1

Procedure:
The title compound is prepared from cyclopropyl-[1-(3-phenyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-amine and 2-pyridin-4-yl-pyrimidine-5-carboxylic acid following a procedure analogous to that described in Example 1. LC (method 2): tR=1.76 min; Mass spectrum (ESI+): m/z=468 [M+H]+.
Reaction SMILES: C([O:5][CH:6]1[CH2:11][C:10]([CH3:13])([CH3:12])[N:9]([O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]([CH3:22])([CH3:21])[CH2:7]1)(=O)C=C.[C:23]([O:47][CH:48]1[CH2:53][C:52]([CH3:55])([CH3:54])[N:51]([OH:56])[C:50]([CH3:58])([CH3:57])[CH2:49]1)(=[O:46])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH:35]1[CH2:40][C:39]([CH3:42])([CH3:41])[N:38]([OH:43])[C:37]([CH3:45])([CH3:44])[CH2:36]1)=[O:33]>>[C:23]([O:47][CH:48]1[CH2:49][C:50]([CH3:58])([CH3:57])[N:51]([O:56][CH2:17][C:16](=[C:15]=[O:14])[O:5][CH:6]2[CH2:11][C:10]([CH3:12])([CH3:13])[N:9]([O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:8]([CH3:22])([CH3:21])[CH2:7]2)[C:52]([CH3:55])([CH3:54])[CH2:53]1)(=[O:46])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH:35]1[CH2:36][C:37]([CH3:44])([CH3:45])[N:38]([O:43][CH2:8][C:7](=[C:6]=[O:5])[O:5][CH:6]2[CH2:11][C:10]([CH3:12])([CH3:13])[N:9]([O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:8]([CH3:21])([CH3:22])[CH2:7]2)[C:39]([CH3:41])([CH3:42])[CH2:40]1)=[O:33]
Reactant: CC1(C)CC(OC(=O)CCCCCCCCC(=O)OC2CC(C)(C)N(O)C(C)(C)C2)CC(C)(C)N1O
Reactant: C=CC(=O)OC1CC(C)(C)N(OC2CCCCC2)C(C)(C)C1
Product: CC1(C)CC(OC(=O)CCCCCCCCC(=O)OC2CC(C)(C)N(OCC(=C=O)OC3CC(C)(C)N(OC4CCCCC4)C(C)(C)C3)C(C)(C)C2)CC(C)(C)N1OCC(=C=O)OC1CC(C)(C)N(OC2CCCCC2)C(C)(C)C1

Procedure:
The title compound is prepared from 1-cyclohexyloxy-2,2,6,6-tetramethylpiperidin-4-yl acrylate and bis(1-hydroxy-2,2,6,6-tetramethylpiperidin-4-yl) sebacate according to the general procedure of Example 2.