Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][CH:14]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:30]1[O:31][C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[N:34]=1>CN1C(=O)CCC1.C(=O)(O)[O-].[Na+]>[O:31]1[C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[N:34]=[C:30]1[N:20]1[CH2:21][CH2:22][CH:17]([CH:14]2[CH2:15][CH2:16][N:11]([C:8]3[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=3)[CH2:12][CH2:13]2)[CH2:18][CH2:19]1
Reactant: CS(=O)(=O)c1ccc(N2CCC(C3CCNCC3)CC2)cc1
Reactant: Clc1nc2ccccc2o1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CS(=O)(=O)c1ccc(N2CCC(C3CCN(c4nc5ccccc5o4)CC3)CC2)cc1
Reaction time: 8 h

Procedure:
The 1[4-(methylsulfonyl)phenyl]-4,4′-bipiperidine (70 mg, 0.22 mmol) and cesium carbonate (212 mg, 0.65 mmol) were slurried in NMP (0.43 ml) and the Chlorobenzoxazole (20.3 mmol) added. The mixture was stirred at 120 C overnight. The slurry was diluted with 15% saturated sodium bicarbonate:water (40 ml) and extracted with DCM (3×25 ml). The combined organic fraction was washed with brine, dried over magnesium sulfate, filtered, and the volatiles removed in vac. The crude material was purified by chromatography on silica gel with 5% acetone:DCM to yield the titled compound. LRMS calc: 478.1 obs: 478.8, 480.8 (M+H).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([C:14]([O:16][CH2:17][C:18](=[O:38])[C:19]2[CH:20]=[CH:21][C:22]3[C:31]4[CH:30]=[C:29]5[CH2:32][CH2:33][CH2:34][C:35](=[O:36])[C:28]5=[CH:27][C:26]=4[O:25][CH2:24][C:23]=3[CH:37]=2)=[O:15])[CH2:3]1.[Br-:39].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl.CO.Cl>[CH3:1][C@@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])[C@H:4]([C:14]([O:16][CH2:17][C:18]([C:19]2[CH:20]=[CH:21][C:22]3[C:31]4[CH:30]=[C:29]5[CH2:32][CH2:33][CH:34]([Br:39])[C:35](=[O:36])[C:28]5=[CH:27][C:26]=4[O:25][CH2:24][C:23]=3[CH:37]=2)=[O:38])=[O:15])[CH2:3]1
Reactant: [Br-]
Reactant: C[C@H]1C[C@@H](C(=O)OCC(=O)c2ccc3c(c2)COc2cc4c(cc2-3)CCCC4=O)N(C(=O)OC(C)(C)C)C1
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CO
Product: C[C@H]1C[C@@H](C(=O)OCC(=O)c2ccc3c(c2)COc2cc4c(cc2-3)CCC(Br)C4=O)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
(2S,4S)-1-tert-butyl 2-(2-oxo-2-(8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl)ethyl) 4-methylpyrrolidine-1,2-dicarboxylate (621 mg, 1.19 mmol) was dissolved in a solution of DCM (10 mL) and MeOH (4 mL), then treated with pyridinium tribromide (421 mg, 1.3 mmol). After stirring at RT for 1.5 h, the reaction mixture was diluted with DCM and 10% HCl, and extracted with DCM. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure and the crude material was carried on without further purification.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[C:34]([O:36][CH3:37])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]=2[O:38][CH3:39])=[CH:7][CH:6]=1)C=C.N12CCN(CC1)CC2.Cl>C(O)C.CC(O)=O.CC(O)=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[CH3:39][O:38][C:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:34]([O:36][CH3:37])=[CH:35][C:26]=1[CH2:25][O:24][CH:12]1[CH:11]([C:8]2[CH:7]=[CH:6][C:5]([OH:4])=[CH:10][CH:9]=2)[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]1
Reactant: C=CCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2cc(OC)c3ccccc3c2OC)cc1
Agent: [Pd]
Agent: C1CN2CCN1CC2
Agent: Cl
Solvent: CC(=O)O
Solvent: CCO
Product: COc1cc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(O)cc2)c(OC)c2ccccc12
Temperature: 2.5 °C
Yield: 91 %

Procedure:
A solution of 315 mg (0.59 mmol) of tert-butyl (3RS,4RS)-4-(4-allyloxy-phenyl)-3-(1,4-dimethoxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylate, 44 mg (0.059 mmol) of bis-(triphenylphosphine)-palladium(II) diacetate and 132 mg (1.18 mmol) of 1,4-diazabicyclo [2.2.2]octane in 10 ml of 95% ethanol was heated to reflux under argon for 2 hours. Subsequently, the reaction mixture was cooled to 0-5° C. and treated with 0.6 ml of 1N hydrochloric acid. Thereafter, the solvent was distilled off under reduced pressure and the residue was partitioned between ethyl acetate and water. After extraction and drying of the organic phase over sodium sulphate it was evaporated under reduced pressure. The residue was purified on silica gel using a 9:1 mixture of methylene chloride and ether as the eluent. There were obtained 265 mg (91% of theory) of tert-butyl (3RS,4RS)-3-(1,4-dimethoxy-naphthalen-2-ylmethoxy)-4-(4-hydroxy-phenyl)-piperidine-1-carboxylate as a yellowish foam; MS: 494 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][C:12]([N:14]2[CH2:19][C@H:18]([CH3:20])[N:17]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH2:16][C@H:15]2[CH3:29])=[O:13])=[C:6]([CH:9]=1)[CH:7]=[O:8].[BH4-].[Na+].Cl.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][C:12]([N:14]2[CH2:19][C@H:18]([CH3:20])[N:17]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH2:16][C@H:15]2[CH3:29])=[O:13])=[C:6]([CH2:7][OH:8])[CH:9]=1
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1C=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1CO
Yield: 98.7 %

Procedure:
To a solution of 5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-benzaldehyde (0.99 g, 2.36 mmol) in dry methanol (25 mL) was added sodium borohydride (0.19 g, 4.92 mmol). After 1 hour the reaction was acidified to pH 2 by the addition of 1N hydrochloric acid. After 5 minutes the reaction was neutralized with 1N sodium hydroxide and the methanol removed by evaporation. The resulting aqueous suspension was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated to give the title compound (0.98 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[S:8][C:7]=1[NH:13][C:14](=[O:20])[CH:15]=[CH:16][C:17](O)=[O:18])=[O:5])[CH3:2].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[NH2:43][C:44]([NH2:46])=[S:45]>CN(C)C=O.C(OCC)(=O)C>[NH2:46][C:44]1[S:45][CH:16]([CH2:15][C:14]([NH:13][C:7]2[S:8][C:9]([CH3:12])=[C:10]([CH3:11])[C:6]=2[C:4]([O:3][CH2:1][CH3:2])=[O:5])=[O:20])[C:17](=[O:18])[N:43]=1
Reactant: CCOC(=O)c1c(NC(=O)C=CC(=O)O)sc(C)c1C
Reactant: NC(N)=S
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(NC(=O)CC2SC(N)=NC2=O)sc(C)c1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 50.6 %

Procedure:
To 2-(3-Carboxy-acryloylamino)-4,5-dimethyl-thiophene-3-carboxylic acid ethyl ester (2.97 g, 10.0 mmol) in 50 mL of N,N-dimethyl-formamide was added N-hydroxy-benzotriazole (1.48 g, 11.0 mmol) and 1-[3-(dimethylamino) propyl]-3-ethyl-carbodiimide hydrochloride (2.88 g, 15.0 mmol). The reaction mixture was stirred at room temperature for 10 minutes and thiourea (0.84 g, 11.0 mmol) was added. The reaction mixture was stirred at room temperature for another 30 minutes and was heated at 60° C. for 12 hours. The reaction mixture was diluted with 250 mL of ethyl acetate and was washed with 100 mL of water and 100 mL of brine. The organic layer was collected, dried over sodium sulfate and concentrated. The residue was load on a 120 g silica gel column and purified by flash chromatography (eluted with a gradient of 0 to 10% ethyl acetate/hexanes). Ethyl 2-{[(2-amino-4-oxo-4,5-dihydro-1,3-thiazol-5-yl) acetyl]amino}-4,5-dimethylthiophene-3-carboxylate (1.80 g, 51% yield) was produced.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][C:12](=[O:15])[C:11]3[N:7]([CH:8]=[CH:9][CH:10]=3)[C:6]=2[CH:16]=1.Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:26]=2[C:27]([NH:29][CH3:30])=[O:28])[C:21]([Cl:36])=[CH:20][N:19]=1>>[Cl:36][C:21]1[C:22]([NH:24][C:25]2[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:26]=2[C:27]([NH:29][CH3:30])=[O:28])=[N:23][C:18]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[O:14][CH2:13][C:12](=[O:15])[C:11]4[N:7]([CH:8]=[CH:9][CH:10]=4)[C:6]=3[CH:16]=2)=[N:19][CH:20]=1
Reactant: Nc1ccc2c(c1)-n1cccc1C(=O)CO2
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Product: CNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)-n2cccc2C(=O)CO3)ncc1Cl

Procedure:
2-[5-Chloro-2-(4-oxo-4,5-dihydro-6-oxa-10b-aza-benz[e]azulen-9-ylamino)-pyrimidin-4-ylamino]-3-fluoro-N-methyl-benzamide was prepared from 9-Amino-6-oxa-10b-aza-benz[e]azulen-4-one and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide in an analogous manner to Example 1223c. Product was obtained as a tan ppt. MP 223-225 (dec) LCMS 493.09 (M+H), HPLC purity 95%, 1H-NMR (DMSO-D6, 400 MHZ) Δ 9.56 (s, 1H), 9.48 (s, 1H), 8.52 (d, J=4.6 Hz, 1H), 8.23 (s, 1H), 7.68 (s, 1H), 7.43 (d, J=7.6 Hz, 1H), 7.34 (s, 1H), 7.17-7.10 (m, 2H), 7.08 (s, 1H), 6.53 (d, J=2.5H, 1H), 4.67 (s, 2H), 2.73 (d, J=4.5 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[CH:11]=1.[N:24]([CH:27]([CH3:29])[CH3:28])=[C:25]=[O:26].N1C=CC=CC=1>C(=O)([O-])O.[Na+]>[CH:27]([NH:24][C:25]([NH:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[CH:11]=1)=[O:26])([CH3:29])[CH3:28]
Reactant: CC(C)N=C=O
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(C)NC(=O)Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c1
Temperature: 80 °C
Reaction time: 23 h
Yield: 61.3 %

Procedure:
A mixture of N-[6-(3-aminophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (19.3 mg, 0.063 mmol), 2-isocyanatopropane (25.3 mg, 0.297 mmol) and pyridine (1.5 mL) was stirred at 80° C. for 23 hr. The reaction mixture was diluted with aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was concentrated, and the residue was purified by preparative HPLC to give the title compound (15.2 mg, 62%).
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4]2[CH:11]=[C:10]([CH:12]=[N:13][CH3:14])[S:9][C:5]=2[N:6]=[CH:7][N:8]=1.COC1C=C(C=CC=1OC)CN=CC1SC2N=CN=CC=2C=1.CC1C=CC(S([CH:47]([C:50]2[CH:55]=[CH:54][CH:53]=[C:52]([I:56])[CH:51]=2)[N+:48]#[C-:49])(=O)=O)=CC=1>>[I:56][C:52]1[CH:51]=[C:50]([C:47]2[N:48]=[CH:49][N:13]([CH3:14])[C:12]=2[C:10]2[S:9][C:5]3[N:6]=[CH:7][N:8]=[C:3]([S:2][CH3:1])[C:4]=3[CH:11]=2)[CH:55]=[CH:54][CH:53]=1
Reactant: CN=Cc1cc2c(SC)ncnc2s1
Reactant: [C-]#[N+]C(c1cccc(I)c1)S(=O)(=O)c1ccc(C)cc1
Agent: COc1ccc(CN=Cc2cc3cncnc3s2)cc1OC
Product: CSc1ncnc2sc(-c3c(-c4cccc(I)c4)ncn3C)cc12

Procedure:
The title compound was prepared by a similar process to that described for Example 6 but using N-[4-(methylthio)thieno[2,3-d]pyrimidin-6-ylmethylidene]methanamine (Intermediate 16) in place of N-(3,4-Dimethoxybenzyl)-N-[thieno[2,3-d]pyrimidin-6-ylmethylidene]amine (intermediate 14) and using (3-iodophenyl)(isocyano)methyl 4-methylphenyl sulfone (Intermediate 53) in place of PhTosMIC. Pale yellow solid (1.50 g, 71%);
Reaction SMILES: CC(C)CCC1NC2C(C=1)=CC=CC=2.[C:15]([C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22]([CH2:27][CH2:28][C:29]([CH3:31])=[CH2:30])=[CH:21]2)([OH:17])=[O:16]>>[C:15]([C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22]([CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])=[CH:21]2)([OH:17])=[O:16]
Reactant: C=C(C)CCc1cc2cc(C(=O)O)ccc2[nH]1
Agent: CC(C)CCc1cc2ccccc2[nH]1
Product: CC(C)CCc1cc2cc(C(=O)O)ccc2[nH]1

Procedure:
Refer to 28b) using 5-carboxy-2-(2-methyl-1-buten-4-yl) indole as the starting material.
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:3]=1[CH:4]=[N:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[Cl:13].[BH4-].[Na+].C(O)C>O>[CH3:1][C:2]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:3]=1[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[Cl:13]
Reactant: Cc1ccc(C=Nc2ccc(Cl)cc2Cl)c(C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1ccc(CNc2ccc(Cl)cc2Cl)c(C)c1

Procedure:
A mixture of 13.9 g. of N-(2,4-dimethylbenzylidene)-2,4-dichloroaniline, 1.89 g. of sodium borohydride and 150 ml of ethanol is stirred under reflux for one hour, allowed to cool and poured into water. Recrystallization from ethanol yields N-(2,4-dimethylbenzyl)-2,4-dichloroaniline, m.p. 88°-90°.
Reaction SMILES: [C:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[CH:15]([CH3:17])[CH3:16])[CH:8]=[CH:7][CH:6]=1)(=[O:3])C.[CH3:18][O-].[Na+].O.Cl>CO>[CH:15]([C:13]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:14]=1[C:5]([O:4][CH2:1][O:3][CH3:18])=[CH:6][CH:7]=[CH:8]2)([CH3:17])[CH3:16]
Reactant: C[O-]
Reactant: CC(=O)Oc1cccc2cccc(C(C)C)c12
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COCOc1cccc2cccc(C(C)C)c12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 95.9 %

Procedure:
8.40 g of 8-isopropyl-1-naphthyl acetate was dissolved in 50 ml of methanol, to which 2.2 g of sodium methoxide was added at room temperature, followed by agitation for 10 minutes as it is. Water was added to the solution, which was rendered acidic by the use of 1N hydrochloric acid, followed by extraction with ethyl acetate. The resultant organic phase was washed with a saturated saline solution and dried with anhydrous magnesium sulfate, from which the solvent was distilled off. The resulting residue was dissolved in 30 ml of dimethylformamide without purification, to which 1.94 g of 60% sodium hydride was added at room temperature. After 10 minutes, it was cooled down to 0° C., to which 5.96 g of chloromethyl methyl ether was added, followed by agitation for 15 minutes as it is. Water was added to the solution which was extracted with ethyl acetate, and th resultant organic phase was washed with a saturated saline solution and dried with anhydrous magnesium sulfate, from which the solvent was distilled off. The resultant residue was purified by silica gel column chromatography (3% ethyl acetate/hexane) to obtain 8.13 g of the captioned compound as a light yellow oily substance.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C@H:6]1[NH:10][CH2:9][C@@H:8]([NH:11][C:12]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]=2[OH:24])=[O:13])[CH2:7]1.[CH:25]1([CH:31]=O)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.COC([C@@H]1C[C@H](N=[N+]=[N-])CN1CC1CCCCC1)=O>>[CH:25]1([CH2:31][N:10]2[C@H:6]([C:2]3[O:1][CH:5]=[CH:4][N:3]=3)[CH2:7][C@H:8]([NH:11][C:12]([C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15]=3[OH:24])=[O:13])[CH2:9]2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: O=CC1CCCCC1
Reactant: O=C(N[C@@H]1CN[C@H](c2ncco2)C1)c1ccc2ccccc2c1O
Agent: COC(=O)[C@@H]1C[C@H](N=[N+]=[N-])CN1CC1CCCCC1
Product: O=C(N[C@H]1C[C@@H](c2ncco2)N(CC2CCCCC2)C1)c1ccc2ccccc2c1O

Procedure:
Hydroxy-naphthalene-2-carboxylic acid ((3S,5S)-1-cyclohexylmethyl-5-oxazol-2-yl-pyrrolidin-3-yl)-amide was prepared from 1-hydroxy-naphthalene-2-carboxylic acid ((3S,5S)-5-oxazol-2-yl-pyrrolidin-3-yl)-amide and cyclohexanecarbaldehyde in a similar fashion as the synthesis of (2S,4S)-4-azido-1-cyclohexylmethyl-pyrrolidine-2-carboxylic acid methyl ester. MS calcd. for C25H30N3O3[(M+H)+] 420, obsd. 419.8.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:16]2[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(S)cc1
Reactant: O=Cc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(Sc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.1 %

Procedure:
A mixture of 4-fluorobenzenethiol (1.0 g), potassium carbonate (2.4 g) and N,N-dimethylformamide (25 mL) was treated with 4-bromobenzaldehyde (0.73 g), and the resulting mixture was stirred at room temperature for 16 hours. The mixture was filtered and the filtrated concentrated under reduced pressure. The residue was purified by crystallisation from a mixture of diethyl ether and cyclohexane to afford the title compound as a white solid (0.89 g).
Reaction SMILES: [NH2:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[F:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=1.CN(C=O)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O>[F:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH:1][C:2]2[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])=[O:19])=[CH:16][CH:15]=1
Reactant: COC(=O)c1cccc(O)c1N
Reactant: O=C(O)c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(O)c1NC(=O)c1ccc(F)cc1
Reaction time: 0.17 h
Yield: 84.7 %

Procedure:
A solution of 1.0 g (4.9 mmol) of methyl 2-amino-3-hydroxybenzoate 9a, 1.03 g (7.4 mmol) of 4-fluorobenzoic acid 9b, 10 mL DMF and 2.9 mL (20.6 mmol) of TEA were placed into a flask and stirred for 10 min. HATU (7.4 mmol, 2.8 g) was added and the reaction was stirred overnight. The reaction mixture was poured into water and extracted with EtOAc. The organics were washed with water and brine and the solvent was evaporated to give 1.2 g of crude product, methyl 2-(4-fluoro-benzoylamino)-3-hydroxy-benzoate, 9c, which was used without purification. MS m/z (M+H+) 290.1.
Reaction SMILES: N#N.[OH-].[K+].[CH3:5][O:6][C:7]12[CH2:14][CH2:13][CH:10]([CH:11]=[CH:12]1)[CH2:9][CH:8]2[C:15]([O:17]C)=[O:16]>CO.O>[CH3:5][O:6][C:7]12[CH2:14][CH2:13][CH:10]([CH:11]=[CH:12]1)[CH2:9][CH:8]2[C:15]([OH:17])=[O:16]
Reactant: COC(=O)C1CC2C=CC1(OC)CC2
Agent: N#N
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC12C=CC(CC1)CC2C(=O)O
Yield: 87.8 %

Procedure:
In a 3 liter flask equipped with a mechanical stirrer, thermometer, reflux condenser, addition funnel and N2 atmosphere, potassium hydroxide (4.59 mole) was dissolved in methanol (1 L). To the resulting hot solution was added, over a five minute period, methyl 1-methoxybicyclo[2.2.2]oct-5-ene-2-carboxylate (1.53 mole) and the resulting light brown solution was heated to reflux for 5 hours. The reaction was then diluted with H2O (700 ml) and stripped under reduced pressure to a tan slimy solid. This solid was dissolved in fresh H2O (1 L) and washed with methylene chloride (1×500 ml). The separated aqueous layer was acidified to pH 1.5 with 420 ml conc. HCl at reduced temperature and extraced with methylene chloride (3×500 ml). The combined organic layers were washed with H2O (1 L) and brine. Drying and stripping under reduced pressure yielded 87.8% of title product as brown solids; mp 77°-81°; pnmr/CDCl3 /TMS/delta 1.65-2.0 (m,6,C3H,C7H,C8H), 2.6-2.8 (m,2,C4H, C2H), 3.4 (s, 3,OCH3), 6.2 (m,2,C5H,C6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[Cl:16])[C:5]([CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:6].[CH2:17](O)[CH2:18][OH:19].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2([CH:7]3[CH2:8][CH2:9][NH:10][CH2:11][CH2:12]3)[O:19][CH2:18][CH2:17][O:6]2)[CH:13]=[CH:14][C:15]=1[Cl:16]
Reactant: OCCO
Reactant: O=C(c1ccc(Cl)c(Cl)c1)C1CCNCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Clc1ccc(C2(C3CCNCC3)OCCO2)cc1Cl
Yield: 51 %

Procedure:
A mixture of 4-(3,4-dichlorobenzoyl)piperidine (1.0 g, 3.9 mmol), ethylene glycol (0.65 ml, 11.6 mmol), p-toluenesulfonic acid mono hydrate (1.48 g, 7.8 mmol), and toluene (100 mL) was refluxed through a Dean-Stark trap for 4 h. After concentration, the residue was stirred with ethyl acetate and dilute aqueous sodium bicarbonate solution. The organic layer was separated, dried over magnesium sulfate, and concentrated in vacuo to give 4-[2-(3,4-dichlorophenyl)-[1,3]dioxolan-2-yl]piperidine (0.6 g, 1.99 mmol).
Reaction SMILES: CO[C:3]1[CH:8]=[C:7]([CH3:9])[O:6][C:5](=[O:10])[C:4]=1[C:11](=[O:24])[CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]=[CH:21][C:22]#[N:23])[CH:15]=1.[CH2:25]([NH2:28])[C:26]#[CH:27]>C1C=CC=CC=1>[CH2:25]([NH:28][C:3]1[CH:8]=[C:7]([CH3:9])[O:6][C:5](=[O:10])[C:4]=1[C:11](=[O:24])[CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]=[CH:21][C:22]#[N:23])[CH:15]=1)[C:26]#[CH:27]
Reactant: C#CCN
Reactant: COc1cc(C)oc(=O)c1C(=O)C=Cc1cccc(C=CC#N)c1
Solvent: c1ccccc1
Product: C#CCNc1cc(C)oc(=O)c1C(=O)C=Cc1cccc(C=CC#N)c1
Temperature: 25 °C
Yield: 31.7 %

Procedure:
To a mixture of 0.20 g of 4-methoxy-3-[3-[3-(2-cyanoethenyl)phenyl]-1-oxo-2-propenyl]-6-methyl-2H-pyran-2-one and 10 ml of benzene was added 34.3 mg of propargylamine, and the mixture was heated under refluxing for 3 hours and 45 minutes. After cooling to room temperature, precipitated crystals were filtered to obtain 68.0 mg of 4-propargylamino-3-[3-[3-(2-cyanoethenyl)phenyl]-1-oxo-2-propenyl]-6-methyl-2H-pyran-2-one [Compound No. (20b)] as a pale brown powder.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O)#[N:16]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:8][C:5]1[CH:4]=[N:3][C:2]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[C:15]#[N:16])=[N:7][CH:6]=1
Reactant: Fc1cnc(Br)nc1
Reactant: N#Cc1ccccc1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: N#Cc1ccccc1-c1ncc(F)cn1
Reaction time: 0.58 h

Procedure:
A suspension of 2-bromo-5-fluoropyrimidine (CAS number 947533-45-1; 301 mg, 1.70 mmol), potassium carbonate (705 mg, 5.10 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (62 mg, 0.085 mmol) in DMF (5 ml) was purged and evacuated with nitrogen. To this was then added (2-cyanophenyl)boronic acid (CAS number 138642-62-3; 300 mg, 2.04 mmol) and the reaction was subjected to microwave irradiation at 140° C. for 10 minutes and then at 130° C. for 35 minutes. The reaction was partitioned between ethyl acetate (50 ml) and water (50 ml) and filtered through diatomaceous earth (commercially sold under the trade mark “Celite”). The organics were washed with brine, dried over magnesium sulfate and concentrated in vacuo. The resulting residue was purified column chromatography (silica, 0-100% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:34][C:35]1[CH:36]=[C:37]([CH:39]=[C:40]([F:42])[CH:41]=1)[NH2:38].[CH3:43][O:44][C:45]1[N:50]=[CH:49][C:48]([N:51]2[CH2:55][CH:54]([CH2:56][CH2:57][CH3:58])[N:53]([CH2:59][C:60](O)=[O:61])[C:52]2=[O:63])=[CH:47][CH:46]=1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[F:34][C:35]1[CH:36]=[C:37]([NH:38][C:60](=[O:61])[CH2:59][N:53]2[CH:54]([CH2:56][CH2:57][CH3:58])[CH2:55][N:51]([C:48]3[CH:49]=[N:50][C:45]([O:44][CH3:43])=[CH:46][CH:47]=3)[C:52]2=[O:63])[CH:39]=[C:40]([F:42])[CH:41]=1
Reactant: CCCC1CN(c2ccc(OC)nc2)C(=O)N1CC(=O)O
Reactant: Nc1cc(F)cc(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCCC1CN(c2ccc(OC)nc2)C(=O)N1CC(=O)Nc1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.7 %

Procedure:
N,N-diisopropylethylamine (0.06 mL), HATU (142 mg), and 3,5-difluoroaniline (48 mg) were added to a solution of [3-(6-methoxypyridin-3-yl)-2-oxo-5-propylimidazolidin-1-yl]acetic acid (100 mg) in chloroform (2 mL), and the mixture was stirred at room temperature overnight. Saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with chloroform and drying over anhydrous magnesium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane/ethyl acetate) to afford the title compound (114 mg).