Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:24])=[C:5]([C:18]([O:20][CH2:21][CH2:22][OH:23])=[O:19])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[C:7]=1[N+:8]([O-:10])=[O:9].[OH2:25].N1[CH:31]=[CH:30]C=CC=1>C(OC(=O)C)(=O)C>[CH3:1][C:2]1[NH:3][C:4]([CH3:24])=[C:5]([C:18]([O:20][CH2:21][CH2:22][O:23][C:30](=[O:25])[CH3:31])=[O:19])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: CC1=C(C(=O)OCCO)C(c2ccccc2Cl)C([N+](=O)[O-])=C(C)N1
Reactant: O
Reactant: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OCCOC(=O)C1=C(C)NC(C)=C([N+](=O)[O-])C1c1ccccc1Cl

Procedure:
1 g of β-hydroxyethyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-chlorophenyl)-pyridine-5-carboxylate is stirred overnight in a mixture of 15 ml of pyridine and 15 ml of acetic anhydride. The mixture is poured into water and extracted with ethyl acetate and the extract is washed with 1 N HCl, water, sodium bicarbonate solution and water again, dried and concentrated. The evaporation residue is crystallized with ethanol, filtered off with suction and washed with ethanol. 800 mg of a yellow-coloured compound of melting point 166° C. which is identical to the compound from Preparation Example 1, process variant A are obtained.
Reaction SMILES: O[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].[OH:12][C@H:13]1[CH2:17][CH2:16][O:15][CH2:14]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.CCCCCC.C(OCC)(=O)C>[CH3:11][O:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[C:3]([O:12][C@@H:13]2[CH2:17][CH2:16][O:15][CH2:14]2)[CH:2]=1
Reactant: COc1ccc(C=O)cc1O
Reactant: O[C@H]1CCOC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(C=O)c(O[C@@H]2CCOC2)c1
Temperature: 5 °C
Reaction time: 16 h
Yield: 66.6 %

Procedure:
3-Hydroxy-4-methoxybenzaldehyde (7.6 g; 50 mmol) was dissolved in THF (200 mL) followed by addition of (S)-3-hydroxytetrahydrofuran (6.0 mL; 75 mmol) and triphenylphosphine (19.7 g; 75 mmol). The resulting solution was cooled to 5° C. and diisopropyl azodicarboxylate (14.8 mL; 75 mmol) was added dropwise over 10 minutes. The clear orange solution was stirred at ambient temperature for 16 hours. Thin layer chromatography analysis using a 1:1 mixture of hexane/ethyl acetate determined the reaction to be complete. The solvent was removed under reduced pressure and the residue was taken up in ethyl acetate (60 mL) and extracted twice with 20% aqueous sodium bisulfite (150 mL/extraction). The extracts were pooled and washed with ethyl acetate (75 mL). The aqueous layer was basified with solid sodium hydroxide (26 g) and then extracted with 3×150 mL of ethyl acetate (150 mL/extraction). The organic extracts were pooled, washed with 40 mL of brine, dried (Na2SO4), and concentrated to afford 7.4 g (66%) of a pale yellow oil. 1H NMR (CDCl3; 300 MHz) δ 2.2-2.4 (m, 2H); 3.8-4.1 (m, 7H); 5.0 (m, 1H); 7.0 (d, 1H); 7.4 (s, 1H); 7.5 (d, 1H); 9.9 (s, 1H). ES-MS [M+H]+=223.2
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([N:9]([CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[S:10]([CH2:13][CH3:14])(=[O:12])=[O:11])[CH:5]=[CH:6][C:7]=1[CH3:8].[C:22]([C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1)([CH3:25])([CH3:24])[CH3:23]>>[C:22]([C:26]1[CH:27]=[CH:28][C:29]([O:32][C:2]2[CH:3]=[C:4]([N:9]([CH2:15][C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)[S:10]([CH2:13][CH3:14])(=[O:12])=[O:11])[CH:5]=[CH:6][C:7]=2[CH3:8])=[CH:30][CH:31]=1)([CH3:25])([CH3:23])[CH3:24]
Reactant: CCS(=O)(=O)N(Cc1cccnc1)c1ccc(C)c(I)c1
Reactant: CC(C)(C)c1ccc(O)cc1
Product: CCS(=O)(=O)N(Cc1cccnc1)c1ccc(C)c(Oc2ccc(C(C)(C)C)cc2)c1

Procedure:
The title compound was prepared following Example 342 using N-(3-iodo-4-methylphenyl)-N-(ethanesulfonyl)pyrid-3-ylmethylamine and 4-tert-butylphenol and purifying via radial chromatography eluting with 50:50 to 53:47 THF/hexanes gave the title compound. 1H NMR (400 MHz) 1.32 (9H, s), 1.39 (3H, t, J=7.8 Hz), 2.19 (3H, s), 3.07 (2H, q, J=7.8 Hz), 4.79 (2H, s), 6.70 (3H, m), 6.92 (1H, dd, J=2.0, 7.8 Hz), 7.16 (1H, d, J=7.8 Hz), 7.20-7.31 (3H, m), 7.67 (1H, d, J=8.3 Hz), 8.31 (1H, bs), 8.50 (1H, bs). HRMS calculated 439.2055 [M+H]+ Found 439.2073.
Reaction SMILES: OS(O)(=O)=O.[NH2:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[C:10]([OH:12])=[O:11].[CH3:18]O>>[CH3:18][O:11][C:10](=[O:12])[C:9]1[CH:13]=[CH:14][C:15]([O:16][CH3:17])=[C:7]([NH2:6])[CH:8]=1
Reactant: CO
Reactant: COc1ccc(C(=O)O)cc1N
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(OC)c(N)c1

Procedure:
Concentrated H2SO4 (9 mL) was added in portions to a stirred solution of -3-amino-4-methoxybenzoic acid (20.06 g, 110.4 mmol) in methanol (280 mL).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[CH:11]=[CH:10][NH:9][C:5]=2[N:6]=[CH:7][N:8]=1.FC1C(C=O)=C(F)C=CC=1NS(CCC)(=O)=O.[F:29][C:30]1[C:35]([CH:36]=O)=[C:34]([F:38])[CH:33]=[CH:32][C:31]=1[NH:39][S:40]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)(=[O:42])=[O:41].C(OC1C2C=CNC=2N=CN=1)C.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>>[F:29][C:30]1[C:35]([CH2:36][C:11]2[C:4]3[C:3]([O:2][CH3:1])=[N:8][CH:7]=[N:6][C:5]=3[NH:9][CH:10]=2)=[C:34]([F:38])[CH:33]=[CH:32][C:31]=1[NH:39][S:40]([C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)(=[O:42])=[O:41]
Reactant: O=Cc1c(F)ccc(NS(=O)(=O)c2ccccc2)c1F
Reactant: COc1ncnc2[nH]ccc12
Agent: CCCS(=O)(=O)Nc1ccc(F)c(C=O)c1F
Agent: CCOc1ncnc2[nH]ccc12
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COc1ncnc2[nH]cc(Cc3c(F)ccc(NS(=O)(=O)c4ccccc4)c3F)c12

Procedure:
were prepared similarly to the protocol of Scheme 7, steps 2 and 3, replacing 4-methyl-7H-pyrrolo[2,3-d]pyrimidine 42 with 4-methoxy-7H-pyrrolo[2,3-d]pyrimidine 3 and propane-1-sulfonic acid (2,4-difluoro-3-formyl-phenyl)-amide 9 with N-(2,4-Difluoro-3-formyl-phenyl)-benzenesulfonamide in step 2 for P-0072 and replacing 4-methyl-7H-pyrrolo[2,3-d]pyrimidine 42 with 4-ethoxy-7H-pyrrolo[2,3-d]pyrimidine 47 in step 2 for P-0075. Alternatively, the intermediate in the reaction to form P-0072 was reduced using triethylsilane and trifluoroacetic acid to form N-[2,4-difluoro-3-(4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-phenyl]-benzenesulfonamide P-0073
Reaction SMILES: [F:1][C:2]1[C:19]([NH:20][S:21]([CH2:24][CH2:25][CH3:26])(=[O:23])=[O:22])=[CH:18][CH:17]=[C:16]([F:27])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]2[CH:15]=[CH:14][NH:13][C:10]2=[N:11][CH:12]=1)=[O:5].[Cl:28]N1C(=O)CCC1=O>CN(C=O)C>[Cl:28][C:15]1[C:9]2[C:10](=[N:11][CH:12]=[C:7]([NH:6][C:4](=[O:5])[C:3]3[C:16]([F:27])=[CH:17][CH:18]=[C:19]([NH:20][S:21]([CH2:24][CH2:25][CH3:26])(=[O:23])=[O:22])[C:2]=3[F:1])[CH:8]=2)[NH:13][CH:14]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]ccc3c2)c1F
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]cc(Cl)c3c2)c1F
Reaction time: 8 h

Procedure:
2,6-Difluoro-3-(propylsulfonamido)-N-(1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide (0.300 g, 0.7607 mmol) was dissolved in DMF (10 mL), and N-chlorosuccinimide (0.122 g, 0.913 mmol) was added and stirred overnight. The solution was partitioned between water and EtOAc. The organic portion was washed with water (3×), brine, dried over Na2SO4 and concentrated to an oil. DCM was added to the oil, and a solid, N-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide (217.4 mg, 66.7%), precipitated out, which was collected by filtration. 1H NMR (400 MHz, DMSO-d6) δ 12.03 (br s, 1H), 11.04 (s, 1H), 9.81 (br s, 1H), 8.40-8.43 (m, 2H), 7.72-7.74 (m, 1H), 7.53-7.59 (m, 1H), 7.26-7.30 (m, 1H), 3.11-3.15 (m, 2H), 1.75-1.80 (m, 2H), 0.98-1.02 (m, 3H); m/z (APCI-neg) M−1=427.1, 429.2.
Reaction SMILES: [CH2:1]([N:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][Si](C)(C)C)=[CH:8][CH:7]=1)[CH2:4][CH3:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].CO>O>[CH2:1]([N:3]([C:6]1[CH:7]=[CH:8][C:9]([C:12]#[CH:13])=[CH:10][CH:11]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCN(CC)c1ccc(C#C[Si](C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: C#Cc1ccc(N(CC)CC)cc1
Temperature: 65 °C
Reaction time: 30 h

Procedure:
A mixture of N,N-diethyl-(4-trimethylsilanylethynyl-phenyl)amine (500 mg 2.03 mmol), K2CO3 (1.5 g 10.8 mmol) and methanol (30 mL) was stirred at 65° C. for 30 h. The reaction mixture was cooled, poured into water and extracted with ethyl acetate (50×3). The combined extract was dried over anhydrous MgSO4. The solvent was removed under reduced pressure and the crude material was further purified by filtration through a short silica gel column with hexane/EAC (0-5%) and the product separated as a semi solid. Yield: 250 mg (72.2%) IR (neat) 2971, 2098, 1607, 1551 cm−1; 1H NMR (400 MHz, CDCl3) δ7.36 (d, J=8.4 Hz, 2H), 6.59 (d, J=8.4 Hz, 2H), 3.36 (q, J=6.8 Hz, 4H), 1.16 (t, 6.8 Hz, 6H); 13CNMR (100 MHz, CDCl3) δ 147.68, 133.31, 110.90, 107.46, 84.96, 74.38, 44.19, 12.41.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:37])[CH:15]([C:20]1[CH:21]=[C:22]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)[CH:23]=[C:24]([OH:26])[CH:25]=1)[CH2:16][CH:17]([CH3:19])[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:39][C:40]1[CH:45]=[CH:44][C:43]([F:46])=[CH:42][C:41]=1[C:47]([F:50])([F:49])[F:48].C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[CH2:1]([CH:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:37])[CH:15]([C:20]1[CH:21]=[C:22]([C:27]2[CH:28]=[CH:29][C:30]([C:33]([F:34])([F:36])[F:35])=[CH:31][CH:32]=2)[CH:23]=[C:24]([O:26][CH2:39][C:40]2[CH:45]=[CH:44][C:43]([F:46])=[CH:42][C:41]=2[C:47]([F:49])([F:48])[F:50])[CH:25]=1)[CH2:16][CH:17]([CH3:19])[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1ccc(CBr)c(C(F)(F)F)c1
Reactant: CC(C)CC(C(=O)N1C(=O)OCC1Cc1ccccc1)c1cc(O)cc(-c2ccc(C(F)(F)F)cc2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)CC(C(=O)N1C(=O)OCC1Cc1ccccc1)c1cc(OCc2ccc(F)cc2C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-benzyl-3-[2-(5-hydroxy-4′-trifluoromethyl-biphenyl-3-yl)-4-methyl-pentanoyl]-oxazolidin-2-one (as prepared in Example 1, step (k))(0.400 g, 0.78 mmol) in acetonitrile (3.9 mL) was added 1-bromomethyl-4-fluoro-2-trifluoromethyl-benzene (0.181 mL, 1.17 mmol) and Cs2CO3 (0.508 g, 1.56 mmol). The resulting white suspension was stirred at room temperature for 1 h. The white solid was filtered off and the solvent was removed in vacuo to obtain relatively pure 4-benzyl-3-{2-[5-(4-fluoro-2-trifluoromethyl-benzyloxy)-4′-trifluoromethyl-biphenyl-3-yl]-4-methyl-pentanoyl}-oxazolidin-2-one.
Reaction SMILES: [CH2:1]([NH:3][CH:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:14][CH3:15])[CH:10]=2)[CH2:5]1)[CH3:2].C(N(CC)CC)C.[CH3:23][O:24][C:25]([CH2:27][CH2:28][C:29](Cl)=[O:30])=[O:26]>C1C=CC=CC=1>[CH2:1]([N:3]([CH:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:14][CH3:15])[CH:10]=2)[CH2:5]1)[C:29](=[O:30])[CH2:28][CH2:27][C:25]([O:24][CH3:23])=[O:26])[CH3:2]
Reactant: CCNC1CCc2cc(OC)ccc2C1
Reactant: COC(=O)CCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCN(C(=O)CCC(=O)OC)C1CCc2cc(OC)ccc2C1
Reaction time: 8 h
Yield: 91.3 %

Procedure:
To a mixture of 8.8 g of N-ethyl-6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine, 6.1 g of triethylamine and 80 ml of anhydrous benzene, 7.1 g of 3-(methoxycarbonyl)-propionyl chloride dissolved in 10 ml of anhydrous benzene was added dropwise. After the resulting solution was heated for 2.5 hours at reflux, the solution was allowed to stand overnight at room temperature (about 25° C.). The reaction solution was washed with a 2N-HCl aqueous solution, water, a 2 N-NaOH aqueous solution and water in order, and dried over anhydrous sodium sulfate. Then, the solution was concentrated under reduced pressure to obtain 12.5 g of N-ethyl-N-[3-(methoxycarbonyl)propionyl]-6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine as a pale-yellow oily product.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].O[CH:12]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:24]=[C:25]([NH:29][C:30](=[O:34])[CH:31]([CH3:33])[CH3:32])[CH:26]=[CH:27][CH:28]=2)[CH2:19][CH2:18]1>>[C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O:1][CH:12]([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:24]=[C:25]([NH:29][C:30](=[O:34])[CH:31]([CH3:33])[CH3:32])[CH:26]=[CH:27][CH:28]=2)[CH2:19][CH2:18]1)(=[O:10])[CH3:9]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(O)c3ccccc3)CC2)c1
Reactant: CC(=O)c1ccccc1O
Product: CC(=O)c1ccccc1OC(CCCCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1)c1ccccc1

Procedure:
Prepared by Procedure A and Scheme AN using 1-(2-hydroxyphenyl)ethanone and N-{3-[1-(5-hydroxy-5-phenylpentyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 527.0 (M+H)+.
Reaction SMILES: [S:1]1[CH2:5][C:4](=[O:6])[NH:3][C:2]1=[O:7].C(O)(=O)C.N1CCCCC1.[Cl:18][CH:19]([C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH3:37])=[CH:32][N:31]=1)[CH2:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1>C1(C)C=CC=CC=1>[Cl:18][CH:19]([C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH3:37])=[CH:32][N:31]=1)[CH2:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([CH:26]=[C:5]2[S:1][C:2](=[O:7])[NH:3][C:4]2=[O:6])=[CH:28][CH:29]=1
Reactant: CCc1ccc(C(Cl)COc2ccc(C=O)cc2)nc1
Reactant: O=C1CSC(=O)N1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: CCc1ccc(C(Cl)COc2ccc(C=C3SC(=O)NC3=O)cc2)nc1

Procedure:
A mixture of 2 g (0.017 mol) thiazolidin-2,4-dione, 2 g (0.034 mol) acetic acid and 3 g (0.03 mol) piperidine were added to a solution of 5 g (0.017 mol) 4-[2-chloro-2-(5-ethyl-pyridin-2-yl)-ethoxy]-benzaldehyde dissolved in 50 mL toluene. Reaction mixture was heated and water was removed azeotropically. After completion of the reaction on TLC, toluene was distilled out completely under reduced pressure. Product was poured into excess of water and extracted with ethyl acetate. After concentrating ethyl acetate in vacuo and making its HCl salt in usual way 4.3 g (60%) desired product obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]2[CH:13]=[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N+:11]([O-])=[CH:10][C:9]=2[C:8]([CH3:21])=[CH:7]1.P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:10]1[C:9]2[C:8]([CH3:21])=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][O:2][CH3:1])[C:14]=2[CH:13]=[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cc2c(c[n+]1[O-])c(C)cn2CCCOC
Product: CCOC(=O)c1cc2c(c(C)cn2CCCOC)c(Cl)n1

Procedure:
A solution of ethyl 1-(3-methoxypropyl)-3-methyl-1H-pyrrolo[3,2-c]pyridine-6-carboxylate 5-oxide (40 mg) in phosphorus oxychloride (2 mL) was stirred at 100° C. for 1 hours. The reaction solution was concentrated, and the resulting residue was dissolved in ethyl acetate. It was sequentially washed with aqueous saturated sodium hydrogen carbonate solution and saturated saline, and dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane→n-hexane/ethyl acetate=1/1) to give ethyl 4-chloro-1-(3-methoxypropyl)-3-methyl-1H-pyrrolo[3,2-c]pyridine-6-carboxylate [REx(105-6)] (23 mg) as a colorless powder.
Reaction SMILES: [C:1](O)(=O)[CH2:2][C:3]([OH:5])=[O:4].N1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.N1C=CC=C[CH:15]=1>>[CH2:10]([CH:11]([CH2:12][CH:13]=[CH2:15])/[CH:1]=[CH:2]/[C:3]([OH:5])=[O:4])[CH3:9]
Reactant: c1ccncc1
Reactant: O=C(O)CC(=O)O
Reactant: C1CCNCC1
Product: C=CCC(/C=C/C(=O)O)CC
Temperature: 100 °C
Reaction time: 17 h
Yield: 83 %

Procedure:
Allyl bromide (7.1 mL, 81.8 mmol) was added to a mixture of (E)-but-1-enyldiisobutylamine (10.0 g, 54.5 mmol) and acetonitrile (30 mL) at room temperature under a nitrogen atmosphere, and the mixture was then stirred at an external temperature of 70° C. for 17 hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure to obtain an iminium salt as a red purple solid. The obtained iminium salt was dissolved in pyridine (100 mL). To the solution, malonic acid (11.3 g, 109.0 mmol) and piperidine (0.81 mL, 8.2 mmol) were then added in this order. The reaction mixture was stirred at an external temperature of 100° C. for 17 hours and then cooled to room temperature. Pyridine was distilled off, and the residue was then separated into aqueous and organic layers by the addition of ethyl acetate and 1 M hydrochloric acid. The organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was then purified by silica gel chromatography (n-hexane:ethyl acetate=5:1→1:1) to obtain the title compound (6.96 g, yield: 83%) as a colorless oil substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[C:20]([CH3:21])=[CH:19][C:18]([N+:22]([O-:24])=[O:23])=[C:17]3[C:13]=2[CH2:14][CH2:15][CH2:16]3)=[CH:7][C:4]=1[CH:5]=[O:6].CC(=CC)C.Cl([O-])=[O:31].[Na+].P([O-])([O-])(O)=O.[Na+].[Na+]>C(O)(C)(C)C>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[C:20]([CH3:21])=[CH:19][C:18]([N+:22]([O-:24])=[O:23])=[C:17]3[C:13]=2[CH2:14][CH2:15][CH2:16]3)=[CH:7][C:4]=1[C:5]([OH:31])=[O:6]
Reactant: COc1ccc(Oc2c(C)cc([N+](=O)[O-])c3c2CCC3)cc1C=O
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: CC(C)(C)O
Product: COc1ccc(Oc2c(C)cc([N+](=O)[O-])c3c2CCC3)cc1C(=O)O
Yield: 108.7 %

Procedure:
2-methoxy-5-(5-methyl-7-nitroindan-4-yloxy)benzaldehyde (1.00 g) was dissolved in tert-butanol (24 mL). To the mixture was added 2-methyl-2-butene (6 mL) at room temperature with stirring. After adding sodium chlorite (553 mg) and an aqueous solution of sodium hydrogen phosphate (250 g/L, 12 mL), the mixture was stirred at room temperature for 2 days, and then extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the title compound (1.14 g).
Reaction SMILES: [O:1]=[C:2]1[CH:9]2[CH2:10][C:5]3([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:6][CH:7]([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2.[Li][CH3:21]>C1COCC1>[C:15]([O:14][C:13](=[O:19])[NH:12][C:5]12[CH2:4][CH:3]3[CH2:11][CH:7]([CH2:8][CH:9]([C:2]3([OH:1])[CH3:21])[CH2:10]1)[CH2:6]2)([CH3:16])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)NC12CC3CC(C1)C(=O)C(C3)C2
Reactant: [Li]C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC12CC3CC(C1)C(C)(O)C(C3)C2
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
At −78° C., to a solution of 7B (400 mg, 1.51 mmol) in 5 mL of THF was added MeLi (1.6 M in ether, 2.36 mL, 3.78 mmol) dropwise. The mixture was stirred at −78° C. for 30 minutes before it was quenched by 5 mL of NH4Cl aq (Sat'd) solution. The mixture was extracted by DCM (5 mL×3) and the combined DCM layers were dried over Na2SO4. Solvent was remove under vacuum and the residue was purified by silica gel chromatography [0 to 5% of MeOH in DCM:Hexane 1:1(v/v)] to give the title compounds (9A) as a mixture of equatorial and axial isomers (310 mg, 7.3%)). LC-MS (ESR): m/z=282 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][N:9]=[C:10]([C:13]#[N:14])[C:11]#[N:12].BrC1C=CC=CC=1N.C(#N)CC#N.O.[NH2:29][NH2:30]>>[NH2:14][C:13]1[C:10](=[N:9][NH:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Br:1])[C:11]([NH2:12])=[N:30][N:29]=1
Reactant: N#CC(C#N)=NNc1ccccc1Br
Reactant: NN
Agent: Nc1ccccc1Br
Solvent: N#CCC#N
Solvent: O
Product: NC1=NN=C(N)C1=NNc1ccccc1Br
Temperature: 25 °C
Yield: 73 %

Procedure:
This compound was prepared using 125 mg (0.5 mmol) of 2-[(2-bromophenyl)-hydrazono]malononitrile, which was derived from 2-bromoaniline (172 mg, 1.0 mmol) and malononitrile (1.5 mmol) as described in Example 8, and hydrazine hydrate. Very little solid had formed after heating the reaction at 75° C. for 1 hr, however, analysis of the reaction solution by TLC indicated that no starting material remained. The solution was allowed to cool to room temperature and the solvent was evaporated. The residue was dissolved in ethyl acetate and then precipitated by the addition of hexanes. The resulting solid was isolated by filtration and dried to yield 102 mg (73%) of the title compound as an orange solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1C=O.[C:8](=[O:11])([O-])[O-].[Na+].[Na+].[CH:14]1(Br)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>CN(C=O)C>[CH:14]1([N:3]2[CH:4]=[C:5]([CH:8]=[O:11])[N:1]=[CH:2]2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=C([O-])[O-]
Reactant: O=Cc1ncc[nH]1
Reactant: BrC1CCCCC1
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1cn(C2CCCCC2)cn1
Temperature: 90 °C
Reaction time: 72 h

Procedure:
To a solution of imidazolecarboxaldehyde (60 mg, 0.63 mmol) in DMF (0.4 mL) was added sodium carbonate (132 mg, 1.26 mmol). The mixture was then treated with a solution of cyclohexylbromide (152 mg, 0.94 mmol) in DMF (0.4 mL) dropwise and stirred at 90° C. for 72 h. The reaction mixture was partitioned between EtOAc (2 mL) and water (2 mL), and the aqueous layer was extracted with EtOAc. The organic layers were combined, dried with Na2SO4, filtered, and concentrated to yield to yield the title compound which was used without further purification (66 mg). (m/z): [M+H]+ calcd for C10H14N2O 179.11; found, 179.2.
Reaction SMILES: CC1C=CC(S(O[C:12]2[CH:21]=[CH:20][C:19]3[C:18](=[O:22])[CH2:17][CH2:16][CH2:15][C:14]=3[CH:13]=2)(=O)=O)=CC=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([SH:30])=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[F:23][C:24]1[CH:29]=[CH:28][C:27]([S:30][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C:18](=[O:22])[CH2:17][CH2:16][CH2:15]3)=[CH:26][CH:25]=1
Reactant: Fc1ccc(S)cc1
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc3c(c2)CCCC3=O)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCCc2cc(Sc3ccc(F)cc3)ccc21
Yield: 77.8 %

Procedure:
To a solution of 5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl 4-methylbenzene-1-sulfonate (5.0 g, 17.0 mmol) in dioxane (75 mL) was added 4-fluorothiophenol (2.6 g, 20.4 mmol), Pd2(dba)3 (392 mg, 0.43 mmol), Xantphos (492 mg, 0.85 mmol) and DIEA (4.4 g, 34.0 mmol). The mixture was heated to reflux overnight under nitrogen. The mixture was filtered and concentrated. The residue was purified by silica gel chromatography (PE:EtOAc=20:1 to 5:1) to give 3.6 g (77%) of the title compound as an off-white solid. 1H NMR (400 MHz, CDCl3): δ 2.08-2.13 (m, 2H), 2.61 (t, J=6.4 Hz, 2H), 2.85 (t, J=6.0 Hz, 2H), 6.94 (br s, 1H), 6.98 (dd, J=8.4 Hz, 1.6 Hz, 1H), 7.10-7.14 (m, 2H), 7.49-7.53 (m, 2H), 7.88 (d, J=8.4 Hz, 1H). [M+H] Calc'd for C16H13FOS, 273. Found, 273.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:12][C@@H:13]([CH2:16][CH3:17])[CH2:14][OH:15].O>ClCCl.C(N(CC)CC)C>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O:15][CH2:14][C@@H:13]([CH3:12])[CH2:16][CH3:17])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC[C@H](C)CO
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC[C@H](C)COS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 82.5 %

Procedure:
To a ice-cooled solution of p-toluenesulphonyl chloride (9.53 g, 50 mmol), (S)-2-methylbutan-1-ol (4.41 g, 50 mmol) in absolute dichloromethane (200 ml), triethylamine (84 ml) was dropwise added. After complete addition and stirring for further 6 h at room temperature, the reaction mixture was poured into water (150 ml), the organic layer was separated and the aqueous phase was further extracted with dichloromethane (2×200 ml). The combined organic extracts were washed with HCl 1N (2×200 ml), with saturated NaCl solution (2×200 ml), dried over magnesium sulphate and evaporated under reduced pressure. The obtained slightly yellow oil was chromatographed on silica (diethylether/petroleumether: 1/3) to give (s)-2-methyl-butyl p-toluenesulphonate as a colourless oil (Yield: 10.0 g, 89%).