Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:9][OH:10])=[N+:6]([O-:8])[CH:7]=1.[H-].[Na+].[CH3:13]I>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:9][O:10][CH3:13])=[N+:6]([O-:8])[CH:7]=1
Reactant: CI
Reactant: [O-][n+]1cc(Br)ccc1CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCc1ccc(Br)c[n+]1[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.9 %

Procedure:
To a solution of 5-bromo-2-hydroxymethyl-pyridine-1-oxide (6.43 g, 31.5 mmol) in THF (200 ml) was added sodium hydride (1.51 g, 63.1 mmol) at 0° C., and then the reaction mixture was stirred at ambient temperature for 1 h. After cooling to 0° C., MeI (2.90 ml, 46.6 mmol) was added. The temperature was raised to ambient temperature and the reaction mixture was heated to 70° C. for 1 h. After cooling to 0° C. the reaction mixture was quenched with MeOH. The solvents were removed, and the crude product was purified by silica gel chromatography using an ethyl acetate/hexane eluent to yield 4.8 g (70%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][CH:13]([CH3:15])[CH3:14])=[C:4]([CH3:16])[CH:3]=1.O.C1(C)C=C[C:21]([S:24](O)(=O)=O)=CC=1>O1CCOCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][CH2:11][N:12]([CH:13]([CH3:14])[CH3:15])[C:21]2=[S:24])=[C:4]([CH3:16])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Cc1cc(Cl)ccc1NCCCNC(C)C
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(Cl)ccc1N1CCCN(C(C)C)C1=S
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.6 %

Procedure:
To a solution of the diamine of Step A (6 g) in dioxane (100 mL) under nitrogen was added N,N′-thiocarbonyl-di-1,2,4-triazole (4.5 g). After stirring at room temperature for 3 hours, para-toluene sulfonic acid monohydrate was added in one portion (9.5 g) and the mixture was heated at reflux for 8 hours. Additional para-toluene sulfonic acid monohydrate was added (1 g) and reflux was resumed for another 2 hours. The mixture was cooled and diluted with ethyl acetate. The precipitate was collected and washed with ethyl acetate. The combined filtrates were washed with brine, dried over magnesium sulfate, and evaporated to dryness. The residue was dissolved in dichloromethane and absorbed onto a column of Merck-60 flash silica gel. Elution with 20% ethyl acetate in hexane provided the title compound as a white crystalline solid (5.26 g, 74.6%). The material was slurried in hexane-ether, sonicated and collected to provide 4.91 g of pure product, m.p. 147-149° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[C:11]([CH3:19])=[CH:10][C:9]=1[NH2:20])(C)(C)C.C(O[C:27](=[O:50])[CH2:28][C:29](=O)[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[S:37][CH:38]=[C:39]([CH2:41][O:42]C3CCCCO3)[N:40]=2)[CH:31]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:42][CH2:41][C:39]1[N:40]=[C:36]([C:32]2[CH:31]=[C:30]([C:29]3[CH2:28][C:27](=[O:50])[NH:20][C:9]4[CH:10]=[C:11]([CH3:19])[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])=[CH:13][C:8]=4[N:7]=3)[CH:35]=[CH:34][CH:33]=2)[S:37][CH:38]=1
Reactant: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2nc(COC3CCCCO3)cs2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCN(C)c1cc2c(cc1C)NC(=O)CC(c1cccc(-c3nc(CO)cs3)c1)=N2

Procedure:
The title compound was prepared from [2-amino-4-methyl-5-(methyl-propyl-amino)-phenyl]-carbamic acid tert-butyl ester (0.21 g) (Example J24) and 3-oxo-3-[3-[4-(tetrahydro-pyran-2-yloxymethyl)-thiazol-2-yl]-phenyl]-propionic acid tert-butyl ester (Example K27) (0.31 g) according to the general procedure M. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (0.09 g).
Reaction SMILES: C1(CCC(O)CCC2C=CC=CC=2)C=CC=CC=1.[OH:19][CH:20]([CH2:29][S:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:21][S:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[C:37]([O:40][CH2:41]C)(=O)C>CCCCCC>[C:31]1([S:30][CH2:29][CH:20]([O:19][CH2:37][O:40][CH3:41])[CH2:21][S:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: OC(CSc1ccccc1)CSc1ccccc1
Reactant: CCOC(C)=O
Agent: OC(CCc1ccccc1)CCc1ccccc1
Solvent: CCCCCC
Product: COCOC(CSc1ccccc1)CSc1ccccc1

Procedure:
Using the procedure of Example 51 but replacing 1,5-diphenyl-3-pentanol with the resultant compound of Example 15 gave, after silica gel chromatography using 15% ethyl acetate in hexane, 44 mg (31%) of the desired compound (Rf 0.27, 20% ethyl acetate in hexane). 1H NMR (CDCl3) δ3.21 (dd, J=15, 6 Hz, 2H), 3.26 (dd, J=15, 6 Hz, 2H), 3.40 (s, 3H), 3.91 (pentet, J=6 Hz, 1H), 4.68 (s, 2H), 7.15-7.35 (m, 10H). Mass spectrum (M +NH4)+ =338.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][N:12]1[C:20]([C:21]2[N:22]([CH3:26])[CH:23]=[CH:24][N:25]=2)=[C:19]2[C:14]([NH:15][C:16](=[O:29])[N:17]([CH3:28])[C:18]2=[O:27])=[N:13]1.Br[CH2:31][CH2:32][CH:33]([CH3:35])[CH3:34].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][N:12]1[C:20]([C:21]2[N:22]([CH3:26])[CH:23]=[CH:24][N:25]=2)=[C:19]2[C:14]([N:15]([CH2:31][CH2:32][CH:33]([CH3:35])[CH3:34])[C:16](=[O:29])[N:17]([CH3:28])[C:18]2=[O:27])=[N:13]1
Reactant: Cn1ccnc1-c1c2c(=O)n(C)c(=O)[nH]c2nn1Cc1c[nH]c2ccc(Cl)cc12
Reactant: CC(C)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)CCn1c(=O)n(C)c(=O)c2c(-c3nccn3C)n(Cc3c[nH]c4ccc(Cl)cc34)nc21

Procedure:
This compound was synthesized by the reaction of 2-[(5-chloro-1H-indol-3-yl)methyl]-5-methyl-3-(1-methyl-1H-imidazol-2-yl)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione and 1-bromo-3-methylbutane using potassium carbonate as a base in DMF at 80° C. Mass: 480.16 (M+H).
Reaction SMILES: O[CH:2]([C:14]([OH:16])=[O:15])[NH:3][C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[CH:17]([SH:20])([CH3:19])[CH3:18].OS(O)(=O)=O>C(O)(=O)C>[CH:17]([S:20][CH:2]([C:14]([OH:16])=[O:15])[NH:3][C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5])([CH3:19])[CH3:18]
Reactant: CC(C)S
Reactant: O=C(NC(O)C(=O)O)OCc1ccccc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC(C)SC(NC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 48 h
Yield: 94 %

Procedure:
α-hydroxy-N-benzyloxycarbonylglycine 22A (5.57 g, 0.027 mol) of Example 1 was stirred with isopropylmercaptan (8.29 g, 0.11 mol) in glacial acetic acid (26.5 mL) at 0° C. Conc H2SO4 (0.27 mL) was added and the mixture stirred for 2 days at room temperature. The mixture was then poured into ice and the organic layer extracted with ethyl acetate. The ethyl acetate solution was washed with water, 5% NaHCO3, dried over MgSO4, solvent removed to give 22B in 94% yield. This was used without further purification.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH:14]=O.[CH3:16][C:17]([S:20]([NH2:22])=[O:21])([CH3:19])[CH3:18].CCOC(C)=O>C1COCC1.[Cl-].[Na+].O>[CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH:14]=[N:22][S:20]([C:17]([CH3:19])([CH3:18])[CH3:16])=[O:21]
Reactant: O=Cc1ccc2oc3ccccc3c2c1
Reactant: CC(C)(C)S(N)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)S(=O)N=Cc1ccc2oc3ccccc3c2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of commercially available dibenzo[b,d]furan-2-carbaldehyde (1.992 g; 10.20 mmol), titanium(IV) ethoxide Ti(OEt)4 (3.98 ml; 19.00 mmol), and 2-methylpropane-2-sulfinamide (1.150 g; 9.49 mmol) in anh. THF (18 ml) was stirred at rt, under nitrogen, for 4 h. AcOEt and brine were added, and the organic layer was further washed with brine, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM) afforded N-(dibenzo[b,d]furan-2-ylmethylene)-2-methylpropane-2-sulfinamide as a pale yellow solid. LC-MS (conditions A): tR=0.96 min.; [M+H]+: 300.33 g/mol.
Reaction SMILES: Cl[C:2]1[C:3](=[O:27])[O:4][C:5]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH:23]([CH3:25])[CH3:24])=[C:18]([Cl:26])[CH:17]=2)([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH2:6][C:7]=1[OH:8].ClC1C(=O)OC(CCC2CCCCC=2)(C2CCCC2)CC=1O.[Cl:50][C:51]1[CH:63]=[CH:62][C:54]2[N:55]([CH:59]([CH3:61])[CH3:60])[C:56]([SH:58])=[N:57][C:53]=2[CH:52]=1.N1C=CC(C2NC(S)=NN=2)=CC=1>>[Cl:26][C:18]1[CH:17]=[C:16]([CH2:15][CH2:14][C:5]2([CH:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)[O:4][C:3](=[O:27])[C:2]([S:58][C:56]3[N:55]([CH:59]([CH3:61])[CH3:60])[C:54]4[CH:62]=[CH:63][C:51]([Cl:50])=[CH:52][C:53]=4[N:57]=3)=[C:7]([OH:8])[CH2:6]2)[CH:21]=[CH:20][C:19]=1[O:22][CH:23]([CH3:25])[CH3:24]
Reactant: CC(C)Oc1ccc(CCC2(C3CCCC3)CC(O)=C(Cl)C(=O)O2)cc1Cl
Reactant: CC(C)n1c(S)nc2cc(Cl)ccc21
Agent: O=C1OC(CCC2=CCCCC2)(C2CCCC2)CC(O)=C1Cl
Agent: Sc1nnc(-c2ccncc2)[nH]1
Product: CC(C)Oc1ccc(CCC2(C3CCCC3)CC(O)=C(Sc3nc4cc(Cl)ccc4n3C(C)C)C(=O)O2)cc1Cl

Procedure:
The title compound was prepared analogously to Example C(4), where 3-Chloro-6-[2-(3-chloro-4-isopropoxy-phenyl)-ethyl]-6-cyclopentyl-4-hydroxy-5,6-dihydro-pyran-2-one (from Step 1 below) was substituted in place of 3-Chloro-6-(2-cyclohex-1-enyl-ethyl)-6-cyclopentyl-4-hydroxy-5,6-dihydro-pyran-2-one and 5-Chloro-1-isopropyl-2-mercapto benzimidazole was substituted in place of 5-Pyridin-4-yl-4H-[1,2,4]triazole-3-thiol of that example. 1H NMR (DMSO-d6): δ 1.13 (d, J=6.1 Hz, 6H), 1.41 (d, J=7.1 Hz, 6H), 1.42-1.8 (m, 10H), 2.08-2.13 (m, 1H), 2.43-2.54 (m 3H), 2.79 (d, J=17.0, 1H), 4.44-4.48 (m, 1H), 4.63-4.69 (m, 1H), 6.89-6.91 (m, 2H), 6.95-7.00 (m, 2H), 7.14 (s, 1H), 7.49 (d, J=8.6 Hz, 1H), 12.0 (brs, 1H); Anal. Calcd. For C31H36Cl2N2O4S.1.0AcOH: C, 59.72; H, 6.07; N, 4.22; Found: C, 59.50; H, 6.16; N, 4.33. ESIMS (MH+): 604.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])[CH:5]=[CH:4][C:3]=1[N:15]1[CH2:20][CH2:19][CH2:18][CH:17]([NH:21][S:22]([C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[C:30]([Cl:35])[CH:31]=3)[CH:26]=2)(=[O:24])=[O:23])[C:16]1=[O:36].Br[CH2:38][C:39]([O:41][CH3:42])=[O:40].C(=O)([O-])[O-].[K+].[K+]>>[CH3:42][O:41][C:39](=[O:40])[CH2:38][N:21]([S:22]([C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[C:30]([Cl:35])[CH:31]=2)[CH:26]=1)(=[O:23])=[O:24])[CH:17]1[CH2:18][CH2:19][CH2:20][N:15]([C:3]2[CH:2]=[CH:7][C:6]([N:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]3=[O:14])=[CH:5][CH:4]=2)[C:16]1=[O:36]
Reactant: COC(=O)CBr
Reactant: O=C1C(NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCCN1c1ccc(-n2ccccc2=O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)CN(C1CCCN(c2ccc(-n3ccccc3=O)cc2)C1=O)S(=O)(=O)c1ccc2cc(Cl)ccc2c1

Procedure:
The compound of Example 2 was treated with methyl bromoacetate in the presence of potassium carbonate using the procedure described for the preparation of compound 9, Part A. Purification by flash chromatography provided the title compound. MS(ESI+) (M+H)+. 1HNMR (CDCl3) δ 8.48 (s, 1H); 7.85 (m, 4H); 7.53 (m, 2H); 7.37 (m, 3H); 7.27 (m, 2H); 6.85 (m, 1H); 6.45 (m, 1H); 4.60 (m, 1H); 4.30 (m, 1H); 3.80 (m, 1H); 3.74 (m, 3H); 3.60 (m, 1H); 3.40 (m, 1H); 2.55 (m, 1H); 2.15 (m, 3H) ppm. MS m/z 580.0 (M+H)+. HRMS calcd for C29H27N3O6SCl: 580.1309. Found: 580.1310.
Reaction SMILES: C([O:3][C:4](=[O:39])[CH:5]=[C:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:38])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C@@H:19]([N:27]3[CH2:32][C@@H:31]([CH3:33])[N:30]([CH2:34][CH:35]=[CH2:36])[CH2:29][C@@H:28]3[CH3:37])[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=3)[CH:14]=2)[CH2:8][CH2:7]1)C.C(O)C.[OH-].[Na+].S(=O)(=O)(O)O>O>[CH2:34]([N:30]1[C@H:31]([CH3:33])[CH2:32][N:27]([C@@H:19]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=2)[C:15]2[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=2)[C:12]([N:9]2[CH2:8][CH2:7][C:6](=[CH:5][C:4]([OH:39])=[O:3])[CH2:11][CH2:10]2)=[O:38])[C@@H:28]([CH3:37])[CH2:29]1)[CH:35]=[CH2:36]
Reactant: C=CCN1C[C@H](C)N([C@@H](c2cccc(O)c2)c2cccc(C(=O)N3CCC(=CC(=O)OCC)CC3)c2)C[C@H]1C
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C=CCN1C[C@H](C)N([C@@H](c2cccc(O)c2)c2cccc(C(=O)N3CCC(=CC(=O)O)CC3)c2)C[C@H]1C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
The preceding ester, Example 137, was hydrolyzed as follows. A 50 mL round bottom flask equipped with a magnetic stir bar was charged with 0.64 g (1.2 mmol, 1 eq) of (1-{3-[(R)-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)(3-hydroxyphenyl)methyl]-benzoyl}-4-piperidinylidene)acetic acid ethyl ester, 5.0 mL ethanol, and 3.0 mL (6 mmol, 5 eq) of 2 N aqueous NaOH solution. The reaction was stirred at room temperature for 3 days and neutralized with 3.0 mL (6 mmol, 5 eq) of 2 N aqueous sulfuric acid. After stirring for 30 minutes, the reaction was filtered to remove the sodium sulfate and the solvent was removed in vacuo. The residue was dissolved in 5 mL of ethanol and filtered through a 0.2 □m polypropylene membrane. The filtrate was concentrated in vacuo, leaving an off-white solid. This material was dissolved in 8 mL of water, filtered through a 0.2 □m polypropylene membrane, and lyophilized to give (1-{3-[(R)-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)(3-hydroxyphenyl)methyl]-benzoyl}-4-piperidinylidene)acetic acid as a fluffy, white solid, 0.598 g. Calculated for C30H37N3O4 0.25 H2SO4 2.0 H2O: %C, 63.87; H, 7.41; N, 7.45. Found: %C, 64.03; H, 7.31; N, 7.42. 1H NMR (300 MHz, D2O with ˜0.1 N NaOD): {tilde over (□)}□brd, J=7.6 Hz, 1H), 7.30-7.25 (m, 2H), 7.14 (d, J=7.2 Hz, 1H), 6.93 (t, J=7.7 Hz, 1H), 6.46-6.37 (m, 2H), 6.29 (d, J=7.3 Hz, 1H), 5.77-5.66 (m, 1H), 5.61 (d, J=13.3 Hz, 1H), 5.10 (d, J=8.3 Hz, 1H), 5.07 (s, 2H), 3.72-3.51 (m, 2H), 3.26-3.22 (m, 3H), 2.76-2.21 (series of m, 8H), 2.02 (brt, 2H), 1.91 (brt, 1H, 0.96 (d, J=6.1 Hz, 3H), 0.82 (d, J=6.1 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:34]=[CH:33][C:5]2[CH:6]([C:16]3[C:17](=[S:32])[NH:18][C:19](=[O:31])[N:20]([CH2:22][C:23]4[S:24][CH:25]=[C:26]([C:28](O)=[O:29])[N:27]=4)[CH:21]=3)[C:7]3[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:8]=3[CH:9]=[CH:10][C:4]=2[CH:3]=1.[CH2:35]([O:37][C:38](=[O:46])[CH2:39][C:40]1[N:41]=[C:42]([NH2:45])[S:43][CH:44]=1)[CH3:36].F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(CC)CC)C>CN(C)C=O>[CH3:15][C:12]1[CH:13]=[CH:14][C:7]2[CH:6]([C:16]3[C:17](=[S:32])[NH:18][C:19](=[O:31])[N:20]([CH2:22][C:23]4[S:24][CH:25]=[C:26]([C:28]([NH:45][C:42]5[S:43][CH:44]=[C:40]([CH2:39][C:38]([O:37][CH2:35][CH3:36])=[O:46])[N:41]=5)=[O:29])[N:27]=4)[CH:21]=3)[C:5]3[CH:33]=[CH:34][C:2]([CH3:1])=[CH:3][C:4]=3[CH:10]=[CH:9][C:8]=2[CH:11]=1
Reactant: Cc1ccc2c(c1)C=Cc1cc(C)ccc1C2c1cn(Cc2nc(C(=O)O)cs2)c(=O)[nH]c1=S
Reactant: CCOC(=O)Cc1csc(N)n1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1csc(NC(=O)c2csc(Cn3cc(C4c5ccc(C)cc5C=Cc5cc(C)ccc54)c(=S)[nH]c3=O)n2)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The product from example 8(0.11 g) and 2-amino-4-thiazoleacetic acid ethyl ester (0.063 g) were dissolved in dry dimethylformamide (5 ml). Bromo-tris(pyrrolidino)-phosphonium hexafluorophosphate (0.11 g) and triethylamine (0.08 ml) were added and the mixture was stirred at room temperature for 24 hours. The reaction mixture was quenched with brine/HCl and extracted with ethyl acetate. The extract was washed with water, dried (MgSO4) and evaporated. The residue was purified by chromatography eluting with 10% ethyl acetate in dichloromethane and used directly in the next step.
Reaction SMILES: [CH3:1][C:2]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=[C:10]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[C:9](=[O:26])[C:3]=1[C:4]([O:6]CC)=[O:5].[OH-].[Na+:28]>CO.O>[CH3:1][C:2]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=[C:10]([C:19]2[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=2)[C:9](=[O:26])[C:3]=1[C:4]([O-:6])=[O:5].[Na+:28]
Reactant: CCOC(=O)c1c(C)n(-c2ccccc2)cc(-c2ccc(Cl)cc2)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1c(C(=O)[O-])c(=O)c(-c2ccc(Cl)cc2)cn1-c1ccccc1

Procedure:
35 g. of crude ethyl 2-methyl-1-phenyl-5-(4'-chlorophenyl)-4-oxonicotinate was suspended in 350 g. of 5% NaOH in 1:1 methanol/water and refluxed for 6 hours. The reaction mixture was cooled. This yielded a precipitate of sodium 2-methyl-1-phenyl-5-(4'-chlorophenyl)-4-oxonicotinate which was collected by filtration and resuspended in dilute aqueous HCl to provide 5.3 g. of 2-methyl-1-phenyl-5-(4'-chlorophenyl)-4-oxonicotinic acid, m.p. (acetonitrile)=209°-209° C.
Reaction SMILES: S(Cl)(Cl)=O.[O:5]1[CH:9]=[CH:8][C:7]([C:10]([OH:12])=O)=[CH:6]1.[NH2:13][NH:14][C:15]([NH2:17])=[S:16].C(=O)(O)[O-].[Na+]>C1COCC1.ClCCl>[O:5]1[CH:9]=[CH:8][C:7]([C:10]([NH:13][NH:14][C:15]([NH2:17])=[S:16])=[O:12])=[CH:6]1
Reactant: O=C(O)c1ccoc1
Reactant: NNC(N)=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: NC(=S)NNC(=O)c1ccoc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.5 %

Procedure:
Thionyl chloride (3 mL) was added to a dichloromethane (10 mL) solution of 3-furancarboxylic acid (2.50 g, 22.3 mmol) under ice cooling, and the mixture was heated to reflux for 2 hours. The solvent was distilled off. After that, the residue was concentrated by the addition of toluene and added to a THF (50 mL) solution of thiosemicarbazide (4.47 g, 49.1 mmol) under ice cooling, and the mixture was stirred overnight at room temperature. To the reaction solution, a saturated aqueous solution of sodium bicarbonate was added. The mixture was subjected to extraction with ethyl acetate and dried over anhydrous sodium sulfate, and then, the solvent was distilled off to obtain 1-(3-furoyl)thiosemicarbazide (3.03 g, 16.4 mmol) (yield: 74%).
Reaction SMILES: [CH:1]1([NH:4][CH2:5][CH2:6][OH:7])[CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:17]=1[S:23](Cl)(=[O:25])=[O:24]>ClCCl>[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:17]=1[S:23]([N:4]([CH:1]1[CH2:3][CH2:2]1)[CH2:5][CH2:6][OH:7])(=[O:24])=[O:25]
Reactant: Cc1cccc(Cl)c1S(=O)(=O)Cl
Reactant: OCCNC1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccc(Cl)c1S(=O)(=O)N(CCO)C1CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
To 2-(cyclopropylamino)ethanol (2 eq.) was added triethylamine (2.5 eq.) and the mixture was cooled to 0° C. To this cold reaction mixture was added 2-chloro-6-methylbenzene sulfonyl chloride (1 eq.) and the mixture was stirred at 25° C. for 2 h. It was diluted with dichloromethane and the organic layer was washed with water and brine and finally dried over sodium sulfate. Evaporation of the organic layer under reduced pressure gave the crude product which was purified by column chromatography (10% ethyl acetate in hexane). Yield: 50%
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([C:9](=O)[CH:10]([C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)[CH2:11][C:12](=O)[CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])[CH2:15][CH2:14]2)[CH:6]=[CH:7][CH:8]=1.[NH2:39][NH2:40].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>CCO>[F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([C:9]2[N:39]=[N:40][C:12]([CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[O:20])[CH2:15][CH2:14]3)=[CH:11][C:10]=2[C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: NN
Reactant: O=C(CC(C(=O)c1cccc(C(F)(F)F)c1)c1ccncc1)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CCO
Product: O=C(OCc1ccccc1)N1CCC(c2cc(-c3ccncc3)c(-c3cccc(C(F)(F)F)c3)nn2)CC1
Reaction time: 4 h
Yield: 73.5 %

Procedure:
Under Ar, a solution of 13 (2.2 g, 4.2 mmol) in EtOH (50 mL) was treated with hydrazine (306 mg, 9.6 mmol). After 4 h, the reaction was concentrated to dryness and the residue was partitioned between water-EtOAc (3×). The EtOAc extracts were backwashed with brine, dried, filtered and concentrated to dryness. The residue was dissolved in toluene (60 mL) and 2,3 dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (1.0 g, 4.5 mmol) was added. After 0.5 h, the reaction was chromatographed on a Still column (60 mm) and the product eluted with 90-100% EtOAc-hexanes to yield 1.6 g of 15.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:19]=[C:18]2[CH2:28][CH3:29])=[CH:13][CH:12]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:30](I)[CH2:31]CC>>[CH2:28]([C:18]1[N:17]([C:14]2[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[CH:12][CH:13]=2)[CH:21]=[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:19]=1)[CH2:29][CH2:30][CH3:31]
Reactant: CCCCI
Reactant: CCc1nc(-c2ccccc2)cn1-c1ccc(CCO[Si](C)(C)C(C)(C)C)cc1
Product: CCCCc1nc(-c2ccccc2)cn1-c1ccc(CCO[Si](C)(C)C(C)(C)C)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 5 from 1-[4-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)phenyl]-2-ethyl-4-phenyl-1H-imidazole and butyl iodide. MS (ESI) m/z 435 [M+H]+.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:18]#[CH:19])[CH:7]=[C:8]3[C:13]=2[O:12][C:11]([CH3:15])([CH3:14])[CH2:10][C:9]3([CH3:17])[CH3:16])[CH2:3][CH2:2]1.[CH2:20]([O:22][C:23](=[O:31])[C:24]1[CH:29]=[CH:28][C:27](I)=[CH:26][CH:25]=1)[CH3:21].C(N(CC)CC)C.O1CCCC1>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C>[CH2:20]([O:22][C:23](=[O:31])[C:24]1[CH:29]=[CH:28][C:27]([C:19]#[C:18][C:6]2[CH:7]=[C:8]3[C:13](=[C:4]([CH:1]4[CH2:3][CH2:2]4)[CH:5]=2)[O:12][C:11]([CH3:14])([CH3:15])[CH2:10][C:9]3([CH3:17])[CH3:16])=[CH:26][CH:25]=1)[CH3:21]
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: C#Cc1cc(C2CC2)c2c(c1)C(C)(C)CC(C)(C)O2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(C#Cc2cc(C3CC3)c3c(c2)C(C)(C)CC(C)(C)O3)cc1

Procedure:
Following general procedure F and using 8-cyclopropyl-6-ethynyl-2,2,4,4-tetramethylchroman (Intermediate 34, 0.1 g, 0.38 mmol), ethyl-4-iodo-benzoate (Reagent A, 0.1 g, 0.34 mmol), triethyl amine (5 mL), tetrahydrofuran(10 mL), copper(I)iodide(0.025 g, 0.13 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.075 g, 0.11 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 5-10% ethyl acetate in hexane as the eluent, the title compound was obtained (0.135 g, 89%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH:4]([C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]2[CH:28]=[CH:27][C:26]([CH:29]=O)=[CH:25][CH:24]=2)=[CH:18][CH:17]=1)[CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]([O:14][CH3:15])[CH:7]=1.[S:32]1[CH2:36][C:35](=[O:37])[NH:34][C:33]1=[O:38].C(O)(=O)C1C=CC=CC=1.N1CCCCC1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:31])[CH:4]([C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]2[CH:28]=[CH:27][C:26]([CH:29]=[C:36]3[S:32][C:33](=[O:38])[NH:34][C:35]3=[O:37])=[CH:25][CH:24]=2)=[CH:18][CH:17]=1)[CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]([O:14][CH3:15])[CH:7]=1
Reactant: COC(=O)C(Cc1cc(OC)cc(OC)c1)c1ccc(Oc2ccc(C=O)cc2)cc1
Reactant: O=C1CSC(=O)N1
Agent: O=C(O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: COC(=O)C(Cc1cc(OC)cc(OC)c1)c1ccc(Oc2ccc(C=C3SC(=O)NC3=O)cc2)cc1
Yield: 81.5 %

Procedure:
To a stirred suspension of 16 (1.81 g, 4.3 mmol) in anhydrous toluene (25 mL), 2,4-thiazolidinedione (0.56 g, 4.74 mmol), benzoic acid (0.68 g, 5.60 mmol) and piperidine (0.60 mL, 6.03 mmol) was added sequentially and heated at reflux temperature with continuous removal of water using a Dean-Stark apparatus for 2 h. Solvent was evaporated to dryness under reduced pressure. The residue obtained was purified by silica gel chromatography, eluted with hexane-ethyl acetate (1:1) to yield 17 (1.82 g, 81%): mp 104-106° C.; 1H NMR (400 MHz, DMSO-d6) δ 12.53 (br s, 1H), 7.76 (s, 1H), 7.60 (d, J=8.7 Hz, 2H), 7.35 (d, J=8.7 Hz, 2H), 7.07 (d, J=4.8 Hz, 2H), 7.03 (d, J=4.8 Hz, 2H), 6.33-6.28 (m, 3H), 4.01 (t, J=7.5 Hz, 1 Hz), 3.66 (s, 6H), 3.56 (s, 3H), 3.22 (dd, J=13.8 and 8.4 Hz, 1H), 2.90 (dd, J=13.5 and 7.2 Hz, 1H); MS (EI) m/z 520[M]+; Anal. (C28H25NO7S) C: calculated, 64.73; found, 65.89; H: calculated, 4.85; found, 5.08, N: calculated, 2.70; found, 2.56.