Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][CH2:12][C:13]2[CH2:14][C:15]3[C:20]([CH:21]=2)=[CH:19][C:18](B2OC(C)(C)C(C)(C)O2)=[CH:17][CH:16]=3)=[CH:9][CH:8]=[C:7]([F:31])[C:3]=1[C:4]([NH2:6])=[O:5].[C:32]1(OS(C(F)(F)F)(=O)=O)[CH2:37][CH2:36][CH2:35][CH2:34][CH:33]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O>[C:32]1([C:18]2[CH:19]=[C:20]3[C:15](=[CH:16][CH:17]=2)[CH2:14][C:13]([CH2:12][O:11][C:10]2[C:2]([F:1])=[C:3]([C:7]([F:31])=[CH:8][CH:9]=2)[C:4]([NH2:6])=[O:5])=[CH:21]3)[CH2:37][CH2:36][CH2:35][CH2:34][CH:33]=1
Reactant: O=S(=O)(OC1=CCCCC1)C(F)(F)F
Reactant: CC1(C)OB(c2ccc3c(c2)C=C(COc2ccc(F)c(C(N)=O)c2F)C3)OC1(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1c(F)ccc(OCC2=Cc3cc(C4=CCCCC4)ccc3C2)c1F
Temperature: 80 °C
Yield: 22.3 %

Procedure:
To a solution of 2,6-Difluoro-3-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-inden-2-ylmethoxy]-benzamide (0.10 g, 0.20 mmol) in 3 ml of anhydrous DMF and water (1.5 ml) was added trifluoromethanesulfonic acid cyclohex-1-enyl ester (0.15 g, 0.60 mmol) and potassium phosphate (0.057 g, 0.20 mmol). The reaction mixture was degassed for 10 minutes followed by addition of dichlorobis(triphenyl phosphine) palladium (II) (0.02 g, 0.03 mmol). The reaction mixture was heated at 80° C. for 1 h under the nitrogen atmosphere. After the completion of the reaction mixture (TLC monitoring), water (25 mL) was added and extracted with ethyl acetate (3×50 mL). The combined organics was washed with water, brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified over silica gel (230-400 M, 45% EtOAc-Hexane) to get the desired product (0.017 g, 19%) as a white solid. 1H NMR (DMSO-d6, 400 MHz): δ 1.63 (m, 4H), 2.20 (m, 2H), 2.45 (m, 2H), 5.67 (s, 2H), 6.29 (m, 1H), 7.12 (m, 1H), 7.37 (m, 1H), 7.57 (m, 2H), 7.90 (br s, 1H), 8.03 (d, J=8.40 Hz, 1H) and 8.18 (br s, 1H). MS ES+ (401.16), HPLC (method II) Rt=14.13 min.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=O)=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl:35][C:36]1[CH:37]=[C:38]([N:43]2[C:47](=[O:48])[C@@:46]3([C@H:52]([C:53]4[CH:60]=[CH:59][C:56]([C:57]#[N:58])=[CH:55][CH:54]=4)[CH2:51][NH:50][CH2:49]3)[N:45]([CH3:61])[C:44]2=[O:62])[CH:39]=[C:40]([Cl:42])[CH:41]=1>CN(C=O)C>[Cl:35][C:36]1[CH:37]=[C:38]([N:43]2[C:47](=[O:48])[C@@:46]3([C@H:52]([C:53]4[CH:54]=[CH:55][C:56]([C:57]#[N:58])=[CH:59][CH:60]=4)[CH2:51][N:50]([C:11]([C:7]4[CH:6]=[C:5]5[C:10](=[CH:9][CH:8]=4)[N:1]=[CH:2][CH:3]=[N:4]5)=[O:13])[CH2:49]3)[N:45]([CH3:61])[C:44]2=[O:62])[CH:39]=[C:40]([Cl:42])[CH:41]=1
Reactant: O=C(O)c1ccc2nccnc2c1
Reactant: CN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]12CNC[C@H]2c1ccc(C#N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]12CN(C(=O)c1ccc3nccnc3c1)C[C@H]2c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24.6 %

Procedure:
To a solution of quinoxaline-6-carboxylic acid (56.2 mg, 0.318 mmol) in 7 ml DMF were added EDCI (62 mg, 0.32 mmol), TEA (53.9 μl, 0.38 mmol) and HOBt (49.3 mg, 0.36 mmol). After 30 min, a solution of Example 15 (103.4 mg, 0.249 mmol) in 1 ml DMF was added. The reaction mixture was then stirred overnight at RT before evaporation to dryness. The residue was partitioned between DCM (50 ml) and 1N solution of HCl (20 ml). The DCM layer was washed with 10% solution of sodium carbonate (2×20 ml), dried over sodium sulfate, concentrated and purified by reverse phase HPLC (gradient from CH3CN/H2O/TFA: 5/95/0.05 to CH3CN/H2O/TFA: 80/20/0.05) to yield the titled compound (35 mg). Retention time: 2.16 min., 571 (M+1) (LCMS conditions: LC Micromass platform (APCI+, DAD (210-400 nm)), Column: TSK gel Super ODS 4.6 mm ID×5 cm, Flow rate: 2.75 mL/min, Gradient: from 100% eluent A to 100% eluent B in 2 min., with a plateau with 100% eluent B during 1 min. Eluent A: H2O (0.05% TFA), Eluent B: CH3CN/H2O/TFA (80/20/0.05)).
Reaction SMILES: [CH2:1]1COC23OCCOC2([C@]2(CC[C@H]4[C@@H]([C@H](C=O)CC5[C@]4(C)CCCC5)[C@@H]2C3)C)[O:2]1.C=[C:31]1[CH:48]2[C@:43]([CH3:50])([CH2:44][CH2:45][C:46](=[O:49])[CH2:47]2)[C@@H:42]2[C@H:33]([C@H:34]3[C@@:38]([CH2:40][CH2:41]2)([CH3:39])[C:37](=[O:51])[CH2:36][CH2:35]3)[CH2:32]1>>[CH:1]([C@@H:32]1[CH2:31][CH:48]2[C@:43]([CH3:50])([CH2:44][CH2:45][C:46](=[O:49])[CH2:47]2)[C@@H:42]2[C@@H:33]1[C@H:34]1[C@@:38]([CH2:40][CH2:41]2)([CH3:39])[C:37](=[O:51])[CH2:36][CH2:35]1)=[O:2]
Reactant: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)CC12
Reactant: C[C@]12CCCCC1C[C@@H](C=O)[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Product: C[C@]12CCC(=O)CC1C[C@@H](C=O)[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 85 %

Procedure:
7α-Formylandrostane-3,17-dione was prepared in 85% yield from 3,3:17,17-bis(ethylendioxy)-7α-formylandrostane (2.36 g) by the procedure described above for the preparation of 6-methyleneandrostane-3,17-dione (II-ac, Prepn. 13). 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 9.95 (1H, d), 2.57-0.80 (21H, m), 0.95 (3H, s), 0.80 (3H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[CH2:18][CH2:19][CH2:20][CH2:21][C:22]=4[CH:23]=[CH:24][C:9]2=3)=[CH:4][CH:3]=1.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([S:33](Cl)(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>N1C=CC=CC=1>[O:16]=[C:12]1[NH:11][C:10]2[C:17]3[CH2:18][CH2:19][CH2:20][CH2:21][C:22]=3[CH:23]=[CH:24][C:9]=2[N:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][S:33]([C:29]3[CH:30]=[CH:31][CH:32]=[C:27]([O:26][CH3:25])[CH:28]=3)(=[O:35])=[O:34])=[CH:7][CH:6]=2)[C:14](=[O:15])[CH2:13]1
Reactant: COc1cccc(S(=O)(=O)Cl)c1
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2c3CCCC2)cc1
Solvent: c1ccncc1
Product: COc1cccc(S(=O)(=O)Nc2ccc(N3C(=O)CC(=O)Nc4c3ccc3c4CCCC3)cc2)c1
Yield: 48.3 %

Procedure:
5-(4-Aminophenyl)-1,5,8,9,10,11-hexahydronaphtho[1,2-b][1,4]diazepine-2,4-dione (65 mg, 0.202 mmol) obtained in Example 55, and 3-methoxybenzenesulfonyl chloride (63 mg, 0.305 mmol) were treated by heating in pyridine (2.0 mL). After the disappearance of the starting materials was confirmed, the same treatment as that of Example 145 was performed to give the title compound (48 mg, yield 48%) as white crystals.
Reaction SMILES: [OH:1][C:2]1([CH2:15][CH:16]=O)[CH2:14][CH2:13][C:5]2([O:10][CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7][O:6]2)[CH2:4][CH2:3]1.[F:18][CH:19]([F:30])[O:20][C:21]1[CH:26]=[CH:25][C:24]([C@@H:27]([NH2:29])[CH3:28])=[CH:23][CH:22]=1>>[F:18][CH:19]([F:30])[O:20][C:21]1[CH:22]=[CH:23][C:24]([C@@H:27]([NH:29][CH2:16][CH2:15][C:2]2([OH:1])[CH2:14][CH2:13][C:5]3([O:6][CH2:7][C:8]([CH3:12])([CH3:11])[CH2:9][O:10]3)[CH2:4][CH2:3]2)[CH3:28])=[CH:25][CH:26]=1
Reactant: C[C@H](N)c1ccc(OC(F)F)cc1
Reactant: CC1(C)COC2(CCC(O)(CC=O)CC2)OC1
Product: C[C@H](NCCC1(O)CCC2(CC1)OCC(C)(C)CO2)c1ccc(OC(F)F)cc1
Yield: 65 %

Procedure:
The title compound is prepared from (9-hydroxy-3,3-dimethyl-1,5-dioxa-spiro[5.5]undec-9-yl)-acetaldehyde and (S)-1-(4-difluoromethoxy-phenyl)-ethylamine following a procedure analogous to that described in Step 3 of Intermediate 2. Yield: 65% of theory; LC (method 5): tR=1.02 min; Mass spectrum (ESI+): m/z=414 [M+H]+.
Reaction SMILES: [BH4-].[Li+].[O:3]([C:10]1[CH:32]=[CH:31][C:13]([CH2:14][O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[S:27](=[O:29])(=[O:28])[NH:26][C:25](=[O:30])[CH:24]=3)=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O1CCCC1>[O:3]([C:10]1[CH:32]=[CH:31][C:13]([CH2:14][O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH:23]3[S:27](=[O:29])(=[O:28])[NH:26][C:25](=[O:30])[CH2:24]3)=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C1C=C(c2ccc(COCc3ccc(Oc4ccccc4)cc3)cc2)S(=O)(=O)N1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1CC(c2ccc(COCc3ccc(Oc4ccccc4)cc3)cc2)S(=O)(=O)N1
Reaction time: 0.42 h
Yield: 105 %

Procedure:
2 M Lithium borohydride in tetrahydrofuran (0.036 mL, 0.072 mmol) was added to 5-(4-[(4-phenoxybenzyl)oxy]methylphenyl)isothiazol-3(2H)-one 1,1-dioxide (40 mg, 0.009 mmol) in tetrahydrofuran (0.5 mL). After stirring for 25 minutes, the reaction was quenched with saturated aqueous ammonium chloride. The product was purified on a 50 mm Luna C18 column using a 20–100% acetonitrile in water gradient with 0.05% trifluoroacetic acid at 30 mL per minute over a 30 minute period. The major product was lyophilized to give a white powder (4 mg, 100%). 1H NMR (400 MHz, CDCl3): δ 7.46 (m, 4H), 7.34 (m, 4H), 7.11 (t, J=7.4 Hz, 1H), 7.01 (m, 4H), 4.98 (t, J=8.4 Hz, 1H), 4.60 (s, 2H), 4.55 (s, 2H), 3.38 (dd, J=8.0 Hz, J′=1.3 Hz, 2H); LCMS found for C23H21NNaO5S (M+Na)+: m/z=446.1.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[N:10]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]1=[O:20].[Cl:21][S:22](O)(=[O:24])=[O:23]>CC#N.O>[O:20]=[C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:18](=[O:19])[N:10]1[CH:2]1[CH2:1][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:22]([Cl:21])(=[O:24])=[O:23])[CH:8]=2)[CH2:3]1
Reactant: O=C1c2ccccc2C(=O)N1C1Cc2ccccc2C1
Reactant: O=S(=O)(O)Cl
Solvent: O
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)N1C1Cc2ccc(S(=O)(=O)Cl)cc2C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of compound 747-C (0.72 g, 2.7 mmol) in MeCN (50 mL) was added chlorosulfonic acid (3.72 g, 32.4 mmol), drop-wise, and the reaction mixture was stirred at ambient temperature for 48 h. The reaction mixture was diluted with H2O, extracted with CH2Cl2, dried over Na2SO4, filtered, and dried to afford 0.976 g of compound 747-D as a brown solid. 1H-NMR (CDCl3) δ 3.26-3.43 (m, 2H,) 3.60-3.78 (m, 2H), 5.26 (t, 1H), 7.46 (d, 1H), 7.68-7.79 (m, 2H), 7.79-7.93 (m, 4H); MS: m/z 384.1 (MNa+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:14]([O:17][C:18]1[CH:19]=[C:20]([NH:25][C:26]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[O:27])[CH:21]=[C:22]([F:24])[CH:23]=1)[CH2:15][CH3:16]>C(N(CC)CC)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:31]2[CH2:32][CH2:33][N:28]([C:26]([NH:25][C:20]3[CH:21]=[C:22]([F:24])[CH:23]=[C:18]([O:17][CH2:14][CH2:15][CH3:16])[CH:19]=3)=[O:27])[CH2:29][CH2:30]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCCOc1cc(F)cc(NC(=O)N2CCNCC2)c1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Product: CCCOc1cc(F)cc(NC(=O)N2CCN(S(=O)(=O)c3ccc([N+](=O)[O-])cc3)CC2)c1

Procedure:
In the manner given in Example 1A, p-nitrobenzenesulfonyl chloride, 1-[[(3-propoxy-5-fluorophenyl)amino]carbonyl]piperazine and triethylamine are stirred at reflux to give 1-[(p-nitrophenyl)-sulfonyl]-4-[[(3-propoxy-5-fluorophenyl)amino]-carbonyl]piperazine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:16])[CH:12]=2)[CH:7]=1)[CH3:5].N1C=CC=CC=1.[Br:24][CH2:25][C:26](Cl)=[O:27]>ClCCl>[CH3:1][O:2][C:3](=[O:17])[CH:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][C:26](=[O:27])[CH2:25][Br:24])[CH:12]=2)[CH:7]=1)[CH3:5]
Reactant: COC(=O)C(C)c1ccc2cc(O)ccc2c1
Reactant: O=C(Cl)CBr
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)C(C)c1ccc2cc(OC(=O)CBr)ccc2c1
Reaction time: 1 h
Yield: 45.9 %

Procedure:
To a solution of 2-(6-hydroxy-naphthalen-2-yl)-propionic acid methyl ester (20 grams) and pyridine (10.3 grams) in dichloromethane (200 ml) maintained at 0-5° C. under N2 atmosphere was added dropwise bromoacetyl chloride (19.6 grams). The reaction was stirred at the same temperature for one hour. The reaction mixture was washed with water (500 ml) and 5% solution of sodium carbonate followed by drying over sodium sulphate and distillation to get crude compound, which was purified by column chromatography using hexane as eluant to get pure 2-[6-(2-bromo-acetoxy)-naphthalen-2-yl]-propionic acid methyl ester (14 grams) as a dark brown syrup. The pure product was characterized using 1H NMR spectroscopy in CDCl3 δ 1.55 (d, 3H, CH3), 3.65 (s, 3H, Ester), 3.82 (q, 1H, CH), 4.08 (s, 2H, OCH2) 7.20 (dd, 1H, Ar), 7.4 (dd, 1H, Ar), 7.57 (d, 1H, Ar), 7.72 (d, 1H, Ar), 7.78 (d, 1H, Ar), 7.84 (d, 1H, Ar).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13](=[O:14])[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:11][N:10]([CH3:21])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH2:24](I)[CH3:25]>CS(C)=O>[CH2:24]([O:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13](=[O:14])[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:11][N:10]([CH3:21])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1)[CH3:25]
Reactant: Cn1cc(-c2ccccc2)c(=O)c(-c2cccc(O)c2)c1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOc1cccc(-c2cn(C)cc(-c3ccccc3)c2=O)c1
Temperature: 25 °C

Procedure:
A 3.2 g. portion of the product of Example 217 was added to a suspension of 0.86 g. of sodium hydride in 50 ml. of dimethylsulfoxide. The mixture was stirred at room temperature, and 3.5 g. of ethyl iodide was added. The mixture was stirred for two and one-half hours more, and extracted with ethyl acetate. The extract was washed with dilute hydrochloric acid and then with water, and dried. The dried extract was then filtered and concentrated to dryness under vacuum. The product was 2.2 g. of 3-(3-ethoxyphenyl)-1-methyl-5-phenyl-4(1H)-pyridone, m.p. 133°-135° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[C:17]([F:20])([F:19])[F:18].C1C(=O)N([Br:28])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:28][CH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[C:17]([F:20])([F:18])[F:19]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2nc3ccccc3o2)cc1C(F)(F)F
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)(F)c1cc(-c2nc3ccccc3o2)ccc1CBr
Temperature: 25 °C

Procedure:
A mixture of 2-[4-methyl-3-(trifluoromethyl)phenyl]-1,3-benzoxazole (600 mg, 2.2 mmol), n-bromosuccinimide (579 mg, 3.25 mmol), benzoyl peroxide (26 mg, 0.11 mmol) in carbon tetrachloride (15 mL) was refluxed for 3 h and then cooled to rt. The white precipitate was filtered and the filtrate was concentrated to dryness. The crude was purified by flash chromatography on silica gel eluting with EtOAc:hexanes (1:1) to afford 2-[4-(bromomethyl)-3-(trifluoromethyl)phenyl]-1,3-benzoxazole.
Reaction SMILES: [SH:1][C:2]1[N:3]([CH3:13])[C:4](=[O:12])[C:5]2[C:10]([CH3:11])=[N:9][O:8][C:6]=2[N:7]=1.[OH-].[Na+].CN(C=O)C.[Cl:21][C:22]1[CH:37]=[CH:36][C:25]([C:26]([C:28]2[CH:35]=[CH:34][C:31]([CH2:32]Br)=[CH:30][CH:29]=2)=[O:27])=[CH:24][CH:23]=1>C(O)C>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([C:26]([C:28]2[CH:35]=[CH:34][C:31]([CH2:32][S:1][C:2]3[N:3]([CH3:13])[C:4](=[O:12])[C:5]4[C:10]([CH3:11])=[N:9][O:8][C:6]=4[N:7]=3)=[CH:30][CH:29]=2)=[O:27])=[CH:36][CH:37]=1
Reactant: Cc1noc2nc(S)n(C)c(=O)c12
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CN(C)C=O
Product: Cc1noc2nc(SCc3ccc(C(=O)c4ccc(Cl)cc4)cc3)n(C)c(=O)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.3 %

Procedure:
To a solution of 6-mercapto-3,5-dimethylisoxazolo-[5,4-d]pyrimidin-4(5H)-one (800 mg) and sodium hydroxide (165 mg) in 50% ethanol (10 ml)-DMF (10 ml) was added 4-(4-chlorobenzoyl)benzyl bromide (1.25 g) and the mixture was stirred at room temperature for 1 hour. This reaction mixture was concentrated and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to provide the title compound as colorless solid (470 mg). 1H-NMR (CDCl3) 8: 2.57(3H,s), 3.55(3H,s), 4.59(2H,s), 7.46(2H,d,J=8.6Hz), 7.58(2H,d,J=8.4Hz), 7.74(2H,d,J=8.4Hz), 7.76(2H,d,J=8.6Hz).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].CCCCCC.[C:19]([O:22][CH2:23][CH3:24])(=[O:21])[CH3:20]>>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:20][C:19]([O:22][CH2:23][CH3:24])=[O:21])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CCOC(C)=O
Reactant: CC(=O)c1ccc(B(O)O)cc1
Solvent: CCCCCC
Product: CCOC(=O)Cc1ccc(C(C)=O)cc1

Procedure:
Ethyl 4-acetylphenylacetate was prepared by the general experimental method from 4-acetylphenylboronic acid (164 mg, 1.00 mmol). After workup by column chromatography (hexane/ethyl acetate, 5:1), ethyl 4-acetylphenylacetate is obtained as a colourless solid in a yield of 60% of theory. 1H NMR (400 MHz, CDCl3): δ=7.90 (d, J=8.2 Hz, 2H), 7.37 (d, J=8.5 Hz, 2H), 4.11-4.17 (m, 2H), 3.66 (s, 2H), 2.58 (s, 3H), 1.20-1.27 (m, 3H) ppm; 13C NMR (151 MHz, CDCl3): δ=197.7, 170.8, 139.5, 136.0, 129.6, 128.6, 61.1, 41.3, 26.6, 14.2 ppm; MS (70 eV), m/z (%): 192 (100), 164 (16), 134 (14), 105 (19), 89 (11); IR (KBr): ν=2981 (w), 1735 (s), 1682 (m), 1274 (m), 1178 (m) cm−1; elemental analysis: (theor): C=69.89, H=6.84, (exp): C=69.95, H=6.99. Melting point: 55-56° C.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[NH2:25][C:26]1[N:31]=[CH:30][CH:29]=[CH:28][N:27]=1>C(Cl)Cl.CN(C)C=O>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([NH:25][C:26]2[N:31]=[CH:30][CH:29]=[CH:28][N:27]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Reactant: Nc1ncccn1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Nc1ncccn1)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 67 %

Procedure:
A solution of 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid (prepared as in Example 38A, 100 mg, 0.35 mmol) in methylene chloride (1 mL) was treated with 2 drops of dry N,N-dimethylformamide. The reaction mixture was cooled to 0° C. and then treated dropwise with oxalyl chloride (34 mL, 0.39 mmol). The reaction mixture was stirred at 0° C. for 10 min and then stirred at 25° C. for 2 h. The reaction mixture was concentrated in vacuo. The resulting residue was dissolved in a small amount of methylene chloride and was slowly added to a cooled (0° C.) solution of 2-aminopyrimidine (67 mg, 0.70 mmol) in methylene chloride (1 mL). The resulting reaction mixture was stirred at 0° C. for 30 min and then stirred at 25° C. for 2 h. The reaction mixture was concentrated in vacuo to remove methylene chloride. The resulting residue was diluted with water and extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 1/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-pyrimidin-2-yl-propionamide (85.4 mg, 67%) as a white solid: mp 103–105° C.; EI-HRMS m/e calcd for C18H19Cl2N3O (M+) 363.0905, found 363.0915.
Reaction SMILES: [C:1]([C:3]1[CH:27]=[CH:26][C:6]([O:7][C:8]2[C:13]([N+:14]([O-])=O)=[CH:12][CH:11]=[C:10]([O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=3)[N:9]=2)=[CH:5][CH:4]=1)#[N:2]>CO.C(OCC)(=O)C.[Pd].[C]>[NH2:14][C:13]1[C:8]([O:7][C:6]2[CH:26]=[CH:27][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)=[N:9][C:10]([O:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]#[N:25])=[CH:22][CH:23]=2)=[CH:11][CH:12]=1
Reactant: N#Cc1ccc(Oc2ccc([N+](=O)[O-])c(Oc3ccc(C#N)cc3)n2)cc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: N#Cc1ccc(Oc2ccc(N)c(Oc3ccc(C#N)cc3)n2)cc1
Reaction time: 1 h
Yield: 86.4 %

Procedure:
10% Pd/carbon (0.24 g) was added under hydrogen atmosphere (balloon pressure) to a stirred solution of 2,6-Bis(4-Cyano phenoxy)-3-nitro pyridine (1.20 g, 3.35 mmol) in 20 ml of methanol:ethyl acetate (1:1) at ambient temperature and the reaction mixture was stirred for 1 h. The reaction mixture was filtered through celite, washed with 20 ml of ethyl acetate and concentrated under reduced pressure. Water was added to the residual mixture and it was extracted with ethyl acetate. Ethyl acetate layer was washed with water followed by brine. The organic layer was dried over sodium sulphate to afford 0.95 g of the title product which was used for the next step without further purification. 1H NMR (DMSO-d6): δ 5.32 (2H, brs), 6.82 (1H, d), 7.15 (1H, d), 7.22 (2H, d), 7.34 (2H, d), 7.80 (4H, m).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10]([CH:11]([CH3:13])[CH3:12])=[C:9]([S:14]S(C3C=CC(C)=CC=3)(=O)=O)[CH:8]=[C:7]([CH3:25])[C:5]=2[N:6]=1.[OH:26][C:27]1[CH2:32][C@@:31]([CH2:36][CH2:37][C:38]2[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=2)([CH:33]([CH3:35])[CH3:34])[O:30][C:29](=[O:45])[CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH2:1][C:2]1[S:3][C:4]2[C:10]([CH:11]([CH3:12])[CH3:13])=[C:9]([S:14][C:28]3[C:29](=[O:45])[O:30][C@:31]([CH2:36][CH2:37][C:38]4[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=4)([CH:33]([CH3:35])[CH3:34])[CH2:32][C:27]=3[OH:26])[CH:8]=[C:7]([CH3:25])[C:5]=2[N:6]=1
Reactant: CC(C)[C@]1(CCc2ccc(O)cc2)CC(O)=CC(=O)O1
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c3nc(N)sc3c2C(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(SC2=C(O)C[C@@](CCc3ccc(O)cc3)(C(C)C)OC2=O)c(C(C)C)c2sc(N)nc12

Procedure:
The title compound was prepared according to General Method 16a using toluene-4-thiosulfonic acid S-(2-amino-7-isopropyl-4-methyl-benzothiazol-6-yl)ester (Example BB-5; 0.35 g, 1.27 mmol), (S)-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one (Example J-10; 0.35 g. 1.27 mmol), potassium carbonate (0.7 g), and DMF (5 mL). The crude reaction mixture was purified by flash chromatography (20% EtOAc in hexanes to 50% EtOAc in hexanes to 5% MeOH in EtOAc as eluents), mp 232-234° C. MS (APCI): 513 (M+H).
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[O:7]1[CH2:11][CH2:10]OC1=O>CCN(CC)CC>[F:1][C:2]([F:6])([F:5])[CH2:3][O:4][CH2:10][CH2:11][OH:7]
Reactant: OCC(F)(F)F
Reactant: O=C1OCCO1
Solvent: CCN(CC)CC
Product: OCCOCC(F)(F)F
Temperature: 100 °C
Reaction time: 24 h

Procedure:
2,2,2-trifluoroethanol (15 g), 1,3-dioxolan-2-one (19.8 g) and Et3N (15 g) were mixed together, and then the mixture was heated to 100° C. and stirred for 24 h. Then the reaction mixture was distilled to obtain intermediate BR (12.7 g).
Reaction SMILES: [NH:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][N:10]=1)[C:6]#[N:7])[NH2:2].CN(C)[CH:13]=[C:14]([C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)[C:15](OCC)=[O:16]>C(O)(=O)C>[C:6]([C:5]1[CH:8]=[CH:9][N:10]=[C:3]([N:1]2[C:15](=[O:16])[C:14]([C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[CH:13][NH:2]2)[CH:4]=1)#[N:7]
Reactant: N#Cc1ccnc(NN)c1
Reactant: CCOC(=O)C(=CN(C)C)c1cccnc1
Solvent: CC(=O)O
Product: N#Cc1ccnc(-n2[nH]cc(-c3cccnc3)c2=O)c1
Reaction time: 0.5 h

Procedure:
545 mg (4.06 mmol) of the compound from Example 1A and 1.07 g (4.88 mmol) of the compound from Example 2A in 15 ml of glacial acetic acid are stirred at RT for 2 h. The mixture is concentrated and the residue is taken up in 300 ml of ethyl acetate and washed repeatedly with saturated sodium bicarbonate solution. The organic phase is dried over sodium sulfate, filtered and concentrated. The residue is taken up in 30 ml of ethanol, 1.33 g (4.88 mmol) of a 25% strength solution of sodium ethoxide in ethanol are added at RT and the mixture is stirred for 30 min. The pH is adjusted to 5 by addition of 1 M hydrochloric acid, and the solid formed is filtered off with suction, washed with diethyl ether and dried under high vacuum.