Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:10][C:11]2[CH:17]=[C:16]([CH2:18][C:19](O)=[O:20])[CH:15]=[CH:14][C:12]=2[N:13]=1.[F:22][C@@H:23]1[CH2:27][NH:26][C@H:25]([CH2:28][O:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[CH2:24]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C>[F:22][C@@H:23]1[CH2:27][N:26]([C:19](=[O:20])[CH2:18][C:16]2[CH:15]=[CH:14][C:12]3[N:13]=[C:9]([NH:8][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[CH3:1])[O:10][C:11]=3[CH:17]=2)[C@H:25]([CH2:28][O:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[CH2:24]1
Reactant: Cc1ccccc1Nc1nc2ccc(CC(=O)O)cc2o1
Reactant: COC(=O)CCCCOC[C@@H]1C[C@H](F)CN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)CCCCOC[C@@H]1C[C@H](F)CN1C(=O)Cc1ccc2nc(Nc3ccccc3C)oc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 167.5 %

Procedure:
In DMF (5 ml), a mixture of 2-(2-methylphenylamino)-6-benzoxazolylacetic acid (357 mg, 1.26 mmol), methyl 5-((2S,4S)-4-fluoro-2-pyrrolidinylmethoxy)pentanoate (295 mg, 1.26 mmol), EDC•HCl (362 mg, 1.89 mmol), HOBt (255 mg, 1.89 mmol) and triethylamine (0.88 ml, 6.30 mmol) was stirred at room temperature for 1 hour. The reaction mixture was poured in ice water (50 ml), followed by extraction with ethyl acetate. The extract was washed with ice water and saturated brine, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column (silica gel: 70 g), whereby from chloroform/acetone (10/1) eluate fractions, the title compound (1.05 g, 100%) was obtained as a colorless oil.
Reaction SMILES: CC1(C)[O:6][C:5]([CH2:11][C:12]([C:15]2[C:23]3[O:22][CH2:21][CH2:20][C:19]=3[CH:18]=[C:17]([S:24][CH3:25])[CH:16]=2)([CH3:14])[CH3:13])([C:7]([F:10])([F:9])[F:8])[CH2:4][O:3]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:14][C:12]([C:15]1[C:23]2[O:22][CH2:21][CH2:20][C:19]=2[CH:18]=[C:17]([S:24][CH3:25])[CH:16]=1)([CH3:13])[CH2:11][C:5]([C:7]([F:8])([F:9])[F:10])([OH:6])[CH2:4][OH:3]
Reactant: CSc1cc2c(c(C(C)(C)CC3(C(F)(F)F)COC(C)(C)O3)c1)OCC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: CSc1cc2c(c(C(C)(C)CC(O)(CO)C(F)(F)F)c1)OCC2
Yield: 84.5 %

Procedure:
A solution of 0.31 g of 7-[2-(2,2-dimethyl-4-trifluoromethyl-[1,3]dioxolan-4-yl)-1,1-dimethylethyl]-5-methylsulfanyl-2,3-dihydrobenzofuran and 0.015 g of p-toluenesulfonic acid (p-TsOH) monohydrate in methanol (10 mL) was stirred at room temperature for 7 days, heated to reflux for 1 minute, and the volatiles removed in vacuo. The residue was diluted with saturated aqueous sodium bicarbonate and filtered. The solid was washed with water and hexanes, and dried to give 0.235 g of 4-methyl-4-(5-methylsulfanyl-2,3-dihydrobenzofuran-7-yl)-2-trifluoromethylpentane-1,2-diol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](I)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH3:12][CH:13]([OH:16])[C:14]#[CH:15].CCN(CC)CC>[Cl-].[Cl-].[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C>[F:1][C:2]1[CH:10]=[C:6]2[C:5]([CH:15]=[C:14]([CH:13]([OH:16])[CH3:12])[O:9][C:7]2=[O:8])=[CH:4][CH:3]=1
Reactant: C#CC(C)O
Reactant: O=C(O)c1cc(F)ccc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(O)c1cc2ccc(F)cc2c(=O)o1
Temperature: 100 °C
Reaction time: 2 h
Yield: 83.8 %

Procedure:
A mixture of 5-fluoro-2-iodobenzoic acid (9.04 g, 34.0 mmol), but-3-yn-2-ol (5.7 mL, 5.46 g, 78.0 mmol), ZnCl2 (4.62 g, 34.0 mmol), Pd(Ph3P)4 (1.96 g, 1.7 mmol), Et3N (14.2 mL, 10.3 g, 102.0 mmol) and DMF (50 mL) was stirred under argon at 100° C. for 2 hours. After the removal of the volatiles under vacuum, the residue was chromatographed (silica gel, ethyl acetate in hexanes, 0-50%) to provide intermediate 7-fluoro-3-(1-hydroxyethyl)-1H-isochromen-1-one as a brown oil (5.93 g, 84%). MS m/z 209.2 [M+H]+; 1H NMR (500 MHz, CDCl3-d): 6 ppm 7.91-7.96 (1H, m), 7.43-7.47 (2H, m), 6.55-6.59 (1H, m), 4.67 (1H, q, J=6.52 Hz), 1.57 (3H, d, J=6.62 Hz).
Reaction SMILES: [CH2:1]([N:3]1[C:8]2=[CH:9][C:10]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12][C:11]=3[CH:24]=[C:7]2[O:6][CH2:5][CH2:4]1)[CH3:2].C(=O)([O-])O.[Na+].[Br:30]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClC(Cl)C>[Br:30][C:9]1[C:10]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12][C:11]=2[CH:24]=[C:7]2[O:6][CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[C:8]=12
Reactant: CCN1CCOc2cc3c(cc21)CCN(C(=O)OC(C)(C)C)CC3
Reactant: BrBr
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CCN1CCOc2cc3c(c(Br)c21)CCN(C(=O)OC(C)(C)C)CC3
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 860 mg of t-butyl 4-ethyl-3,4,6,7,9,10-hexahydro[1,4]oxazino[2,3-h][3]benzazepine-8(2H)-carboxylate in 25 ml of dichloroethane was added 1.1 g of sodium hydrogen carbonate, and further, a solution of 200 μl of bromine in 5 ml of dichloroethane was added dropwise thereto over about 30 minutes, followed by stirring at room temperature. To the reaction mixture was slowly added a 3% aqueous sodium thiosulfate solution, followed by stirring vigorously and extracting with chloroform twice. The combined organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by silica gel chromatography (elution solvent: HEX-EtOAc) to obtain 490 mg of t-butyl 5-bromo-4-ethyl-3,4,6,7,9,10-hexahydro[1,4]oxazino[2,3-h][3]benzazepine-8(2H)-carboxylate.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[C:6]([C:9]([F:12])([F:11])[F:10])=[N:7][O:8][C:4]=2[C:3]=1[CH2:15][CH2:16][CH3:17].[Si:18]([O:25][CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]1O)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>>[Si:18]([O:25][CH2:26][C@H:27]1[CH2:28][CH2:29][CH2:30][CH2:31][C@H:32]1[O:1][C:2]1[CH:14]=[CH:13][C:5]2[C:6]([C:9]([F:12])([F:11])[F:10])=[N:7][O:8][C:4]=2[C:3]=1[CH2:15][CH2:16][CH3:17])([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)OCC1CCCCC1O
Reactant: CCCc1c(O)ccc2c(C(F)(F)F)noc12
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCCc1c(O[C@@H]2CCCC[C@@H]2CO[Si](C)(C)C(C)(C)C)ccc2c(C(F)(F)F)noc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 6-hydroxy-7-propyl-3-(trifluoromethyl)-1,2-benzisoxazole (730 mg, 2.98 mmol), 2-({tert-butyl(dimethyl)silyloxy}methyl)-cyclohexanol (800 mg, 3.28 mmol) from this Example step 1, and triphenylphosphine (1.02 g, 3.874 mmol) was dissolved in dry benzenes (16 mL). Diisopropylazodicarboxylate (0.78 mL, 3.874 mmol) was added dropwise. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated in vacuo and the residue purified by chromatography on silica gel using acetone and hexane (1:99) to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[C:7]([N:13]1[CH2:20][CH:19]3[CH:15]([CH2:16][NH:17][CH2:18]3)[CH2:14]1)[CH:6]=[N:5]2.[CH3:21][O:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[C:25]([N:32]2[N:36]=[CH:35][CH:34]=[N:33]2)[CH:24]=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[C:7]([N:13]1[CH2:14][CH:15]3[CH2:16][N:17]([C:27]([C:26]4[CH:30]=[CH:31][C:23]([O:22][CH3:21])=[CH:24][C:25]=4[N:32]4[N:36]=[CH:35][CH:34]=[N:33]4)=[O:28])[CH2:18][CH:19]3[CH2:20]1)[CH:6]=[N:5]2
Reactant: COc1ccc(C(=O)O)c(-n2nccn2)c1
Reactant: Fc1cc2ncc(N3CC4CNCC4C3)nc2cc1F
Product: COc1ccc(C(=O)N2CC3CN(c4cnc5cc(F)c(F)cc5n4)CC3C2)c(-n2nccn2)c1

Procedure:
The title compound was prepared in a manner analogous to Example 15, utilizing Intermediate 44 and Intermediate 54 in the last step MS (ESI): mass calculated for C24H21F2N7O2, 477.17; m/z found 478.1 [M+H]+. 1H NMR (500 MHz, CDCl3) 8.26 (d, J=14.7, 1H), 7.71 (s, 2H), 7.63 (dd, J=10.6, 8.5, 1H), 7.49 (t, J=7.1, 1H), 7.41 (dd, J=11.4, 8.0, 1H), 7.33 (t, J=6.7, 1H), 6.95 (dt, J=8.4, 4.2, 1H), 3.99-3.85 (m, 5H), 3.83-3.69 (m, 2H), 3.70-3.57 (m, 1H), 3.52 (dd, J=11.0, 3.5, 1H), 3.44 (s, 1H), 3.19-3.09 (m, 1H), 3.09-2.97 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][N:16]([CH:19]2[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH:20]2[O:32][CH2:33][C:34]2[CH:43]=[CH:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=2)[C:15](=[O:44])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48]>>[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48].[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][N:16]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH:20]2[O:32][CH2:33][C:34]2[CH:43]=[CH:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=2)[C:15](=[O:44])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2ccc(OCCCOCc3ccccc3)cc2=O)C(OCc2ccc3ccccc3c2)C1
Solvent: O=C(O)C(F)(F)F
Product: O=c1cc(OCCCOCc2ccccc2)ccn1C1CCNCC1OCc1ccc2ccccc2c1

Procedure:
In an analogous manner to that described in Example 145 (i), from tert-butyl (3'RS,4'RS)-4-(3-benzyloxy-propoxy)-3'-(naphthalen-2-ylmethoxy)-2-oxo-3',4',5',6'-tetrahydro-2H,2'H-[1,4']bipyridine-1'-carboxylate by cleavage of the BOC group by means of trifluoroacetic acid there was obtained (3'RS,4'RS)-4-(3-benzyloxy-propoxy)-3'-(naphthalen-2-ylmethoxy)-1',2',3',4',5',6'-hexahydro-[1,4']bipyridin-2-one trifluoroacetate as a colourless solid; MS: 499 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH2:10][C:9](O[Si](C)(C)C)=[C:8](O[Si](C)(C)C)[CH2:7][C:6]=1[C:21]([O:23][CH3:24])=[O:22])=[O:4].[I:25][C:26]1[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=1[NH2:28]>C(O)(=O)C>[CH3:1][O:2][C:3](=[O:4])[C:5]1[C:6](=[CH:7][C:8]([NH:28][C:27]2[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=2[I:25])=[C:9]([NH:28][C:27]2[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=2[I:25])[CH:10]=1)[C:21]([O:23][CH3:24])=[O:22]
Reactant: Nc1ccccc1I
Reactant: COC(=O)C1=C(C(=O)OC)CC(O[Si](C)(C)C)=C(O[Si](C)(C)C)C1
Solvent: CC(=O)O
Product: COC(=O)c1cc(Nc2ccccc2I)c(Nc2ccccc2I)cc1C(=O)OC

Procedure:
A solution of 2.4 g (6 mmol) of 4,5-bis(trimethylsilyloxy)cyclohexa-1,4-diene-1,2-dicarboxylic acid dimethyl ester (Example 1a) and 5.3 g (24 mmol) of 2-iodoaniline in 24 ml of glacial acetic acid is boiled under reflux for 2 hours. The reaction mixture is cooled, the solvent is evaporated off and the dark-brown residue is dissolved in dichloromethane and the solution is washed in succession with 20 ml of 1N HCl, 50 ml of saturated NaHCO3 and twice with 20 ml of water, dried with sodium sulfate and concentrated by evaporation. The residue obtained after concentration by evaporation is chromatographed on silica gel with ethyl acetate/hexane 2:1 and the product fractions are concentrated by evaporation, yielding the title compound in the form of a yellow foam: 1H-NMR (DMSO-d6): δ=7.91 (dxd, J1 =8, J2 =1, 2H), 7.39 (dxdxd, J1 =10, J2 =8, J3 =1, 2H), 7.32 (br s, 2H), 7.22-7.05 (m, 2H), 7.01 (s, 2H), 6.88 (txd, Jt =8, Jd =1, 2H), 3.73 (s, 6H).
Reaction SMILES: [CH2:1]([O:4][CH:5]1[CH2:20][CH:9]2[CH2:10][O:11][C:12]3[C:17]([C:8]2([S:21]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH2:7][CH2:6]1)=[C:16]([F:18])[CH:15]=[CH:14][C:13]=3[F:19])[CH:2]=C.[O:31]=[O+][O-].[BH4-].[Na+]>CO.C(Cl)Cl>[Cl:30][C:27]1[CH:26]=[CH:25][C:24]([S:21]([C:8]23[CH2:7][CH2:6][CH:5]([O:4][CH2:1][CH2:2][OH:31])[CH2:20][CH:9]2[CH2:10][O:11][C:12]2[C:17]3=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])(=[O:23])=[O:22])=[CH:29][CH:28]=1
Reactant: C=CCOC1CCC2(S(=O)(=O)c3ccc(Cl)cc3)c3c(F)ccc(F)c3OCC2C1
Reactant: O=[O+][O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: O=S(=O)(c1ccc(Cl)cc1)C12CCC(OCCO)CC1COc1c(F)ccc(F)c12
Temperature: 25 °C
Yield: 93 %

Procedure:
A solution of 8-allyloxy-10a-(4-chloro-benzenesulfonyl)-1,4-difluoro-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromene (1.55 g, 3.41 mmol) in 1:1 MeOH/CH2Cl2 (30 mL) at −78° C. was purged with O3 until a blue color persisted. The reaction mixture was then purged with nitrogen until the blue color dissipated, NaBH4 (0.39 g, 10.2 mmol) was added and the reaction mixture was warmed slowly to ambient temperature, After 18 h, the reaction mixture was quenched with saturated aqueous NH4Cl and concentrated in vacuo. The residue was diluted with water and extracted with CH2Cl2 (3×). The combined organic extracts were washed with saturated aqueous NaHCO3, dried over MgSO4 and concentrated in vacuo to afford the title compound (1.46 g, 93%): 1H NMR (CDCl3 400 MHz) δ 7.60 (d, J=8.8 Hz, 2H), 7.50 (d, J=8.8 Hz, 2H), 7.06 (m, 1H), 6.41 (m, 1H), 5.23 (dd, J=11.7, 3.7 Hz, 1H), 4.13 (d, J=11.7 Hz, 1H), 3.76 (t, J=5.1 Hz, 2H), 3.56-3.50 (m, 3H), 2.99 (m, 1H), 2.40-2.30 (m, 2H), 1.96-1.84 (m, 2H), 1.60 (br s, 1H), 1.54 (m, 1H), 1.16 (m, 1H).
Reaction SMILES: [H-].[Na+].[C:3]1([CH3:31])[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:30][CH2:29][CH2:28][C@H:13]2[C:14]([NH:16][C@H:17]([C:25]([NH2:27])=[O:26])[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:15])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[C:32]1([CH3:42])[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1>C1COCC1>[C:32]1([CH3:42])[CH:37]=[CH:36][C:35]([S:38]([NH:27][C:25](=[O:26])[C@H:17]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[NH:16][C:14](=[O:15])[C@@H:13]2[CH2:28][CH2:29][CH2:30][N:12]2[S:9]([C:6]2[CH:7]=[CH:8][C:3]([CH3:31])=[CH:4][CH:5]=2)(=[O:11])=[O:10])(=[O:40])=[O:39])=[CH:34][CH:33]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)N[C@@H](Cc2ccccc2)C(N)=O)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)NC(=O)[C@H](Cc2ccccc2)NC(=O)[C@@H]2CCCN2S(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
N-(Toluene-4-sulfonyl)-L-proline was reacted with L-phenylalanine amide using the procedure described in Method 12 to yield N-(toluene-4-sulfonyl)-L-prolyl-L-phenylalanine amide. To a solution of NaH (60% mineral oil—prewashed with THF) in THF at 0° C. was added N-(toluene-4-sulfonyl)-L-prolyl-L-phenylalanine amide and the reaction was stirred at 0° C. for 45 minutes. Toluene-4-sulfonyl chloride was added and the reaction was stirred for 16 hours at room temperature. The reaction mixture was extracted with EtOAc (3×50 mL) and 0.2 N HCl (50 mL), and the combined organic layers were washed successively with sat. NaHCO (50 mL), and sat. NaCl (2×50 mL), dried over MgSO4, filtered, and concentrated to yield the title compound as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:6]=[C:5]([NH:15][S:16]([CH2:19][CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])(=[O:18])=[O:17])[C:4]=1[O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32][CH3:33].C[OH:35]>>[OH:35][CH2:22][C:21]([CH3:24])([CH3:23])[CH2:20][CH2:19][S:16]([NH:15][C:5]1[C:4]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH3:33])=[C:3]([O:2][CH3:1])[N:8]=[C:7]([C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:6]=1)(=[O:17])=[O:18]
Reactant: CO
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)CCC(C)(C)C)nc(-c2ncccn2)nc1OC
Product: COc1ccccc1Oc1c(NS(=O)(=O)CCC(C)(C)CO)nc(-c2ncccn2)nc1OC
Reaction time: 48 h

Procedure:
Streptomyces rimosus subsp. rimosus ATCC10970 maintained on a quarter strength ATCC172 agar slope was inoculated as a loopful of spores into a 300 ml Erlenmeyer flask containing 50 ml of AS-7H inoculum medium. This was allowed to incubate for 2 days at 28° C., 200 rpm on an Infors Multitron™ Shaker with 1″ throw. 2 mls of this inoculum medium was then transferred to twenty six 300 ml Erlenmeyer flask containing 50 ml of AP-5H production medium and incubated under the same conditions for a further 24 hours. At this point 4.5 mg of N-[6-methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-3,3-dimethyl-1-butanesulfonamide (Preparation 1) dissolved in 0.5 ml of methanol was added to each of the flasks and the fermentation allowed to continue under the same conditions for a further 20 hours. The flask was then extracted with 200 mls of ethyl acetate and the combined ethyl acetate solubles concentrated to dryness to give a gum solid, 430 mg .
Reaction SMILES: [Cl:1]Cl.[Cl:3][CH:4]([Cl:13])[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].C([O-])(=O)C.[Na+]>>[Cl:3][C:4]([Cl:1])([Cl:13])[C:5]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:6]
Reactant: O=C(c1ccccc1)C(Cl)Cl
Reactant: ClCl
Agent: CC(=O)[O-]
Agent: [Na+]
Product: O=C(c1ccccc1)C(Cl)(Cl)Cl

Procedure:
The synthetic method described in U.S. Pat. No. 4,642,384 involves the preparation of 2,5-bis(2,2,2-trifluoroethoxy)-.,a-dichloroacetophenone as an intermediate by chlorinating the a-unsubstituted 2,5-bis(2,2,2-trifluoroethoxy)acetophenone with chlorine gas at a moderate temperature, such as 50-60° C. The α,α-dichloroacetophenone intermediate is further chlorinated in the presence of a buffering base, such as sodium acetate, at a slightly higher temperature, such as 80-100° C. to yield the α,α,α-trichloroacetophenone. The α,α,α-trichloroacetophenone is reacted with 2-aminomethylpyridine to yield a benzamide, and the pyridine ring is reduced to yield 2,5-bis(2,2,2-trifluoroethoxy)-N-(2-piperidylmethyl)-benzamide.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([C:12]([O:14]CC)=[O:13])[NH:7]2)#[N:2].O[Li].O>C(O)C>[C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([C:12]([OH:14])=[O:13])[NH:7]2)#[N:2]
Reactant: CCOC(=O)c1cc2c(C#N)cccc2[nH]1
Agent: [Li]O
Solvent: CCO
Solvent: O
Product: N#Cc1cccc2[nH]c(C(=O)O)cc12
Yield: 87.1 %

Procedure:
To a solution of ethyl 4-cyano-1H-indole-2-carboxylate (I-3a: 330 mg, 1.542 mmol) in ethanol (10 mL) was added LiOH.H2O (129 mg, 3.08 mmol) and the mixture was refluxed for 16 h. The solvent was evaporated under reduced pressure and the residue diluted with water (10 mL). The aqueous layer was acidified with 10% aq. HCl solution to pH 6.0 and the precipitated solid was filtered. The residue was washed with water and dried under vacuum to afford 250 mg (87%) of 4-cyano-1H-indole-2-carboxylic acid (I-3b) as an off-white solid.
Reaction SMILES: [CH:1](=[O:10])[C:2]1[C:3]([O:8][CH3:9])=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH2:11](Br)[CH3:12].[Mg].O1CCCC1.[Cl-].[NH4+].O>O1CCCC1>[CH3:9][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH:1]([OH:10])[CH2:11][CH3:12]
Reactant: CCBr
Reactant: COc1ccccc1C=O
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CCC(O)c1ccccc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
o-Anisaldehyde (2.72 g) was dissolved in tetrahydrofuran (50 ml), and 0.93M magnesium ethylbromide—tetrahydrofuran solution (31.3 ml) was added dropwise under ice-cooling over 10 min. The mixture was stirred at room temperature for 2 hr. The reaction mixture was ice-cooled, and saturated aqueous ammonium chloride solution (40 ml) and water (40 ml) were added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1) to give the title compound (3.15 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:13]([CH:14]=O)=[CH:12][N:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:22]1[CH2:26][C:25](=[O:27])[NH:24][C:23]1=[O:28].N1CCCCC1>C(O)C>[CH2:1]([O:8][C:9]1[C:13](/[CH:14]=[C:26]2/[C:25](=[O:27])[NH:24][C:23](=[O:28])[S:22]/2)=[CH:12][N:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CSC(=O)N1
Reactant: O=Cc1cn(-c2ccccc2)nc1OCc1ccccc1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1NC(=O)/C(=C/c2cn(-c3ccccc3)nc2OCc2ccccc2)S1
Yield: 87.8 %

Procedure:
A mixture of 3-benzyloxy-1-phenyl-1H-pyrazole-4-carbaldehyde (2.50 g), 1,3-thiazolidine-2,4-dione (1.05 g), piperidine (0.15 g) and ethanol (80 mL) was heated under reflux for 1 hr. The reaction mixture was concentrated, and the obtained crystals were washed with ethanol to give (5Z)-5-[(3-benzyloxy-1-phenyl-1H-pyrazol-4-yl)methylene]-1,3-thiazolidine-2,4-dione as yellow crystals (2.97 g, yield 87%). Recrystallization from tetrahydrofuran-hexane gave yellow prism crystals. melting point: >300° C.
Reaction SMILES: Br.[O:2]1[CH2:7][CH2:6][N:5]([C:8]([NH2:10])=[NH:9])[CH2:4][CH2:3]1.[Cl:11][C:12]([SH:15])(Cl)Cl.[OH-].[Na+]>ClCCl.O>[Cl:11][C:12]1[S:15][N:10]=[C:8]([N:5]2[CH2:6][CH2:7][O:2][CH2:3][CH2:4]2)[N:9]=1
Reactant: SC(Cl)(Cl)Cl
Reactant: N=C(N)N1CCOCC1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: Clc1nc(N2CCOCC2)ns1
Temperature: 25 °C
Yield: 54.6 %

Procedure:
To a solution of morpholinoformamidine hydrobromide (2.00 g, 9.52 mmol) and perchloromethyl mercaptan (1.02 ml, 9.52 mmol) in dichloromethane (10 ml) was added dropwise a solution of sodium hydroxide (1.52 g, 38.1 mmol) in water (4 ml) under ice-cooling. Then, the reaction mixture was stirred under ice-cooling for 1 hour and at room temperature for 1 hour. The organic layer was separated, washed with water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to give 1.07 g (54.6%) of the desired product as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12]([NH:14][NH:15]S(C2C=CC(C)=CC=2)(=O)=O)=[CH:11][C:10](=[O:26])[CH2:9]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:34][C:35]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=O>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12]2[N:14]=[N:15][CH:34]=[C:35]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:11]=2[C:10](=[O:26])[CH2:9]1
Reactant: O=C(CBr)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)NNC2=CC(=O)CC(c3ccccc3Cl)C2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=C1CC(c2ccccc2Cl)Cc2nncc(-c3ccccc3)c21
Temperature: 80 °C
Reaction time: 3 h
Yield: 39.8 %

Procedure:
A mixture of 5-(2-chlorophenyl)-1-[2-(4-methylphenylsulfonyl)hydrazino]cyclohexen-3-one (1.35 g), anhydrous potassium carbonate (1.19 g), 2-bromoacetophenone (0.893 g) and methanol (30 ml) was stirred at 80° C. for 3 hours. Under reduced pressure, the solvent was evaporated, and the residue was extracted with ethyl acetate. The organic layer was concentrated, and the residue was purified with silica gel column chromatography to give 7-(2-chlorophenyl)-4-phenyl-5,6,7,8-tetrahydrocinnolin-5-one (0.46 g) as oil.
Reaction SMILES: [C:1]([O:4][C:5]1[C:14]([CH3:15])=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[CH3:16])(=[O:3])[CH3:2].CC(N=NC(C#N)(C)C)(C#N)C.C1C(=O)N([Br:36])C(=O)C1>C(Cl)(Cl)(Cl)Cl.C(Cl)(Cl)Cl>[C:1]([O:4][C:5]1[C:6]([CH3:16])=[CH:7][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:13][C:14]=1[CH2:15][Br:36])(=[O:3])[CH3:2]
Reactant: COC(=O)c1cc(C)c(OC(C)=O)c(C)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc(C)c(OC(C)=O)c(CBr)c1
Temperature: 25 °C

Procedure:
A solution of methyl 4-acetoxy-3,5-dimethylbenzoate (2.4 g) in carbon tetrachloride (35 mL) was treated with AIBN (azobisisobutrylnitrile, 0.177 g, 0.1 equivalent) and NBS (N-bromosuccinimide, 2.117 g, 1.1 equivalents). The reaction was heated at reflux under a nitrogen atmosphere for 6 h. The reaction was cooled to room temperature and diluted with chloroform (30 mL). This solution was washed with water (4×50 mL) and then dried over anhydrous magnesium sulfate, filtered and evaporated to dryness. An off-white, waxy solid was recovered. Yield=4.63 g. The crude bromide was used as such for the following reaction.