Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.Cl.[F:24][C:25]([F:34])([F:33])[C:26]([NH:28][CH:29]1[CH2:32][NH:31][CH2:30]1)=[O:27].C(N(CC)CC)C>CS(C)=O.O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:31]4[CH2:32][CH:29]([NH:28][C:26](=[O:27])[C:25]([F:34])([F:33])[F:24])[CH2:30]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: O=C(NC1CNC1)C(F)(F)F
Agent: Cl
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn(C2CC2)c2c(F)c(N3CC(NC(=O)C(F)(F)F)C3)c(F)cc2c1=O
Yield: 22 %

Procedure:
A mixture of 1 g (3.2 mmoles) of ethyl 1-cyclopropyl-6,7,8-trifluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylate, 0.98 g (4.8 mmoles) of 3-trifluoroacetamidoazetidine hydrochloride and 2 ml of triethylamine is heated in 15 ml of dimethyl sulphoxide for 4 hours at 80°-5° C. It is diluted with water and extracted with chloroform. The organic phase is washed with water and evaporated yielding 0.31 g (22% of ethyl 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(3-trifluoroacetamido-1-azetidinyl)-4-oxo-3-quinolinecarboxylate which is then hydrolysed by heating a mixture of 0.1 g (0.22 mmoles) of this ester with 5 ml of 1N sodium hydroxide and 5 ml of ethanol. The mixture is cooled, evaporated and acidified with acetic acid. Filtering and washing with water yields 70 mg (96%) of 1-cyclopropyl-6,8-difluoro-7-(3-amino-1-azetidinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, melting at 214°-6° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:4]([CH3:22])=[CH:5][C:6]=1[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)(=[O:16])=[O:15].[Cl-].[Cl-].C([Al+2])C.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(Cl)Cl.C1(C)C=CC=CC=1>[C:34]([C:5]1[C:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[S:14]([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)(=[O:15])=[O:16])=[C:2]([CH3:1])[N:3]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:4]=1[CH3:22])(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)Cn1c(C)cc(Cc2ccccc2S(=O)(=O)N2CCCC2)c1C
Agent: CC[Al+2]
Agent: CC[Al](Cl)Cl
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)Cn1c(C)c(Cc2ccccc2S(=O)(=O)N2CCCC2)c(C(=O)c2ccccc2)c1C
Temperature: 25 °C
Reaction time: 5.25 h
Yield: 91.5 %

Procedure:
In a small vial charged with ethyl 2-(2,5-dimethyl-3-(2-(pyrrolidin-1-ylsulfonyl)benzyl)-1H-pyrrol-1-yl)acetate (143.7 mg, 0.355 mmol) in DCM (4 mL), at 0° C., was added dropwise a solution of ethylaluminum dichloride (444 μL, 0.444 mmol) in toluene. The reaction mixture turned deep rose color and benzoyl chloride (61.9 μL, 0.533 mmol) was added. The resulting mixture became orange and slowly was allowed to warm to rt. The reaction was stirred 5.25 h and then cooled once again and an additional 800 μL of EtAlCl2 and 150 μL of benzoyl chloride were added. The reaction was once again allowed to warm to room temperature slowly with stirring and stirred an additional 15.25 h at room temperature. The reaction was then quenched by the addition of water and dichloromethane and the water layer was extracted with DCM (3×). The organic layer was dried with MgSO4, and concentrated under vacuum. The crude product was added to a 40 g ISCO silica gel column and purified with a gradient of 0% to 60% EtOAc/hexanes. The product was obtained as a light orange foam (165.2 mg, 0.325 mmol, 91% yield). 1H NMR (CDCl3/400 MHz) δ (ppm) 7.92 (dd, 1H), 7.68 (dd, 2H), 7.46 (t, 1H), 7.38-7.32 (m, 3H), 7.20 (t, 1H), 7.10 (d, 1H), 4.56 (s, 2H), 4.30 (s, 2H), 4.24 (q, 2H), 3.23-3.17 (m, 4H), 2.03 (s, 3H), 1.98 (s, 3H), 1.84-1.78 (m, 4H), 1.29 (t, 3H). MS m/z: 509.40 (M+1).
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][OH:4].COC([C:9]1[C:17]2[N:16]=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[NH:14][C:13]=2[CH:12]=[C:11]([O:24][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[CH:10]=1)=O>CO>[CH3:1][NH:2][C:3]([C:17]1[CH:13]=[CH:12][C:11]([O:24][C:10]2[C:11]([O:24][C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)=[CH:12][C:13]3[NH:14][C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=4)=[N:16][C:17]=3[CH:9]=2)=[CH:10][CH:9]=1)=[O:4]
Reactant: CN
Reactant: CO
Reactant: COC(=O)c1cc(Oc2cccnc2)cc2[nH]c(-c3ccccn3)nc12
Product: CNC(=O)c1ccc(Oc2cc3nc(-c4ccccn4)[nH]c3cc2Oc2cccnc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.05 ml of a 40% methylamine/methanol solution was added to a methanol (1 ml) solution of 3.0 mg of 5-(4-methoxycarbonyl-2-pyridin-2-yl-6-(pyridin-3-yloxy)-1H-benzimidazole obtained in Example 10, and the reaction liquid was stirred overnight at room temperature. The solvent was evaporated away under reduced pressure, and this was purified through partitioning thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol=20/1) to obtain the entitled compound.
Reaction SMILES: [NH:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[C:10](=O)[CH3:11].[C:13]([NH:16][NH2:17])([NH2:15])=[NH:14].[ClH:18]>C(O)C.Cl>[ClH:18].[ClH:18].[NH:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[C:10](=[N:17][NH:16][C:13]([NH2:15])=[NH:14])[CH3:11]
Reactant: CC(=O)c1cc2ccncc2[nH]1
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Product: CC(=NNC(=N)N)c1cc2ccncc2[nH]1
Temperature: 25 °C
Yield: 161.8 %

Procedure:
A mixture of 1-(1H-pyrrolo[2,3-c]pyridin-2-yl)ethanone (Example 70) (90 mg, 0.56 mmol) and aminoguanidine hydrochloride (65 mg, 0.59 mmol) in ethanol (5.6 mL) and 6 N HCl (0.47 mL) was heated under reflux for 1.5 h. The reaction mixture was cooled to room temperature and the precipitate was filtered, rinsed with ethanol and diethyl ether, and dried under vacuum at 45° C. to provide [[1-(1H-pyrrolo[2,3-c]pyridin-2-yl)ethylidene]amino]guanidine dihydrochloride (138 mg, 86%) as a white solid: mp 314-318° C. dec.; 1H NMR (300 MHz, CD3OD) δ2.50 (3H, s), 7.40 (1H, s), 8.10-8.27 (2H, m), 9.04 (1H, s); ESI MS m/z 217 [C10H12N6+H]+; HPLC (Method A) >99% (AUC), tR=9.01 min.
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[C:32]1[CH:37]=[CH:36][C:35](=[O:38])[N:34]([CH3:39])[CH:33]=1)\[CH2:4][C@H:5]([C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]2)=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12].Cl.O1CCOCC1.C(=O)([O-])O.[Na+]>C(O)C>[OH:1]/[N:2]=[C:3](/[C:32]1[CH:37]=[CH:36][C:35](=[O:38])[N:34]([CH3:39])[CH:33]=1)\[CH2:4][C@H:5]([C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]2)=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12]
Reactant: Cc1ccccc1[C@H](C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCO
Product: Cc1ccccc1[C@H](C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(C2CCNCC2)cc1
Yield: 49.3 %

Procedure:
(R,E)-tert-Butyl 4-(4-(3-(hydroxyimino)-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1-o-tolylpropyl)phenyl)piperidine-1-carboxylate (example 506, 30 mg) was dissolved in ethanol (0.8 mL) and hydrochloric acid solution (4.0 M in 1,4-dioxane (170 μl, 680 μmol) was added, then after 14 h the reaction mixture was poured onto aq. sat. sodium hydrogencarbonate solution and extracted 2 times with dichloromethane. The combined organic layers were washed with brine dried over magnesium sulfate, filtered and evaporated. The residue was triturated with ethyl acetate/heptane to afford the title compound (12 mg, 41%). Light yellow solid; MS (ESI+): m/z=: 430.5 [M+H]+).
Reaction SMILES: [CH3:1][S-:2].[Na+].[Cl:4][C:5]1[CH:10]=[C:9]([S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2F)(=[O:13])=[O:12])[CH:8]=[CH:7][C:6]=1[NH:21][C:22](=[O:30])[C@:23]([OH:29])([CH3:28])[C:24]([F:27])([F:26])[F:25].[Cl-].[NH4+]>CN1C(=O)CCC1>[Cl:4][C:5]1[CH:10]=[C:9]([S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[S:2][CH3:1])(=[O:13])=[O:12])[CH:8]=[CH:7][C:6]=1[NH:21][C:22](=[O:30])[C@:23]([OH:29])([CH3:28])[C:24]([F:27])([F:26])[F:25]
Reactant: C[S-]
Reactant: C[C@@](O)(C(=O)Nc1ccc(S(=O)(=O)c2ccccc2F)cc1Cl)C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CSc1ccccc1S(=O)(=O)c1ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c1
Temperature: 120 °C
Yield: 62.5 %

Procedure:
Sodium methanethiolate (49.5 mg) was added to a solution of (R)-N-[2-chloro-4-(2-fluorophenylsulphonyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Method 63) (0.15 g) in NMP (1.5 ml) and the mixture was heated at 120° C. for 18 hours then cooled. Saturated aqueous ammonium chloride solution (15 ml) was added and the mixture was extracted with ethyl acetate (2×50 ml). The organic extracts were combined, washed with brine and dried. Volatile material was removed by evaporation and the residue was purified by chromatography on a silica gel Mega Bond Elut column eluting with 0-20% ethyl acetate/hexane to give the title compound (0.10 g) as a solid. NMR: (CDCl3): 1.75 (s, 3H), 2.4 (s, 3H), 3.6 (brs, 1H), 7.3 (t, 1H), 7.35 (t, 1H), 7.55 (m, 1H), 7.9 (dd, 1H), 8.05 (d, 1H), 8.25 (dd, 1H), 8.6 (d, 1H), 9.25 (brs, 1H); MS (ESP−): 452.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[C:9]([C:13](=[O:16])[CH2:14][CH3:15])=[C:8]2[C:3]=1[C:4]([CH2:18][CH2:19][CH3:20])=[CH:5][C:6](=[O:17])[O:7]2.CO[CH:23](OC)[CH2:24][C:25]([CH3:28])(O)[CH3:26]>N1C=CC=CC=1>[CH3:26][C:25]1([CH3:28])[O:1][C:2]2[C:3]3[C:4]([CH2:18][CH2:19][CH3:20])=[CH:5][C:6](=[O:17])[O:7][C:8]=3[C:9]([C:13](=[O:16])[CH2:14][CH3:15])=[C:10]([OH:12])[C:11]=2[CH:23]=[CH:24]1
Reactant: COC(CC(C)(C)O)OC
Reactant: CCCc1cc(=O)oc2c(C(=O)CC)c(O)cc(O)c12
Solvent: c1ccncc1
Product: CCCc1cc(=O)oc2c(C(=O)CC)c(O)c3c(c12)OC(C)(C)C=C3
Yield: 79.1 %

Procedure:
A mixture of 3 (2.60 g, 9.42 mmol) and 4,4-dimethoxy-2-methylbutan-2-ol (5.54 g, 37.7 mmol) were dissolved in anhydrous pyridine (6.5 mL). The mixture was refluxed under nitrogen for three days. After removal of the solvent in vacuo, the residue was dissolved in ethyl acetate. The ethyl acetate was washed several times with 1N HCl and brine. It was then dried over Na2SO4. The crude product obtained by evaporation in vacuo was purified by silica gel column chromatography, eluting with 25% ethyl acetate/hexane to afford 2.55 g of 4 in 78.6% yield, mp 96°-98° C. 1H-NMR (CDCl3) δ 1.05 (3H, t, J=7.3 Hz, CH3); 1.22 (3H, t, J=7.5 Hz, CH3); 1.53 (6H, s, 2 CH3); 1.75 (2H, m, CH2); 2.92 (2H, t, J=7.1 Hz, CH2); 3.35 (2H, q, J=7.1 Hz, CH2); 5.56 (1H, d, J=10.0 Hz, H3); 5.98 (1H, s, H9); 6.72 (1H, d, J=10.0 Hz, H4); MS (EI): 343 (5.7, M+1); 342 (22.5, M+); 327 (100, M-CH3); IR (KBr): 1728 (vs, C=O) cm-1 ; Anal. calcd. for C20H22O5 : C, 70.16; H, 6.48; Found: C, 70.45; H, 6.92.
Reaction SMILES: [C:1]([NH:4][C:5]1S[C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=[CH:19][C:7]=2[C:6]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21])(=[O:3])[CH3:2]>[Ni]>[CH2:23]([O:22][C:20](=[O:21])[CH:6]([CH:7]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:8]1)[CH2:5][NH:4][C:1](=[O:3])[CH3:2])[CH3:24]
Reactant: CCOC(=O)c1c(NC(C)=O)sc2c1C=CC=CC=CC=CC=C2
Agent: [Ni]
Product: CCOC(=O)C(CNC(C)=O)C1CCCCCCCCCCC1
Yield: 98.5 %

Procedure:
Ethyl 2-acetamidocyclododeca[b]thiophene-3-carboxylate (2.3366 g, 6.65 mmol) was reductively desulfurized using Raney nickel to yield the title compound as a yellow oil (2.1314 g, 6.55 mmol, 98.5%); TLC: RF0.75 (Solvent I), 0.46 (Solvent J); IR (cm−1): 3316 (NH), 2903 (CH aliphatic), 1725 (ester C═O), 1661 (amide C═O); 1H nmr (DMSO-d6): δ 7.88 (br s, 1H), 4.05 (q, 2H, J=8.1 Hz), 3.59 (m, 2H), 2.45 (m, 1H), 1.74 (s, 3H), 1.50 (m, 1H), 1.28 (m, 22H), 1 .15 (t, 3H, J=8.1 Hz).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N:4][S:5][C:6]=1[CH2:7][OH:8].C(N(CC)CC)C.[C:16](Cl)(=[O:20])[O:17][CH2:18][CH3:19].O>O1CCCC1>[C:16](=[O:20])([O:8][CH2:7][C:6]1[S:5][N:4]=[N:3][C:2]=1[CH3:1])[O:17][CH2:18][CH3:19]
Reactant: Cc1nnsc1CO
Reactant: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)OCc1snnc1C
Temperature: 25 °C
Reaction time: 22 h
Yield: 65.1 %

Procedure:
In 5 ml of tetrahydrofuran was dissolved 0.50 g (3.8 mmol) of 4-methyl-1,2,3-thiadiazol-5-ylmethanol. After adding 0.80 g (7.6 mmol) of triethylamine and 0.60 g (5.7 mmol) of ethyl chlorocarbonate, the resulting mixture was stirred at room temperature for 22 hours. Then, water was added to the reaction mixture to stop the reaction, the objective product was extracted with ethyl acetate, the organic layer was washed with water and dried, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography using 5:1 mixture of n-hexane and ethyl acetate. Thus, 0.50 g of the objective compound was obtained.
Reaction SMILES: [N:1]([CH2:4][CH:5]([C:7]1[C:12]2[O:13][CH2:14][C:15](=[O:17])[NH:16][C:11]=2[C:10]([O:18][CH2:19][C:20]2C=CC=CC=2)=[CH:9][CH:8]=1)[OH:6])=[N+]=[N-].[H][H].C([OH:30])C>[Pd]>[C:19]([OH:30])(=[O:18])[CH3:20].[NH2:1][CH2:4][CH:5]([C:7]1[C:12]2[O:13][CH2:14][C:15](=[O:17])[NH:16][C:11]=2[C:10]([OH:18])=[CH:9][CH:8]=1)[OH:6]
Reactant: [N-]=[N+]=NCC(O)c1ccc(OCc2ccccc2)c2c1OCC(=O)N2
Reactant: CCO
Reactant: [H][H]
Agent: [Pd]
Product: CC(=O)O
Product: NCC(O)c1ccc(O)c2c1OCC(=O)N2
Reaction time: 18 h

Procedure:
A mixture of 8-(2-azido-1-hydroxyethyl)-5-(benzyloxy)-2H-benzo[b][1,4]oxazin-3(4H)-one, Isomer 1 (example 11, step g) (0.67 g) in ethanol (30 mL) with 10% palladium on carbon catalyst (0.210 g) was stirred vigorously under 4 bar pressure of hydrogen for 18 hours. The catalyst was filtered off and the solvent evaporated off under reduced pressure. The residue was dissolved in acetic acid (15 mL) and ethanol (15 mL) and the mixture stirred with 10% palladium on carbon catalyst (0.210 g) under 4 bar pressure of hydrogen for 18 hours. The mixture was filtered and fresh 10% palladium on carbon catalyst (0.210 g) was added and stirring under 4 bar pressure of hydrogen was continued for 18 hours. The mixture was filtered and fresh 10% palladium on carbon catalyst (0.210 g) added and stirring under 4 bar pressure of hydrogen was continued for 18 hours. The mixture was filtered and the solvent removed under reduced pressure. The residue was triturated with acetonitrile (30 mL) to afford the subtitled compound. Yield 0.33 g.
Reaction SMILES: BrC1C=NC([O:8][CH2:9][CH2:10][O:11][C:12]2[C:16]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)=[C:15]([NH:24][S:25]([C:28]3[CH:33]=[CH:32][C:31]([C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[N:14]([CH3:38])[N:13]=2)=NC=1.C[OH:40]>>[OH:40][CH2:35][C:34]([C:31]1[CH:32]=[CH:33][C:28]([S:25]([NH:24][C:15]2[N:14]([CH3:38])[N:13]=[C:12]([O:11][CH2:10][CH2:9][OH:8])[C:16]=2[C:17]2[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=2)(=[O:27])=[O:26])=[CH:29][CH:30]=1)([CH3:37])[CH3:36]
Reactant: CO
Reactant: Cc1ccc(-c2c(OCCOc3ncc(Br)cn3)nn(C)c2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Product: Cc1ccc(-c2c(OCCO)nn(C)c2NS(=O)(=O)c2ccc(C(C)(C)CO)cc2)cc1
Reaction time: 48 h

Procedure:
Streptomyces rimosus subsp. rimosus ATCC10970 maintained on a ¼ strength ATCC172 agar slope was inoculated as a loopful of spores into five 300 ml Erlemneyer flask containing 50 ml of AS7-H 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 each of sixty 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 10 mg of N-[3-{2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy}-1-methyl-4-(4-methylphenyl)-1H-pyrazol-5-yl]-4-(tert-butyl)benzenesulfonamide (Example 3) 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 6 hours. Each flask was then extracted with 200 mls of ethyl acetate and the combined ethyl acetate solubles concentrated to dryness to give a gum solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])(C)(C)C.C(O[C:26](=[O:42])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][N:33]=[C:32]([C:36]2[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=2)[CH:31]=1)=O)(C)(C)C>>[N:33]1[CH:34]=[CH:35][C:30]([C:28]2[CH2:27][C:26](=[O:42])[NH:19][C:9]3[CH:10]=[C:11]([C:15]([F:16])([F:17])[F:18])[C:12]([CH3:14])=[CH:13][C:8]=3[N:7]=2)=[CH:31][C:32]=1[C:36]1[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CC(=O)c1ccnc(-c2cccnc2)c1
Product: Cc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1ccnc(-c3cccnc3)c1)=N2

Procedure:
The title compound was prepared from (2-amino-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J20) (116 mg, 0.4 mmol) and 3-[2,3′]bipyridinyl-4-yl-3-oxo-propionic acid tert-butyl ester (Example K57) (119 mg, 0.4 mmol) according to the general procedure M and subsequent treatment of the crude product according to the general procedure N. Obtained as a light yellow solid (95 mg).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([NH2:17])([CH3:16])[CH3:15])[N:5]=[C:4]([CH3:18])[C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20].[O:24]1[CH2:29][CH2:28][CH:27]([CH2:30][C:31](O)=[O:32])[CH2:26][CH2:25]1>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([CH3:16])([NH:17][C:31](=[O:32])[CH2:30][CH:27]2[CH2:28][CH2:29][O:24][CH2:25][CH2:26]2)[CH3:15])[N:5]=[C:4]([CH3:18])[C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: O=C(O)CC1CCOCC1
Reactant: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)N)c2c1N
Product: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)NC(=O)CC3CCOCC3)c2c1N

Procedure:
Prepared as in Example Da from ethyl 4-amino-5-(2-amino-2-methylpropoxy)-2-methylquinoline-3-carboxylate (Example Db) and 2-(tetrahydro-2H-pyran-4-yl)acetic acid as a yellow solid (37%). 1H NMR (400 MHz, DMSO-d6) δ 1.05-1.08 (m, 2H), 1.30-1.38 (m, 11H), 1.79 (m, 1H), 1.97 (d, J=4.0 Hz, 2H), 2.56 (s, 3H), 3.07 (t, J=8.0 Hz, 2H), 3.61 (d, J=8.0 Hz, 2H), 4.28-4.34 (m, 4H), 6.87 (d, J=8.0 Hz, 1H), 7.23 (d, J=8.0 Hz, 1H), 7.49 (t, J=8.0 Hz, 1H), 7.73 (s, 1H), 8.21 (s, 2H). MS 444 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:16][C:17]1[CH:18]=[C:19]([S:29]([NH:32][CH3:33])(=[O:31])=[O:30])[CH:20]=[CH:21][C:22]=1[O:23][CH2:24][C:25]([F:28])([F:27])[F:26]>CC(O)C>[ClH:1].[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][N:3]=[C:2]2[NH:16][C:17]1[CH:18]=[C:19]([S:29]([NH:32][CH3:33])(=[O:30])=[O:31])[CH:20]=[CH:21][C:22]=1[O:23][CH2:24][C:25]([F:27])([F:26])[F:28]
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: CNS(=O)(=O)c1ccc(OCC(F)(F)F)c(N)c1
Solvent: CC(C)O
Product: CNS(=O)(=O)c1ccc(OCC(F)(F)F)c(Nc2ncnc3cc(OC)c(OC)cc23)c1
Product: Cl
Temperature: 25 °C
Yield: 70.7 %

Procedure:
A mixture of 4-chloro-6,7-bis(methyloxy)quinazoline (100 mg, 0.445 mmol) and 3-amino-N-methyl-4-[(2,2,2-trifluoroethyl)oxy]benzenesulfonamide (139 mg, 0.490 mmol) in i-PrOH (2 mL) was subjected to microwave irradiation (100° C., 2 bar) for 30 minutes before being cooled to room temperature. The solid that formed was collected by filtration and washed with isopropanol to give 3-{[6,7-bis(methyloxy)-4-quinazolinyl]amino}-N-methyl-4-[(2,2,2-trifluoroethyl)oxy]benzenesulfonamide hydrochloride (160 mg, 70%) as a pale yellow solid.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([Cl:25])[C:9]=1[NH:10][C:11]1[C:20]2[C:15](=[C:16]([OH:23])[C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[NH:14][C:13](=[O:24])[CH:12]=1.Br[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]>CS(C)=O>[Cl:3][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([Cl:25])[C:9]=1[NH:10][C:11]1[C:20]2[C:15](=[C:16]([O:23][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[NH:14][C:13](=[O:24])[CH:12]=1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1O
Reactant: CCOC(=O)CCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)CCCCCOc1c(OC)ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c12
Temperature: 30 °C
Reaction time: 1 h

Procedure:
Sodium hydride (54 mg, 1.35 mmol) was added to a solution of 4-(3,5-dichloropyridin-4-ylamino)-8-hydroxy-7-methoxyquinolin-2(1H)-one (380 mg, 1.08 mmol) and DMSO (20 ml) at rt under N2. After 1 h, ethyl 6-bromohexanoate (770 mg, 3.45 mmol) was added, and the mixture was heated at 30° C. for 5 h. The reaction was quenched with drops of water, poured into 0.5 M KH2PO4, and extracted with EtOAc (100 mL×3). The combined extracts were washed with water and then brine, dried, filtered, concentrated, and purified by silica gel chromatography (ethyl acetate: pet. ether) to give ethyl 6-(4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2-oxo-1,2-dihydroquinolin-8-yloxy)hexanoate: MS (ESI): 494.0.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17](O)=O.C([N:22](CC)CC)C>C1(C)C=CC=CC=1>[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17]1[S:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1](=[O:10])[N:22]=1
Reactant: COC(=O)c1ccccc1S
Reactant: O=C(O)c1cccs1
Reactant: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=c1nc(-c2cccs2)sc2ccccc12
Yield: 73.4 %

Procedure:
A mixture of methyl thiosalicylate (1.60 g, 9.5 mmol), 2-thiophenecarboxylic acid (1.04 g, 9.5 mmol), triethylamine (2.0 ml, 14.3 mmol) and toluene (2 ml) was refluxed for 12 hrs. After cooling, the precipitated crystals were collected by filtration and recrystallized from methanol-ether to give the titled compound (1.71 g, 73%).
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:16])[CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:6][CH:5]=1)[CH3:3].[C:17](OC=C)(=[O:19])[CH3:18]>C(OC(C)C)(C)C>[C:17]([O:1][C@@H:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:16])[CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:6][CH:5]=1)[CH3:3])(=[O:19])[CH3:18].[OH:1][C@H:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:16])[CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:6][CH:5]=1)[CH3:3]
Reactant: CC(O)c1ccc(C(=O)CC(C)(C)C)cc1
Reactant: C=COC(C)=O
Solvent: CC(C)OC(C)C
Product: CC(=O)O[C@H](C)c1ccc(C(=O)CC(C)(C)C)cc1
Product: C[C@H](O)c1ccc(C(=O)CC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49 %
Yield: 36 %

Procedure:
Dissolve 1-[4-(1-hydroxyethyl)-phenyl]-3,3-dimethylbutan-1-one (1.519 g, 6.905 mmol) in diisopropyl ether (20 mL). Add 4 Å molecular sieves powder (1.5 g), vinyl acetate (2 mL) and lipase Candida Antarctica acrylic resin (150 mg). Stir the mixture at room temperature overnight. Remove the solid residue by filtration. Concentrate the filtrate in vacuo and purify the crude mixture by chromatography on silica gel eluting with hexane/EtOAc (4:1) to give (R)-1-(1-acetoxy-ethyl)-4-(3,3-dimethyl-butyryl)-benzene as colorless oil (0.661 g, 36%) and (S)-1-[4-(1-hydroxyethyl)-phenyl]-3,3-dimethylbutan-1-one as a light yellow oil (0.737 g, 49%).