Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([NH:5][CH2:6][CH2:7][CH2:8][N:9]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:16][CH:15]=2)=[CH:12][S:11][C:10]1=[N:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)=[O:4].[NH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1.C(=O)([O-])O.[Na+]>CN(C)C=O>[F:33][C:30]1[CH:31]=[CH:32][C:27]([N:26]=[C:10]2[N:9]([CH2:8][CH2:7][CH2:6][NH:5][C:3](=[O:4])[CH2:2][N:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)[C:13]([C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:16][CH:15]=3)=[CH:12][S:11]2)=[CH:28][CH:29]=1
Reactant: C1CCNC1
Reactant: O=C(CBr)NCCCn1c(-c2ccc(N3CCOCC3)cc2)csc1=Nc1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(CN1CCCC1)NCCCn1c(-c2ccc(N3CCOCC3)cc2)csc1=Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of the compound (200 mg) obtained in Example 356, pyrrolidine (0.32 ml) and N,N-dimethylformamide (2 ml) was stirred at room temperature for 8 hours. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography [chloroform:methanol (97:3)] to give the title compound (123 mg) as oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:14]([O-:16])=[O:15])=[CH:5][C:6]([CH3:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9].C1C(=O)N([Br:24])C(=O)C1.C(Cl)Cl.O>CC#N.CC(N=NC(C#N)(C)C)(C#N)C>[Br:24][CH2:13][C:6]1[CH:5]=[C:4]([N+:14]([O-:16])=[O:15])[C:3]([O:2][CH3:1])=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1cc(OC)c([N+](=O)[O-])cc1C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CC#N
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1cc(OC)c([N+](=O)[O-])cc1CBr
Temperature: 70 °C
Yield: 31.4 %

Procedure:
A mixture of methyl 5-methoxy-2-methyl-4-nitrobenzoate (1.11 g, 5 mmol) and NBS (1.07 g, 6 mmol) in MeCN (20 mL) was degassed and then AIBN (18 mg, 0.11 mmol) was added. The mixture was heated to 70° C. for 18 h. DCM (50 mL) and water (50 mL) were added and the organic phase was passed through a hydrophobic frit. The solvent was removed in vacuo and purification of the residue via silica gel column chromatography (0-100% EtOAc in iso-hexane) in order to remove baseline impurities gave methyl 2-(bromomethyl)-5-methoxy-4-nitrobenzoate (477 mg, 31%) as an off-white solid. LCMS (10 cm_ESCI_Bicarb_MeCN): [M−Br]−=224 at 3.92 min. 1H NMR (400 MHz, CDCl3): δ 7.92 (s, 1H), 7.66 (s, 1H), 4.88 (s, 2H), 4.02 (s, 3H), 4.00 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH:5]=[C:4]([Cl:18])[N:3]=1.O.[NH2:20][NH2:21]>O1CCCC1>[Cl:18][C:4]1[CH:5]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[N:7]=[C:2]([NH:20][NH2:21])[N:3]=1
Reactant: NN
Reactant: COc1ccc(CNc2cc(Cl)nc(Cl)n2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CNc2cc(Cl)nc(NN)n2)cc1

Procedure:
A 5.57 g portion of 2,6-dichloro-4-(4-methoxybenzyl)aminopyrimidine was suspended in 20 ml of tetrahydrofuran, mixed with 3.0 ml of hydrazine monohydrate and heated under reflux for 24 hours. After evaporation of the solvent under a reduced pressure, water was added to the residue and the resulting precipitate was collected by filtration to obtain 5.06 g of 4-chloro-2-hydrazino-6-(4-methoxybenzyl)aminopyrimidine as a white solid. This was suspended in 150 ml of ethanol and mixed with 3.37 g of ethoxymethyleneacetoacetic acid ethyl ester at room temperature, and the mixture was stirred for 1 hour and then heated under reflux for 15 hours. By concentrating the reaction solution to dryness under a reduced pressure, 7.22 g of the title compound was obtained as a white solid.
Reaction SMILES: CC[O-].[Na+].S(O)(O)(=O)=O.[CH3:10][O:11][C:12]([NH2:14])=[NH:13].C[CH2:16][CH:17]([C:22](OCC)=[O:23])[C:18](OC)=[O:19]>C(O)C>[CH3:10][O:11][C:12]1[N:14]=[C:18]([OH:19])[C:17]([CH3:16])=[C:22]([OH:23])[N:13]=1
Reactant: CCOC(=O)C(CC)C(=O)OC
Reactant: COC(=N)N
Agent: CC[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: COc1nc(O)c(C)c(O)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 72.7 %

Procedure:
13.8 g (200 mmoles) of sodium ethylate is added to a solution of 10 g (58 mmoles) of methoxyformamidine sulphate in 100 ml of ethanol cooled down to 0° C. and the mixture is stirred for 15 minutes; then a solution of 9 ml (52 mmoles) of diethyl methyl malonate in 50 ml of ethanol is added followed by stirring overnight at ambient temperature. The reaction mixture is evaporated to dryness under reduced pressure (2 kPa). The residue is taken up in 100 ml of a saturated solution of sodium chloride and extracted with 800 and 200 ml of n-butanol. The organic phases are dried over sodium sulphate, filtered and evaporated to dryness under reduced pressure (2 kPa). 5.9 g of expected product is obtained in the form of a white solid.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:25][CH2:24][C@@:23]2([CH3:26])[C@H:4]([CH2:5][C@@H:6]([OH:28])[C@@H:7]3[C@@H:22]2[CH2:21][CH2:20][C@@:19]2([CH3:27])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12](C)[CH2:13]CC(O)=O)[CH2:3]1.[OH2:29].[CH3:30]O>>[OH:28][C@@H:6]1[CH2:5][C:4]2[C@:23]([CH3:26])([CH2:24][CH2:25][C:2](=[O:1])[CH:3]=2)[C@@H:22]2[C@@H:7]1[C@H:8]1[C@:19]([CH3:27])([CH2:20][CH2:21]2)[C@@H:11]([C@@H:12]([CH:30]=[O:29])[CH3:13])[CH2:10][CH2:9]1
Reactant: O
Reactant: CO
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Product: C[C@H](C=O)[C@H]1CC[C@H]2[C@@H]3[C@H](O)CC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 24 h
Yield: 32 %

Procedure:
Pseudomonas putida D4014-A357-3A strain was inoculated to a slant medium of Medium 1 (as mentioned above) and cultured at 30° C. for one day. Then, 2 loopfuls of the bacterial cells grown were inoculated to a liquid medium (10 ml) of Medium 3 (as mentioned above) containing 3α,7α-dihydroxy-5β-cholanic acid and subjected to shake culture at 30° C. overnight. The obtained culture broth was inoculated to 100 ml of Medium 3 (as mentioned above) having the same composition in a 500 ml Sakaguchi flask and cultured at 30° C., 200 rps for 48 hr. The total amount of 3α,7α-dihydroxy-5β-cholanic acid subjected to the culture was 1.1 g (2.8 mmol). The obtained culture broth was centrifuged at 5000 rpm for 30 min, and water (100 ml) was added to a mixture of the obtained bacterial cells and the product to allow dispersing. The mixture was again subjected to centrifugation to wash the mixture. Methanol (200 ml) was added to the mixture to dissolve the product, and the mixture was filtered to give a clear methanol solution. Water (30 ml) was added to the methanol solution and methanol was partly evaporated in a rotary evaporator. Then, the resulting concentrate was cooled, and the precipitated solid was collected by filtration and dried to give (20S)-7α-hydroxy-pregn-4-en-3-one-20-carbaldehyde (310 mg, 0.90 mmol, yield 32%) having the following property.
Reaction SMILES: FC1C=CC(Br)=CC=1[O:9]C1C=CC=CC=1.[Mg].C(OCC(F)=C[C:24]1([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH:34](F)F)=[CH:29][CH:28]=2)[CH2:26][CH2:25]1)(=O)C>O1CCCC1>[CH2:34]1[O:33][C:30]2[CH:29]=[CH:28][C:27]([CH:24]3[CH2:25][CH2:26]3)=[CH:32][C:31]=2[O:9]1
Reactant: CC(=O)OCC(F)=CC1(c2ccc(OC(F)F)cc2)CC1
Reactant: Fc1ccc(Br)cc1Oc1ccccc1
Agent: [Mg]
Solvent: C1CCOC1
Product: c1cc2c(cc1C1CC1)OCO2
Yield: 143.3 %

Procedure:
The method of Example 25 was repeated using a Grignard reagent, prepared from 4-fluoro-3-phenoxyphenyl bromide (0.31 g), tetrahydrofuran (2 ml) and magnesium (20 mg) and 1-(3-acetoxy-2-fluoroprop-1-enyl)-1-(4-difluoro-methoxyphenyl)cyclopropane (Example 24) (0.155 g). The residue after evaporation was purified by preparative thin layer chromatography (solvent: diethyl ether/hexane; 1:9) and then preparative high performance liquid chromatography (column: C18; solvent: methanol; flow rate: 8 ml/min) to afford 1-(4-difluoromethoxyphenyl)-3-(4-fluoro-3-phenoxyphenyl)prop-1-enyl)-1-(3,4-methylenedioxyphenyl)cyclopropane (120 mg, 54%).
Reaction SMILES: C(OC(=O)C)(=[O:3])C.C1(N[C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[CH:14][CH:13]=2)CC1.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH:25]1([CH:26]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[CH:14][CH:13]=2)[C:27]([NH2:22])=[O:3])[CH2:23][CH2:24]1
Reactant: c1ccncc1
Reactant: c1ccc2c(NC3CC3)ccnc2c1
Reactant: CC(=O)OC(C)=O
Product: NC(=O)C(c1ccnc2ccccc12)C1CC1
Yield: 98.7 %

Procedure:
Acetic anhydride (18.3 g) was added to a solution of cyclopropyl-quinolin-4-yl-amine (6.6 g) in pyridine (50 ml) and the mixture was heated under reflux over night. After cooling, the solvent was removed under reduce pressure and then the mixture was washed with dichloromethane (200 ml) and an aqueous solution of sodium carbonate (200 ml). The organic layer was separated and dried over sodium sulfate. The solvent was removed under reduce pressure and the crude compound was purified by flash chromatography on silicagel using dichloromethane/methanol (98/2) as eluent to give cyclopropyl-quinolin-4-yl-acetamide (8 g, 98.7% yield).
Reaction SMILES: C([N:4]1[C:12]2[CH:7]([N:8](C(=O)C)[CH2:9][N:10](C(=O)C)[C:11]=2Cl)[N:6]([C@@H:20]2[O:26][C@H:25]([CH2:27][OH:28])[C@@H:23]([OH:24])[C@H:21]2[OH:22])[CH2:5]1)(=O)C.CN([CH:32]1[CH2:37][CH2:36][CH:35]=[CH:34][CH2:33]1)C.[CH2:38]([N:40](CC)[CH2:41]C)C>C(O)CCC>[CH3:38][N:40]([CH2:41][CH:32]1[CH2:37][CH2:36][CH:35]=[CH:34][CH2:33]1)[C:11]1[C:12]2[N:4]=[CH:5][N:6]([C:7]=2[N:8]=[CH:9][N:10]=1)[C@@H:20]1[O:26][C@H:25]([CH2:27][OH:28])[C@@H:23]([OH:24])[C@H:21]1[OH:22]
Reactant: CN(C)C1CC=CCC1
Reactant: CC(=O)N1CN(C(C)=O)C2C(=C1Cl)N(C(C)=O)CN2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: CCN(CC)CC
Solvent: CCCCO
Product: CN(CC1CC=CCC1)c1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reaction time: 16 h

Procedure:
6.2 g. triacetyl-6-chloro-9-(β-D-ribofuranosyl)-purine, 2.5 g. methyl-cyclohex-3-enyl-methylamine and 2.8 ml. triethylamine were left to stand at ambient temperature for 16 hours in 100 ml. butanol. The reaction mixture was then mixed with 150 ml. diethyl ether, extracted twice with water and the organic phase evaporated to dryness in a vacuum. The residue was dissolved in 100 ml. 25% methanolic ammonia and left to stand for a few days at ambient temperature. 3.4 g. (60% of theory) N(6)-methyl-N(6)-cyclohex-3-enyl-methyl-adenosine crystallized out directly from the methanolic solution; m.p. 154°- 156° C.
Reaction SMILES: [CH2:1]([Cl:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1>C(#N)C>[Cl-:8].[CH2:1]([N+:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ccccc1
Reactant: Cc1ccncc1
Solvent: CC#N
Product: Cc1cc[n+](Cc2ccccc2)cc1
Product: [Cl-]
Temperature: 25 °C
Yield: 93.1 %

Procedure:
A solution of 2.53 g of benzyl chloride (20 mmol), 1.86 g of 4-picoline (20 mmol) and 20 mL of acetonitrile was refluxed for three hours, cooled to room temperature and then frozen in refrigerator. Pale pink crystals precipitated from the solution, which were collected by filtration and washed with ether (3×5 mL) to afford 4.09 g of the product (92% yield). 1HNMR (DMSO-d6, 400 MHz): δ 9.1 (s, 2H), 8.0 (d, 2H, J=6.24), 7.5 (s, 2H), 7.4 (m, 3H), 5.8 (s, 2H), 2.6 (s, 3h); 13C NMR (DMSO-d6, 100 MHz): δ 159.0, 143.5, 134.3, 128.9, 128.8, 128.3, 61.9, 21.1.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5](=[O:8])[N:4]([CH2:9][C:10]([OH:12])=[O:11])[N:3]=1>CO.[Pd]>[O:8]=[C:5]1[N:4]([CH2:9][C:10]([OH:12])=[O:11])[N:3]=[CH:2][CH:7]=[CH:6]1
Reactant: O=C(O)Cn1nc(Cl)ccc1=O
Agent: [Pd]
Solvent: CO
Product: O=C(O)Cn1ncccc1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
[3-Chloro-6-oxopyridazin-1(6H)-yl]acetic acid (1.00 g, 5.30 mmol) in methanol (40 mL) was added 100 mg of 10% Pd/C. After the reaction mixture was stirred at ambient temperature under a H2 balloon for 1 h, the Pd was filtered off through celite. The filtrate was concentrated in vacuo and purified by reverse phase HPLC (TMC Pro-Pac C18; 0-40% 0.1% trifluoroacetic acid in acetonitrile/0.1% trifluoroacetic acid in water gradient). Removal of the volatiles in vacuo afforded the title compound as a white crystalline. 1H NMR (D2O): δ 8.06 (dd, J=3.9, 1.4 Hz, 1H), 7.56 (dd, J=9.4, 3.9 Hz, 1H), 7.12 (dd, J=9.4, 1.5 Hz, 1H), 4.95 (s, 2H). LC/MS 155.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].[N+]([C:14]1[O:18][C:17]([CH:19]=[O:20])=[CH:16][CH:15]=1)([O-])=O>CS(C)=O.[Cl-].[Na+].O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:14]2[O:18][C:17]([CH:19]=[O:20])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Reactant: Oc1ccc(F)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=Cc1ccc(Oc2ccc(F)cc2)o1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 97.7 %

Procedure:
To a solution of 4-fluorophenol (2.39 g, 21.3 mmol) in dimethylsulfoxide (20 mL) was added sodium hydride (785 mg, 19.6-23.6 mmol, 60-72% in oil), and the solution was stirred at room temperature for 20 minutes. Next, a solution of 5-nitro-furan-2-carbaldehyde (3 g, 21.3 mmol) in dimethylsulfoxide (10 mL) was added dropwise, the solution was then stirred for 2 hours at room temperature. The reaction mixture was poured into brine, and the mixture was extracted with ethyl acetate. The fractionated organic layer was dried over anhydrous magnesium sulfate, then concentrated, and the title compound (4.3 g, 20.8 mmol, 98%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:26])/[CH:16]=[CH:17]/[C:18]3[CH:23]=[CH:22][C:21]([CH2:24]Cl)=[CH:20][CH:19]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.CO[CH2:29][CH2:30][NH:31]C.[C:33](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:15](=[O:26])/[CH:16]=[CH:17]/[C:18]3[CH:19]=[CH:20][C:21]([CH2:24][NH:31][CH:30]4[CH2:33][CH2:29]4)=[CH:22][CH:23]=3)=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CNCCOC
Reactant: O=C([O-])[O-]
Reactant: O=C(/C=C/c1ccc(CCl)cc1)Nc1ccc(-c2ccc(Cl)cc2)cc1
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(/C=C/c1ccc(CNC2CC2)cc1)Nc1ccc(-c2ccc(Cl)cc2)cc1
Reaction time: 24 h

Procedure:
A reaction mixture of 100 mg (0.26 mmol) of (E)-N-(4′-chlorobiphenyl-4-yl)-3-(4-chloromethylphenyl)acrylamide, 70 mg (0.77 mmol) of 2-methoxyethylmethylamine, and 140 mg (1 mmol) of potassium carbonate in 10 mL of acetone is agitated for 24 hours at reflux temperature. The reaction mixture is evaporated down. The residue is purified by column chromatography on silica gel (eluant: dichloromethane/ethanol/ammonia (20/1/0.1)). Yield: 92 mg (81% of theory); melting point: 222° C.-223° C.; C26H27ClN2O2 (M=434.96); calc.: molecular ion peak (M+H)+: 435/37(Cl); found: molecular ion peak (M+H)+: 435/37(Cl); Rf value: 0.4 (silica gel, dichloromethane/methanol/ammonia (20:1:0.1)).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)=[O:3].[F:18][C:19]([F:26])([F:25])[C:20](OCC)=[O:21].C[O-].[Na+].CO>CCOCC>[CH2:11]([O:10][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH2:1][C:20](=[O:21])[C:19]([F:26])([F:25])[F:18])=[CH:5][CH:6]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)C(F)(F)F
Reactant: CC(=O)c1ccc(OCc2ccccc2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: O=C(CC(=O)C(F)(F)F)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 64.4 h
Yield: 95.3 %

Procedure:
A solution of 4-benzyloxyacetophenone (6.50 g, 29 mmol) in ether (70 mL) was cooled to 0° C. and treated with ethyl trifluoroacetate (4.12 g, 29 mmol) and 25% sodium methoxide in methanol (6.39 g, 30 mmol). The reaction was warmed to room temperature and stirred for 64.4 hours. The reaction was quenched with 3 N HCl (15 mL), extracted with ethyl acetate, washed with brine, dried over anhyd. MgSO4, filtered and concentrated in vacuo to give the title compound as a yellow solid (8.91 g, 96%): mp 92.4-96.5° C. 1H NMR (CDCl3) 15.30 (br s, 1 H), 8.86 (d, 2 H, J=8.9 Hz), 7.43 (m, 5 H), 7.08 (d, 2 H, J=8.9 Hz), 6.50 (s, 1 H) 5.16 (s, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:5]([NH2:6])=[C:4]([F:12])[C:3]=1F.[N:14]1([CH2:20][CH2:21][OH:22])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[Cl:1][C:2]1[C:3]([N:17]2[CH2:18][CH2:19][N:14]([CH2:20][CH2:21][OH:22])[CH2:15][CH2:16]2)=[C:4]([F:12])[C:5]([NH2:6])=[C:7]([N+:9]([O-:11])=[O:10])[CH:8]=1
Reactant: OCCN1CCNCC1
Reactant: Nc1c([N+](=O)[O-])cc(Cl)c(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Nc1c([N+](=O)[O-])cc(Cl)c(N2CCN(CCO)CC2)c1F
Temperature: 50 °C
Yield: 67.3 %

Procedure:
To a solution of 6.79 g of 4-chloro-2,3-difluoro-6-nitroaniline (which was synthesized following WO9856761 or WO9835977) and 4.70 g of 1-piperazine ethanol in 30 ml of dimethylsulfoxide, 9.23 g of potassium carbonate was added, followed by an hour's stirring at 50° C. After cooling the reaction liquid to room temperature, water was added thereto, followed by extraction with chloroform. The chloroform layer was dried on anhydrous magnesium sulfate, the solvent was distilled off and 6.98 g of the title compound in crude form was obtained as a yellow oily substance.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:37]([CH3:38])=[CH:36][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[CH:26]=[C:27]5[C:32](=[CH:33][CH:34]=4)[NH:31][C:30](=[O:35])[CH:29]=[CH:28]5)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[C:46]([O-])([O-])=O.[Cs+].[Cs+].CI>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C@@H:6]([C:12]1[C:37]([CH3:38])=[CH:36][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[CH:26]=[C:27]5[C:32](=[CH:33][CH:34]=4)[N:31]([CH3:46])[C:30](=[O:35])[CH:29]=[CH:28]5)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:39]1[CH:40]=[CH:41][C:42]([Cl:45])=[CH:43][CH:44]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-c4ccc5[nH]c(=O)ccc5c4)c3)sc2c1-c1ccc(Cl)cc1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-c4ccc5c(ccc(=O)n5C)c4)c3)sc2c1-c1ccc(Cl)cc1
Temperature: 80 °C

Procedure:
To a solution of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(2-(2-oxo-1,2-dihydroquinolin-6-yl)pyridin-4-yl)benzo[d]thiazol-6-yl)acetate (13.0 mg, 0.020 mmol) in DMF (0.8 mL) was added Cs2CO3 (13.0 mg, 0.041 mmol) and methyl iodide (3.0 μL, 0.050 mmol). The reaction mixture was heated at 80° C. for 3 h. After cooling, the reaction mixture was diluted with EtOAc, extracted with H2O, brine, dried over Na2SO4, filtered and concentrated and purified by flash column chromatography (silica gel, 0 to 100% ethyl acetate/hexanes) to give the desired product. LCMS-ESI+ (m/z): [M+H]+ calcd for C37H35ClN3O4S: 652.2; found: 652.3.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:10][CH:9]2NC2C3N=NN(C4CC(CO)C(O)C4O)C=3N=C(SCCC(F)(F)F)N=2)=[CH:4][CH:3]=1.[OH2:37].[OH-].[Li+].O.[O:41]1[CH2:45]CCC1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[CH2:10][C@H:9]2[C:45]([OH:41])=[O:37])=[CH:6][CH:7]=1
Reactant: O
Reactant: OCC1CC(n2nnc3c(NC4CC4c4ccc(F)cc4)nc(SCCC(F)(F)F)nc32)C(O)C1O
Reactant: C1CCOC1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)[C@@H]1C[C@H]1c1ccc(F)cc1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
A suspension of the product from step b) (3.74 g) and lithium hydroxide monohydrate (4.11 g) in tetrahydrofuran (100 ml)/ water (3 ml) was stirred at 50° C. for 24 hours. The reaction mixture was concentrated in vacuo, and the residue dissolved in water (100 ml), acidified with 2N HCl and extracted into dichloromethane (3×75 ml). The organics were dried and concentrated. Purification (SiO2, isohexane:diethylether 2:1 as eluant) gave the subtitle compound as a colourless solid (1.78 g).
Reaction SMILES: [SH:1][CH2:2][C:3]([O:5][CH3:6])=[O:4].F[C:8]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:9]=1[CH:10]=O.C(OCC)(=O)C>CC#N.CCCCCC>[F:16][C:13]1[CH:14]=[CH:15][C:8]2[S:1][C:2]([C:3]([O:5][CH3:6])=[O:4])=[CH:10][C:9]=2[CH:12]=1
Reactant: O=Cc1cc(F)ccc1F
Reactant: COC(=O)CS
Solvent: CC#N
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2cc(F)ccc2s1
Yield: 33.8 %

Procedure:
TEA (3.705 g, 36.619 mmol) was added to a solution of methyl 2-mercaptoacetate (3.293 g, 30.985 mmol) in CH3CN (12.5 mL). This was followed by the addition of 2,5-difluorobenzaldehyde (4 g, 28.169 mmol) in CH3CN (12.5 mL) and the resulting reaction mass was refluxed overnight under nitrogen atmosphere. The reaction was monitored by TLC (5% ethyl acetate in hexane). The reaction mass was concentrated under reduced pressure to obtain the crude product. Purification by column chromatography on silica gel (15% ethyl acetate in hexane) afforded 2 g of the product (33.89% yield).
Reaction SMILES: [CH:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([C:15]([OH:17])=O)=[CH:12][CH:13]=2)[CH:8]=[C:7]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=2)[N:6]=1)([CH3:3])[CH3:2].[CH3:25][O:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([C:15]([N:30]3[CH2:31][CH2:32][CH:27]([O:26][CH3:25])[CH2:28][CH2:29]3)=[O:17])=[CH:12][CH:13]=2)[CH:8]=[C:7]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=2)[N:6]=1)([CH3:3])[CH3:2]
Reactant: Cc1cc(Nc2cc3cc(C(=O)O)ccc3c(OC(C)C)n2)n[nH]1
Reactant: COC1CCNCC1
Product: COC1CCN(C(=O)c2ccc3c(OC(C)C)nc(Nc4cc(C)[nH]n4)cc3c2)CC1

Procedure:
Similar procedure as described in example 384 was used, starting from 1-Isopropoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinoline-6-carboxylic acid and 4-Methoxy-piperidine to give [1-Isopropoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-6-yl]-(4-methoxy-piperidin-1-yl)-methanone. LC-MS: m/e 424 (MH+).
Reaction SMILES: IC.[F-].[CH2:4]([N+](CCCC)(CCCC)CCCC)CCC.[C:21]([O:25][C:26](=[O:54])[NH:27][C:28]([C:30]1[S:31][C:32]([S:52][CH3:53])=[C:33]([S:35]([C:38]2[CH:39]=[C:40]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=3[Cl:51])[CH:41]=[C:42]([OH:44])[CH:43]=2)(=[O:37])=[O:36])[CH:34]=1)=[NH:29])([CH3:24])([CH3:23])[CH3:22]>C1COCC1.CCOC(C)=O>[C:21]([O:25][C:26](=[O:54])[NH:27][C:28]([C:30]1[S:31][C:32]([S:52][CH3:53])=[C:33]([S:35]([C:38]2[CH:39]=[C:40]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=3[Cl:51])[CH:41]=[C:42]([O:44][CH3:4])[CH:43]=2)(=[O:36])=[O:37])[CH:34]=1)=[NH:29])([CH3:24])([CH3:23])[CH3:22]
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cc(O)cc(-c2ccccc2Cl)c1
Agent: [F-]
Solvent: CI
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(-c2ccccc2Cl)cc(S(=O)(=O)c2cc(C(=N)NC(=O)OC(C)(C)C)sc2SC)c1
Reaction time: 2 h
Yield: 62.3 %

Procedure:
Iodomethane (3 μL, 0.045 mmol) and tetrabutylammonium fluoride (1M in THF, 14 μL, 0.014 mmol) was added to a solution of {[4-(2′-chloro-5-hydroxy-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester ((Example 19: step b) 5 mg, 0.009 mmol) in THF. After stirring for 2 hours, the solution was diluted with EtOAc (20 mL). The organic layer was washed with water (2×4 mL) and brine (5 mL), and was dried over MgSO4. Removal of the solvent in vacuo followed by purification of the residue (preparative TLC; 30% EtOAc in hexanes) afforded the title compound (3.1 mg, 62%). 1H-NMR (CDCl3): δ 7.84 (s, 1H), 7.64 (t, 1H, J=1.6 Hz), 7.53 (dd, 1H, J=1.6, 2.6 Hz), 7.47 (m, 1H), 7.33 (m, 3H), 7.21 (dd, 1H, J=1.6, 2.6 Hz), 3.89 (s, 3H), 2.60 (s, 3H), 1.52 (s, 9H). ESI-MS (m/z): Calcd. for C13H13BrN2O3S3: 421.4; found: 421.1.