Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1CCOCC1.C([O:10][C:11]1[C:23]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:21]=[C:20]([CH2:28][O:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][C:39]([C:42]([C:47]([O:49][CH2:50][CH:51]=[CH2:52])=[O:48])=[CH:43][N:44]([CH3:46])[CH3:45])=[C:38]([F:53])[CH:37]=3)=[CH:32][CH:31]=2)[C:12]=1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])C=C.O>O1CCCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[OH:10][C:11]1[C:23]([C:24]([F:26])([F:27])[F:25])=[CH:22][CH:21]=[C:20]([CH2:28][O:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][C:39]([C:42]([C:47]([O:49][CH2:50][CH:51]=[CH2:52])=[O:48])=[CH:43][N:44]([CH3:45])[CH3:46])=[C:38]([F:53])[CH:37]=3)=[CH:32][CH:31]=2)[C:12]=1[C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14]
Reactant: C=CCOC(=O)C(=CN(C)C)c1ccc(-c2ccc(OCc3ccc(C(F)(F)F)c(OCC=C)c3C(=O)OC(C)(C)C)cc2)cc1F
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCN1
Solvent: C1CCOC1
Product: C=CCOC(=O)C(=CN(C)C)c1ccc(-c2ccc(OCc3ccc(C(F)(F)F)c(O)c3C(=O)OC(C)(C)C)cc2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.2 %

Procedure:
Morpholine (0.02 ml, 0.23 mmol) and tetrakis(triphenylphosphine)palladium (0) (6 mg, 0.005 mmol) were successively added to a solution of tert-butyl 2-(allyloxy)-6-{[(4′-{1-[(allyloxy)carbonyl]-2-(dimethylamino)vinyl}-3′-fluoro-1,1′-biphenyl-4-yl)oxy]methyl}-3-(trifluoromethyl)benzoate (67 mg, 0.10 mmol) obtained in Example (93-1) in tetrahydrofuran (1 ml), and the mixture was stirred at room temperature for 1 hour. After the reaction mixture was poured into water and the mixture was extracted with ethyl acetate, the organic layer was successively washed with water and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was subjected to silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=10/1-1/>99) to give crude tert-butyl 2-hydroxy-6-{[(4′-{1-[(allyloxy)carbonyl]-2-(dimethylamino)vinyl}-3′-fluoro-1,1′-biphenyl-4-yl)oxy]methyl}-3-(trifluoromethyl)benzoate (42 mg).
Reaction SMILES: [OH:1][C:2]1[CH:23]=[C:22]([I:24])[CH:21]=[CH:20][C:3]=1[C:4](=[O:19])[CH:5]=[CH:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[C:9]([O:17][CH3:18])[CH:8]=1.[OH-:25].[Na+].OO>CO>[OH:25][C:5]1[C:4](=[O:19])[C:3]2[C:2](=[CH:23][C:22]([I:24])=[CH:21][CH:20]=2)[O:1][C:6]=1[C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[C:9]([O:17][CH3:18])[CH:8]=1
Reactant: COc1cc(C=CC(=O)c2ccc(I)cc2O)cc(OC)c1OC
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: CO
Product: COc1cc(-c2oc3cc(I)ccc3c(=O)c2O)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 24 h

Procedure:
To a stirring solution of 32 (0.165 g, 0.4 mmol) in methanol (4.4 ml) and 16% aqueous sodium hydroxide solution (0.6 ml, 2.4 mmol, 6.4 egu) at 0° C. was added 15% aqueous hydrogen peroxide (0.6 ml, 2.6 mmol, 7.1 equ) dropwise. The solution was stirred at 0° C. for ten minutes then sealed and placed in a refrigerator for 24 hours. The reaction was then filtered and then collected solid separated between 1N HCl and dichloromethane. The organic layer was then dried (MgSO4) and concentrated to give 3-hydroxy-7-iodo-2-(3,4,5-trimethoxyphenyl)-chromen-4-one as a yellow solid. Meanwhile filtrate was acidified (1N HCl) and the precipitated solid, 3-hydroxy-7-iodo-2-(3,4,5-trimethoxyphenyl)-chromen-4-one, collected. (Total yield 0.130 g, 76%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[C:9](B2OC(C)(C)C(C)(C)O2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].COCCOC.Br[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([N:37]2[CH:41]=[CH:40][CH:39]=[N:38]2)=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C(OCC)(=O)C.O>[N:37]1([C:34]2[CH:35]=[CH:36][C:31]([CH2:30][C:9]3[C:10]([O:12][CH3:13])=[CH:11][C:2]([OH:1])=[C:3]([CH:8]=3)[C:4]([O:6][CH3:7])=[O:5])=[CH:32][CH:33]=2)[CH:41]=[CH:40][CH:39]=[N:38]1
Reactant: BrCc1ccc(-n2cccn2)cc1
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(OC)cc1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1cc(Cc2ccc(-n3cccn3)cc2)c(OC)cc1O
Temperature: 80 °C
Reaction time: 8 h
Yield: 54.6 %

Procedure:
To a solution of methyl 2-hydroxy-4-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (0.80 g) in a mixed solvent of DME (12.0 mL)-water (4.00 mL) were added 1-(4-(bromomethyl)phenyl)-1H-pyrazole (0.62 g), tetrakis(triphenylphosphine)palladium(0) (0.15 g) and sodium carbonate (0.55 g), and the mixture was stirred overnight at 80° C. under argon atmosphere. The reaction mixture was allowed to be cooled to room temperature, water and ethyl acetate were added thereto, and the mixture was partitioned. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.48 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([N:9]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][P:23]([O:28][CH2:29][CH3:30])([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][CH:17]=2)[C:10](=[O:14])OCC)[CH:5]=[C:4]([O:31][CH2:32][CH2:33][O:34][CH3:35])[N:3]=1>CC(O)=O>[NH2:1][C:2]1[C:7]2[NH:8][C:10](=[O:14])[N:9]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][P:23](=[O:24])([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27])=[CH:18][CH:17]=3)[C:6]=2[CH:5]=[C:4]([O:31][CH2:32][CH2:33][O:34][CH3:35])[N:3]=1
Reactant: CCOC(=O)N(Cc1ccc(CP(=O)(OCC)OCC)cc1)c1cc(OCCOC)nc(N)c1N
Solvent: CC(=O)O
Product: CCOP(=O)(Cc1ccc(Cn2c(=O)[nH]c3c(N)nc(OCCOC)cc32)cc1)OCC
Yield: 63 %

Procedure:
A solution of ethyl (2,3-diamino-6-(2-methoxyethoxy)pyridin-4-yl)(4-((diethoxyphosphoryl)methyl)benzyl)carbamate (1 equiv.) in AcOH (0.15 M) was heated in a microwave at 100° C. for 5 min. At this point the volatiles were removed in vacuo. The resulting residue was purified by a COMBIFLASH™ system using a gradient of 0-10% MeOH/DCM to provide the title compound (63% over two steps) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([NH2:11])=[S:10].Br[CH2:13][C:14]([C:16]1[CH:25]=[CH:24][C:23]2[NH:22][C:21](=[O:26])[C:20]3[NH:27][CH:28]=[CH:29][C:19]=3[C:18]=2[CH:17]=1)=O.[CH2:30]([C:32]([O-:34])=[O:33])[CH3:31]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[S:10][CH:13]=[C:14]([C:16]2[CH:25]=[CH:24][C:23]3[NH:22][C:21](=[O:26])[C:20]4[NH:27][CH:28]=[CH:29][C:19]=4[C:18]=3[CH:17]=2)[N:11]=1.[CH2:30]([C:32]([O-:34])=[O:33])[CH3:31]
Reactant: NC(=S)Nc1ccccc1Cl
Reactant: O=C(CBr)c1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Agent: CCC(=O)[O-]
Solvent: CCO
Product: O=c1[nH]c2ccc(-c3csc(Nc4ccccc4Cl)n3)cc2c2cc[nH]c12
Temperature: 90 °C
Reaction time: 6 h
Yield: 26.7 %

Procedure:
74 mg (1.2 mmol) of (2-chlorophenyl)-thiourea is added to a suspension of 124 mg (0.33 mmol) of 8-(2-bromo-acetyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in 3.5 mL of ethanol. The mixture is stirred at 90° C. for 6 hours then the mixture is cooled to room temperature. The solvent is evaporated, then the product is purified by preparative LCMS. After drying, 41 mg (27%) of 8-[2-(2-chlorophenylamino)-thiazol-4-yl]-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate is obtained in the form of a beige solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH2:16])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1.[CH3:24][N:25]1[C:29]([C:30]([F:33])([F:32])[F:31])=[C:28]([C:34](O)=[O:35])[CH:27]=[N:26]1>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH:16][C:34]([C:28]3[CH:27]=[N:26][N:25]([CH3:24])[C:29]=3[C:30]([F:33])([F:31])[F:32])=[O:35])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1
Reactant: Cn1ncc(C(=O)O)c1C(F)(F)F
Reactant: NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1nc(N)sc1-c1cccc(F)c1
Product: Cn1ncc(C(=O)NC[C@@H]2C[C@@H]3C[C@@H]3N2C(=O)c2nc(N)sc2-c2cccc(F)c2)c1C(F)(F)F

Procedure:
prepared by reaction of [2-amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl)-methanone with 1-methyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid. LC-MS (basic): tR=0.79 min; [M+H]+=509.2.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH:27]([CH3:28])[C:26](=[O:29])[NH:25][C:24]4=[O:30])=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH3:31]I>>[CH3:1][C:2]1[C:3]([N:9]2[CH2:10][CH2:11][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH:27]([CH3:28])[C:26](=[O:29])[N:25]([CH3:31])[C:24]4=[O:30])=[CH:19][CH:18]=3)=[O:16])[CH2:13][CH2:14]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)NC(=O)C4C)cc3)CC2)c(C)c1
Reactant: CI
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)N(C)C(=O)C4C)cc3)CC2)c(C)c1

Procedure:
Using 1-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}-5-methylimidazolidine-2,4-dione (50 mg) described in Example 450 and methyl iodide (9.2 μL) and by the reaction and treatment in the same manner as in Example 36, the title compound (26 mg) was obtained.
Reaction SMILES: [F:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(C(Cl)=O)=O.[NH2:25][C:26]1[C:27]([F:34])=[C:28]([OH:33])[CH:29]=[CH:30][C:31]=1[F:32].C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C=O)C.C1COCC1>[F:34][C:27]1[C:28]([OH:33])=[CH:29][CH:30]=[C:31]([F:32])[C:26]=1[NH:25][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[CH:9]=[C:10]([CH3:11])[C:2]=1[F:1]
Reactant: Nc1c(F)ccc(O)c1F
Reactant: Cc1cc(-c2cccc(F)c2)cc(C(=O)O)c1F
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1cc(-c2cccc(F)c2)cc(C(=O)Nc2c(F)ccc(O)c2F)c1F
Temperature: 0 °C
Reaction time: 2 h
Yield: 42.6 %

Procedure:
To a solution of 2-fluoro-5-(3-fluorophenyl)-3-methyl-benzoic acid (558 mg, 2.25 mmol, 1.0 eq) in DCM (30 mL) at 0° C. was added (COCl)2 (856 mg, 0.57 mL, 6.74 mmol, 3 eq) and DMF (2 drops). The reaction was stirred at 0° C. for 2 h then the solvent was removed in vacuo. The residue was taken up in THF (30 mL) and added to a suspension of 3-amino-2,4-difluorophenol (intermediate X(a)) (330 mg, 2.36 mmol, 1.05 eq) and NaHCO3 (566 mg, 6.74 mmol, 3.0 eq) in THF (30 mL) at 0° C. The reaction was stirred for 3 h at 0° C. then quenched by addition of 1 M HCl and the aqueous layer extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The crude residue was purified by chromatography (MeOH:DCM, 0:1 to 1:50) to give the title compound as a solid (360 mg, 43%).
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([C:8]1[C:12]([CH:13]2[CH2:15][CH2:14]2)=[CH:11][N:10]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=[CH:18][CH:17]=2)[CH:9]=1)(O)=[O:6]>C(Cl)(Cl)Cl>[Cl:3][C:5]([C:8]1[C:12]([CH:13]2[CH2:15][CH2:14]2)=[CH:11][N:10]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=[CH:18][CH:17]=2)[CH:9]=1)=[O:6]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cn(-c2ccnc3ccccc23)cc1C1CC1
Solvent: ClC(Cl)Cl
Product: O=C(Cl)c1cn(-c2ccnc3ccccc23)cc1C1CC1
Reaction time: 1 h
Yield: 100 %

Procedure:
10 mL (137 mmol) of sulphinyl chloride are added to 1.05 g (3.78 mmol) of 3-carboxy-4-cyclopropyl-1-(quinolin-4-yl)-1H-pyrrole dissolved in 20 mL of chloroform at a temperature in the region of 20° C. under an argon atmosphere. After stirring for one hour at the reflux temperature of the solvent, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa). The residue is dissolved in 20 mL of chloroform and then concentrated to dryness again, giving 1.12 g (3.78 mmol) of 3-chlorocarbonyl-4-cyclopropyl-1-(quinolin-4-yl)-1H-pyrrole in the form of a yellow solid, which is used directly in the following step.
Reaction SMILES: [Si:1]([O:18][CH2:19][C@H:20]1[C@@H:24]([OH:25])[CH:23]=[CH:22][CH2:21]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl>[Si:1]([O:18][CH2:19][C@H:20]1[C:24](=[O:25])[CH:23]=[CH:22][CH2:21]1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](OC[C@@H]1CC=C[C@@H]1O)(c1ccccc1)c1ccccc1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C)[Si](OC[C@@H]1CC=CC1=O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
(1S,5S)-5-({[tert-Butyl(diphenyl)silyl]oxy}methyl)cyclopent-2-en-1-ol (460. mg, 1.30 mmol) was dissolved in DCM (15.0 mL) and pyridinium dichromate (1.47 g, 3.91 mmol) was added. The mixture was stirred at rt overnight, at which point LC/MS indicated complete conversion. The mixture was diluted with DCM (15.0 mL), filtered and concentrated in vacuo. Silica gel chromatography eluting with 0 to 50% EtOAc in hexanes afforded the title compound (400. mg, 79%). LC/MS: Rt=2.42 min, ES+ 351 (AA standard).
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[NH:15]([C:22]1[CH:30]=[C:29]([C:31](O)=[O:32])[C:28]([NH:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:27][C:23]=1[C:24](O)=[O:25])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.ClC1C=C(C=CC=1)NC1C=C(C(O)=O)C(NC2C=CC=C(Cl)C=2)=CC=1C(O)=O>>[CH:38]1[CH:39]=[C:40]2[C:31]([C:29]3[C:28]([NH:34][C:35]2=[CH:36][CH:37]=1)=[CH:27][C:23]1[C:24]([C:21]2[C:16]([NH:15][C:22]=1[CH:30]=3)=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:25])=[O:32]
Reactant: O=C(O)c1cc(Nc2ccccc2)c(C(=O)O)cc1Nc1ccccc1
Agent: O=C(O)c1cc(Nc2cccc(Cl)c2)c(C(=O)O)cc1Nc1cccc(Cl)c1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: O=c1c2ccccc2[nH]c2cc3c(=O)c4ccccc4[nH]c3cc12
Temperature: 85 °C

Procedure:
385 parts of polyphosphoric acid, containing 85.0% P2O5, are introduced into a pressure vessel. Then 69.3 parts of 2,5-dianilinoterephthalic acid and 7.7 parts of 2,5-di(3-chloro-anilino)terephthalic acid are introduced with stirring at from 80 to 90° C. and the mixture is heated at 125° C. for 1 hour during which ring closure takes place to form the quinacridone. The reaction mixture is then introduced into a second pressure vessel where it is hydrolyzed under pressure and with stirring with a mixture of 1733 parts of water at 140° C. During this hydrolysis the temperature rises to 160° C. The mixture is stirred at 160° C. for 0.5 hour. Then it is cooled to 60° C. and the mixed crystal pigment is filtered off with suction, washed to neutrality with water and dried at 80° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:30])[C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C@@H:14]([CH3:31])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:39][CH2:40][CH2:41][N:42]1[CH2:46][CH2:45][CH2:44][CH2:43]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:30])[C:23]3[CH:24]=[CH:25][C:26]([O:29][CH2:39][CH2:40][CH2:41][N:42]4[CH2:46][CH2:45][CH2:44][CH2:43]4)=[CH:27][CH:28]=3)[C@@H:14]([CH3:31])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:6][CH:7]=1
Reactant: BrCCCN1CCCC1
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(O)cc2)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCCCN3CCCC3)cc2)c2ccccc21
Temperature: 80 °C
Yield: 8 %

Procedure:
(2S,4R)-N-(4-Chloro-phenyl)-N-[1-(4-hydroxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-acetamide (0.1 g, 0.23 mmol) was dissolved in DMF (5 mL) at room temperature. K2CO3 (0.317 g, 2.3 mmol) was added. 1-(3-Bromo-propyl)-pyrrolidine (0.177 g, 0.92 mmol) was added and the reaction was allowed to heat to 80° C. overnight. The reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and water, then extracted three times with ethyl acetate, dried over MgSO4, filtered and concentrated down. The crude residue was purified by silica gel chromatography (10% methanol/90% dichloromethane) to afford the product (0.01 g, 8%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=13)[N:7]([CH2:15][CH2:16][NH:17][C:18](=O)[CH3:19])[CH:6]=[CH:5]2.P(Cl)(Cl)(Cl)=O.[OH-].[Na+].[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32]>C(O)C.C(OCC)C>[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32].[CH3:1][C:2]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8]2[N:7]3[CH2:15][CH2:16][N:17]=[C:18]([CH3:19])[C:6]3=[CH:5][C:4]=2[CH:3]=1
Reactant: CC(=O)NCCn1ccc2cc(C)c3ccccc3c21
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Solvent: O=P(Cl)(Cl)Cl
Product: CC1=NCCn2c1cc1cc(C)c3ccccc3c12
Temperature: 100 °C
Yield: 17 %

Procedure:
N-[2-(5-Methyl-1H-benzo[g]indol-1-yl)ethyl]acetamide (0.3 g) was treated with 3 ml of phosphorous oxychloride under argon and the mixture was heated to 100° C. for 30 minutes. The cooled mixture was added to 250 g of ice-water and treated with 30 ml of 28% sodium hydroxide solution. The mixture was extracted once with 100 ml of methylene chloride and twice with 50 ml of methylene chloride each time, the organic phases were combined, dried with MgSO4 and freed from solvent. The residue, 0.14 g of brown oil, was chromatographed on 10 g of aluminium oxide (neutral, III) with methylene chloride as the eluent. The crude product, 90 mg of yellow-brown, amorphous solid was dissolved in 1 ml of ethanol and 3 ml of diethyl ether and treated with 1.1 equivalents of a saturated solution of fumaric acid in ethanol. There were obtained 58 mg (17%) of 10,11-dihydro-5,8-dimethylbenzo[g] pyrazino[1,2-a]indole fumarate (2:1); m.pt.: 184°-186° C. (dec.).
Reaction SMILES: C(OC([N:8]1[C:12]2[N:13]=[CH:14][N:15]=[C:16]([N:17]3[CH2:24][C:21]4([CH2:23][CH2:22]4)[N:20]([S:25](=[O:37])(=[O:36])[NH:26][CH2:27][CH2:28][O:29]C4CCCCO4)[CH2:19][CH2:18]3)[C:11]=2[CH:10]=[CH:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>>[OH:29][CH2:28][CH2:27][NH:26][S:25]([N:20]1[CH2:19][CH2:18][N:17]([C:16]2[C:11]3[CH:10]=[CH:9][NH:8][C:12]=3[N:13]=[CH:14][N:15]=2)[CH2:24][C:21]21[CH2:23][CH2:22]2)(=[O:37])=[O:36]
Reactant: CC(C)(C)OC(=O)n1ccc2c(N3CCN(S(=O)(=O)NCCOC4CCCCO4)C4(CC4)C3)ncnc21
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(NCCO)N1CCN(c2ncnc3[nH]ccc23)CC12CC2

Procedure:
4-{4-[2-(Tetrahydro-pyran-2-yloxy)-ethylsulfamoyl]-4,7-diaza-spiro[2.5]oct-7-yl}-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid tert-butyl ester (intermediate 16) was treated with TFA (1 mL) at rt for 1 h. The crude reaction mixture was concentrated in vacuo and redissolved in DMSO (0.5 mL). The pure compound was obtained by standard preparative HPLC purification of the reaction mixture.
Reaction SMILES: [N:1]1([C:6]2[N:11]=[C:10]([CH2:12][OH:13])[CH:9]=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1>ClCCCl.O=[Mn]=O>[N:1]1([C:6]2[N:11]=[C:10]([CH:12]=[O:13])[CH:9]=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: OCc1cccc(-n2cccn2)n1
Agent: O=[Mn]=O
Solvent: ClCCCl
Product: O=Cc1cccc(-n2cccn2)n1
Temperature: 25 °C

Procedure:
A solution of (6-(1H-pyrazol-1-yl)pyridin-2-yl)methanol (295 mg; 1.68 mmol) in anh. DCE (6 ml) was treated with MnO2 (1.174 g; 13.51 mmol), and the resulting mixture was stirred at reflux, under nitrogen, for 2 h. After cooling to rt, the resulting reaction mixture was filtered over celite, and the separated solids were washed with DCM. The filtrate was concentrated to dryness under reduced pressure giving 6-(1H-pyrazol-1-yl)picolinaldehyde as an off-white solid. LC-MS (conditions C): tR=0.74 min.; [M+H]+: 173.88 g/mol.
Reaction SMILES: N.[H][H].[CH3:4][CH:5]1[CH:10]([CH3:11])[CH2:9][CH:8]=[C:7]([CH3:12])[C:6]1=[O:13].C[N:15]1CCCCC1>[Pd].[Zn]>[CH3:4][CH:5]1[CH:10]([CH3:11])[CH2:9][CH:8]=[C:7]([CH3:12])[C:6]1=[O:13].[CH3:4][C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]([CH3:12])[C:6]=1[NH2:15]
Reactant: [H][H]
Reactant: CN1CCCCC1
Agent: [Pd]
Agent: CC1=CCC(C)C(C)C1=O
Agent: N
Product: Cc1ccc(C)c(N)c1C

Procedure:
1,000 parts by volume of catalyst are introduced into a fluidised bed reactor, having a capacity of 1.3 liters or 1,300 parts by volume. The catalyst consists of 0.5% by weight of Pd, 0.11% by weight of Zn and 0.1% by weight of Cd on Al2O3 and has a particle size of from 0.2 to 0.6 mm. The reactor is set to 230° C. and, per hour, a correspondingly preheated mixture of 200,000 parts by volume of ammonia and 10,000 parts by volume of hydrogen is passed in. Per hour, a solution of 50 parts of 2,3,6-trimethylcyclohex-5-en-1-one in 50 parts of N-methylpiperidine is sprayed continuously into the fluidised catalyst bed produced by the gas stream. The reaction product is isolated by cooling the exit gases, and is distilled. 100 parts of 2,3,6-trimethyl-cyclohex-5-en-1-one give 89 parts of 2,3,6-trimethylaniline; yield: 91%.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]([CH3:18])[N:16]=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)(=O)=O.[N:21]1[CH:26]=[CH:25][CH:24]=[C:23](B(O)O)[CH:22]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.C(O)C>[CH3:18][N:17]1[C:13]([C:10]2[CH:11]=[CH:12][C:7]([C:23]3[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=3)=[CH:8][CH:9]=2)=[CH:14][CH:15]=[N:16]1
Reactant: Cn1nccc1-c1ccc(OS(=O)(=O)C(F)(F)F)cc1
Reactant: OB(O)c1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nccc1-c1ccc(-c2cccnc2)cc1
Yield: 143.2 %

Procedure:
A mixture of 4-(1-methyl-1H-pyrazol-5-yl)phenyl trifluoromethanesulfonate (200 mg), 3-pyridylboronic acid (88 mg), bis(triphenylphosphine)palladium(II) dichloride (14 mg), potassium carbonate (135 mg), dimethylformamide (1.4 mL) and ethanol (0.70 mL) was reacted in a microwave reactor (80° C., 25 minutes). Thereafter, water was added to the reaction solution, and the obtained mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated saline, and was then dried over anhydrous magnesium sulfate, followed by vacuum concentration, so as to obtain the title compound (220 mg) in the form of a light yellow oily substance.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[Br:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1.Cl.O1CCOCC1>C(O)CCC>[Br:12][C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:2]2[S:3][C:4]3[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:5]=3[N:6]=2)=[CH:15][CH:14]=1
Reactant: Nc1ccc(Br)cc1
Reactant: Clc1ccc2nc(Cl)sc2c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCCCO
Product: Clc1ccc2nc(Nc3ccc(Br)cc3)sc2c1
Temperature: 65 °C

Procedure:
A mixture of 2,6-dichlorobenzothiazole (0.71 g, 3.5 mmol) and 4-bromoaniline (0.61 g, 3.5 mmol) in n-butanol (6 mL) was heated at 60-70° C. under nitrogen to obtain a solution, to which 4 M HCl in dioxane (0.43 mL, 1.73 mmol) was then slowly added dropwise. The reaction mixture was then heated at 90° C. for 18 h. Upon cooling to rt, the reaction mixture was concentrated under reduced pressure. The resulting solid was triturated with ethanol and collected by filtration. This yielded 1.09 g (93%) of the title compound. LC/MS m/z 339 (MH+); retention time 3.98 min. 1H NMR (CD3OD) δ 7.31 (d, 1H), 7.42-7.58 (m, 5H), 7.61 (d, 1H).