Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([NH:12][C:13](=[O:44])[O:14][CH2:15][C@@H:16]([N:30]([CH3:43])[C:31]([NH:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[C:36]=1[Cl:42])=[O:32])[CH2:17][NH:18][C:19](=[O:29])[CH2:20][NH:21]C(OC(C)(C)C)=O)=[CH:5]2.C(O)(C(F)(F)F)=O.Cl>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([NH:12][C:13](=[O:44])[O:14][CH2:15][C@@H:16]([N:30]([CH3:43])[C:31]([NH:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[C:36]=1[Cl:42])=[O:32])[CH2:17][NH:18][C:19](=[O:29])[CH2:20][NH2:21])=[CH:5]2
Reactant: CN(C(=O)NCc1cccc(F)c1Cl)[C@@H](CNC(=O)CNC(=O)OC(C)(C)C)COC(=O)Nc1cc2cc(F)ccc2cn1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C(=O)NCc1cccc(F)c1Cl)[C@@H](CNC(=O)CN)COC(=O)Nc1cc2cc(F)ccc2cn1
Reaction time: 1 h
Yield: 99.6 %

Procedure:
To a solution of (S)-3-(2-tert-butoxycarbonylaminoacetamido)-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)propyl 6-fluoroisoquinolin-3-ylcarbamate (0.87 g, 1.37 mmol) in DCM (30.0 mL) was added TFA (3.0 mL). The mixture was stirred for 1 h. The mixture was concentrated and dissolved in EtOAc. The EtOAc solution was washed with Na2CO3, brine, dried over Na2SO4, and filtered. To the filtrate was added HCl (4 M in dioxane, 0.7 mL, 2.8 mmol,). The organic solvent was removed under reduced pressure to give (S)-3-(2-aminoacetamido)-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)propyl 6-fluoroisoquinolin-3-ylcarbamate (730 mg, 93%) as a HCl salt. LRMS (M+H+) m/z 535.2.
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1C(C2C=CC=CC=2)=CSC=1[C:35](OC)=[O:36].C(OCC)(OCC)OCC.COC1C(N)=CC=CC=1>C(O)(=O)C>[CH3:35][O:36][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[N:7]1[C:12](=[O:13])[C:11]2[S:14][CH:15]=[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:10]=2[N:9]=[CH:8]1
Reactant: COC(=O)c1scc(-c2ccccc2)c1N
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Solvent: CC(=O)O
Solvent: COc1ccccc1N
Solvent: CCOC(OCC)OCC
Product: COc1ccccc1-n1cnc2c(-c3ccccc3)csc2c1=O
Yield: 71 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (200 mg, 0.86 mmol), triethyl orthoformate (2 ml), o-anisidine (201 mg, 1.63 mmol), and acetic acid (0.2 ml) were used to give 204 mg (0.61 mmol, 71% yield) of the title compound.
Reaction SMILES: [S:1]1[C:5]([C:6]([NH2:8])=O)=[CH:4][CH:3]2[S:9][CH:10]=[CH:11][CH:2]12.O=P(Cl)(Cl)Cl>ClCCl>[S:1]1[C:5]([C:6]#[N:8])=[CH:4][CH:3]2[S:9][CH:10]=[CH:11][CH:2]12
Reactant: NC(=O)C1=CC2SC=CC2S1
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: N#CC1=CC2SC=CC2S1
Yield: 67 %

Procedure:
3a,6a-Dihydro-thieno[3,2-b]thiophene-2-carboxylic acid amide 2 (4.0 g, 21.6 mmol) was mixed with 50 mL of POCl3 and the mixture was heated to reflux for 2 hours before POCl3 was removed with a rotary evaporator. Dichloromethane (100 mL) was added and then 100 mL of ice water was added dropwise. The organic layer was further washed with water (30 mL) twice before the solvent was removed. The brown oil obtained was passed through a short column of silica gel with dichloromethane as eluent. After removal of the solvent, a yellow oil was obtained (2.4 g, yield 67%). 1H NMR (CDCl3, 500 MHz): δ 7.80 (s, 1H), 7.72 (d, 1H, J=5.0), 7.30 (d, 1H, J=5.0); 13C NMR (CDCl3, 500 MHz): δ 143.39, 138.27, 133.52, 129.72, 119.38, 114.60, 110.27.
Reaction SMILES: CC([O-])(CC)C.[Na+].Cl[C:9]1[N:14]=[C:13]2[O:15][C:16]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[C:17]([C:18](=[O:21])[NH:19][CH3:20])[C:12]2=[CH:11][C:10]=1[C:29]1[CH:30]=[CH:31][C:32]([O:38][CH3:39])=[C:33]([CH:37]=1)[C:34]([OH:36])=[O:35].[F:40][C:41]([F:45])([F:44])[CH2:42][NH2:43]>>[F:28][C:25]1[CH:26]=[CH:27][C:22]([C:16]2[O:15][C:13]3=[N:14][C:9]([NH:43][CH2:42][C:41]([F:45])([F:44])[F:40])=[C:10]([C:29]4[CH:30]=[CH:31][C:32]([O:38][CH3:39])=[C:33]([CH:37]=4)[C:34]([OH:36])=[O:35])[CH:11]=[C:12]3[C:17]=2[C:18](=[O:21])[NH:19][CH3:20])=[CH:23][CH:24]=1
Reactant: NCC(F)(F)F
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc(Cl)c(-c3ccc(OC)c(C(=O)O)c3)cc12
Agent: CCC(C)(C)[O-]
Agent: [Na+]
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc(NCC(F)(F)F)c(-c3ccc(OC)c(C(=O)O)c3)cc12
Temperature: 90 °C
Reaction time: 1 h
Yield: 13.1 %

Procedure:
Sodium 2-methylbutan-2-olate (333 mg, 3.02 mmol), 5-(6-chloro-2-(4-fluorophenyl)-3-(methylcarbamoyl)furo[2,3-b]pyridin-5-yl)-2-methoxybenzoic acid (275 mg, 0.605 mmol), 2,2,2-trifluoroethanamine (299 mg, 3.02 mmol), Chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2′-4′-6′-tri-1-propyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl]palladium(II) (48 mg, 0.060 mmol) were combined, degassed, and taken up in dioxane (12 ml) at rt and then was heated to 90° C. The reaction was allowed to stir for 1 h. The mixture was then diluted with EtOAc and washed with 1M HCl aq, and sat NaCl aq. The organic phase was concentrated the resulting residue was purified by preparative reverse phase HPLC on a C18 column using a suitably buffered H2O/CH3CN gradient, and concentrated to give the expected product 5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-((2,2,2-trifluoroethyl)amino)furo[2,3-b]pyridin-5-yl)-2-methoxybenzoic acid (41 mg, 0.079 mmol, 13% yield) consistent by LCMS. LC-MS retention time: 1.87 min; m/z (MH+): 518. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 3u C18 2.0×30 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 1 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% MeOH/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% MeOH/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: CO[CH:3]1[CH:7]([CH:8]=[O:9])[CH2:6][CH:5](OC)O1.[C:12]([NH:15][CH2:16][CH2:17][NH2:18])(=[O:14])[CH3:13].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>>[C:12]([NH:15][CH2:16][CH2:17][N:18]1[CH:5]=[CH:6][C:7]([CH:8]=[O:9])=[CH:3]1)(=[O:14])[CH3:13]
Reactant: CC(=O)NCCN
Reactant: COC1CC(C=O)C(OC)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(=O)NCCn1ccc(C=O)c1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
8.5 g (0.053 mol) of 2,5-dimethoxytetrahydrofuran-3-aldehyde and 5.4 g (0.053 mol) of 2-(acetylamino)-ethylamine are stirred at 60° C. for 1 hour. After addition of 0.05 g of p-toluenesulphonic acid hydrate, the mixture is stirred at 80° C. for 90 minutes and cooled, sodium bicarbonate solution is added and the mixture is extracted with methylene chloride and then with pentanol. The organic phases are concentrated and chromatographed over a silica gel column with methylene chloride/methanol =95:5 as the mobile phase. The product isolated is crystallized from ethyl acetate/ligroin.
Reaction SMILES: FC1C=CC=CC=1C1C2C=C([N+]([O-])=O)C=CC=2N(C)C(=O)C(C)(C)N=1.[Cl:26][C:27]1[C:37]2[N:36](C)[C:35](=[O:39])[C:34]([CH3:41])([CH3:40])[N:33]=[C:32]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[F:48])[C:31]=2[CH:30]=[C:29]([N+:49]([O-:51])=[O:50])[CH:28]=1>C(O)(C)C.C(Cl)Cl>[Cl:26][C:27]1[C:37]2[NH:36][C:35](=[O:39])[C:34]([CH3:41])([CH3:40])[N:33]=[C:32]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[F:48])[C:31]=2[CH:30]=[C:29]([N+:49]([O-:51])=[O:50])[CH:28]=1
Reactant: CN1C(=O)C(C)(C)N=C(c2ccccc2F)c2cc([N+](=O)[O-])cc(Cl)c21
Agent: CN1C(=O)C(C)(C)N=C(c2ccccc2F)c2cc([N+](=O)[O-])ccc21
Solvent: CC(C)O
Solvent: ClCCl
Product: CC1(C)N=C(c2ccccc2F)c2cc([N+](=O)[O-])cc(Cl)c2NC1=O

Procedure:
From 120 g (0.33 mol) of 9-chloro-5-(o-fluorophenyl)-1,3-dihydro-3,3-dimethyl-7-nitro-2H-1,4-benzodiazepin-2-one there is obtained, in analogy to the details in paragraph (c) of Example 1, 9-chloro-5-(o-fluorophenyl)-1,3-dihydro-1,3,3-trimethyl-7-nitro-2H-1,4-benzodiazepin-2-one of melting point 146°-147° (isopropanol/methylene chloride).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][N:3]=1.Cl[CH2:13][C:14](=O)[CH3:15].[OH-].[Na+]>CO>[CH3:15][C:14]1[N:1]=[C:2]2[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][N:3]2[CH:13]=1
Reactant: CC(=O)CCl
Reactant: COC(=O)c1ccnc(N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1ccn2cc(C)nc2c1

Procedure:
A mixture of 15 parts of methyl 2-amino-4-pyridinecarboxylate, 13.75 parts of 1-chloro-2-propanone and 160 parts of absolute methanol was stirred and refluxed for 18 hours. The reaction mixture was treated with a sodium hydroxide solution 1N in methanol. The solvent was evaporated in vacuo and the residue was dissolved in trichloromethane. The solution was filtered and the filtrate was evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 4-methyl-2-pentanone. The product was filtered off, washed with 2,2'-oxybispropane and dried, yielding 9.7 parts of methyl 2-methylimidazo[1,2-a]pyridine-7-carboxylate; mp. 149.1° C. (intermediate 12).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)=[C:7]2[CH3:19].Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27]>CN(C)C=O>[CH3:29][O:28][C:26]([CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][N:9]1[C:10]2[C:6](=[CH:5][C:4]([Cl:3])=[CH:12][CH:11]=2)[C:7]([CH3:19])=[C:8]1[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)=[O:27]
Reactant: Cc1c(-c2cccnc2)[nH]c2ccc(Cl)cc12
Reactant: COC(=O)CCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCCCCn1c(-c2cccnc2)c(C)c2cc(Cl)ccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 1.39 g of a 50% sodium hydride suspension in mineral oil dissolved in 30 ml of dimethylformamide was added under nitrogen at 0°-5° dropwise while stirring a solution of 6.59 g of 5-chloro-3-methyl-2-(3-pyridyl)indole (prepared as described in U.S. Pat. No. 3,468,894) in 60 ml of dimethylformamide. After addition was complete the suspension was stirred at 0° for 1/2 hour. While maintaining the temperature at 0° a solution of 6.06 g of methyl 6-bromohexanoate in 10 ml of dimethylformamide was added dropwise. The reaction mixture was allowed to reach room temperature and was stirred at room temperature for 5 hours, and poured into 400 ml of ice water. The resulting mixture was extracted with ethyl acetate (3×300 ml). The ethyl acetate extract was washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated to dryness to give 1-(5-methoxycarbonylpentyl)-5-chloro-3-methyl-2-(3-pyridyl)indole as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:26])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:14]([F:25])[CH:13]=3)[O:11][C:6]=2[C:5]([F:27])=[C:4]([CH3:28])[C:3]=1[F:29].CN(C)C=O.[H-].[Na+].I[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]>O>[F:29][C:3]1[C:4]([CH3:28])=[C:5]([F:27])[C:6]2[O:11][C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:14]([F:25])[CH:13]=3)=[CH:9][C:8](=[O:26])[C:7]=2[C:2]=1[NH:1][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]
Reactant: Cc1c(F)c(N)c2c(=O)cc(-c3ccc(NC(=O)C(C)(C)C)c(F)c3)oc2c1F
Reactant: CCCCCCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCNc1c(F)c(C)c(F)c2oc(-c3ccc(NC(=O)C(C)(C)C)c(F)c3)cc(=O)c12
Temperature: 25 °C
Reaction time: 20 h
Yield: 53.3 %

Procedure:
653 mg (1.62 mmol) of the above 5-amino-6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-7-methyl-4H-1-benzopyran-4-one was dissolved ion 20 mL of dimethylformamide under argon atmosphere, 200 mg (5.00 mmol) of sodium hydride (60% oil dispersion) and 0.48 mL (3.2 mmol) of 1-iodohexane were added under ice-cooling and the mixture was stirred at room temperature for 20 hours. Water was added to the reaction solution and the mixture was extracted twice with ethyl acetate. The organic layer was washed once with water and once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by medium pressure liquid chromatography to give 422 mg of 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-5-(1-hexylamino)-7-methyl-4H-1-benzopyran-4-one (yield: 54%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH2:23])=[CH:20][CH:19]=1>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:23][CH2:22][C:21]2[CH:24]=[CH:25][C:18]([F:17])=[CH:19][CH:20]=2)[N:3]=1
Reactant: NCc1ccc(F)cc1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Solvent: CCN(CC)CC
Product: Fc1ccc(CNc2nc(Cl)nc3c2ncn3C2CCCC2)cc1

Procedure:
2-Chloro-6-[(4-fluorobenzyl)amino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 4-fluorobenzylamine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[C:10]([CH2:12][O:13]C(=O)C)[CH:9]=[CH:8][C:7]=1[Br:17])(=O)C.C(OCC1C=CC=C(COC(=O)C)C=1Br)(=O)C.[OH-].[Na+]>CO>[OH:4][CH2:5][C:6]1[CH:11]=[C:10]([CH2:12][OH:13])[CH:9]=[CH:8][C:7]=1[Br:17]
Reactant: CC(=O)OCc1ccc(Br)c(COC(C)=O)c1
Agent: CC(=O)OCc1cccc(COC(C)=O)c1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: OCc1ccc(Br)c(CO)c1
Temperature: 10 °C
Reaction time: 1 h
Yield: 83.9 %

Procedure:
An about 93:7 mixture (36.7 g) of 2,4-bis(acetoxymethyl)-bromobenzene and 2,6-bis(acetoxymethyl)bromobenzene was dissolved in methanol (183 ml) and cooled to 10° C. To this solution was added dropwise 10% aqueous sodium hydroxide solution (133 g). The reaction mixture was stirred at room temperature for 1 hr, and the solvent (about 200 ml) was evaporated. The residue was neutralized with dilute hydrochloric acid (about 200 ml). To the neutralized solution was added toluene (150 ml) and the mixture was stirred at 80-85° C. for 1 hr and cooled. The resulting crystals were collected by filtration and dried under reduced pressure to give an about 93:7 mixture (22.2 g, 83.7%) of 2,4-bis(hydroxymethyl)bromobenzene and 2,6-bis(hydroxymethyl)-bromobenzene as almost white crystals. 2,4-bis(Hydroxymethyl)-bromobenzene was isolated by preparative HPLC and used in the measurement.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([CH:6]=[C:7]2[CH2:14][CH2:13][CH2:12][NH:11][C:9](=[O:10])[CH2:8]2)=[CH:4][CH:3]=1.CO>[Ir].ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:14][CH2:13][CH2:12][NH:11][C:9](=[O:10])[CH2:8]2)=[CH:15][CH:16]=1
Reactant: O=C1CC(=Cc2ccc(F)cc2)CCCN1
Agent: [Ir]
Solvent: ClCCl
Solvent: CO
Product: O=C1CC(Cc2ccc(F)cc2)CCCN1
Yield: 94.5 %

Procedure:
This example describes the preparation of I where n=3 and R1=p-fluorophenyl. In a nitrogen-filled glove box, a Fisher-Porter tube was charged with iridium catalyst prepared as in Example 1 (10 mg, 0.012 mmol) and 3-(p-fluorobenzylidene)caprolactam (250 mg, 1.1 mmol). Methanol (3 mL) and dichloromethane (3 mL) were added and the system was flushed 4 times with hydrogen and pressured to 60 psi (0.5 MPa) H2. After 18 h the reaction mixture was filtered through a short pad of silica. The solvent was removed at reduced pressure to afford 3-(p-fluorobenzyl)caprolactam (230 mg, 92%) as a white crystalline solid. Chiral HPLC analysis (Chiralpak AS, 60% heptane, 39.2% isopropanol, 0.4% trifluoroacetic acid, 0.4% n-hexylamine, 40° C.) indicated that conversion was 100% and the enantiomeric excess was 67%. 19F NMR δ −117.99; 13C NMR δ 28.93, 29.47, 29.94, 36.73, 42.28, 45.65, 115.18 (d, J=21 Hz), 130.81, 136.47, 161.49 (d, J=241 Hz), 179.79; 1H NMR: δ 1.43 (m, 3H), 1.70 (m, 1H), 1.76 (m, 1H), 1.91 (m, 1H), 2.54 (app. dd, 1H), 2.67 (m, 1H), 3.12-3.31 (m, 3H), 6.78 (br s, 1H), 6.96 (m, 2H), 7.14 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:25])([CH3:24])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1.C(N(CC)CC)C.[S:34]1[CH:38]=[CH:37][CH:36]=[C:35]1[S:39](Cl)(=[O:41])=[O:40].O>ClCCl>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([S:39]([C:35]4[S:34][CH:38]=[CH:37][CH:36]=4)(=[O:41])=[O:40])[C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:25])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: CC(C)(C#N)c1ccc(-n2c(=O)[nH]c3cnc4ccc(Br)cc4c32)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C#N)c1ccc(-n2c(=O)n(S(=O)(=O)c3cccs3)c3cnc4ccc(Br)cc4c32)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(4-(8-bromo-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)-2-methylpropanenitrile (Intermediate 1, 50 mg, 0.12 mmol) and triethylamine (24.4 mg, 0.36 mmol) in dichloromethane (6 ml) was added thiophene-2-sulfonyl chloride (32.88 mg, 0.18 mmol) at 0° C. The reaction was stirred at RT for 3 hours. The reaction mixture was poured into cold water and organic layer was separated. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine dried over sodium sulfate and evaporated to dryness. The crude product was purified by column chromatography (silica gel, 2% acetone in chloroform) to obtain the title compound. Yield: 14 mg (17.16%); 1H NMR (DMSO-d6, 300 MHz): δ 9.37 (s, 1H), 8.229-8.246 (d, 1H, J=5.1 Hz), 8.160-8.172 (d, 1H, J=3.6 Hz), 7.982-8.012 (d, 1H, J=9 Hz), 7.822-7.850 (d, 2H, J=8.4 Hz), 7.779-7.785 (d, 1H, J=1.8 Hz), 7.720-7.748 (d, 2H, J=8.4 Hz), 7.31 (t, 1H, J=4.2 Hz), 6.763-6.770 (d, 1H, J=2.1 Hz), 1.78 (s, 6H).
Reaction SMILES: FC1C=C(F)C=CC=1C1C=C(CO)C(=O)N(CC(C)C)N=1.[F:22][C:23]1[CH:24]=[C:25]([C:31]2[CH:32]=[C:33]([C:38]([O:40][CH3:41])=[O:39])[C:34](=[O:37])[NH:35][N:36]=2)[CH:26]=[CH:27][C:28]=1[O:29][CH3:30].[F:42][C:43]1[CH:44]=[C:45]([CH:48]=[CH:49][C:50]=1[F:51])[CH2:46]Br>>[F:42][C:43]1[CH:44]=[C:45]([CH:48]=[CH:49][C:50]=1[F:51])[CH2:46][N:35]1[C:34](=[O:37])[C:33]([C:38]([O:40][CH3:41])=[O:39])=[CH:32][C:31]([C:25]2[CH:26]=[CH:27][C:28]([O:29][CH3:30])=[C:23]([F:22])[CH:24]=2)=[N:36]1
Reactant: COC(=O)c1cc(-c2ccc(OC)c(F)c2)n[nH]c1=O
Reactant: Fc1ccc(CBr)cc1F
Agent: CC(C)Cn1nc(-c2ccc(F)cc2F)cc(CO)c1=O
Product: COC(=O)c1cc(-c2ccc(OC)c(F)c2)nn(Cc2ccc(F)c(F)c2)c1=O
Yield: 92.1 %

Procedure:
Following the procedure of Example 1 (6), 6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and 3,4-difluorobenzyl bromide were reacted to yield the title compound as a yellow crystalline powder (yield: 92.1%)
Reaction SMILES: C(O[C:4]([C:6]1[C:7](=[O:24])[O:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:10]=2)=[O:5])C.[NH2:25][CH2:26][C:27]([O-:29])=[O:28].[Na+]>COC(O)C>[OH:16][C:15]1[C:14]2[C:9](=[CH:10][C:11]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:12][CH:13]=2)[O:8][C:7](=[O:24])[C:6]=1[C:4]([NH:25][CH2:26][C:27]([OH:29])=[O:28])=[O:5]
Reactant: CCOC(=O)c1c(O)c2ccc(Oc3ccccc3)cc2oc1=O
Reactant: NCC(=O)[O-]
Agent: COC(C)O
Agent: [Na+]
Product: O=C(O)CNC(=O)c1c(O)c2ccc(Oc3ccccc3)cc2oc1=O
Yield: 105.5 %

Procedure:
A mixture of 4-hydroxy-2-oxo-7-phenoxy-2H-chromene-3-carboxylic acid ethyl ester (84 mg, 0.248 mmol) and sodium glycinate (121 mg, 1.24 mmol) in methoxyethanol (5 mL) was refluxed for 15 h; then cooled, the solvent was removed, the residue was redissolved in water, acidified with 2 M HCl, the precipitates were collected and freeze dried to give the desired title product (93 mg). ESI (m/z): 356 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[N:13][C:12]([C:15]#[CH:16])=[CH:11][N:10]=1.I[C:18]1[CH:34]=[CH:33][C:21]([O:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][C:28]([CH3:32])([OH:31])[CH2:27][CH2:26]2)=[CH:20][CH:19]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[CH:11][C:12]([C:15]#[C:16][C:18]2[CH:34]=[CH:33][C:21]([O:22][CH2:23][CH2:24][N:25]3[CH2:26][CH2:27][C:28]([CH3:32])([OH:31])[CH2:29][CH2:30]3)=[CH:20][CH:19]=2)=[N:13][CH:14]=1
Reactant: C#Cc1cnc(-c2ccc(Cl)cc2Cl)cn1
Reactant: CC1(O)CCN(CCOc2ccc(I)cc2)CC1
Product: CC1(O)CCN(CCOc2ccc(C#Cc3cnc(-c4ccc(Cl)cc4Cl)cn3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The product was prepared analogously to Example 48.1c from 180 mg (0.72 mmol) of 2-(2,4-dichlorophenyl)-5-ethynylpyrazine and 260 mg (0.72 mmol) of 1-[2-(4-iodophenoxy)ethyl]-4-methylpiperidin-4-ol (IP 15) (stirring the reaction mixture overnight at RT). Yield: 16 mg (5% of theoretical); C26H25Cl2N3O2 (M=482.401); calc.: molpeak (M+H)+482/484/486 (2 Cl); found: molpeak (M+H)+:482/484/486 (2 Cl); HPLC-MS: 7.5 minutes (method G).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9](=[O:27])[C:10](=[CH:14][C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:24]=2[O:23][C:22]([CH3:25])=[CH:21][C:20]3=[O:26])[C:11](=O)[CH3:12])[CH:6]=[CH:7][CH:8]=1.[NH2:28]/[C:29](/[CH3:37])=[CH:30]\[C:31]([O:33][CH2:34][CH2:35][CH3:36])=[O:32]>CC(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[C:9]([C:10]1[CH:14]([C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:24]=2[O:23][C:22]([CH3:25])=[CH:21][C:20]3=[O:26])[C:30]([C:31]([O:33][CH2:34][CH2:35][CH3:36])=[O:32])=[C:29]([CH3:37])[NH:28][C:11]=1[CH3:12])=[O:27]
Reactant: CCCOC(=O)/C=C(/C)N
Reactant: COc1cccc(C(=O)C(=Cc2cccc3c(=O)cc(C)oc23)C(C)=O)c1
Solvent: CC(C)O
Product: CCCOC(=O)C1=C(C)NC(C)=C(C(=O)c2cccc(OC)c2)C1c1cccc2c(=O)cc(C)oc12

Procedure:
245 mg (0.67 mmol) of 1-(3-methoxyphenyl)-2-[(2-methyl-4-oxo-4H-chromen-8-yl)methylene]-butane-1,3-dione are heated with 96 mg (0.67 mmol) of n-propyl 3-aminocrotonate in 5 ml of 2-propanol under reflux overnight. The solvent is removed in vacuo, and the residue is purified by preparative HPLC. 94 mg (28% of theory) of the title compound are obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=2[F:16])=[C:6]([CH3:17])[C:5](=[O:18])[N:4]2[CH2:19][CH2:20][O:21][C:3]=12.[CH2:22]([O:29][CH2:30][CH2:31][CH2:32][C:33]1([S:36](Cl)(=[O:38])=[O:37])[CH2:35][CH2:34]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>N1C=CC=CC=1>[F:16][C:10]1[CH:11]=[C:12]([I:15])[CH:13]=[CH:14][C:9]=1[NH:8][C:7]1[C:2]([NH:1][S:36]([C:33]2([CH2:32][CH2:31][CH2:30][O:29][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:35][CH2:34]2)(=[O:38])=[O:37])=[C:3]2[O:21][CH2:20][CH2:19][N:4]2[C:5](=[O:18])[C:6]=1[CH3:17]
Reactant: O=S(=O)(Cl)C1(CCCOCc2ccccc2)CC1
Reactant: Cc1c(Nc2ccc(I)cc2F)c(N)c2n(c1=O)CCO2
Solvent: c1ccncc1
Product: Cc1c(Nc2ccc(I)cc2F)c(NS(=O)(=O)C2(CCCOCc3ccccc3)CC2)c2n(c1=O)CCO2
Yield: 28.2 %

Procedure:
Using the same reaction conditions and workup as described for the preparation of Example 7A, 8-amino-7-(2-fluoro-4-iodo-phenylamino)-6-methyl-2,3-dihydro-oxazolo[3,2-a]pyridin-5-one (I-7f: 0.5 g, 1.246 mmol) in pyridine (5 ml) was reacted with 1-(3-benzyloxy-propyl)-cyclopropanesulfonyl chloride (0.39 mg, 1.371 mmol) to afford the crude product. Purification by column chromatography on silica gel (2% MeOH in CHCl3) afforded 0.23 g of the product (28% yield). LCMS: 93.01%, m/z=654.0 (M+1). HPLC: 74.6%
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([NH:8]C(=O)C)=[N:6][CH:7]=1.Cl>C(O)C>[F:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: CC(=O)Nc1cc(C)c(F)cn1
Agent: Cl
Solvent: CCO
Product: Cc1cc(N)ncc1F
Yield: 88.4 %

Procedure:
The N1-(5-fluoro-4-methyl-2-pyridyl)acetamide (4.25 g, 25.3 mmol) obtained in (D) was dissolved in ethanol (3ml), added with 6 M aqueous hydrochloric acid (3ml) and refluxed by heating for 1 hour and 30 minutes. The reaction mixture was left stand for cooling and the solvent was concentrated. The resulting residue was dissolved in distilled water, and the system was made basic with 1 N aqueous sodium hydroxide and extracted twice with chloroform. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated to obtain the title compound (2.82 g, 88%) as solid.