Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[N:6]=[C:7]([NH:10][CH:11]3[C:15]4[C:16]([O:20][CH3:21])=[CH:17][CH:18]=[CH:19][C:14]=4[O:13][CH2:12]3)[O:8][CH2:9][C:4]=2[CH:3]=1.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[N:26]=1>>[CH3:21][O:20][C:16]1[C:15]2[CH:11]([NH:10][C:7]3[O:8][CH2:9][C:4]4[CH:3]=[C:2]([NH:24][C:25]5[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:33])([F:32])[F:34])[N:26]=5)[CH:23]=[CH:22][C:5]=4[N:6]=3)[CH2:12][O:13][C:14]=2[CH:19]=[CH:18][CH:17]=1
Reactant: COc1cccc2c1C(NC1=Nc3ccc(Br)cc3CO1)CO2
Reactant: Nc1cccc(C(F)(F)F)n1
Product: COc1cccc2c1C(NC1=Nc3ccc(Nc4cccc(C(F)(F)F)n4)cc3CO1)CO2
Yield: 12.3 %

Procedure:
The title compound (28 mg, 12%), light brown foam, MS (ISP): m/e=457.3 (M+H+), was prepared in accordance with the general method of Example 35 from rac-(6-bromo-4H-benzo[d][1,3]oxazin-2-yl)-(4-methoxy-2,3-dihydro-benzofuran-3-yl)-amine (Example 54) (188 mg, 0.5 mmol) and commercially available 2-amino-6-trifluoromethyl-pyridine (162 mg, 1.0 mmol).
Reaction SMILES: [CH:1]1([C:7]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([CH3:25])=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22](O)=[O:23])=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:26]=[S:27]1(=[O:42])[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][C:35]2[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][CH:36]=2)[CH2:29][CH2:28]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C.O>[O:42]=[S:27]1(=[O:26])[CH2:28][CH2:29][N:30]([CH2:33][CH2:34][C:35]2[CH:40]=[CH:39][C:38]([NH:41][C:22]([C:19]3[CH:20]=[CH:21][C:16]([C:14]4[CH:15]=[C:10]([NH:9][C:7]([CH:1]5[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]5)=[O:8])[CH:11]=[CH:12][C:13]=4[CH3:25])=[CH:17][CH:18]=3)=[O:23])=[CH:37][CH:36]=2)[CH2:31][CH2:32]1
Reactant: Cc1ccc(NC(=O)C2CCCCC2)cc1-c1ccc(C(=O)O)cc1
Reactant: Nc1ccc(CCN2CCS(=O)(=O)CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)C2CCCCC2)cc1-c1ccc(C(=O)Nc2ccc(CCN3CCS(=O)(=O)CC3)cc2)cc1
Reaction time: 16 h

Procedure:
A mixture of 5′-(Cyclohexanecarbonyl-amino)-2′-methyl-biphenyl-4-carboxylic acid (40 mg), 4-[2-(1,1-dioxo-1lambda*6*-thiomorpholin-4-yl)-ethyl]-phenylamine (30 mg), EDAC (23 mg), HOBT (16 mg) and N-Methylmorpholine (26 μl) in dry DMF (1 ml) was stirred for 16 hrs. This mixture was then diluted with water (8 ml) and the tan solid produced collected and dried (45 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]2[N:17]=[C:16]([CH3:18])[C:15](C=O)=[C:11]2[O:12][C:13]=1[CH3:14].C1C=C(Cl)C=C(C(OO)=[O:29])C=1.C([O-])([O-])=O.[K+].[K+].CO>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]2[N:17]=[C:16]([CH3:18])[C:15]([OH:29])=[C:11]2[O:12][C:13]=1[CH3:14]
Reactant: Cc1nn2c(-c3ccc(Cl)cc3Cl)c(C)oc2c1C=O
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: Cc1nn2c(-c3ccc(Cl)cc3Cl)c(C)oc2c1O
Temperature: 0 °C

Procedure:
3-(2,4-Dichloro-phenyl)-2,6-dimethyl-pyrazolo[5,1-b]oxazole-7-carbaldehyde (750 mg, 2.426 mmol) and m-CPBA (897 mg, 3.64 mmol) are stirred in DCM (10.5 ml) at RT for 3 hours, whereupon the reaction mixture is diluted with DCM (120 ml). The organic phase is washed with sat. NaHCO3 (70 ml) and the phases separated via a phase separator. Back extraction of the aqueous phase with DCM (50 ml) is carried out and the combined organic phases are concentrated in vacuo. The resultant yellow gum is dissolved in MeOH (16.80 ml) and K2CO3 (1676 mg, 12.13 mmol) is added. The reaction is stirred at RT for 30 mins before the MeOH is removed in vacuo. The resulting solid is diluted with water (˜100 ml) and the product is extracted into EtOAc (2×100 ml). The combined organic extracts are washed with brine, dried over MgSO4 and concentrated in vacuo. The crude product is isolated as a light orange solid which is dissolved DCM (15 ml), cooled to 0° C. and the resultant solid collected by filtration to afford the title compound as a pale yellow solid. MS: m/z 297.15 [M+H]+.
Reaction SMILES: [OH:1][N:2]=[CH:3][C:4]1[N:5]=[C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[S:7][CH:8]=1.ClN1C(=O)CCC1=O.[F:30][C:31]1[C:36]([CH:37]=[CH2:38])=[C:35]([F:39])[CH:34]=[CH:33][C:32]=1[OH:40].C(=O)([O-])O.[K+]>C(OCC)(=O)C.O>[F:30][C:31]1[C:32]([OH:40])=[CH:33][CH:34]=[C:35]([F:39])[C:36]=1[CH:37]1[O:1][N:2]=[C:3]([C:4]2[N:5]=[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]3)[S:7][CH:8]=2)[CH2:38]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C=NO)cs2)CC1
Reactant: C=Cc1c(F)ccc(O)c1F
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2nc(C3=NOC(c4c(F)ccc(O)c4F)C3)cs2)CC1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 4-{4-[(hydroxyimino)methyl]-1,3-thiazol-2-yl}piperidine-1-carboxylate (1.278 g) in ethyl acetate (80 ml) was added, at room temperature, N-chlorosuccinimide (658 mg). After stirring at 60° C. for 30 min, 2,4-difluoro-3-vinylphenol (705 mg), potassium hydrogencarbonate (822 mg) and then one drop of water were added, at room temperature, to the reaction mixture. After stirring overnight at room temperature, the reaction mixture was admixed with ethyl acetate and water and extracted with ethyl acetate. The organic extracts were dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by chromatography. This gave tert-butyl 4-{4-[5-(2,6-difluoro-3-hydroxyphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidine-1-carboxylate (658 mg).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][OH:8].[CH2:9]=O>[Cl-].[In+3].[Cl-].[Cl-].C(#N)C>[S:1]1[C:2]2[CH2:6][CH2:7][O:8][CH2:9][C:3]=2[CH:4]=[CH:5]1
Reactant: C=O
Reactant: OCCc1cccs1
Agent: [Cl-]
Agent: [In+3]
Solvent: CC#N
Product: c1cc2c(s1)CCOC2
Temperature: 25 °C
Yield: 65.8 %

Procedure:
20.0 g of 2-thiopheneethanol, 6.1 g of paraformaldehyde, and 1.7 g of indium(III) chloride were added to 1,500 mL of acetonitrile, and the resulting mixture was refluxed for 2 hours. The reaction solution was cooled to room temperature and concentrated by evaporation under reduced pressure. The residue thus obtained was distilled under reduced pressure to obtain 14.4 g (yield of 66%) of the title compound as an oil form.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8]S(C(F)(F)F)(=O)=O)[C:5]([N+:16]([O-:18])=[O:17])=[C:4]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:3]=1.[CH2:24](O)[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[O:20]1[CH:21]=[CH:22][CH:23]=[C:19]1[C:4]1[C:5]([N+:16]([O-:18])=[O:17])=[C:6]([O:8][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:7]=[C:2]([NH2:1])[N:3]=1
Reactant: OCCc1ccccc1
Reactant: Nc1nc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c(-c2ccco2)n1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: Nc1nc(OCCc2ccccc2)c([N+](=O)[O-])c(-c2ccco2)n1

Procedure:
From trifluoro-methanesulfonic acid 2-amino-6-furan-2-yl-5-nitro-pyrimidin-4-yl ester, phenethylalcohol and DBU in DME. ES-MS m/e (%): 327 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:16]=2)(=[O:14])=[O:13])[C:5]([C:8](O)=[O:9])=[N:6][CH:7]=1.[F:26][C:27]1[CH:28]=[CH:29][C:30]2[O:35][CH2:34][CH2:33][NH:32][C:31]=2[CH:36]=1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CCN(CC)CC>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([S:12]([NH:11][C:4]2[C:5]([C:8]([N:32]3[C:31]4[CH:36]=[C:27]([F:26])[CH:28]=[CH:29][C:30]=4[O:35][CH2:34][CH2:33]3)=[O:9])=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)(=[O:14])=[O:13])=[CH:16][C:17]=1[C:22]([F:23])([F:25])[F:24]
Reactant: O=C(O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: Fc1ccc2c(c1)NCCO2
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Product: O=C(c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1)N1CCOc2ccc(F)cc21

Procedure:
6-Fluoro-3,4-dihydro-2H-benzo[1,4]oxazine 5-chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)picolinic acid, T3P, and Et3N were reacted according to the procedure D to provide the title compound. HPLC purification provided 4-chloro-N-[5-chloro-2-(6-fluoro-2,3-dihydro-benzo[1,4]oxazine-4-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide: Reverse phase HPLC gradient acetonitrile 0.1% TFA 20-95% in 4 min: 3.041 min MS m/z: 550.1 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[C:15]([N:18]1[CH2:24][CH2:23][CH2:22][N:21]([C:25]2[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=2)[CH2:20][CH2:19]1)(=[O:17])[CH3:16].OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1>CC(N(C)C)=O.C(Cl)Cl>[C:15]([N:18]1[CH2:24][CH2:23][CH2:22][N:21]([C:25]2[CH:26]=[CH:27][C:28]([C:29]3[NH:6][C:4](=[O:5])[C:3]4[C:2](=[CH:10][C:9]([O:11][CH3:12])=[CH:8][C:7]=4[O:13][CH3:14])[N:1]=3)=[CH:31][CH:32]=2)[CH2:20][CH2:19]1)(=[O:17])[CH3:16]
Reactant: CC(=O)N1CCCN(c2ccc(C=O)cc2)CC1
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCCN(C(C)=O)CC4)cc3)nc2c1
Temperature: 150 °C
Yield: 41.1 %

Procedure:
To a mixture of 2-amino-4,6-dimethoxybenzamide (0.377 g, 1.92 mmol) and 4-(4-acetyl-1,4-diazepan-1-yl)benzaldehyde (0.520 g, 2.11 mmol) in DMA (20 mL) was added NaHSO3 (0.240 g, 2.3 mmol) followed by p-TsOH (0.037 g, 0.192 mmol) and the reaction heated at 150° C. for 6 hours. The mixture was cooled to room temperature, diluted with CH2Cl2 (150 mL), washed with brine (2×150 mL), dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified by flash chromatography on silica gel, eluting with 1:1 CH2Cl2/92:7:1 CHCl3/MeOH/concentrated NH4OH to 100% 92:7:1 CHCl3/MeOH/concentrated NH4OH, to afford the title compound (0.333 g, 41%) as a yellow solid. 1H NMR (300 MHz, CDCl3): δ 9.12 (s, 1H), 7.88-7.91 (m, 2H), 6.78-6.82 (m, 3H), 6.42 (d, J=2.2 Hz, 1H), 3.98 (s, 3H), 3.93 (s, 3H), 3.62-3.80 (m, 6H), 3.36-3.48 (m, 2H), 1.98-2.12 (m, 5H). ESI MS m/z 421 [M−H]−.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][CH2:10][CH3:11])[C:4](=[O:12])[CH:3]=1.O[C:14]1C=CN(CCC(C)C)C(=O)C=1.C(N1C=CC(O)=CC1=O)CCC.C(OC1C=CNC(=O)C=1)C1C=CC=CC=1.BrCCC(C)C>>[Br:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][CH:10]([CH3:14])[CH3:11])[C:4](=[O:12])[CH:3]=1
Reactant: CC(C)CCn1ccc(O)cc1=O
Reactant: CCCCn1ccc(Br)cc1=O
Agent: CCCCn1ccc(O)cc1=O
Agent: O=c1cc(OCc2ccccc2)cc[nH]1
Solvent: CC(C)CCBr
Product: CC(C)CCn1ccc(Br)cc1=O

Procedure:
Intermediate D4 was prepared following the same procedure implemented for the synthesis of D3, using 4-hydroxy-1-(3-methylbutyl)-1H-pyridin-2-one as starting material, which was prepared by the same method used for the synthesis of intermediate D2, by reaction of 4-benzyloxy-1H-pyridin-2-one with 1-bromo-3-methylbutane.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[NH:11][C:10](=[O:13])[CH2:9][CH2:8][C:7]=2[C:6]([CH:14]=[O:15])=[CH:5][CH:4]=1.[CH2:16](O)[CH2:17][OH:18].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:15]1[CH2:16][CH2:17][O:18][CH:14]1[C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[C:12]2[C:7]=1[CH2:8][CH2:9][C:10](=[O:13])[NH:11]2
Reactant: COc1ccc(C=O)c2c1NC(=O)CC2
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(C2OCCO2)c2c1NC(=O)CC2
Yield: 70 %

Procedure:
8-Methoxy-2-oxo-1,2,3,4-tetrahydroquinoline-5-carboxaldehyde (42 g) was suspended in toluene (400 ml), and ethylene glycol (33.7 ml) and p-toluenesulfonic acid monohydrate (0.78 g) were added, and the resulting mixture was heated under reflux in a Dean-Stark apparatus for 4.5 hours. The reaction mixture was cooled, and 10 ml of an aqueous solution containing 1.72 g of sodium bicarbonate was added. Stirring was carried out for some time, and the produced solid was collected by filtration. The solid was washed with water and toluene and dried at 60° C. to thereby obtain 35.5 g (yield: 70%) of 5-(1,3-dioxolan-2-yl)-8-methoxy-3,4-dihydro-1H-quinolin-2-one as white crystals.
Reaction SMILES: C(O)(C(F)(F)F)=O.[O:8]1[C:12]([C:13]([C:20]2[CH:25]=[CH:24][C:23]([O:26]C3CCCCO3)=[CH:22][CH:21]=2)=[CH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][N:10]=[CH:9]1.C([O-])(O)=O.[Na+]>C(Cl)Cl.[Pd]>[OH:26][C:23]1[CH:24]=[CH:25][C:20]([CH:13]([C:12]2[O:8][CH:9]=[N:10][CH:11]=2)[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:21][CH:22]=1
Reactant: CCOC(=O)C=C(c1ccc(OC2CCCCO2)cc1)c1cnco1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CC(c1ccc(O)cc1)c1cnco1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.7 %

Procedure:
TFA (10 mL) was added to a solution of 75.3 (14 mmol) in dry DCM (100 mL) and stirred at room temperature for 2 hours. To the reaction mixture was slowly added solid NaHCO3 with stirring. The reaction was then washed with saturated NaHCO3 (2×), dried over Na2SO4, and concentrated under reduced pressure. The residue was then re-dissolved in EtOH, stirred with Pd—C (1.48 g, 0.7 mmol) under hydrogen at room temperature for 14 hours. The Pd—C was removed by filtration through celite with EtOAc as eluant. After concentration, the residue was chromatographed (silica gel, 1:1 EtOAc/hexane) to afford compound 75.4 (1.3 g, 5 mmol). MS ESI (pos.) m/e 262.1 (M+H).
Reaction SMILES: C([Li])CCC.CCCCCC.[C:12](#[N:14])[CH3:13].[Cl:15][C:16]1[CH:17]=[C:18]([C:23](=[O:27])[CH2:24][O:25][CH3:26])[CH:19]=[CH:20][C:21]=1[Cl:22]>C1COCC1>[Cl:15][C:16]1[CH:17]=[C:18]([C:23]([OH:27])([CH2:24][O:25][CH3:26])[CH2:13][C:12]#[N:14])[CH:19]=[CH:20][C:21]=1[Cl:22]
Reactant: CC#N
Reactant: COCC(=O)c1ccc(Cl)c(Cl)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COCC(O)(CC#N)c1ccc(Cl)c(Cl)c1
Reaction time: 0.25 h
Yield: 94.8 %

Procedure:
To a solution of 1.6 M n-butyllithium/hexane solution (20 ml) in THF (50 mL) was added dropwise a solution of acetonitrile (1.23 g) in THF (5 mL) at −78° C., and the mixture was stirred for 15 min, and at −40° C. for 15 min. A solution of 1-(3,4-dichlorophenyl)-2-methoxyethanone (5.00 g) in THF (30 mL) was added dropwise at −78° C., and the mixture was gradually warmed with stirring to room temperature, and stirred for 20 min. The reaction mixture was quenched with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate (0%-100%)) to give the title compound (5.63 g).
Reaction SMILES: ClC1C=C(/C=C/C(N2CCC(=O)NCC2)=O)C=CC=1Cl.[F:21][C:22]1[CH:23]=[C:24]([CH:30]=[CH:31][C:32]=1[F:33])/[CH:25]=[CH:26]/[C:27]([OH:29])=O.Cl.Cl.[N:36]1([CH2:42][CH2:43][CH2:44][N:45]2[C:51](=[O:52])[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>>[F:21][C:22]1[CH:23]=[C:24](/[CH:25]=[CH:26]/[C:27]([N:48]2[CH2:49][CH2:50][C:51](=[O:52])[N:45]([CH2:44][CH2:43][CH2:42][N:36]3[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]3)[CH2:46][CH2:47]2)=[O:29])[CH:30]=[CH:31][C:32]=1[F:33]
Reactant: O=C1CCNCCN1CCCN1CCCCC1
Reactant: O=C(O)/C=C/c1ccc(F)c(F)c1
Agent: Cl
Agent: O=C1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCN1
Product: O=C(/C=C/c1ccc(F)c(F)c1)N1CCC(=O)N(CCCN2CCCCC2)CC1

Procedure:
In analogy to the procedure described in intermediate 1A, (E)-3,4-difluorocinnamic acid and 4-(3-piperidin-1-yl-propyl)-[1,4]diazepan-5-one-dihydrochloride (intermediate 4B, suspended in CH2Cl2 with 4 equivalent of Et3N) gave after purification on catridges, Si-Amine, 70 ml, 20 g (EtOAc) the title compound as a white powder. MS: 406.2 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[C:4]([CH3:15])[C:3]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][O:23][C:24]2[CH:37]=[CH:36][C:27]3[C@H:28]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH2:29][O:30][C:26]=3[CH:25]=2)[CH:17]=1.[CH3:38][S:39](Cl)(=[O:41])=[O:40].C(N(CC)CC)C.O>ClCCl>[CH3:15][C:4]1[CH:5]=[C:6]([O:8][CH:9]2[CH2:10][CH2:11][N:12]([S:39]([CH3:38])(=[O:41])=[O:40])[CH2:13][CH2:14]2)[CH:7]=[C:2]([CH3:1])[C:3]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][O:23][C:24]2[CH:37]=[CH:36][C:27]3[C@H:28]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH2:29][O:30][C:26]=3[CH:25]=2)[CH:17]=1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(OC5CCNCC5)cc4C)c3)ccc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(OC5CCN(S(C)(=O)=O)CC5)cc4C)c3)ccc21
Yield: 138 %

Procedure:
(5)-Methyl 2-(6-((2′,6′-dimethyl-4′-(piperidin-4-yloxy)biphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 4a (26 mg, 0.05 mmol) was dissolved in 5 mL of dichloromethane, followed by addition of methanesulfonyl chloride (6 mg, 0.05 mmol) and triethylamine (15 mg, 0.15 mmol). The reaction solution was reacted for 1 hour. The resulting solution was mixed with 10 mL of water, and concentrated under reduced pressure to obtain the crude title compound (S)-methyl 2-(6-((2′,6′-dimethyl-4′-((1-(methylsulfonyl)piperidin-4-yl)oxy)biphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 5a (40 mg) as a white solid, which was directly used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[C:6]([OH:12])[C:5]=1[CH3:13].[Br:15]Br>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:14])[C:4]1[C:5]([CH3:13])=[C:6]([OH:12])[CH:7]=[C:8]([O:10][CH3:11])[C:9]=1[Br:15]
Reactant: COC(=O)c1cc(OC)cc(O)c1C
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: COC(=O)c1c(C)c(O)cc(OC)c1Br
Reaction time: 2 h
Yield: 85 %

Procedure:
To a solution of 23.5 g of 3-hydroxy-5-methoxy-2-methylbenzoic acid methyl ester in 1.3 l of chloroform was added over 1 h at -50° to -60° C. a solution of 19.2 g of bromine in 0.2 l of chloroform. Stirring was continued for 2.5 h at -40° C. and for 2 h at 0° C. The reaction mixture was evaporated in vacuo at 0° C.; the residue was dissolved in a mixture of toluene/ethanol (1:1, v/v) and the solvent was again evaporated in vacuo. This procedure was repeated twice with toluene/ethanol (1:1, v/v), and finally once with toluene. The residue was chromatographed on silica gel using ethyl acetate as eluent and the pure product was crystallized from ethyl acetate to yield 28 g of 2-bromo-3-methoxy-5-hydroxy-6-methylbenzoic acid methyl ester as white crystals, m.p. 105°-110° C.
Reaction SMILES: C([N:4]1[C:9]([NH2:10])=[CH:8][CH:7]=[CH:6][CH:5]1[C:11]([OH:13])=O)(=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.ClN1[C:38](=[O:39])[CH2:37]CC1=O.[CH:41]1([CH2:44][N:45]2[C:53]3[N:52]=[C:51]([CH2:54][C:55]4[CH:60]=[CH:59][C:58]([NH:61][CH3:62])=[CH:57][CH:56]=4)[NH:50][C:49]=3[C:48](=[O:63])[N:47]([CH2:64][C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][C:66]=3[F:71])[C:46]2=[O:72])[CH2:43][CH2:42]1>ClCCl>[CH:41]1([CH2:44][N:45]2[C:53]3[N:52]=[C:51]([CH2:54][C:55]4[CH:56]=[CH:57][C:58]([N:61]([CH3:62])[C:11]([C:5]5[CH:6]=[CH:7][CH:8]=[C:9]([NH:10][C:38](=[O:39])[CH3:37])[N:4]=5)=[O:13])=[CH:59][CH:60]=4)[NH:50][C:49]=3[C:48](=[O:63])[N:47]([CH2:64][C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][C:66]=3[F:71])[C:46]2=[O:72])[CH2:43][CH2:42]1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(=O)N1C(N)=CC=CC1C(=O)O
Reactant: CNc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(=O)Nc1cccc(C(=O)N(C)c2ccc(Cc3nc4c([nH]3)c(=O)n(Cc3ccccc3F)c(=O)n4CC3CC3)cc2)n1
Yield: 139.3 %

Procedure:
N-Acetyl-6-amino-pyridine-2-carboxylic acid (12.4 mg, 0.069 mmol) was placed in a flask and dry dichloromethane (1 mL) was added. The resulting suspension was stirred in an ice-water bath and PPh3 (18.5 mg, 0.071 mmol) was added followed by N-chlorosuccinimide (8.9 mg, 0.067 mmol). This mixture was stirred in the cooling bath for ½ h and then the cooling bath removed. After stirring at room temperature for 15 min, 3-cyclopropylmethyl-8-[4-(methylamino)-benzyl]-1-(2-fluorobenzyl)-3,7-dihydropurine-2,6-dione (57.7 mg, 0.131 mmol) was added. The reaction was then stirred at room temperature for 48 h. The solids were filtered off and washed with dichloromethane and the filtrate diluted with dichloromethane (20 mL) and washed once with saturated aqueous sodium bicarbonate, dried and concentrated to give 55.6 mg of a yellow foam. The product was purified by chromatography using silica gel eluted with 96:4 chloroform/methanol to give recovered starting material and the stated product (6.6 mg). MS, m/z(M+)=618.2237.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:19]([OH:21])=O)=[N:4][C:5]2[C:6]=1[C:7](C)=[C:8]1[C:16]([CH:17]=2)=[C:15]2[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]2)=[N:9]1.[C:22]([C:29]1NC=CN=1)([C:24]1[NH:25]C=C[N:28]=1)=O.[N-]1C=CN=[CH:35]1.[H-].[Na+]>O1CCCC1.CCOCC>[CH3:1][C:2]1[C:3]([C:19]2[O:21][N:28]=[C:24]([CH2:22][CH3:29])[N:25]=2)=[N:4][C:5]2[C:17]=1[C:16]([CH3:35])=[C:8]1[C:7]([CH:6]=2)=[C:15]2[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]2)=[N:9]1
Reactant: CC1=c2c(cc3c(c2C)N=c2ccccc2=3)N=C1C(=O)O
Reactant: c1c[n-]cn1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCc1noc(C2=Nc3cc4c(c(C)c3=C2C)N=c2ccccc2=4)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 36 %

Procedure:
3,4-Dimethylpyrrolo[3,2-b]carbazole-2-carboxylic acid (2.78 g, 10.0 mmol), (prepared as described in WO93/01512) and carbonyl diimidazole (1.85 g, 11.4 mmol) were dissolved in freshly distilled tetrahydrofuran (50 ml) in an oven-dried flask under a nitrogen atmosphere. The resulting orange solution was stirred at room temperature for three hours, by which time it was an orange suspension, and complete conversion of the acid to the imidazolide intermediate was verified by TLC. Meanwhile, in a second oven-dried flask, ethylamidoxime (2.2 g, 25 mmol) was dissolved in THF (50 ml). To this was added crushed 3 Å sieves (3.3 g) and the mixture was stirred at room temp for 45 min. Sodium hydride (60% dispersion in mineral oil, 0.804 g, 20 mmol) was added and the mixture stirred for a further 2.5 hours. The contents of the two flasks were combined and stirred at room temp for 18 hours, by which time TLC showed complete consumption of the imidazolide intermediate. The solvent was removed in vacuo to give a yellow solid. Chromatography on silica (eluting with ethyl acetate/petrol, gradient 8% -15% ethyl acetate) gave a yellow solid. The majority of this material was dissolved in ether, leaving an insoluble orange impurity. The solution was filtered, and the solvent removed in vacuo to give the title compound as a yellow powder (1.2 g, 36%) which decomposes above 45° C. δH [2H6 ]-DMSO 11.69 (1H, s, 1-NH), 10.69 (1H, s, 5-NH), 8.09 (1H, d, J 7.5, 9-H), 7.90 (1H, s, 10-H), 7.30-7.48 (2H, m, 6-H, 7-H), 7.09 (1H ddd, J 7.5, 5.5, 2, 8-H), 2.99 and 2.95 (2×3H, 2×s, 3-CH3 and 4-CH3), 2.85 (2H, q, 7.5, CH2 CH3), 1.36 (3H, t, 7.5, CH2CH3).