Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:19][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)[C:8]2[C:13]([C:14]=1[CH2:15][NH:16][CH3:17])=[CH:12][C:11]([F:18])=[CH:10][CH:9]=2)=[O:5])[CH3:2].[C:30](Cl)(=[O:32])[CH3:31]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:19][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)[C:8]2[C:13]([C:14]=1[CH2:15][N:16]([C:30](=[O:32])[CH3:31])[CH3:17])=[CH:12][C:11]([F:18])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(CNC)c2cc(F)ccc2n1Cc1cccc2ccccc12
Reactant: CC(=O)Cl
Product: CCOC(=O)c1c(CN(C)C(C)=O)c2cc(F)ccc2n1Cc1cccc2ccccc12

Procedure:
5-Fluoro-3-methylaminomethyl-1-naphthalen-1-ylmethyl-1H-indole-2-carboxylic acid ethyl ester (from Example 86.1.) was reacted with acetyl chloride as described in Example 77.1. to give 3-[(acetyl-methyl-amino)-methyl]-5-fluoro-1-naphthalen-1-ylmethyl-1H-indole-2-carboxylic acid ethyl ester which was hydrolyzed as described in the general procedure B (Exp. 2.2) to give the title compound as a pale yellow solid. MS: 403.5 ([M−H]−).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[F:11][C:12]1[CH:13]=[C:14]([NH:25][S:26]([C:29]2[CH:38]=[CH:37][CH:36]=[CH:35][C:30]=2[C:31](OC)=[O:32])(=[O:28])=[O:27])[CH:15]=[C:16]([O:18][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[CH:17]=1.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+].C(OCC)(=O)C>O1CCCC1>[F:11][C:12]1[CH:13]=[C:14]([NH:25][S:26]([C:29]2[CH:38]=[CH:37][CH:36]=[CH:35][C:30]=2[CH2:31][OH:32])(=[O:28])=[O:27])[CH:15]=[C:16]([O:18][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[CH:17]=1
Reactant: COC(=O)c1ccccc1S(=O)(=O)Nc1cc(F)cc(Oc2cccnc2)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=S(=O)(Nc1cc(F)cc(Oc2cccnc2)c1)c1ccccc1CO
Reaction time: 1 h

Procedure:
A solution of 1.0M diisobutylaluminum hydride in tetrahydrofuran (7.50 ml) was added to a solution of methyl 2-({[3-fluoro-5-(pyridin-3-yloxy)phenyl]amino}sulfonyl)benzoate (1.50 g) in tetrahydrofuran (22 ml) at 0° C., and the reaction solution was stirred at the same temperature for 1 hour. A saturated aqueous solution of Rochelle salt and ethyl acetate were added to the reaction solution, and the mixture was stirred for 30 minutes, followed by being extracted with ethyl acetate. The combined organic layers were washed with a saturated saline solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resultant residue was purified by silica gel chromatography to yield the title compound as a colorless oily substance.
Reaction SMILES: [C:1]1([C:7]2([N:14]3[CH2:19][CH2:18][CH:17]([N:20]4[C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=5[N:22]=[C:21]4[N:29]4[CH2:35][CH:34]5[N:36](C(OC(C)(C)C)=O)[CH:31]([CH2:32][CH2:33]5)[CH2:30]4)[CH2:16][CH2:15]3)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:31]12[NH:36][CH:34]([CH2:33][CH2:32]1)[CH2:35][N:29]([C:21]1[N:20]([CH:17]3[CH2:18][CH2:19][N:14]([C:7]4([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]4)[CH2:15][CH2:16]3)[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[N:22]=1)[CH2:30]2
Reactant: CC(C)(C)OC(=O)N1C2CCC1CN(c1nc3ccccc3n1C1CCN(C3(c4ccccc4)CCCCCC3)CC1)C2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(C2(N3CCC(n4c(N5CC6CCC(C5)N6)nc5ccccc54)CC3)CCCCCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.1 %

Procedure:
A mixture of t-butyl 3-{1-[1-(1-phenylcycloheptyl)-4-piperidinyl]-1H-benzimidazol-2-yl}-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (57.8 mg, 0.099 mmol), trifluoroacetic acid (1 ml), and CH2Cl2 (3 ml) was stirred at room temperature for 0.5 hours. After evaporation of the solvent, the residue was treated with 10% HCl solution in MeOH (1.5 ml) at room temperature and allowed to stand for 0.5 hours. The reaction mixture was concentrated to give 44.6 mg (77.6%) of white amorphous solid as an HCl salt.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH3:11])=[N:9][CH:10]=1.[Li]C(C)(C)C.[Br:17]C(Cl)(Cl)C(Cl)(Cl)Br.[NH4+].[Cl-]>C1COCC1>[Br:17][C:6]1[C:5]([O:4][CH2:3][O:2][CH3:1])=[CH:10][N:9]=[C:8]([CH3:11])[CH:7]=1
Reactant: ClC(Cl)(Br)C(Cl)(Cl)Br
Reactant: COCOc1ccc(C)nc1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: C1CCOC1
Product: COCOc1cnc(C)cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.7 %

Procedure:
A solution of 1000 mg (6.53 mmol) 5-methoxymethoxy-2-methyl-pyridine (J.-P. Behr et al. Bioorg. Med. Chem. Lett. 2003, 13(10), 1713) in 10 mL THF was cooled to −78° C., where 4.03 mL (6.85 mmol) t-BuLi (1.7M solution in pentane) was added. The resulting mixture was stirred under argon for 1 h, then 2.126 g (6.53 mmol) 1,2-dibromotetrachloroethane (in 5 mL THF) was added. Stirring was continued for 1 h at −78° C. and the reaction mixture was warmed to rt. Saturated NH4Cl solution was added and the aqueous mixture was extracted with EtOAc (2×). The combined organic layers were washed with H2O and brine, dried (MgSO4) and filtered. The filtrate was concentrated in vacuo to leave a residue that was purified on silica gel (EtOAc/hexane=1:1) to afford 920 mg of the title compound as an oil. LCMS: tR=0.29 min, M+H=232 (79Br), 234 (81Br) (method J).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:12][CH:13]([CH3:15])[CH3:14])=[C:7]([CH:11]=1)[C:8]([OH:10])=O)#[N:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[F:47][C:48]([F:62])([F:61])[C:49]1[CH:54]=[CH:53][C:52]([N:55]2[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]2)=[CH:51][CH:50]=1>C1COCC1>[CH:13]([O:12][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:11][C:7]=1[C:8]([N:58]1[CH2:57][CH2:56][N:55]([C:52]2[CH:51]=[CH:50][C:49]([C:48]([F:61])([F:62])[F:47])=[CH:54][CH:53]=2)[CH2:60][CH2:59]1)=[O:10])([CH3:15])[CH3:14]
Reactant: CC(C)Oc1ccc(C#N)cc1C(=O)O
Reactant: FC(F)(F)c1ccc(N2CCNCC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(C#N)cc1C(=O)N1CCN(c2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3.6 mmol 5-cyano-2-isopropoxy-benzoic acid (compound 1.13) in 20 ml THF were added 4.0 mmol TBTU, 21.6 mmol N-ethyldiisopropylamine and 4.0 mmol 1-(4-trifluoromethyl-phenyl)-piperazine (commercial). The reaction was then stirred at RT for 16 h, concentrated in vacuo, and purified by chromatography on silica gel (eluant: ethyl acetate/heptane 1:1) to afford the title compound. MS (m/e): 418.3 (M+H+, 100%)
Reaction SMILES: C([O:3][C:4](=[O:17])[C:5]1[CH:10]=[C:9]([F:11])[C:8]([Cl:12])=[CH:7][C:6]=1[NH:13][CH:14]1[CH2:16][CH2:15]1)C.[Li+].[OH-].CO>C1COCC1>[Cl:12][C:8]1[C:9]([F:11])=[CH:10][C:5]([C:4]([OH:17])=[O:3])=[C:6]([NH:13][CH:14]2[CH2:15][CH2:16]2)[CH:7]=1
Reactant: CCOC(=O)c1cc(F)c(Cl)cc1NC1CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc(F)c(Cl)cc1NC1CC1
Reaction time: 8 h
Yield: 82.2 %

Procedure:
A solution of 4-chloro-2-cyclopropylamino-5-fluoro-benzoic acid ethyl ester (Example B-3, 4.10 g, 15.9 mmol) in THF (100 mL) was reacted with an aqueous solution of 1.0 N LiOH (45 mL, 45 mmol) and methanol (40 mL) and allowed to stir overnight. The mixture was then concentrated to one-third volume and acidified with 1.0 N HCl. The mixture was extracted with ethyl acetate, the organic layers combined, dried with sodium sulfate, and concentrated to provide 3.0 g of the title compound as an oil.
Reaction SMILES: [ClH:1].[OH:2][C@H:3]1[C@@H:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH2:8][C:7]2[C:18]([N+:22]([O-:24])=[O:23])=[CH:19][CH:20]=[CH:21][C:6]=2[N:5]([CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])[C:4]1=[O:30].[C:31](OC(=O)C)(=[O:33])[CH3:32]>>[ClH:1].[C:31]([O:2][C@H:3]1[C@@H:9]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)[CH2:8][C:7]2[C:18]([N+:22]([O-:24])=[O:23])=[CH:19][CH:20]=[CH:21][C:6]=2[N:5]([CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])[C:4]1=[O:30])(=[O:33])[CH3:32]
Reactant: COc1ccc([C@H]2Cc3c(cccc3[N+](=O)[O-])N(CCN(C)C)C(=O)[C@H]2O)cc1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Product: COc1ccc([C@H]2Cc3c(cccc3[N+](=O)[O-])N(CCN(C)C)C(=O)[C@H]2OC(C)=O)cc1
Temperature: 100 °C

Procedure:
A stirred suspension of the hydrochloride salt of (cis)-3-(hydroxy)-1-[2-(dimethylamino)ethyl]-1,3,4,5-tetrahydro-4-(4-methoxyphenyl)-6-nitro-2H-1-benzazepin-2-one, monohydrochloride (approximately 1.93 mmol) in 30 ml of acetic anhydride was heated to 100° C. (oil bath) and the resulting solution heated at 110°-120° C. for 4.5 hours. After removing the bulk of acetic anhydride on a rotary evaporator at 0.2 mm, the solid residue (2 g) was rubbed under 10 ml of ethyl acetate and diluted portionwise with 20 ml of ether. After cooling overnight, the colorless solid was filtered under argon, washed with ether and dried in vacuo; yield, 0.84 g; melting point 198°-200° C. (dec.), s. 192° C.
Reaction SMILES: C(O)(=[O:3])C.[CH2:5]([N:12]1[CH2:18][C:16](=[O:17])[NH:15][C:13]1=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.BrBr.C(=O)(O)[O-].[Na+]>O.C(OCC)(=O)C>[OH:3][CH:18]1[N:12]([CH2:5][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:13](=[O:14])[NH:15][C:16]1=[O:17]
Reactant: O=C1CN(Cc2ccccc2)C(=O)N1
Reactant: CC(=O)O
Agent: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1NC(=O)N(Cc2ccccc2)C1O

Procedure:
In a solvent mixture of 250 ml of acetic acid and 40 ml of ethyl acetate was dispersed 190 g of 1-benzylhydantoin and the mixture was refluxed under heating with stirring. To the mixture was added dropwise 164 g of bromine over a period of one hour, and the mixture was refluxed under heating for 30 minutes. The solvent was distilled off under a reduced pressure and the residue was allowed to stand for cooling. To the residue were added dropwise an aqueous sodium bicarbonate solution prepared by dissolving 53 g of sodium bicarbonate in 400 ml of water and then 200 ml of water. The reaction vessel was cooled with water and the crystals thus-deposited were collected by filtration, washed with water and dried to obtain 182 g of 5-hydroxy-1-benzylhydantoin as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]2[CH:10]=[N:11][N:12]3[CH:17]=[CH:16][CH:15]=[N:14][C:13]=23)[CH:3]=1.COC1C=C(OC)C=CC=1C[N:23]([C:36]1[S:40][N:39]=[CH:38][N:37]=1)[S:24]([C:27]1[CH:32]=[C:31]([F:33])[C:30](F)=[CH:29][C:28]=1[F:35])(=[O:26])=[O:25].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.ClCCl.FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:30]2[C:31]([F:33])=[CH:32][C:27]([S:24]([NH:23][C:36]3[S:40][N:39]=[CH:38][N:37]=3)(=[O:25])=[O:26])=[C:28]([F:35])[CH:29]=2)=[C:4]([C:9]2[CH:10]=[N:11][N:12]3[CH:17]=[CH:16][CH:15]=[N:14][C:13]=23)[CH:3]=1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(F)cc2F)c(OC)c1
Reactant: Oc1ccc(Cl)cc1-c1cnn2cccnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Nc1ncns1)c1cc(F)c(Oc2ccc(Cl)cc2-c2cnn3cccnc23)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 68 %

Procedure:
To a solution of 4-chloro-2-(pyrazolo[1,5-a]pyrimidin-3-yl)phenol (0.150 g, 0.61 mmol) and N-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (0.285 g, 0.64 mmol) in dimethylsulfoxide (5 mL) was added potassium carbonate (0.127 g, 0.92 mmol) and the mixture was stirred at ambient temperature for 4 h. The mixture was partitioned between ethyl acetate (100 mL) and water (20 mL). The organic phase was washed with brine (2×10 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue obtained was dissolved in dichloromethane (3 mL) and trifluoroacetic acid (3 mL). The reaction mixture was stirred for 3 h at ambient temperature and concentrated in vacuo. The residue was suspended in a mixture of dichloromethane and methanol (1:1, 50 mL) and filtered through a pad of diatomaceous earth. The filtrate was concentrated in vacuo and the residue that was triturated in ethyl acetate to afford 4-(4-chloro-2-(pyrazolo[1,5-a]pyrimidin-3-yl)phenoxy)-2,5-difluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide as a beige solid in 68% yield (0.233 g): 1H NMR (300 MHz, DMSO-d6) δ9.20 (d, J=6.6 Hz, 1H), 8.77-8.70 (m, 1H), 8.61-8.45 (m, 3H), 7.82 (dd, J=9.1, 6.3 Hz, 1H), 7.38 (dd, J=8.3, 2.1 Hz, 1H), 7.28 (d, J=8.7 Hz, 1H), 7.23-7.09 (m, 2H); MS (ES+) m/z 520.7 (M+1), 522.7 (M+1).
Reaction SMILES: [ClH:1].C([S:5][CH:6]1[CH2:11][CH2:10][N:9]([CH:12]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:13]([CH:15]2[CH2:17][CH2:16]2)=[O:14])[CH2:8]/[C:7]/1=[CH:25]\[C:26]1[N:30]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[N:29]=[CH:28][N:27]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[ClH:1].[CH:15]1([C:13](=[O:14])[CH:12]([N:9]2[CH2:10][CH2:11][CH:6]([SH:5])/[C:7](=[CH:25]/[C:26]3[N:30]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[N:29]=[CH:28][N:27]=3)/[CH2:8]2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[CH2:17][CH2:16]1
Reactant: COC(=O)Cn1ncnc1/C=C1\CN(C(C(=O)C2CC2)c2ccccc2F)CCC1SC(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)Cn1ncnc1/C=C1\CN(C(C(=O)C2CC2)c2ccccc2F)CCC1S
Yield: 64.2 %

Procedure:
Following a procedure similar to that described in Example 151, (E)-4-(acetylsulfanyl)-1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-3-{[1-(methoxycarbonylmethyl)-1H-1,2,4-triazol-5-yl]methylidene}piperidine hydrochloride (140 mg) was treated with potassium carbonate and the crude product was purified by preparative HPLC (YMC-Pack ODS-A; YMC, eluent: acetonitrile/0.024 N hydrochloric acid, 30/70, v/v) to afford the title compound (82.7 mg, yield: 64%) as a colourless amorphous solid.
Reaction SMILES: Cl.[O:2]=[C:3]1[CH:8]=[CH:7][C:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][CH:4]1[NH2:21].CN(C)[CH:24]=[CH:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>CO>[O:2]=[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:5][CH:4]1[NH:21][CH:24]=[CH:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: NC1CC(c2ccccc2)(c2ccccc2)C=CC1=O
Reactant: CCOC(=O)C=CN(C)C
Agent: Cl
Solvent: CO
Product: CCOC(=O)C=CNC1CC(c2ccccc2)(c2ccccc2)C=CC1=O
Temperature: 0 °C
Reaction time: 60 h

Procedure:
0.27 g of 2-oxo-5,5-diphenylcyclohex-3-enylamine hydrochloride is dissolved in 3 cm3 of methanol and the solution is cooled to a temperature in the region of 0° C. 0.14 cm3 of ethyl 3-dimethylaminoacrylate is added to the preceding solution and the mixture is stirred for about 60 hours at a temperature in the region of 20° C. The reaction mixture is then concentrated to dryness under reduced pressure (13 kPa) and the residue is taken up in 12 cm3 of tetrahydrofuran. 0.3 g of ethyl 3-(2-oxo-5,5-diphenylcyclohex-3-enylamino)acrylate is obtained in the form of an orange-coloured oil, which is used without further modification in subsequent syntheses and the characteristics of which are as follows:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH3:10].C([O-])([O-])=O.[K+].[K+].[C:17]([O:20][CH2:21][CH2:22]Br)(=[O:19])[CH3:18]>CC(C)=O.C(OCC)C>[C:17]([O:20][CH2:21][CH2:22][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH3:10])(=[O:19])[CH3:18]
Reactant: CC(=O)OCCBr
Reactant: Cc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC(C)=O
Product: CC(=O)OCCOc1ccc(C=O)cc1C
Yield: 97.5 %

Procedure:
A mixture of 4-hydroxy-3-methyl-benzaldehyde (7.0 g, 51.4 mmol), K2CO3 (21.32 g, 154.2 mmol) and 2-bromoethyl acetate (25.8 g, 154.2 mmol) in acetone (250 mL) is refluxed for 18 h before it is diluted with diethyl ether (300 mL) and washed with water (3×250 mL). The washings are extracted with diethyl ether (200 mL). The combined organic extracts are dried over MgSO4 and concentrated. The remaining residue is purified by column chromatography on silica gel eluting with heptane/EA 1:1 to afford the title compound (11.14 g) as colourless solid. 1H NMR (CDCl3):δ 9.85 (s, 1H), 7.72-7.67 (m, 2H), 6.92-6.88 (m, 1H), 4.51-4.46 (m, 2H), 4.29-4.25 (m, 2H), 2.27 (s, 3H), 2.11 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17](S(CC)(=O)=O)=[C:16]([C:25]#[N:26])[CH:15]=2)=[O:12])=[CH:4][CH:3]=1.Br[C:28]1C=CC(CCCC(O)=O)=C(C)C=1.NC1C=C(C=CC=1)C#N>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:25]#[N:26])[CH:15]=2)=[O:12])=[C:6]([CH3:28])[CH:7]=1
Reactant: CCS(=O)(=O)c1ccc(NC(=O)CCCc2ccc(Br)cc2)cc1C#N
Reactant: Cc1cc(Br)ccc1CCCC(=O)O
Agent: N#Cc1cccc(N)c1
Product: Cc1cc(Br)ccc1CCCC(=O)Nc1cccc(C#N)c1
Yield: 76 %

Procedure:
Using a procedure analogous to that used to prepare 6C, 55B (216 mg, 0.84 mmol) was reacted with 3-aminobenzonitrile to afford 55C (228 mg, 76%) as a solid. MS (ESI) m/z 358.1 (M+H)+.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][NH:11]2)=[CH:7][C:6]=1[O:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([NH2:21])[CH:16]=1)([CH3:3])[CH3:2].[H-].[Na+].[CH3:24][NH:25][C:26](=O)[O:27]C1C=CC=CC=1.[Cl-].[NH4+]>CN(C)C=O.C(OCC)(=O)C.O>[NH2:21][C:17]1[CH:16]=[C:15]([O:14][C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][C:5]=2[O:4][CH:1]([CH3:3])[CH3:2])[N:11]([C:26]([NH:25][CH3:24])=[O:27])[CH:10]=[CH:9]3)[CH:20]=[CH:19][N:18]=1
Reactant: CNC(=O)Oc1ccccc1
Reactant: CC(C)Oc1cc2[nH]ccc2cc1Oc1ccnc(N)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CNC(=O)n1ccc2cc(Oc3ccnc(N)c3)c(OC(C)C)cc21
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 98 %

Procedure:
4-((6-Isopropoxy-1H-indol-5-yl)oxy)pyridin-2-amine described in Production Example 17-6 (65.6 mg, 0.232 mmol) was dissolved in N,N-dimethylformamide (1.5 mL), 50-72% oily sodium hydride (16.7 mg) was added under nitrogen atmosphere at 0° C., and the mixture was stirred at room temperature for 50 minutes. The mixture was cooled to 0° C. again, phenyl methylcarbamate described in Production Example 1-7 (69.2 mg, 0.458 mmol) was added, and the mixture was stirred at room temperature for 3 hours. A saturated aqueous ammonium chloride solution, water, and ethyl acetate were added to the reaction mixture for partition. The aqueous layer was extracted with ethyl acetate and the combined organic layer was washed with water and then with a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate and then filtered, then the filtrate was concentrated under vacuum. The residue was dissolved in dichloromethane and the resultant was purified with NH silica gel column chromatography (n-heptane:ethyl acetate=3:7-0:1-ethyl acetate:methanol=99:1-19:1), then the target fraction was concentrated under vacuum to obtain the title compound (77.0 mg, 98%).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:8][CH3:9])[C:4](OC)=[O:5].[CH3:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH2:16])=[CH:13][CH:12]=1>CCOC(C)=O>[CH3:1][O:2][CH:3]([O:8][CH3:9])[C:4]([NH:16][CH2:15][C:14]1[CH:17]=[CH:18][C:11]([CH3:10])=[CH:12][CH:13]=1)=[O:5]
Reactant: Cc1ccc(CN)cc1
Reactant: COC(=O)C(OC)OC
Solvent: CCOC(C)=O
Product: COC(OC)C(=O)NCc1ccc(C)cc1
Temperature: 140 °C

Procedure:
A mixture of methyl dimethoxyacetate (1.35 g, 9.96 mmol) and 4-methylbenzylamine (1.21 g, 9.98 mmol) in a sealable tube was heated in a microwave reactor to 140° C. for 50 min. The reaction mixture was diluted with EtOAc (≈60 mL), washed with diluted aq. HCl, water, sat. NaHCO3 solution, and brine, and dried over MgSO4. The EtOAc extract was filtered, concentrated, and dried in vacuo overnight to give the title compound as pale yellow oil. It was used for the next step without further purification. 1H NMR (400 MHz, CDCl3): δ=7.20-7.13 (AA′BB′, 4H), 6.82 (brs, 1H), 4.75 (s, 1H), 4.44 (d, J=5.6 Hz, 2H), 3.40 (s, 6H), 2.34 (s, 3H). MS(ES+): m/z=246.10 (43) [MNa+], 224.11 (91) [MH+], 192.14 (8) [MH+-MeOH], 160.06 (80) [MH+-2 MeOH]. HPLC: tR=2.84 min (polar—5 min, ZQ3).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]2[CH:11]=[C:10]([CH3:12])[C:9](B(O)O)=[CH:8][CH:7]=2)=[CH:4][CH:3]=1.[C:18]([O-:21])(=[O:20])[CH3:19].[C:22]([O-:25])(=[O:24])[CH3:23].[C:26]([O-:29])(=[O:28])[CH3:27].C([O-])(=O)C.[Pb+4:34].CCCCCC.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[C:18]([O-:21])(=[O:20])[CH3:19].[C:22]([O-:25])(=[O:24])[CH3:23].[C:26]([O-:29])(=[O:28])[CH3:27].[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]2[CH:11]=[C:10]([CH3:12])[C:9]([Pb+3:34])=[CH:8][CH:7]=2)=[CH:4][CH:3]=1
Reactant: [Pb+4]
Reactant: Cc1cc(-c2ccc(Cl)cc2)ccc1B(O)O
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Product: Cc1cc(-c2ccc(Cl)cc2)ccc1[Pb+3]
Temperature: 25 °C
Yield: 55.5 %

Procedure:
4′-Chloro-3-methylbiphen-4-ylboronic acid (6.0 g, 0.024 mol) is added in one portion to a mixture of lead tetraacetate (13.0 g, 0.029 mol) and mercuric acetate (0.38 g, 5 mol %) in chloroform (50 ml) under an atmosphere of nitrogen. The reaction mixture is stirred at ambient temperature until dissolution is complete, and then heated at 40° C. for 4 hours. The reaction mixture is cooled to ambient temperature, filtered through a plug of diatomaceous earth and the filtrate is concentrated under reduced pressure to give an orange solid. Trituration with hexane (50 ml) affords a yellow solid which is dried under high vacuum. This solid is then dissolved in chloroform (100 ml), anhydrous potassium carbonate (42.5 g, 0.3 mol) is added and the suspension is stirred rapidly for 10 minutes. The mixture is filtered through a plug of diatomaceous earth, and the filtrate is concentrated under reduced pressure to give 4′-chloro-3-methylbiphen-4-yllead triacetate (7.8 g) as a cream solid.
Reaction SMILES: B(Br)(Br)Br.[F:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([F:16])[C:13]=1[O:14]C)[C:9]#[N:10]>ClCCl>[F:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([F:16])[C:13]=1[OH:14])[C:9]#[N:10]
Reactant: COc1c(F)cc(C#N)cc1F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: N#Cc1cc(F)c(O)c(F)c1
Reaction time: 8 h
Yield: 80.6 %

Procedure:
BBr3 (6.61 g, 0.0264 mol) was added to 3,5-difluoro-4-methoxybenzonitrile (1.5 g, 0.0088 mol; see step (iii) above) in dichloromethane (15 mL) at −78° C. Stirring was continued at room temperature overnight under a nitrogen atmosphere. The reaction mixture was then quenched with ice water and extracted with dichloromethane. The organic layer was washed with water and brine, and dried over sodium sulfate. Solvent evaporation under reduced pressure yielded 1.1 g (80.6%) of the sub-title compound as a grey solid.