Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([N:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]2=[O:20])[C:3]=1[CH3:21].[O:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:29]=[C:30]3[NH:36][CH2:35][C:34]4([CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)[C:31]3=N[CH:33]=2)[CH2:24][CH2:23]1.[C:42]1(C)C=CC=CC=1>>[F:12][C:10]1[CH:9]=[C:8]([F:13])[CH:7]=[C:6]2[C:11]=1[C:2]([N:36]1[C:30]3[C:31](=[CH:42][CH:33]=[C:28]([N:25]4[CH2:24][CH2:23][O:22][CH2:27][CH2:26]4)[CH:29]=3)[C:34]3([CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)[CH2:35]1)=[C:3]([CH3:21])[C:4]([N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]1=[O:20])=[N:5]2
Reactant: Cc1c(-n2ccccc2=O)nc2cc(F)cc(F)c2c1Br
Reactant: Cc1ccccc1
Reactant: c1nc2c(cc1N1CCOCC1)NCC21CCOCC1
Product: Cc1c(-n2ccccc2=O)nc2cc(F)cc(F)c2c1N1CC2(CCOCC2)c2ccc(N3CCOCC3)cc21

Procedure:
Prepared according to procedure Y using 1-(4-bromo-5,7-difluoro-3-methylquinolin-2-yl)pyridin-2(1H)-one (35.0 mg, 0.100 mmol) and 6′-morpholino-1′,2,2′,3,5,6-hexahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridine] in toluene to give 1-(5,7-difluoro-3-methyl-4-(6-(4-morpholinyl)-2′,3′,5′,6′-tetrahydrospiro[indole-3,4′-pyran]-1(2H)-yl)-2-quinolinyl)-2(1H)-pyridinone. 1H NMR (400 MHz, chloroform-d) δ ppm 8.41-8.47 (1H, m), 7.94-8.01 (1H, m), 7.74 (1H, d, J=2.3 Hz), 7.35 (1H, ddd, J=7.4, 5.0, 0.9 Hz), 7.27-7.32 (2H, m), 6.94 (1H, ddd, J=12.5, 8.6, 2.5 Hz), 6.03 (1H, d), 4.08-4.22 (3H, m), 4.01-4.06 (1H, m), 3.72-3.81 (4H, m), 3.37-3.57 (2H, m), 3.13 (4H, dd, J=6.2, 3.8 Hz), 2.52-2.69 (2H, m), 2.38 (3H, s), 1.72-1.93 (2H, m). Mass Spectrum (ESI) m/e=
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH2:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([C:21]2[N:26]=[C:25]([NH:27][C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)[C:24]([O:34][CH3:35])=[CH:23][N:22]=2)=[N:13]1)[C:5]([OH:7])=[O:6].CN.O1CCCC1.F[P-](F)(F)(F)(F)F.[CH3:50][N:51](C(ON1C2=NC=CC=C2N=N1)=[N+](C)C)C.C(N(C(C)C)C(C)C)C>CS(C)=O>[CH:5]([OH:7])=[O:6].[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH2:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([C:21]2[N:26]=[C:25]([NH:27][C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)[C:24]([O:34][CH3:35])=[CH:23][N:22]=2)=[N:13]1)[C:5]([NH:51][CH3:50])=[O:7]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COc1cnc(-c2nn(Cc3ccc(C(=O)O)cc3Cl)c3ccccc23)nc1Nc1ccncc1
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CNC(=O)c1ccc(Cn2nc(-c3ncc(OC)c(Nc4ccncc4)n3)c3ccccc32)c(Cl)c1
Product: O=CO

Procedure:
130.9 mg of 3-chloro-4-({3-[5-methoxy-4-(pyridin-4-ylamino)pyrimidin-2-yl]-1H-indazol-1-yl}methyl)benzoic acid (28-1, 0.269 mmol, 1. eq.), 1.1 ml of dimethylsulfoxide, 269 μl of 2 M methanamine in tetrahydrofuran (0.538 mmol, 2 eq.), 225 mg of N-[(dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylidene]-N-methylmethanaminium hexafluorophosphate (HATU; 0.591 mmol, 2.2 eq.) and 140 μl of N-ethyl-N-(propan-2-yl)propan-2-amine (0.806 mmol, 3 eq.) were stirred at 50° C. bath temperature for 5 hours. The reaction mixture was filtered off and purified by preparative HPLC to yield 91 mg (0.17 mmol, 62%) of the analytically pure target compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=O.[BH3-]C#[N:16].[Na+].[ClH:18]>CO>[ClH:18].[NH2:16][CH:8]1[CH2:7][CH2:6][CH2:5][C:4]2[C:3]([O:2][CH3:1])=[CH:12][CH:11]=[CH:10][C:9]1=2
Reactant: [BH3-]C#N
Reactant: COc1cccc2c1CCCC2=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1cccc2c1CCCC2N
Yield: 79 %

Procedure:
50 mmol of 5-methoxy-1-tetralone, 0.5 mol of NH4OAc and 35 mmol of NaBH3CN are stirred in 150 ml of absolute MeOH at room temperature for 24 hours. The mixture is acidified to pH 2 with concentrated HCl and evaporated, the residue is taken up in 50 ml of H2O and the mixture is extracted by shaking 2-3×with ether. Any precipitates which arise are filtered off and combined with the H2O phase. The H2O phase is brought to pH 10 with solid KOH, saturated with NaCl and extracted by shaking 3×with ethyl acetate. After drying with Na2SO4, the organic phase is evaporated, the residue is dissolved in ether and the product is precipitated as the hydrochloride by passing the HCl. Yield: 79%; melting point: 250° C.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]CC)=[O:9].[CH2:17]([N:24]1[C:32]2[C:27](=[CH:28][C:29](/[C:33](/[CH3:39])=[C:34](\[CH3:38])/[C:35](O)=[O:36])=[CH:30][CH:31]=2)[CH:26]=[CH:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([N:24]1[C:32]2[C:27](=[CH:28][C:29](/[C:33](/[CH3:39])=[C:34](\[CH3:38])/[C:35]([NH:1][C:2]3[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=3[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:36])=[CH:30][CH:31]=2)[CH:26]=[CH:25]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(=O)CCCOc1ccccc1N
Reactant: C/C(C(=O)O)=C(/C)c1ccc2c(ccn2Cc2ccccc2)c1
Product: C/C(C(=O)Nc1ccccc1OCCCC(=O)O)=C(/C)c1ccc2c(ccn2Cc2ccccc2)c1

Procedure:
0.84 g of compound 29 was obtained in a similar manner to those described in the Examples 1 and 2 using 1.13 g of ethyl 4-(2-aminophenoxy)butyrate and 0.78 g of 3-(1-benzylindol-5-yl)-2-methylisocrotonic acid obtained according to the procedures described in the Reference Examples 1-4.
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(N(C(C)C)C(C)C)C>CC#N>[F:13][C:10]1[CH:11]=[CH:12][C:7]([CH:2]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:3]([O:5][CH3:6])=[O:4])=[CH:8][CH:9]=1
Reactant: COC(=O)C(Br)c1ccc(F)cc1
Reactant: C1CCNCC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(c1ccc(F)cc1)N1CCCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.4 %

Procedure:
Methyl 2-bromo-2-(4-fluorophenyl)acetate (538 mg, 2.18 mmol) was dissolved in CH3CN (6.6 ml) and piperidine (258 μl, 2.61 mmol) and N-ethyl-N-isopropylpropan-2-amine (456 μl, 2.61 mmol) were added sequentially. The solution was stirred at room temperature for 3 hours, then the solvent was evaporated and the crude was purified with flash chromatography (Petroleum ether/EtOAc=9/1) to collect methyl 2-(4-fluorophenyl)-2-(piperidin-1-yl)acetate (320 mg, 58.5% yield) as a colourless oil.
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[N:14]=[C:13]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])[CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9].Cl[C:22]1C=CC(C(O)=O)=C(OCC(F)(F)F)N=1.FC(F)(F)COC1N=C(OCC(F)(F)F)C=CC=1C(O)=O>CO>[Cl:5][C:6]1[N:14]=[C:13]([O:15][CH2:16][C:17]([F:20])([F:18])[F:19])[CH:12]=[CH:11][C:7]=1[C:8]([O:10][CH3:22])=[O:9]
Reactant: O=C(O)c1ccc(OCC(F)(F)F)nc1Cl
Reactant: O=C(O)c1ccc(Cl)nc1OCC(F)(F)F
Agent: O=C(O)c1ccc(OCC(F)(F)F)nc1OCC(F)(F)F
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COC(=O)c1ccc(OCC(F)(F)F)nc1Cl
Reaction time: 3 h
Yield: 67 %

Procedure:
Thionyl chloride (4.7 mL, 63.9 mmol) is added dropwise a solution of 2-chloro-6-(2,2,2-trifluoroethoxy)nicotinic acid including 6-chloro-2-(2,2,2-trifluoroethoxy)nicotinic acid and 2,6-bis(2,2,2-trifluoroethoxy)nicotinic acid (4.08 g, Step-1) in methanol (50 mL) and refluxed with stirring for 3 hours. After removal of solvent, the residue is purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (20:1) to give 2.90 g (67% yield) of the title compound including methyl 6-chloro-2-(2,2,2-trifluoroethoxy)nicotinate as a white solid. This material is used for the next reaction (Step-3) without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7]([O:18][CH3:19])=[CH:6][C:3]=1[C:4]#[N:5].CO[CH:22](OC)[N:23]([CH3:25])[CH3:24]>C1(C)C=CC=CC=1>[CH2:11]([O:10][C:8]1[C:7]([O:18][CH3:19])=[CH:6][C:3]([C:4]#[N:5])=[C:2]([N:1]=[CH:22][N:23]([CH3:25])[CH3:24])[CH:9]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COc1cc(C#N)c(N)cc1OCc1ccccc1
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Product: COc1cc(C#N)c(N=CN(C)C)cc1OCc1ccccc1
Temperature: 105 °C
Yield: 90.2 %

Procedure:
2-amino-4-(benzyloxy)-5-methoxybenzonitrile (100 g, 394 mmol) in toluene (1400 ml) was treated with dimethylformamide dimethylacetal (100 ml, 940 mmol) at reflux with slow distillation of solvent to maintain the internal temperature at 105° C. After 3 hours the solution was cooled and filtered to remove a small amount of solid. The filtrate was evaporated in vacuo, the residue triturated with diethyl ether, the solid collected by suction filtration and dried in vacuo to yield N′-(5-(benzyloxy)-2-cyano-4-methoxyphenyl)-N,N-dimethylimidoformamide (110 g, 90% yield) as a brown solid:
Reaction SMILES: [O:1]([C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:22][CH2:23][C:24](Cl)=[O:25]>ClCCl>[Cl:22][CH2:23][C:24]([NH:12][C:11]1[CH:10]=[CH:9][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:13]=1)=[O:25]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc(Oc2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)Nc1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To a solution of 4-phenoxyaniline (1.85 g, 10 mmoles) and triethylamine (2.07 ml, 15 mmoles) in 25 ml dry dichloromethane, is added stepwise a solution of chloroacetyl chloride (1.18 g, 10.5 mmoles) in 10 ml dry dichloromethane. The resulting reaction mixture is stirred for 1 hour at room temperature. Afterwards said reaction mixture is washed with 2×30 ml HCl (2 N) 1×30 ml water, dried with sodium sulfate and the solvent evaporated. 2.48 g. (Yield 95%) of 2-chloro-N-(4-phenoxyphenyl)acetamide were obtained.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][O:14][C:15]1[C:20]([O:21][CH3:22])=[C:19]([O:23][CH3:24])[CH:18]=[C:17]([CH3:25])[C:16]=1[CH:26]([C:28]1[C:29]([Cl:39])=[N:30][C:31]([Cl:38])=[CH:32][C:33]=1[C:34]([F:37])([F:36])[F:35])[OH:27].[CH:40](=[O:42])[CH3:41]>O.O1CCCC1>[CH3:13][O:14][C:15]1[C:20]([O:21][CH3:22])=[C:19]([O:23][CH3:24])[CH:18]=[C:17]([CH3:25])[C:16]=1[CH:26]([C:28]1[C:29]([Cl:39])=[N:30][C:31]([Cl:38])=[C:32]([CH:40]([OH:42])[CH3:41])[C:33]=1[C:34]([F:35])([F:37])[F:36])[OH:27]
Reactant: CC=O
Reactant: COc1cc(C)c(C(O)c2c(C(F)(F)F)cc(Cl)nc2Cl)c(OC)c1OC
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1cc(C)c(C(O)c2c(Cl)nc(Cl)c(C(C)O)c2C(F)(F)F)c(OC)c1OC
Temperature: -50 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
9.6 ml (14 mmol) of n-butyllithium (1.5 M hexane solution) was dropwise added to a tetrahydrofuran (16 ml) solution of 2.0 ml (14 mmol) of diisopropylamine at 0° C., followed by stirring for 30 minutes. The solution was cooled to −50° C., a tetrahydrofuran (11 ml) solution of 2.9 g (7 mmol) of (2,3,4-trimethoxy-6-methylphenyl)(2,6-dichloro-4-trifluoromethyl-3-pyridyl)methanol was added thereto, followed by stirring for 30 minutes, then the solution was cooled to −78° C., and acetaldehyde in an excess amount was added thereto, followed by stirring for 2 hours. 30 ml of water was added to the mixture to terminate the reaction, and tetrahydrofuran was distilled off under reduced pressure. Extraction with ethyl acetate was carried out, the organic layer was dried over anhydrous sodium sulfate and subjected to filtration, and the solvent was distilled off under reduced pressure. The crude product thus obtained was purified by silica gel column chromatography to obtain 2.5 g (yield 78%) of (2,3,4-trimethoxy-6-methylphenyl)(2,6-dichloro-5-(1-hydroxyethyl)-4-trifluoromethyl-3-pyridyl)methanol.
Reaction SMILES: [OH-].[Na+].[SH:3][C:4]1[S:5][C:6]([CH3:9])=[N:7][N:8]=1.Cl[CH2:11][C:12]([OH:14])=[O:13].Cl>O.CO.C(O)C>[C:12]([CH2:11][S:3][C:4]1[S:5][C:6]([CH3:9])=[N:7][N:8]=1)([OH:14])=[O:13]
Reactant: O=C(O)CCl
Reactant: Cc1nnc(S)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CCO
Product: Cc1nnc(SCC(=O)O)s1
Temperature: 25 °C
Yield: 75 %

Procedure:
Aqueous solution of sodium hydroxide 8.8 g (0.22 mol) in 15 ml of water was added to a mixture of 2-mercapto-5-methyl-1,3,4-thiadiazole 26.4 g (0.20 mol), chloroacetic acid 27.0 g (0.22 mol) and ethanol 300 ml with stirring at room temperature. After 20 minutes of stirring it was heated to 50° C., and further aqueous solution of sodium hydroxide 8.8 g (0.22 mol) in 15 ml of water was added slowly drop by drop. After stirring for 3 hours at 50° C., it was cooled to room temperature, and water was added till reaction liquid became uniform. Hydrochloric acid was added for neutralization. Prepared crystal was collected by filtration and 28.7 g (0.150 mol) of 2-carboxymethylthio-5-methyl-1,3,4-thiadiazole was obtained by recrystallization in methanol. Yield 75%.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([N:9]2[C:21]3[C:20]4[N:19]=[C:18]([S:22][CH3:23])[N:17]=[CH:16][C:15]=4[CH:14]=[CH:13][C:12]=3[C:11]([C:24]([NH2:26])=[O:25])=[N:10]2)[CH2:5][CH2:4]1.[CH2:27]([N:29]=[C:30]=[O:31])[CH3:28].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH2:27]([NH:29][C:30]([NH:2][CH:3]1[CH2:8][CH2:7][CH:6]([N:9]2[C:21]3[C:20]4[N:19]=[C:18]([S:22][CH3:23])[N:17]=[CH:16][C:15]=4[CH:14]=[CH:13][C:12]=3[C:11]([C:24]([NH2:26])=[O:25])=[N:10]2)[CH2:5][CH2:4]1)=[O:31])[CH3:28]
Reactant: CCN=C=O
Reactant: CSc1ncc2ccc3c(C(N)=O)nn(C4CCC(N)CC4)c3c2n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCNC(=O)NC1CCC(n2nc(C(N)=O)c3ccc4cnc(SC)nc4c32)CC1
Temperature: 100 °C
Reaction time: 18 h
Yield: 11.1 %

Procedure:
30 mg (0.084 mmol) of 1-(4-aminocyclohexyl)-8-(methylsulfanyl)-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide hydrochloride were dissolved in 2 ml of dimethylformamide. To the obtained solution 32 μl (0.42 mmol) of ethylisocyanate, 60 μl (0.336 mmol) of DIPEA, were added. The mixture was stirred at 100° C. for 18 hours, the solution was portioned between ethyl acetate and saturated aqueous solution of NaHCO3, and the organic layer was washed with brine, dried over Na2SO4 and evaporated under vacuum. The crude was purified by silica gel chromatography (DCM/MeOH/NH4OH 95/5/1) to provide 1-{4-[(ethylcarbamoyl)amino]cyclohexyl}-8-(methylsulfanyl)-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide 4 mg (11%) as a white solid. LC/MS (254) HPLC method 2 Rt 4.38 min. 1H NMR (401 MHz, DMSO-d6) δ 9.47 (s, 1H), 8.27 (d, J=8.67 Hz, 1H), 7.74 (d, J=8.67 Hz, 1H), 7.59 (s, 2H), 6.06 (d, J=7.08 Hz, 1H), 5.89-6.02 (m, 1H), 5.81 (t, J=5.49 Hz, 1H), 3.78-3.88 (m, 1H), 3.00-3.07 (m, 2H), 2.71-2.74 (m, 3H), 2.15-2.29 (m, 2H), 1.99-2.11 (m, 3H), 1.90 (dd, J=3.54, 13.67 Hz, 2H), 1.65-1.79 (m, 2H), 1.01 (t, J=7.20 Hz, 3H). HRMS (ESI) calcd for C20H25N7O2S [M+H]+ 428.1863 found 428.1852.
Reaction SMILES: C[C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]2[C:3]=1[CH:4]([C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1[O:22][CH3:23])[O:5][C:6]2=[O:13].[CH2:24]([SiH](CC)CC)C.O>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:24][C:10]1[CH:9]=[C:8]([O:11][CH3:12])[C:7]([C:6]([OH:5])=[O:13])=[C:3]([CH2:4][C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[O:22][CH3:23])[CH:2]=1
Reactant: CC[SiH](CC)CC
Reactant: COc1ccc(OC)c(C2OC(=O)c3c(OC)ccc(C)c32)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: COc1ccc(OC)c(Cc2cc(C)cc(OC)c2C(=O)O)c1
Temperature: 25 °C

Procedure:
4-Methyl-7-methoxy-3-(2',5'-dimethoxyphenyl)-1-(3H)-isobenzofuranone (17 g) and triethylsilane (15 g) were dissolved in dichloromethane (200 ml) and stirred at room temperature under nitrogen. Titanium tetrachloride (5N in CCl4, 25 ml) was added by syringe. The reaction mixture was stirred at room temperature for 4 hours. Water (10 ml) was added dropwise and the reaction mixture was concentrated down. The resulting slurry was dissolved (with heating) in 2N NaOH (aq) and filtered through celite. The filtrate was washed with diethyl ether (2×200 ml) and acidified with concentrated HCl (aq). The resulting precipitate was collected by filtration and dried to give 4-methyl-6-methoxy-2-(2',5'-dimethoxybenzyl)benzoic acid, m.p. 172°-174° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:12].Br[CH2:14][C:15](Cl)=[O:16]>>[NH:1]1[C:15](=[O:16])[CH2:14][O:12][C:3]2[CH:4]=[CH:5][C:6]3[C:11]([C:2]1=2)=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: Nc1c(O)ccc2ccccc12
Reactant: O=C(Cl)CBr
Product: O=C1COc2ccc3ccccc3c2N1

Procedure:
1-Amino-2-naphthol and bromoacetyl chloride are reacted in the same manner as described in Example 32 to give 1H-naphtho[2,1-b][1,4]oxazin-2(3H)-one.
Reaction SMILES: [F:1][CH:2]([F:22])[C:3]([NH:5][CH2:6][CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[NH:10][C:9]=1[C:18]([NH:20][CH3:21])=[O:19])=[O:4].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[CH2:34](I)[CH3:35]>O>[F:22][CH:2]([F:1])[C:3]([NH:5][CH2:6][CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:34][CH3:35])[CH:15]=2)[NH:10][C:9]=1[C:18]([NH:20][CH3:21])=[O:19])=[O:4]
Reactant: CCI
Reactant: CNC(=O)c1[nH]c2ccc(O)cc2c1CCNC(=O)C(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc2[nH]c(C(=O)NC)c(CCNC(=O)C(F)F)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 3-{2-[(difluoroacetyl)amino]ethyl}-5-hydroxy-N-methyl-1H-indole-2-carboxamide (102 mg) and N,N-dimethyl formamide (3.00 mL) were added potassium carbonate (55.2 mg) and ethyl iodide (0.0318 mL), followed by stirring at room temperature for 2 hours, then warming to 60° C., and stirring overnight. To this mixture was added water, followed by extraction with ethyl acetate, and the organic layer was washed with saturated brine and subsequently dried over anhydrous sodium sulfate. The insoluble materials were separated by filtration, the filtrate was concentrated under reduced pressure, and then the obtained residue was purified by silica gel chromatography (chloroform:methanol=100:0 to 94:6) to obtain a colorless solid. The obtained solid was washed with hexane:ethyl acetate=2:1 to obtain 3-{2-[(difluoroacetyl)amino]ethyl}-5-ethoxy-N-methyl-1H-indole-2-carboxamide (9.00 mg) as a colorless solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:18])[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:4]([O:19][CH3:20])[CH:3]=1.C([Li])CCC.CCCCCC.[B:32](OC(C)C)([O:37]C(C)C)[O:33]C(C)C>O1CCCC1>[CH3:20][O:19][C:4]1[CH:3]=[C:2]([B:32]([OH:37])[OH:33])[CH:7]=[CH:6][C:5]=1[NH:8][C:9](=[O:18])[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COc1cc(Br)ccc1NC(=O)CCc1ccccc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cc(B(O)O)ccc1NC(=O)CCc1ccccc1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 23.3 %

Procedure:
A solution of N1-(4-bromo-2-methoxyphenyl)-3-phenylpropanamide (1.004 g, 3 mmol) in anhydrous tetrahydrofuran (30 mL) at −78° C. was treated with a solution of 1.6 M n-butyl lithium in hexane (4.7 mL, 7.5 mmol). The reaction mixture was stirred at −78° C. for 40 min. Tri-isopropyl borate(1.05 mL, 4.5 mmol) was added to this reaction mixture, and stirred at −78° C. for 20 min. The acetone/dry ice bath was removed. The reaction mixture was stirred for 4 h at room temperature. The reaction mixture was quenched with 2.5 N hydrochloric acid solution (30 mL). The organic layer was removed under reduced pressure. Ethyl acetate was added to the acidic aqueous layer. The layers were partitioned, and the aqueous layer was extracted with ethyl acetate (250 mL). The combined organic layer was washed with water and brine, dried over magnesium sulfate, filtered and evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel, using 1:1 dichloromethane:ethyl acetate as eluent. The gradient was changed to 15% methanol in dichloromethane to remove the baseline product to give 0.209 g (23%) of 3-methoxy-4-[(3-phenylpropanoyl)amino]phenylboronic acid. 1H NMR (DMSO-d6, 400 MHz) δ 9.08 (s, 1H), 7.89-7.95 (m, 3H), 7.45-7.42 (s, 1H), 7.35-7.16 (m, 5H), 3.82 (s, 3H), 2.91-2.81 (m, 2H), 2.74-2.70 (s, 2H); HPLC Waters 2690 Alliance HPLC (Symmetry Shield RP18 3.5 μm, 2.1×50 mm; 5%-95% acetonitrile-0.1 M ammonium acetate over 15 min, 0.5 mL/min) Rt 5.389 min (95%).
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]1[C:16]([F:17])=[C:15]2[C:11]([C:12]([NH:26][C:27](=[O:31])[CH2:28][CH2:29][CH3:30])=[N:13][N:14]2[CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])=[CH:10][CH:9]=1.[Br:32]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl.ClCCl>[Br:32][C:9]1[CH:10]=[C:11]2[C:15](=[C:16]([F:17])[C:8]=1[F:7])[N:14]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:23])[CH3:24])[N:13]=[C:12]2[NH:26][C:27](=[O:31])[CH2:28][CH2:29][CH3:30]
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2c(F)c(F)ccc12
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2c(F)c(F)c(Br)cc12
Reaction time: 0.17 h

Procedure:
0.87 cm3 of pyridine is added to 1 g of N-[6,7-difluoro-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide, described previously, in 30 cm3 of chloroform, followed by addition of 0.56 cm3 of bromine, and the mixture is refluxed overnight. 50 cm3 of dichloromethane and 50 cm3 of aqueous 10% sodium thiosulphate solution are added to the reaction medium. After stirring for 10 minutes, the insoluble material is removed by filtration on a sinter funnel and the organic phase is washed with 50 cm 3 of water and with 50 cm3 of saturated sodium chloride solution. The organic phase is separated out after settling of the phases has taken place, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2 kPa; 45° C.). The crude product, 1.1 g, is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 3 cm), eluting with a cyclohexane/ethyl acetate mixture (90/10 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.). After drying (90 Pa; 45° C.), 230 mg of N-(5-bromo-6,7-difluoro-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl)butanamide are obtained in the form of a colourless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][CH2:10][CH2:11][CH2:12][OH:13].Cl.[N-]=[C:16]=[O:17].[K+]>O>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]2[N:9]([CH2:10][CH2:11][CH2:12][OH:13])[C:16](=[O:17])[NH:1][C:2]=2[CH:7]=1
Reactant: [N-]=C=O
Reactant: Nc1cc(Cl)ccc1NCCCO
Agent: Cl
Agent: [K+]
Solvent: O
Product: O=c1[nH]c2cc(Cl)ccc2n1CCCO
Reaction time: 20 h
Yield: 32 %

Procedure:
To a stirred solution of 40 parts of 3-[(2-amino-4-chlorophenyl)amino]-1-propanol in 140 parts of water and 24 parts of a hydrochloric acid solution 10N is added dropwise a solution of 18 parts of potassium isocyanate in 40 parts of water (exothermic reaction: temperature rises to 35° C.). Upon completion, stirring is continued first for 30 minutes at room temperature and further for 20 hours at reflux temperature. The reaction mixture is allowed to stirr over week-end without heating. The precipitated product is filtered off and treated with a diluted hydrochloric acid solution in 4-methyl-2-pentanone. The whole is stirred and the layers are separated. The 4-methyl-2-pentanone-phase is washed with water, dried, filtered and evaporated, yielding 18 parts (32%) of 5-chloro-1,3-dihydro-1-(3-hydroxypropyl)-2H-benzimidazol-2-one; mp. 148.8° C.