Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[N:7]([CH2:20][CH2:21][O:22][CH3:23])[C:6]=2[C:5]([O:24][CH3:25])=[CH:4][C:3]=1I.[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[N:7]([CH2:20][CH2:21][O:22][CH3:23])[C:6]=2[C:5]([O:24][CH3:25])=[CH:4][C:3]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(Br)c(I)cc(OC)c21
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(Br)c(-c3ccccc3)cc(OC)c21
Temperature: 100 °C
Reaction time: 12 h
Yield: 29.5 %

Procedure:
A mixture of 150 mg (0.283 mmol) 4-bromo-5-iodo-2-(4-isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-1H-benzoimidazole (example 30), 38 mg (0.312 mmol) phenylboronic acid, 60 mg (0.567 mmol) sodium carbonate and 16 mg (0.014 mmol) tetrakis(triphenylphosphine)palladium in 6 ml toluene/water (3:1) is stirred at 100° C. for 12 h. Then the reaction mixture is poured on water and extracted (3×) with ethyl acetate. The combined organic layers are washed with water (2×) and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by flash-chromatography on silica gel (hexane:EtOAc=3:1) to afford 40 mg of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[C:4]([NH:6][C:7]1[S:8][C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)=[C:10]([C:12](OC)=[O:13])[N:11]=1)=[O:5].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[F:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[C:4]([NH:6][C:7]1[S:8][C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)=[C:10]([CH2:12][OH:13])[N:11]=1)=[O:5]
Reactant: COC(=O)c1nc(NC(=O)c2c(F)cccc2F)sc1-c1cccc(F)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(Nc1nc(CO)c(-c2cccc(F)c2)s1)c1c(F)cccc1F
Yield: 92 %

Procedure:
The title compound was prepared by reducing Methyl 2-(2,6-difluorobenzamido)-5-(3-fluorophenyl)thiazole-4-carboxylate with lithium aluminum hydride (2 equiv) in THF. Yield: 92%. H-NMR(CDCl3) 7.50-6.90 (7H, m), 4.60 (2H, s). MS (ESI) [MH+] 365.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([C:10]2[C:14]3[CH:15]=[N:16][CH:17]=[CH:18][C:13]=3[N:12]([C:19]([CH3:30])([CH3:29])[CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH:11]=2)=[O:9])[CH:3]=1.[C:31]([C:33]1[CH:38]=[CH:37][C:36]([CH2:39][C:40](O)=[O:41])=[CH:35][CH:34]=1)#[N:32]>>[Si:22]([O:21][CH2:20][C:19]([N:12]1[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[C:10]([C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:40](=[O:41])[CH2:39][C:36]3[CH:37]=[CH:38][C:33]([C:31]#[N:32])=[CH:34][CH:35]=3)[CH:7]=[CH:6][N:5]=2)=[O:9])=[CH:11]1)([CH3:30])[CH3:29])([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:23])[CH3:24]
Reactant: N#Cc1ccc(CC(=O)O)cc1
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cc(N)ccn2)c2cnccc21
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cc(NC(=O)Cc3ccc(C#N)cc3)ccn2)c2cnccc21

Procedure:
Prepared according to the method described for Method M (Example 206) using (4-aminopyridin-2-yl)[1-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-dimethylethyl)-1H-pyrrolo[3,2-c]pyridin-3-yl]methanone (Preparation 27) and 4-cyanophenylacetic acid. The residue was purified using silca gel column chromatography eluting with EtOAc to afford the title compound that was taken directly on to the next step.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])([C:17]([OH:19])=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]([O-])([O-])=O.[Cs+].[Cs+].CI>C(#N)C>[C:24]([O:23][C:21]([NH:20][C:14]1([C:17]([O:19][CH3:28])=[O:18])[CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:12][CH2:13]1)=[O:22])([CH3:27])([CH3:26])[CH3:25]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(C(=O)OCc2ccccc2)CC1
Agent: [Cs+]
Solvent: CC#N
Solvent: CI
Product: COC(=O)C1(NC(=O)OC(C)(C)C)CCN(C(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 100.4 %

Procedure:
To an ice-cold solution of 1-((benzyloxy)carbonyl)-4-((tert-butoxycarbonyl)amino)piperidine-4-carboxylic acid (0.50 g, 1.32 mmol) in ACN (15 mL) was added Cs2CO3 (0.52 g, 1.59 mmol) and the resulting reaction mixture stirred at the same temperature for 10 min followed by addition of MeI (0.4 mL, 4.2 mmol). The reaction mixture was stirred for 1 h at rt. After completion of reaction (by TLC), the mixture was passed through celite and solvent was evaporated under reduced pressure to obtain a white solid compound (0.52 g, 96% yield). MS: 393.31 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9])[CH3:2].[C:10]1(C)C(O)=CC=C[CH:11]=1>>[CH2:10]([C:5]1[C:4]2[O:9][CH:2]=[CH:1][C:3]=2[CH:8]=[CH:7][CH:6]=1)[CH3:11]
Reactant: Cc1ccccc1O
Reactant: CCc1ccccc1O
Product: CCc1cccc2ccoc12

Procedure:
h. 7-Ethyl-benzofuran is prepared by the method described in J. Chem. Soc. 1920, 1934, but using o-ethylphenol inate of o-cresol. The MS. of the product thus obtained shows the following ion peaks with the relative intensities given within brackets: 131 (100%), 146 (38%) and 77 (10%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]([CH:19]=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[C:22]1([CH3:34])[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.CCN(C(C)C)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]([CH2:19][N:31]2[CH2:32][CH2:33][CH:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH3:34])[CH2:29][CH2:30]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccccc1C1CCNCC1
Reactant: O=CC1CN(Cc2ccccc2)CC1c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1C1CCN(CC2CN(Cc3ccccc3)CC2c2ccccc2)CC1
Yield: 84.1 %

Procedure:
The title compound was prepared from 21 mg of 1-Benzyl-3-(SR)-formyl-4-(SR)-phenylpyrrolidine, 16 mg of 4-(2-tolyl)-piperidine-hydrochloride, 0.013 mL of DIEA and 23 mg of sodium triacetoxy-borohydride using a procedure analogous to that described in Example 9, Step B to provide 27 mg of the title compound. HPLC (YMC "Octyl" 4.6×250 mm column, 60:40 v/v H2O/CH3CN+0.5% TFA, 1.5 mL/min, 200 nm): Retention Time: 6.69 min. 1H NMR (300 MHz, CDCl3): δ1.58-1.74 (m, 6H), 1.91-1.99 (m, 2H), 2.28 (s, 3H), 2.47-2.82 (m, 6H), 2.98-3.00 (m, 3H), 3.70 (ABq, J=13 Hz, 2H), 7.04-7.40 (m, 14H). Mass Spectrum (ESI): 425.2 (M+H).
Reaction SMILES: ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[OH:23][CH2:24][CH:25]1[CH2:33][CH:32]2[CH:28]([CH2:29][NH:30][CH2:31]2)[C:27]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[F:41])([OH:34])[CH2:26]1.[CH3:42][O:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[CH2:50][C:51](O)=[O:52]>ClCCl>[OH:23][CH2:24][CH:25]1[CH2:33][CH:32]2[CH:28]([CH2:29][N:30]([C:51](=[O:52])[CH2:50][C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=3[O:43][CH3:42])[CH2:31]2)[C:27]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[F:41])([OH:34])[CH2:26]1
Reactant: COc1ccccc1CC(=O)O
Reactant: OCC1CC2CNCC2C(O)(c2ccccc2F)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COc1ccccc1CC(=O)N1CC2CC(CO)CC(O)(c3ccccc3F)C2C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.7 %

Procedure:
0.066 g of 1-hydroxybenzotriazole and 1.15 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride are added to a solution, cooled to 0° C., of 1.48 g of (3aRS,4RS,6SR,7aSR)-6-hydroxymethyl-4-(2-fluorophenyl)perhydroisoindol-4-ol and 0.98 g of 2-methoxyphenylacetic acid in 20 cm3 of dichloromethane. The mixture is stirred at room temperature for 18 hours and then the organic phase is washed with 20 cm3 of water and subsequently with 20 cm3 of saturated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 2.8 cm, height 20 cm), eluting under a pressure of 0.5 bar of nitrogen with ethyl acetate and collecting fractions of 20 cm3. Fractions 27 to 50 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 1.33 g of (3aRS,4RS,6SR,7aSR)-6-hydroxymethyl-4-(2-fluorophenyl)-2-(2-methoxyphenylacetyl)perhydroisoindol-4-ol are obtained in the form of a thick white foam.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH3:15][C:16]1[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=1[NH2:18]>C1COCC1>[CH3:15][C:16]1[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=1[NH:18][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: Cc1ccccc1N
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Solvent: C1CCOC1
Product: Cc1ccccc1Nc1c([N+](=O)[O-])cnc2ccccc12
Yield: 43 %

Procedure:
4-Chloro-3-nitroquinoline (J. Med. Chem. 1974, 17, 245) (2.08 g, 0.01 mol) and 2-methylaniline (2.14 g, 0.02 mol) were dissolved in THF (50 ml) and the mixture stirred at reflux for 16 hours, during which time a pale yellow solid was deposited. After cooling, the solvent was evaporated and the residue dissolved in 2M HCl (80 ml). The acidic solution was extracted with CHCl3 (×3) and the chloroform solution washed with aqueous NaHCO3 and water. Drying and evaporation of the chloroform gave an orange-yellow solid which was crystallised from absolute ethanol to give the title compound (1.2 g, 43%) as orange needles, m.p. 137°-138°.
Reaction SMILES: [Br:1]Br.[C:3]([C:6]1[N:7]=[C:8]([C:11]([NH2:13])=[O:12])[S:9][CH:10]=1)(=[O:5])[CH3:4]>CO>[Br:1][CH2:4][C:3]([C:6]1[N:7]=[C:8]([C:11]([NH2:13])=[O:12])[S:9][CH:10]=1)=[O:5]
Reactant: BrBr
Reactant: CC(=O)c1csc(C(N)=O)n1
Solvent: CO
Product: NC(=O)c1nc(C(=O)CBr)cs1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
Bromine (1.3 g) was added slowly to a suspension of 4-acetylthiazole-2-carboxamide (1.3 g) in methanol (50 ml). The mixture was stirred for 3.5 hours at room temperature. The solvent was removed under reduced pressure to give 4-bromoacetylthiazole-2-carboxamide. The above residue and diaminomethylenethiourea (900 mg) were suspended in ethanol (50 ml) and the mixture was refluxed for 24 hours. The resulting precipitate was collected by filtration and suspended in water (50 ml). The mixture was alkalized to pH 11 with a saturated aqueous potassium carbonate solution. The resulting precipitate was collected by filtration. Recrystallization from methanol afforded 4-[2-(diaminomethyleneamino)thiazol-4-yl]thiazole-2-carboxamide (1.05 g).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][S:11]([C:14]3[CH:19]=[C:18]([CH2:20][C:21](=[O:23])[CH3:22])[CH:17]=[CH:16][C:15]=3[Cl:24])(=[O:13])=[O:12])=[CH:9][C:4]=2[O:3][CH2:2]1.C(O[CH:30](N(C)C)[N:31]([CH3:33])[CH3:32])(C)(C)C>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][S:11]([C:14]3[CH:19]=[C:18](/[C:20](=[CH:30]\[N:31]([CH3:33])[CH3:32])/[C:21](=[O:23])[CH3:22])[CH:17]=[CH:16][C:15]=3[Cl:24])(=[O:13])=[O:12])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(=O)Cc1ccc(Cl)c(S(=O)(=O)Nc2ccc3c(c2)OCO3)c1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Product: CC(=O)/C(=C/N(C)C)c1ccc(Cl)c(S(=O)(=O)Nc2ccc3c(c2)OCO3)c1

Procedure:
This compound is prepared analogously to Example 1-39 by replacing 2-Chloro-N-(3-cyano-phenyl)-5-(2-oxo-propyl)-benzenesulfonamide with N-Benzo[1,3]dioxol-5-yl-2-chloro-5-(2-oxo-propyl)-benzenesulfonamide and by replacing N,N-dimethylformamide dimethyl acetyl with t-butoxy-bis(dimethylamino) methane to afford the title compound.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C@@H:3]([O:17][CH3:18])[CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:22]1[N:27]=[C:26]([NH:28][C:29]2[CH:38]=[CH:37][CH:36]=[CH:35][C:30]=2[C:31]([NH:33][CH3:34])=[O:32])[C:25]([Cl:39])=[CH:24][N:23]=1>>[Cl:39][C:25]1[C:26]([NH:28][C:29]2[CH:38]=[CH:37][CH:36]=[CH:35][C:30]=2[C:31]([NH:33][CH3:34])=[O:32])=[N:27][C:22]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH2:4][C@H:3]([O:17][CH3:18])[C:2]([F:1])([F:19])[F:20])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:23][CH:24]=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CO[C@@H](CN1CCc2ccc(N)cc2CC1)C(F)(F)F
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCN(C[C@H](OC)C(F)(F)F)CC3)ncc1Cl

Procedure:
2-{5-Chloro-2-[3-((S)-3,3,3-trifluoro-2-methoxy-propyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-N-methyl-benzamide was prepared from 3-((S)-3,3,3-trifluoro-2-methoxy-propyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide in an analogous manner to Example 328c. Product isolated as a yellow solid (57 mg, 26%). m.p.=160-162° C.; LCMS (m/e) 549 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 11.08 (s, 1H), 8.68 (d, 1H, J=8.5 Hz), 8.11 (s, 1H), 7.50 (d, 1H, J=7.9 Hz), 7.48-7.42 (m, 1H), 7.36 (s, 1H), 7.30-7.25 (m, 1H), 7.13-7.07 (m, 1H), 7.04 (d, 1H, J=8.0 Hz), 3.76-3.67 (m, 1H), 3.62 (s, 3H), 3.06 (d, 3H, J=4.7 Hz), 2.94-2.86 (m, 4H), 2.86-2.82 (m, 2H), 2.79-2.73 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([CH2:10][CH2:11]OS(C)(=O)=O)[S:7][C:6]=2[CH:17]=1.[CH3:18][NH:19][CH3:20]>CO>[CH3:18][N:19]([CH3:20])[CH2:11][CH2:10][C:8]1[S:7][C:6]2[CH:17]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=2[CH:9]=1
Reactant: CNC
Reactant: Cc1ccc2cc(CCOS(C)(=O)=O)sc2c1
Solvent: CO
Product: Cc1ccc2cc(CCN(C)C)sc2c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
In a closed pressure vessel methanesulfonic acid 2-(6-methyl-benzo[b]thiophen-2-yl)-ethyl ester from the previous step was taken up in MeOH (30 mL) and a 40% solution of dimethylamine in MeOH (30 mL) was added. The mixture was stirred for 2 hours at 90° C., cooled down to room temperature and concentrated in vacuo to afford 3.55 g of dimethyl-[2-(6-methyl-benzo[b]thiophen-2-yl)-ethyl]-amine (97%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([CH:13]=O)=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7](=[O:15])[NH:8]2.C(O)(=O)C>[C].[Pd].C(O)C>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7](=[O:15])[NH:8]2
Reactant: COc1ccc(C=O)c2c1CCC(=O)N2
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccc(C)c2c1CCC(=O)N2
Reaction time: 1 h
Yield: 88.6 %

Procedure:
5-Methoxy-2-oxo-1,2,3,4-tetrahydroquinoline-8-carboxaldehyde (1.00 g) and 10% palladium carbon (100 mg) were added to a mixed solvent of acetic acid (10 ml) and ethanol (10 ml), followed by catalytic reduction at 50° C. for 1 hour. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to extraction with ethyl acetate, and the extract was washed twice with water, washed with a saturated sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized from an ethyl acetate-diethyl ether mixed solvent to thereby obtain 826 mg (yield: 89%) of 5-methoxy-8-methyl-3,4-dihydro-1H-quinolin-2-one as a white powder.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([F:11])=[C:6]([F:10])[CH:7]=[CH:8][CH:9]=1)[CH3:2].C([Li])(CC)C.[O:17]1[C:21]2([CH2:26][CH2:25][CH:24]([CH:27]3[CH2:32][CH2:31][C:30](=[O:33])[CH2:29][CH2:28]3)[CH2:23][CH2:22]2)[O:20][CH2:19][CH2:18]1.[Cl-].[NH4+]>C1COCC1>[O:17]1[C:21]2([CH2:22][CH2:23][CH:24]([CH:27]3[CH2:32][CH2:31][C:30]([C:7]4[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[C:5]([F:11])[C:6]=4[F:10])([OH:33])[CH2:29][CH2:28]3)[CH2:25][CH2:26]2)[O:20][CH2:19][CH2:18]1
Reactant: O=C1CCC(C2CCC3(CC2)OCCO3)CC1
Reactant: CCOc1cccc(F)c1F
Agent: [Cl-]
Agent: [Li]C(C)CC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOc1ccc(C2(O)CCC(C3CCC4(CC3)OCCO4)CC2)c(F)c1F
Reaction time: 2 h

Procedure:
3-Ethoxy-1,2-difluorobenzene (s65) (10.0 g) and THF (200 ml) were placed in a reaction vessel under an atmosphere of nitrogen, and cooled to −74° C. sec-Butyllithium (1.00 M, in n-hexane-cyclohexane; 64.0 ml) was added dropwise in the temperature range of −74° C. to −70° C., and the stirring was continued for another 2 hours. 4-(1,4-Dioxaspiro[4.5]decan-8-yl)-cyclohexanone (s66) (12.8 g) in THF (50 ml) solution was added dropwise in the temperature range of −75° C. to −70° C., and the stirring was continued for another 8 hours while the mixture was allowed to come to 25° C. The reaction mixture was treated with an aqueous solution of ammonium chloride (3%), and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. Distillation of the solvent under reduced pressure gave 4-(1,4-dioxaspiro[4.5]decan-8-yl)-1-(4-ethoxy-2,3-difluorophenyl)-cyclohexanol. The compound was mixed with p-toluenesulfonic acid (0.68 g) and toluene (200 ml), and the mixture was heated to reflux for 2 hours while distilled water was removed. After the reaction mixture had been cooled to 30° C., it was treated with water, and the aqueous layer was extracted with toluene. The combined organic layers were washed with a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and the residue was purified by column chromatography with toluene as an eluent and silica gel as a stationary phase powder. Pd/C (0.3 g) was added to the purified product and the mixture was stirred at room temperature under a hydrogen atmosphere until hydrogen absorption had ceased. After the reaction had been completed, Pd/C was removed, and then solvent was distilled off. The residue was purified by recrystallization from a mixed solvent of THF and heptane (THF:heptane=1:9 by volume) to give 8-[4-(4-ethoxy-2,3-difluorophenyl)-cyclohexenyl]-1,4-dioxaspiro[4.5]decane (s67) (7.7 g). The yield based on the compound (s65) was 35.2%.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:23][C:24]([O:26]CC)=[O:25])[CH:8]=2)[N:3]=1.[OH-].[Na+]>O1CCCC1>[NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:15][C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:22]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:23][C:24]([OH:26])=[O:25])[CH:8]=2)[N:3]=1
Reactant: CCOC(=O)Cc1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(CC(=O)O)ccc2n1
Temperature: 23 °C
Reaction time: 12 h

Procedure:
2.7 g of ethyl 2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]acetate are dissolved in 40 ml of tetrahydrofuran, and 25 ml of 2N sodium hydroxide solution are added. The mixture is stirred at 23° C. for 12 h, evaporated to dryness in vacuo, taken up in 10 ml of water and adjusted to pH 2 using 7 ml of 25% hydrochloric acid. The resultant precipitate is filtered off and dried in vacuo.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH2:18][C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:20][C:21]1[C:25]([C:26]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:27])=[CH:24][NH:23][C:22]=1[CH:34]=O>N1CCCCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18](=[CH:34][C:22]4[NH:23][CH:24]=[C:25]([C:26]([N:28]5[CH2:29][CH2:30][O:31][CH2:32][CH2:33]5)=[O:27])[C:21]=4[CH3:20])[C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1c(C(=O)N2CCOCC2)c[nH]c1C=O
Reactant: O=C1Cc2c(ncnc2Nc2ccc(F)c(Cl)c2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1c(C(=O)N2CCOCC2)c[nH]c1C=C1C(=O)Nc2ncnc(Nc3ccc(F)c(Cl)c3)c21
Temperature: 25 °C
Reaction time: 96 h
Yield: 32.3 %

Procedure:
A mixture of 4-(3-chloro-4-fluoro-phenylamino)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (70 mg, 0.25 mmol), 3-methyl-4-(morpholine-4-carbonyl)-1H-pyrrole-2-carbaldehyde (66.7 mg, 0.3 mmol) and piperidine (3 drops) in ethanol (2 mL) was stirred at room temperature for 4 days. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 39 mg (32%) of the title compound. 1H NMR (360 MHz, DMSO-d6) δ 13.30 (br s, 1H, NH), 11.69 (br s, 1H, NH), 9.16 (br s, 1H), 8.31 (s, 1H), 7.72 (dd, J=2.8 & 6.7 Hz, 1H), 7.46 (d, J=2.8 Hz, 1H), 7.43 (m, 1H), 7.41 (s, 1H), 7.35 (t, J=9 Hz, 1H), 3.59 (m, 4H, 2×CH2), 3.51 (m, 4H, 2×CH2), 2.21 (s, 3H, CH2). MS 483 [M++1].
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4](=NN)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11].[OH-].[K+]>C(O)COCCO>[Cl:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[CH2:4][C:3]1[CH:14]=[CH:15][CH:16]=[CH:17][C:2]=1[NH2:1]
Reactant: NN=C(c1ccccc1N)c1ccccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Product: Nc1ccccc1Cc1ccccc1Cl

Procedure:
In the manner given in Preparation 11, 2-amino-2'-chlorobenzophenone hydrazone is refluxed with potassium hydroxide in diethylene glycol to give 2-(o-chlorobenzyl)aniline.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:26])[CH3:25])[CH2:20][CH2:19]2)=[N:4][CH:5]=[C:6]([N+:8]([O-])=O)[CH:7]=1>C(OCC)(=O)C>[NH2:8][C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:18]2[CH2:19][CH2:20][N:21]([C:24](=[O:26])[CH3:25])[CH2:22][CH2:23]2)=[N:4][CH:5]=1
Reactant: CC(=O)N1CCN(c2ccccc2Oc2ncc([N+](=O)[O-])cc2Cl)CC1
Solvent: CCOC(C)=O
Product: CC(=O)N1CCN(c2ccccc2Oc2ncc(N)cc2Cl)CC1
Reaction time: 18 h

Procedure:
Compound of step i (3.15 g, 8.34 mmol) was dissolved in ethyl acetate (50 mL). Stannous chloride dihydrate (7.52 g, 33.36 mmol) was added at room temperature (25° C.) and stirring was continued for 18 hours. Solvent was removed under vacuum and chloroform (50 mL) was added. 1 N sodium hydroxide solution was added until a clear solution was obtained. Separated the organic layer was separated and extracted with chloroform. The chloroform layer was washed with brine & water successively, dried over sodium sulfate and concentrated under vacuum to obtain crude product that was further purified by column chromatography (silica gel-˜200 mesh, 1% methanol in chloroform) to obtain the title compound.
Reaction SMILES: [Br:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([N+:12]([O-])=O)[C:5]([NH:15][CH:16]([CH2:18]C(OCC)=O)[CH3:17])=[CH:4][CH:3]=1.[Sn](Cl)Cl.[C:27](OCC)(=[O:29])C.C(=O)([O-])O.[Na+]>C(O)C>[Br:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]2[C:5]([NH:15][C:16]([CH3:17])([CH3:18])[C:27](=[O:29])[NH:12]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(C)Nc1ccc(Br)c(C(=O)OC)c1[N+](=O)[O-]
Reactant: CCOC(C)=O
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COC(=O)c1c(Br)ccc2c1NC(=O)C(C)(C)N2
Yield: 70 %

Procedure:
Methyl 6-bromo-3-[(2-ethoxycarbonyl)propan-2-yl]amino-2-nitrobenzoate (Reference Compound No. 1-(5), 105 mg, 0.26 mmol) was dissolved in anhydrous ethanol (4.5 mL), tin (II) chloride (247 mg, 1.30 mmol) was added thereto, and then the reaction mixture was refluxed for 5 hours. After cooling down, ethyl acetate (25 mL) was added to the reaction mixture, the mixture was neutralized with aqueous sodium hydrogen carbonate solution, and then filtered on celite. After the filtrate was partitioned, the water layer was extracted with ethyl acetate (10 mL, twice), the combined organic layer was washed with water (50 mL, twice) and saturated brine (50 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (56.3 mg) as a pale yellow solid. (Yield 70%)