Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[N:11]([CH2:12][C:13]([N:15]3[CH2:20][CH2:19][CH:18](NC)[CH2:17][CH2:16]3)=[O:14])[N:10]=[C:9]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[CH:8]=2)=[CH:4][CH:3]=1.[CH2:31]([N:33](CC)CC)C.Cl[C:39]([O:41][CH3:42])=[O:40]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[N:11]([CH2:12][C:13]([N:15]3[CH2:16][CH2:17][CH:18]([CH2:31][NH:33][C:39](=[O:40])[O:41][CH3:42])[CH2:19][CH2:20]3)=[O:14])[N:10]=[C:9]([C:23]3[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=3)[CH:8]=2)=[CH:29][CH:30]=1
Reactant: CNC1CCN(C(=O)Cn2nc(-c3ccncc3)cc2Cc2ccc(F)cc2)CC1
Reactant: COC(=O)Cl
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)NCC1CCN(C(=O)Cn2nc(-c3ccncc3)cc2Cc2ccc(F)cc2)CC1
Reaction time: 0.17 h

Procedure:
To a solution of 1-{[5-(4-fluorobenzyl)-3-pyridin-4-yl-1H-pyrazol-1-yl]acetyl}-N-methylpiperidin-4-amine (150 mg, 0.37 mmol) in DCM (3 mL) at room temperature was added triethylamine (56 μL, 0.40 mmol) followed by methyl chloroformate (29 μL, 0.37 mmol) and the solution stirred for 10 minutes. The solution was then loaded directly onto a pre-wetted Biotage 25M column for flash chromatography and eluted with 2-8% MeOH/DCM to yield the title compound as a white solid, 122 mg, 71%. 1H NMR (400 MHz, DMSO-D6) δ ppm 8.52 (2 H, d, J=4.80 Hz), 7.66 (2 H, d, J=5.05 Hz), 7.30 (2 H, dd, J=8.34, 5.81 Hz), 7.15 (2 H, t, J=8.72 Hz), 6.52 (1 H, s), 5.10-5.27 (2 H, m), 4.38 (1 H, d, J=12.63 Hz), 3.99-4.16 (1 H, m), 3.85-4.00 (3 H, m), 3.59 (3 H, s), 3.04-3.16 (1 H, m), 2.70 (3 H, s), 2.56-2.67 (1 H, m), 1.41-1.75 (4 H, m); m/z (APCI+) for C25H28N5O3F 466.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH2:13][C:14]1[CH:18]=[CH:17][NH:16][N:15]=1.O=[C:20]([CH2:27][CH2:28][CH3:29])[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>>[Cl:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]1[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:20]([CH2:27][CH2:28][CH3:29])[NH:13][C:14]2=[N:15][NH:16][CH:17]=[C:18]12
Reactant: CCCC(=O)CC(=O)OCC
Reactant: O=Cc1cccc([N+](=O)[O-])c1Cl
Reactant: Nc1cc[nH]n1
Product: CCCC1=C(C(=O)OCC)C(c2cccc([N+](=O)[O-])c2Cl)c2c[nH]nc2N1

Procedure:
To a solution of 2-chloro-3-nitrobenzoic acid (5.0 g) in THF (50 ml) was added borane-tetrahydrofuran complex (1M THF solution, 30 ml) under ice-cooling and the mixture was stirred at room temperature for 24 hours. To the reaction mixture was added a saturated aqueous sodium hydrogencarbonate solution and the mixture was extracted with ethyl acetate. The extract was washed with water and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated to give a pale-yellow solid (3.7 g). The obtained pale-yellow solid (1.6. g) and manganese dioxide (1.7 g) were heated under reflux in toluene for 4.5 hours. The insoluble material was filtered off and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (4:1)) to give 2-chloro-3-nitrobenzaldehyde (1.3 g) as a pale-yellow solid. Subsequently, the title compound was prepared from 2-chloro-3-nitrobenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])[CH:18]=2)[CH2:9][CH:10]([OH:15])[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:6][CH:7]=1.C(O)(=O)C.[CH:34](=O)[CH:35]([CH3:37])[CH3:36].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C>[CH3:34][CH:35]([CH3:37])[CH2:36][NH:1][C:2]1[CH:3]=[C:4]([N:8]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:28])([F:29])[CH:25]([F:26])[F:27])[CH:18]=2)[CH2:9][CH:10]([OH:15])[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C=O
Reactant: Nc1cccc(N(Cc2cccc(OC(F)(F)C(F)F)c2)CC(O)C(F)(F)F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CC(C)CNc1cccc(N(Cc2cccc(OC(F)(F)C(F)F)c2)CC(O)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 27.8 %

Procedure:
The 3-[(3-aminophenyl)[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol (50 mg, 0.12 mmol) was dissolved in 1 mL of dichloroethane. Acetic acid (8 μL, 0.14 mmol) followed by isobutyraldehyde (11.7 μL, 0.13 mmol) and solid NaBH(OAc)3 (37.3 mg, 0.18 mmol) were added. The solution was stirred at room temperature for 18 hours. The reaction was filtered through pre-wetted celite eluting with ethyl acetate. The solvent was evaporated, and the residue was purified by reverse phase HPLC eluting with 10% to 90% acetonitrile in water to afford 16.1 mg (29%) of the desired 3-[[3-[(2-methylpropyl)amino]phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as a yellow oil, which was greater pure by reverse phase HPLC analysis. HRMS calcd. for C22H26F7N2O2: 483.1883 [M+H]+, found: 483.1932. 1H NMR (CDCl3) δ 1.0 (m, 6H), 2.0 (m, 1H), 3.0 (m, 2H), 3.6 (dd, 1H), 3.8 (dd, 1H), 4.3 (m, 1H), 4.6 (m, 2H), 5.9 (tt, 1H), 6.6 (d, 1H), 6.7 (d, 1H), 6.9-7.4 (m, 6H).
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:27])[CH2:7][CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][C:22]([S:25][CH3:26])=[CH:21][N:20]=3)[CH:13]=2)[CH2:9][C:10]=1[OH:11])(=O)[CH2:2][CH3:3].Cl.[CH2:29]([O:31][NH2:32])[CH3:30].C([O-])(=O)C.[Na+].O>ClCCl.C(O)C>[CH2:29]([O:31][N:32]=[C:1]([C:5]1[C:10](=[O:11])[CH2:9][CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][C:22]([S:25][CH3:26])=[CH:21][N:20]=3)[CH:13]=2)[CH2:7][C:6]=1[OH:27])[CH2:2][CH3:3])[CH3:30]
Reactant: CCC(=O)C1=C(O)CC(c2cccc(Oc3ccc(SC)cn3)c2)CC1=O
Reactant: CCON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: CCON=C(CC)C1=C(O)CC(c2cccc(Oc3ccc(SC)cn3)c2)CC1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 2.1 g (0.0055 mol) of 2-propionyl-3-hydroxy-5-(3-(5-(methylthio)-2-pyridyloxy)phenyl)cyclohex-2-en-1-one, 0.45 g (0.0061 mol) of ethoxyamine hydrochloride and 0.50 g (0.0061 mol) of sodium acetate in 8 mL of dichloromethane and 12 mL of absolute ethanol was stirred under a nitrogen atmosphere at room temperature for about 20 hours. The reaction mixture was poured into 100 mL of water and extracted thrice with 10 mL portions of dichloromethane. The solvent extracts were combined, dried over MgSO4, filtered through silica gel and the solvent removed by evaporation leaving a residue which solidified upon standing. Recrystallization of the residue from hexane gave the above named product in a yield of 2.2 g (94 percent of theoretical). The product melted at 75°-78° C.; 1H NMR (CDCl3): δ1.08-1.52 (m, 6H, both --CH2CH3 's), 2.45 (s, 3H, --SCH3), 2.60-3.65 (m, 7H, --CH(CH2)2 and --CH2CH3), 6.80-7.55 (m, 5H, ArH's), 7.75 (dd, J=9 Hz and 2H, 1H, ArH), 8.18 (d, J=2 Hz, ArH), 15.1 (br s, 1H, enol H) (Compound 4).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([N+:9]([O-])=O)[C:3]=1[OH:12].[H][H]>[Pt]=O.CO>[NH2:9][C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[C:3]=1[OH:12]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(Cl)cc(Cl)c1O
Agent: O=[Pt]
Solvent: CO
Product: Nc1cc(Cl)cc(Cl)c1O

Procedure:
The starting material, 2,4-dichloro-6-nitrophenol (260 g, 1 mole, 20% in water), was mixed with methanol (2 liters) and platinum oxide catalyst, and the resulting slurry was reacted with hydrogen at 4.2 kg/cm2 (60 psi) and room temperature.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:27]2[N:36]=[CH:35][C:34]3[C:29](=[C:30]([F:41])[CH:31]=[C:32]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH:33]=3)[C:28]2=[O:42])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[N:23]([CH3:24])[N:22]=[N:21][CH:20]=2)[C:15](=[O:25])[N:14]([CH3:26])[CH:13]=1)(=O)C.[OH-].[Li+]>C(O)(C)C.C1COCC1.O>[C:37]([C:32]1[CH:33]=[C:34]2[C:29](=[C:30]([F:41])[CH:31]=1)[C:28](=[O:42])[N:27]([C:7]1[C:6]([CH2:5][OH:4])=[C:11]([C:12]3[CH:17]=[C:16]([NH:18][C:19]4[N:23]([CH3:24])[N:22]=[N:21][CH:20]=4)[C:15](=[O:25])[N:14]([CH3:26])[CH:13]=3)[CH:10]=[CH:9][N:8]=1)[N:36]=[CH:35]2)([CH3:40])([CH3:38])[CH3:39]
Reactant: CC(=O)OCc1c(-c2cc(Nc3cnnn3C)c(=O)n(C)c2)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(C)O
Solvent: O
Product: Cn1nncc1Nc1cc(-c2ccnc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2CO)cn(C)c1=O
Temperature: 30 °C
Reaction time: 1 h
Yield: 13.8 %

Procedure:
A mixture of 154c (85 mg, 0.15 mmol) and lithium hydroxide (36 mg, 1.5 mmol) in i-propanol/THF (1:1, 4 mL) and water (1 mL) was stirred at 30° C. for 1 h. The mixture was evaporated under reduced pressure and the residue was extracted diluted with water (5 mL). It was then with ethyl acetate (2×10 mL). The combined ethyl acetate extract was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford the title compound (11 mg, 16%) as a white solid. MS-ESI: [M+H]+ 531.4. 1H NMR (500 MHz, DMSO-d6) δ 8.54-8.53 (m, 2H), 8.03 (s, 1H), 7.91 (d, J=1.5 Hz, 1H), 7.80-7.76 (m, 1H), 7.75 (s, 1H), 7.55 (d, J=2.5 Hz, 1H), 7.52 (d, J=5.0 Hz, 1H), 6.89 (d, J=2.5 Hz, 1H), 5.04 (t, J=5.0 Hz, 1H), 4.34 (d, J=5.0 Hz, 2H), 3.88 (s, 3H), 3.63 (s, 3H), 1.40 (s, 9H).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]1[N:13]=[CH:12][C:11]([C:14]2[N:19]=[C:18]([NH2:20])[CH:17]=[CH:16][CH:15]=2)=[CH:10][N:9]=1.[CH3:23][S-:24].[Na+].[CH2:26]=O>C1COCC1.O>[CH3:23][S:24][CH2:26][NH:20][C:18]1[CH:17]=[CH:16][CH:15]=[C:14]([C:11]2[CH:10]=[N:9][C:8]([N:4]3[CH2:5][CH2:6][CH2:7][C@H:3]3[C:2]([F:1])([F:21])[F:22])=[N:13][CH:12]=2)[N:19]=1
Reactant: Nc1cccc(-c2cnc(N3CCC[C@H]3C(F)(F)F)nc2)n1
Reactant: C=O
Reactant: C[S-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CSCNc1cccc(-c2cnc(N3CCC[C@H]3C(F)(F)F)nc2)n1
Temperature: 90 °C
Yield: 75.4 %

Procedure:
A 350 mL pressure vessel was charged with (S)-6-(2-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-yl)pyridine-2-amine (Intermediate 3, 10 g, 32.3 mmol) and sodium methanethiolate (4.53 g, 64.7 mmol), which were dissolved in a mixture of THF (64.7 mL) and water (43.1 mL). Aqueous 37% formaldehyde (5.25 mL, 64.7 mmol) was added and the reaction mixture was heated to 90° C. for 2 hours. Another 2 eq. of aqueous 37% formaldehyde were added and the reaction mixture was heated for an additional 2 hours. The reaction mixture was then cooled to 25° C. The layers were separated in the separatory funnel and the aqueous layer was extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified using silica gel chromatography, eluting with EtOAc:Hex (30:70) to yield 9 g (24.36 mmol, 75%) of the title product as an oil; 1H NMR (300 MHz, DMSO-d6) δ 9.07 (s, 2H), 7.56-7.43 (m, 1H), 7.41 (t, J=6.6 Hz, 1H), 7.13 (d, J=7.3 Hz, 1H), 6.51 (d, J=8.2 Hz, 1H), 5.18-4.98 (m, 1H), 4.59 (d, J=6.7 Hz, 2H), 3.69 (dd, J=10.3, 4.9 Hz, 2H), 2.21-2.0 (m, 4H), 2.12 (s, 3H); m/z found [M+H]+=370.35.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[C:9]([N:11]1[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]1)=[O:10])(C)(C)C.[ClH:27].O1CCOCC1>>[ClH:27].[NH2:7][C@H:8]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=1)[C:9]([N:11]1[CH2:12][CH2:13][CH:14]([OH:17])[CH2:15][CH2:16]1)=[O:10]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(F)cc1)C(=O)N1CCC(O)CC1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@H](Cc1ccc(F)cc1)C(=O)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(R)-[1-(4-Fluoro-benzyl)-2-(4-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-carbamic acid-tert-butyl ester (2.6 mmol) was dissolved in 4M HCl-dioxane (2 mL) at 0° C. The solution was stirred 2 hours at 25° C., concentrated and the residue triturated with ether. Yield, 920 mg, 124%; HPLC (60/40) 2.23 minutes (98%).
Reaction SMILES: CN(C)C1C=CC(C=[CH:8][CH:9]=[O:10])=CC=1.CN(C)C1C=CC(C=O)=CC=1.[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:28]=1[CH:29]=O>>[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:28]=1[CH:29]=[CH:8][CH:9]=[O:10]
Reactant: CN(C)c1ccc(C=CC=O)cc1
Reactant: COc1ccc(OC)c(C=O)c1
Agent: CN(C)c1ccc(C=O)cc1
Product: COc1ccc(OC)c(C=CC=O)c1

Procedure:
Using the procedure described by Konig et al., supra, for the preparation of 4-dimethylaminocinnamaldehyde but replacing the 4-dimethylaminobenzaldehyde employed as starting material by 2,5-dimethoxybenzaldehyde, there was obtained 2,5-dimethoxycinnamaldehyde.
Reaction SMILES: [BH4-].[Li+].C([O:5][C:6]([CH:8]1[CH:12]([OH:13])[CH2:11][N:10]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:9]1)=O)C>O1CCCC1.CO.C(Cl)(Cl)Cl>[CH2:17]([O:16][C:14]([N:10]1[CH2:9][CH:8]([CH2:6][OH:5])[CH:12]([OH:13])[CH2:11]1)=[O:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)C1CN(C(=O)OCc2ccccc2)CC1O
Agent: [BH4-]
Agent: [Li+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: CO
Product: O=C(OCc1ccccc1)N1CC(O)C(CO)C1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To the solution of lithium borohydride (0.305 g, 13 mmol) in anhydrous tetrahydrofuran (25 mL) was added a solution of ethyl ester 73 (2.69 g, 9.2 mmol) in THF (25 mL) over a period of 30 mins at 0° C. After the addition the reaction mixture was brought to room temperature and stirred further under argon. The completion of the reaction was ascertained by TLC after 4 h. (Rf=0.3 in 10% MeOH/CHCl3). The reaction mixture was evaporated to dryness and cooled to 0° C. To the residue 3N HCl (40 mL) was added slowly. After stirring for 30 mins the product was extracted with dichloromethane (3×75 mL). The combined organic layer was washed with brine and dried over sodium sulfate. Organic layer was filtered and evaporated to dryness. Compound 74 was purified by column chromatography first by eluting with dichloromethane/methanol (5%) (1.98 g, 85%).
Reaction SMILES: OC1[CH:7]=[CH:6][C:5]([C:8]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)([CH2:10][CH3:11])[CH3:9])=CC=1.[CH3:19]C(=C)C>C1(C)C=CC=CC=1>[OH:18][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[C:8]([CH3:9])([CH2:10][CH3:11])[CH2:5][C:6]2([CH3:7])[CH3:19]
Reactant: CCC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: C=C(C)C
Solvent: Cc1ccccc1
Product: CCC1(C)CC(C)(C)c2cc(O)ccc21

Procedure:
121 g (0.5 mol) of 2,2-bis-(4-hydroxyphenyl)-butane, 22 g of an acid-activated fuller's earth and 90 g (1.6 mol) of isobutylene are stirred in an autoclave for 6 hours at 180° C. After cooling, the reaction mixture is taken up in 150 ml of toluene, the catalyst filtered off and the solvent evaporated. The residue is fractionated through a 1 meter glass-packed column, giving at a boiling temperature of 155° to 160° C./12 Torr 37 g of a fraction from which 24.8 g (20 % of the theoretical) of 5-hydroxy-1,3,3-trimethyl-1-ethyl indane (V) melting at 86° C. are obtained by recrystallisation from 90 ml of petroleum ether. ##STR23##
Reaction SMILES: [NH2:1][CH:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.CN1CCOCC1.[Cl:17][C:18]1[CH:19]=[C:20]([C:30](Cl)=[O:31])[C:21]2[O:26][CH2:25][C:24](=[O:27])[N:23]([CH3:28])[C:22]=2[CH:29]=1>C(Cl)(Cl)Cl>[ClH:17].[Cl:17][C:18]1[CH:19]=[C:20]([C:30]([NH:1][CH:2]2[CH:7]3[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]3)[CH2:3]2)=[O:31])[C:21]2[O:26][CH2:25][C:24](=[O:27])[N:23]([CH3:28])[C:22]=2[CH:29]=1
Reactant: CN1C(=O)COc2c(C(=O)Cl)cc(Cl)cc21
Reactant: NC1CN2CCC1CC2
Solvent: ClC(Cl)Cl
Solvent: CN1CCOCC1
Product: CN1C(=O)COc2c(C(=O)NC3CN4CCC3CC4)cc(Cl)cc21
Product: Cl

Procedure:
To a solution of 3.0 g of 3-aminoquinuclidine and 3.0 g of N-methylmorpholine in 60 ml of chloroform is added 6.2 g of 6-chloro-3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzoxazine-8-carboxylic acid chloride under cooling and stirring followed by stirring for 2 hours. The resultant solution is washed with water, aqueous sodium hydrogen carbonate and then water, and dried over magnesium sulfate. After the solvent is distilled off under reduced pressure, the residue is recrystallized from ethanol-isopropyl ether and treated with ethanolic hydrochloric acid to give 6-chloro-3,4-dihydro-4-methyl-3-oxo-N-(3-quinuclidinyl)-2H-1,4-benzoxazine-8-carboxamide hydrochloride, melting at 281° C. with decomposition.
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.S(=O)(=O)(O)O.[N+:14]([O-:17])([OH:16])=[O:15]>>[Br:1][C:2]1[C:7]([OH:8])=[C:6]([N+:14]([O-:16])=[O:15])[CH:5]=[CH:4][N:3]=1.[Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([N+:14]([O-:17])=[O:15])[N:3]=1
Reactant: Oc1cccnc1Br
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1ccc(O)c(Br)n1
Product: O=[N+]([O-])c1ccnc(Br)c1O
Temperature: 0 °C
Reaction time: 12 h

Procedure:
To a solution of 13 g (73.2 mmol) 2-bromo-3-pyridinol (Fluka 18292) in 40 ml of cone, sulfuric acid 5.1 ml (74 mmol) of nitric acid (65%) are added at 0° C. The reaction mixture is stirred at 0° C. for 12 h, then poured on water and extracted 2× with EtOAc. The combined organic layers are washed with water and saturated NaCl solution, dried over MgSO4, filtered and the filtrate is concentrated in vacuo. The residue is purified by chromatography (silicagel, EtOAc) to afford 5.3 g of 2-bromo-4-nitro-pyridin-3-ol and 2 g of 2-bromo-6-nitro-pyridin-3-ol.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6]([CH3:9])=[N:7][O:8][C:4]=2[C:3]=1[C:12]([O:14][CH3:15])=[O:13].[CH3:16][O:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[N:21]=[C:20](S(C)(=O)=O)[N:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:16][O:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[N:21]=[C:20]([O:1][C:2]2[CH:11]=[CH:10][C:5]3[C:6]([CH3:9])=[N:7][O:8][C:4]=3[C:3]=2[C:12]([O:14][CH3:15])=[O:13])[N:19]=1
Reactant: COC(=O)c1c(O)ccc2c(C)noc12
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1c(Oc2nc(OC)cc(OC)n2)ccc2c(C)noc12
Temperature: 70 °C
Reaction time: 2 h
Yield: 73.8 %

Procedure:
A mixture comprising 1.3 g of methyl 6-hydroxy-3-methyl-benzisoxazol-7-carboxylate, 1.4 g of 4,6-dimethoxy-2-methylsulfonylpyrimidine and 1 g of potassium carbonate in 20 ml of N,N-dimethylformamide, was heated and stirred at 70° C. for two hours. The mixture was returned to room temperature, poured into ice water and extracted with ethyl acetate. The organic layer was washed with water and then dried over anhydrous sodium sulfate. Then, it was concentrated under reduced pressure, and the obtained crystals were thoroughly washed with isopropyl ether to obtain 1.6 g (yield: 73%) of the desired compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.N1C=CC=CC=1.[C:18]1([S:24](Cl)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(#N)C.C(OCC)(=O)C>[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[C:2]([NH:1][S:24]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:26])=[O:25])[CH:3]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1cnc2ccccc2c1
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cnc2ccccc2c1)c1ccccc1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
To a solution of 3-aminoquinoline (7.2 g, 50 mmol) in acetonitrile (150 mL) was added pyridine (25 mL) and the resulting mixture was cooled to 0° C. A solution of benzenesulfonyl chloride (7 mL, 55 mmol) in acetonitrile (20 mL) was added dropwise over 30 minutes. The mixture was allowed to warm to rt and stirred for 18 hours. The mixture was diluted with ethyl acetate (100 mL) and washed successively with 1N HCl, brine and saturated CuSO4, dried (MgSO4), and concentrated in vacuo to afford an oil. Purification by flash silica gel column chromatography eluting with 30% ethyl acetate in hexanes afforded compound C (13. g g, 95%) as a white solid. MS; (M+H)+=285
Reaction SMILES: C(OC(=O)[CH2:10][N:11]([C:13]1[CH:18]=[C:17]([CH3:19])[N:16]=[C:15]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]3)=[C:23]([O:33][CH3:34])[CH:22]=2)[N:14]=1)[CH3:12])C1C=CC=CC=1.[CH3:36][Mg]Cl.C([O:42][CH2:43][CH3:44])(=O)C>O1CCCC1>[CH3:34][O:33][C:23]1[CH:22]=[C:21]([NH:20][C:15]2[N:14]=[C:13]([N:11]([CH3:12])[CH2:10][C:43]([CH3:44])([OH:42])[CH3:36])[CH:18]=[C:17]([CH3:19])[N:16]=2)[CH:26]=[CH:25][C:24]=1[N:27]1[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]1
Reactant: COc1cc(Nc2nc(C)cc(N(C)CC(=O)OCc3ccccc3)n2)ccc1-n1cnc(C)c1
Reactant: CCOC(C)=O
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: COc1cc(Nc2nc(C)cc(N(C)CC(C)(C)O)n2)ccc1-n1cnc(C)c1
Temperature: 0 °C
Yield: 100 %

Procedure:
A solution of ({2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-6-methyl-pyrimidin-4-yl}-methyl-amino)-acetic acid benzyl ester (32 mg, 0.07 mmol) in 2 mL of tetrahydrofurane was cooled in an ice-bath and treated with a 3 molar solution of methyl magnesium chloride in tetrahydrofurane (0.15 mL, 1.5 mmol). The mixture was stirred for 10 minutes in the ice-bath and for additional 2 hours at 20° C. Hydrolysis and extraction with ethyl acetate gave the title compound as a yellowish sticky gum (27 mg, 100%). MS ISP (m/e): 397.3 (100) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.62 (s, 1H), 7.52 (s, 1H), 7.37 (d, 1H), 7.30-7.10 (m, 2H), 6.86 (s, 1H), 5.98 (s, 1H), 3.834 (s, 3H), 3.62 (s, 2H), 3.19 (s, 3H), 2.33 (s, 3H), 2.29 (s, 3H), 1.25 (s, 6H).
Reaction SMILES: CO[C:3]1[C:8]([O:9]C)=[CH:7][CH:6]=[CH:5][C:4]=1[C:11](=[O:23])[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([O:21]C)=[CH:17][CH:16]=1)=[O:14]>CC(O)=O.O>[OH:9][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[O:14][C:13]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)=[CH:12][C:11]2=[O:23]
Reactant: COc1ccc(C(=O)CC(=O)c2cccc(OC)c2OC)cc1
Solvent: CC(=O)O
Solvent: O
Product: O=c1cc(-c2ccc(O)cc2)oc2c(O)cccc12
Temperature: 110 °C
Yield: 51.9 %

Procedure:
1-(2,3-Dimethoxy-phenyl)-3-(4-methoxy-phenyl)-propane-1,3-dione (3.1 g, 9.86 mmol) was dissolved in mixture of Hi (10 mL) and AcOH (10 mL) and heated at 110° C. for 4 days. The reaction mixture was cooled to rt, diluted with water and solids were filtered. The solid product was washed with water, dried and purified by column chromatography, using 30% EtOAc in dichloromethane to give 1.3 g (52%) of 8-hydroxy-2-(4-hydroxy-phenyl)-4H-chromen-4-one. MS (ES) m/z: 255.08 (M+1), and 154.15.
Reaction SMILES: Br[C:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10]([S:11][CH3:12])[C:5]=2[S:4][CH:3]=1.[F:13][C:14]1[CH:19]=[C:18]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:17]=[CH:16][C:15]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Na+].[Na+]>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.O1CCOCC1>[F:13][C:14]1[CH:19]=[C:18]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:17]=[CH:16][C:15]=1[C:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10]([S:11][CH3:12])[C:5]=2[S:4][CH:3]=1
Reactant: CSc1ncnc2c(Br)csc12
Reactant: CC1(C)OB(c2ccc(S(C)(=O)=O)cc2F)OC1(C)C
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: C1COCCO1
Product: CSc1ncnc2c(-c3ccc(S(C)(=O)=O)cc3F)csc12
Temperature: 100 °C

Procedure:
7-bromo-4-methylsulfanylthieno[3,2-d]pyrimidine (270 mg, 1.03 mmol) was added to 1,4-dioxane (10 mL), and 2-(2-fluoro-4-methanesulfonyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.5 eq), tetrakis(triphenylphosphine)palladium(0) (71 mg, 0.06 eq), 2N aqueous sodium carbonate (3.1 mL, 3 eq) were sequentially added thereto while stirring. The reaction mixture was degassed with Ar(g), heated to 100° C., and stirred at 100° C. for 4 hours. After completion of the reaction using sodium bicarbonate, the reaction mixture was extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, dried, and concentrated under reduced pressure to obtain a foamy residue. The residue was crystallized in the presence of diethyl ether to obtain the title compound as a yellowish solid.