Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH:5]([C:11]1[S:12][N:13]=[C:14]2[C:19]=1[C:18](=[O:20])[N:17]([CH3:21])[C:16](=[O:22])[N:15]2[CH3:23])C(OCC)=O)[CH3:2].[H-].[Na+]>C(O)C>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:11]1[S:12][N:13]=[C:14]2[C:19]=1[C:18](=[O:20])[N:17]([CH3:21])[C:16](=[O:22])[N:15]2[CH3:23])[CH3:2]
Reactant: CCOC(=O)C(C(=O)OCC)c1snc2c1c(=O)n(C)c(=O)n2C
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)Cc1snc2c1c(=O)n(C)c(=O)n2C

Procedure:
To a stirred solution of Step 4 intermediate (13.8 g, 38.8 mmol) in dry ethanol (155 ml) was added a catalytic amount of sodium hydride (60% dispersion in mineral oil, 355 mg, 8.87 mmol) at room temperature and the reaction mixture was refluxed for 48 h under nitrogen atmosphere. Excess of solvent was removed under reduced pressure and the residue was cooled in ice bath, 1 N HCl was added slowly to the reaction mixture, solid obtained was collected by filtration and dried to give 9.1 g of the product as a yellow solid; 1H NMR (300 MHz, DMSO-d6) δ 1.34 (t, J=6.9 Hz, 3H), 3.40 (s, 3H), 3.63 (s, 3H), 4.30 (q, J=6.9 Hz, 2H), 4.50 (s, 2H)
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]([CH2:7][CH2:8][O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)[CH:6]=1.C([Mg]Cl)(C)C.CO[B:23]1[O:27][C:26]([CH3:29])([CH3:28])[C:25]([CH3:31])([CH3:30])[O:24]1.[Cl-].[NH4+]>C1COCC1>[O:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH:10]1[O:9][CH2:8][CH2:7][N:5]1[CH:6]=[C:2]([B:23]2[O:27][C:26]([CH3:29])([CH3:28])[C:25]([CH3:31])([CH3:30])[O:24]2)[CH:3]=[N:4]1
Reactant: COB1OC(C)(C)C(C)(C)O1
Reactant: Ic1cnn(CCOC2CCCCO2)c1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1(C)OB(c2cnn(CCOC3CCCCO3)c2)OC1(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.3 %

Procedure:
To a solution of 4-iodo-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-pyrazole (8.7 g, 27.1 mmol) in THF (75 mL) at 0° C. under argon was added isopropylmagnesium chloride as a 2 M solution in THF (27.1 mL, 54.3 mmol). The reaction was stirred for 1 h at 0° C. To it was added 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (6.7 mL, 40.7 mmol) and the mixture was stirred for an additional 1 h while allowing to warm to room temperature. It was then treated with saturated ammonium chloride (100 mL) solution and the product was extracted with EtOAc (3×100 mL). The combined organics were washed with brine, dried over sodium sulfate, and filtered. Crude material was concentrated under reduced pressure to afford 7.1 g (81%) of 1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole as a clear yellow oil. The material was taken on crude to the next step. MS m/z=323.2 [M+1]+. Calc'd for C16H27BN2O4: 322.2
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1.Cl[C:18]1[O:19][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:21][N:22]=1>C1COCC1>[CH3:3][N:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:16]=[CH:15][C:13]([NH:14][C:18]3[O:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][N:22]=3)=[CH:12][CH:11]=2)[CH2:8][CH2:9]1
Reactant: Clc1ncc(-c2ccccc2)o1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCN(c2ccc(Nc3ncc(-c4ccccc4)o3)cc2)CC1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
Sodium hydride (60% in mineral oil, 0.51 g, 0.013 mol) was suspended in dry THF (8 mL) under an atmosphere of nitrogen. The suspension was treated with 4-(4-methylpiperazin-1-yl)-aniline (0.23 g9 1.0 mmol) and 2-chloro-5-phenyl-1,3-oxazole (0.19 g, 1.0 mmol) and heated to 60° C. and stirred for 18 h. The reaction was cooled to RT and quenched with methanol (10 drops). Silica gel was added and the solvent was evaporated under reduced pressure to dryness and purified by silica gel chromatography using 10% methanol in dichloromethane to elute the title compound (0.10 g, 31%). 1H NMR (400 MHz, d6-DMSO): δ 2.21 (s, 3H), 2.45 (m, 4H), 3.04 (m, 4H), 6.91 (d, J=8.97, 2H), 7.24 (t, J=7.32, 1H), 7.41 (m, 3H), 7.47 (d, J=8.97, 2H), 7.55 (d, J=7.51, 2H), 9.99 (s, 1H). MS (ES+, m/z)=335 (m+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:8]=[C:9]([NH:17]C(=O)OC(C)(C)C)[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=2)[CH:4]=[CH:5][N:6]=1.N1(C2C=C(NC(=O)OC(C)(C)C)C=C(C(F)(F)F)C=2)CCOCC1>>[CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[C:11]([C:13]([F:16])([F:14])[F:15])[CH:10]=[C:9]([NH2:17])[CH:8]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1nccn1-c1cc(NC(=O)OC(C)(C)C)cc(C(F)(F)F)c1
Agent: CC(C)(C)OC(=O)Nc1cc(N2CCOCC2)cc(C(F)(F)F)c1
Product: Cc1nccn1-c1cc(N)cc(C(F)(F)F)c1

Procedure:
Utilising the procedure described in Example 90c but employing [3-(2-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-carbamic acid, 1,1-dimethylethyl ester (Example 91c) in lieu of [3-(4-morpholinyl)-5-(trifluoromethyl)phenyl]-carbamic acid, 1,1-dimethylethyl ester, afforded the title compound as a yellow crystalline solid, m.p. 130-133° C.
Reaction SMILES: [F:1][CH2:2][C:3]([CH2:7][F:8])([OH:6])[C:4]#[CH:5].[H-].[Na+].[CH3:11][S:12](Cl)(=[O:14])=[O:13]>O1CCCC1>[CH3:11][S:12]([O:6][C:3]([CH2:7][F:8])([C:4]#[CH:5])[CH2:2][F:1])(=[O:14])=[O:13]
Reactant: CS(=O)(=O)Cl
Reactant: C#CC(O)(CF)CF
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CC(CF)(CF)OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
An amount (1.2 g) of 1-fluoro-2-fluoromethyl-3-butyn-2-ol was dissolved in tetrahydrofuran (10 ml); to the solution under cooling with ice, 60% oily sodium hydride (0.48 g) was added under a nitrogen atmosphere. The solution was stirred for 30 minutes under cooling with ice and then methanesulfonyl chloride (1.1 ml) was added dropwise. The solution was stirred for 2.5 hours while its temperature was raised to room temperature. To the reaction mixture, etcher was added, followed by extraction with diethyl ether. The extract was washed with water and a saturated aqueous solution of sodium chloride, and dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluent; 30% ethyl acetate/hexane) to give the titled compound (1.6 g).
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][OH:10])[CH:4]=1.Br[CH:12](C)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].O>C1COCC1>[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][O:10][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:4]=1
Reactant: OCc1cccnc1
Reactant: CC(Br)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)COCc1cccnc1
Temperature: 25 °C
Yield: 59.9 %

Procedure:
To a suspension of 1.24 g of sodium hydride (60% oil dispersion; 31 mmol) in 90 mL of THF were added dropwise 3.27 g of 3-pyridinemethanol (30 mmol) in 10 mL of dry THF at room temperature over 5 min. The resulting white suspension was stirred at room temperature for an hour, to which was then added dropwise 6.27 g of tert-butyl 2-bromopropionate (30 mmol) in 10 mL of dry THF at room temperature over 5 min. The mixture was stirred at room temperature for 11.5 hours. After adding water, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried and evaporated. The residue was purified by column chromatography on silica gel (eluent: n-hexane:ethyl acetate=1:1) to give 4.01 g of tert-butyl (pyridin-3-yl)methoxyacetate (Yield: 56.3%) as a dark brown oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][CH:22]=3)[O:18][C:19]=2[CH3:20])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:29][CH:30]=3)[O:18][C:19]=2[CH3:20])(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(-c2nc(CS(=O)(=O)c3ccc(C(C)(C)C)cc3)c(C)o2)cc1
Agent: Cl
Product: Cc1oc(-c2ccc(C(=O)O)cc2)nc1CS(=O)(=O)c1ccc(C(C)(C)C)cc1
Yield: 89.4 %

Procedure:
Reaction of benzoate 22 (97 mg, 0.23 mmol) and 6 M HCl (5 mL) gave acid 23 (85 mg, 89%) as a white solid: mp (H2O) 220-222° C.; 1H NMR δ 13.15 (br s, 1H, CO2H), 8.02 (dd, J=8.7, 1.9 Hz, 2H, H-2, H-6), 7.88 (ddd, J=8.7, 1.9, 1.5 Hz, 2H, H-3, H-5), 7.70 (ddd, J=8.6, 2.0, 1.9 Hz, 2H, H-2′, H-6′), 7.63 (ddd, J=8.6, 2.0, 1.9 Hz, 2H, H-3′, H-5′), 4.64 (s, 2H, CH2SO2), 2.14 (s, 3H, CH3), 1.29 [s, 9H, C(CH3)3]; MS m/z 415.5 (MH+, 100%). Anal. calcd for C22H23NO5S.H2O: C, 61.24; H, 5.84; N, 3.25. Found: C, 61.32; H, 5.50; N, 3.14%.
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9][S:10][C:11](SC)=[CH:12][C:13]([C:15]1[C:20]([Cl:21])=[CH:19][C:18]([C:22]([F:25])([F:24])[F:23])=[CH:17][C:16]=1[Cl:26])=O>C(O)C>[Cl:21][C:20]1[CH:19]=[C:18]([C:22]([F:23])([F:24])[F:25])[CH:17]=[C:16]([Cl:26])[C:15]=1[C:13]1[CH:12]=[C:11]([S:10][CH3:9])[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=1
Reactant: NNc1ccccc1
Reactant: CSC(=CC(=O)c1c(Cl)cc(C(F)(F)F)cc1Cl)SC
Solvent: CCO
Product: CSc1cc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nn1-c1ccccc1

Procedure:
Phenylhydrazine (0.11 ml) was added to a solution of 0.8 g of 3,3-bis[methylthio]-1-(2,6-dichloro-4-trifluoromethylphenyl)-2-propen-1-one in 10 ml of ethanol at room temperature, and the mixture was refluxed for 1 hour. The solvent was distilled of under reduced pressure to obtain a residue, which was purified by column chromatography on silica gel (eluent: ether/hexane=1/6), giving 0.17 g of the desired compound in the form of a pale brown oil (yield 43.6%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:18]([O-])=O)[CH:5]=[C:6]([Cl:17])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1.N>Cl.CCO.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH2:18])[CH:5]=[C:6]([Cl:17])[C:7]=1[O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=1
Reactant: COc1ccc(Oc2c(Cl)cc([N+](=O)[O-])cc2Cl)cc1
Agent: Cl
Agent: N
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(Oc2c(Cl)cc(N)cc2Cl)cc1
Yield: 119.7 %

Procedure:
To a solution of stannous chloride dihydrate (32.38 g, 0.14 mol) in concentrated HCl (11 mL) was added 3,5-dichloro-4-(4-methoxy-phenoxy)nitrobenzene (11.3 g, 0.03 mol) in EtOH (56.5 mL). The reaction mixture was refluxed for about 2 h. The resulting mixture was brought at 20-30° C. and diluted with ethyl acetate. The mixture was made alkaline with ammonia solution. Resulting solid was filtered through cellite. The organic phase was washed with water, brine, dried over sodium sulphate, filtered and concentrated to give 3,5-Dichloro-4-(4-methoxy-phenoxy)-phenylamine (10.2 g; % Yield: 99%).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH2:12][C:13]#[N:14])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].NC1C=C[NH:19][N:18]=1>>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]([NH2:14])[NH:18][N:19]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc(C(=O)CC#N)cc1
Reactant: Nc1cc[nH]n1
Product: CC(C)Oc1ccc(-c2cc(N)[nH]n2)cc1
Yield: 94 %

Procedure:
The product was prepared from 3-(4-isopropoxy-phenyl)-3-oxo-propionitrile according to general procedure for aminopyrazole synthesis (route A2). The solvent was removed under reduced pressure, water (10 mL) was added, and the title product (1.0 g, 94% yield) was precipitated as a yellow solid and used for the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)#[N:23]>CN(C)C=O.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@@H:17]([OH:18])[CH2:19][N:33]4[CH2:32][CH2:31][N:30]([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=5[C:22]#[N:23])[CH2:35][CH2:34]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(-c3ccc(OC[C@@H]4CO4)cc3)noc2c1
Reactant: N#Cc1ccccc1N1CCNCC1
Solvent: CN(C)C=O
Solvent: CCO
Product: N#Cc1ccccc1N1CCN(C[C@H](O)COc2ccc(-c3noc4cc(F)ccc34)cc2)CC1

Procedure:
The title compound is prepared from a mixture of (S)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 1-(2-cyanophenyl)piperazine in ethanol essentially as described above in Example 21. Purity by LC/MS=100%, [M+H]+=473.
Reaction SMILES: [C:1]([N:3]=[C:4](SC)[S:5][CH3:6])#[N:2].[NH:9]([C:11]1[N:12]=[N:13][C:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:15]([CH3:17])[N:16]=1)[NH2:10]>C(Cl)Cl.CO>[NH2:2][C:1]1[N:9]([C:11]2[N:12]=[N:13][C:14]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[C:15]([CH3:17])[N:16]=2)[N:10]=[C:4]([S:5][CH3:6])[N:3]=1
Reactant: CSC(=NC#N)SC
Reactant: Cc1nc(NN)nnc1-c1ccccc1
Solvent: CO
Solvent: ClCCl
Product: CSc1nc(N)n(-c2nnc(-c3ccccc3)c(C)n2)n1
Reaction time: 40 h
Yield: 89.2 %

Procedure:
A solution of dimethyl N-cyanodithioimidocarbonate (2.65 g) in methylene chloride (15 ml) was added to a solution of 3-hydrazino-5-methyl-6-phenyl-1,2,4-triazine (3.52 g) in methanol (20 ml) and stirring was continued for 40 hours at room temperature. The resultant precipitates were collected by filtration, washed with methanol, and dried to give 3-(5-amino-3-methylthio-1,2,4-triazol-1-yl)-5-methyl-6-phenyl-1,2,4-triazine (4.67 g).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][CH2:8][C:9]([OH:11])=O)[N:3]=[N:2]1.S(Cl)([Cl:14])=O>C(Cl)Cl>[NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][CH2:8][C:9]([Cl:14])=[O:11])[N:3]=[N:2]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CCCc1c[nH]nn1
Solvent: ClCCl
Product: O=C(Cl)CCCc1c[nH]nn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution/suspension of 4-(1H-1,2,3-triazol-4-yl)butanoic acid (150 mg, 0.967 mmol) in dry DCM (10 mL) was added thionyl chloride (0.847 mL, 11.60 mmol) at RT. After 30 mins some solid still remained so a further 0.4 ml thionyl chloride was added and the reaction mixture allowed to stir at RT for 2 hrs. The reaction mixture was concentrated under reduced pressure to afford the title product which was used in the next step without further purification.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[NH2:13][C:14]1[C:25]([Br:26])=[CH:24][CH:23]=[CH:22][C:15]=1[C:16]([NH:18][CH:19]1[CH2:21][CH2:20]1)=[O:17]>C(Cl)Cl>[Br:26][C:25]1[CH:24]=[CH:23][CH:22]=[C:15]2[C:14]=1[NH:13][C:2](=[O:4])[N:18]([CH:19]1[CH2:20][CH2:21]1)[C:16]2=[O:17]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1c(Br)cccc1C(=O)NC1CC1
Solvent: ClCCl
Product: O=c1[nH]c2c(Br)cccc2c(=O)n1C1CC1
Reaction time: 17 h
Yield: 249.8 %

Procedure:
Triphosgene (Sigma-Aldrich; 2.79 g, 9.41 mmol) was added to a solution of 2-amino-3-bromo-N-cyclopropylbenzamide (723a; 6.00 g, 23.52 mmol) in DCM (235 mL) at RT. The mixture was heated to reflux and stirred overnight (17 h). The mixture turned cloudy upon heating. The next morning the reaction mixture was cooled and concentrated to afford 8-bromo-3-cyclopropylquinazoline-2,4(1H,3H)-dione (723b; 6.61 g, 23.51 mmol, 100% yield) as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.09 (d, J=8.02 Hz, 1H), 8.06 (br. s., 1H), 7.78 (dd, J=7.82, 1.17 Hz, 1H), 7.10 (t, J=7.92 Hz, 1H), 2.74-2.84 (m, 1H), 1.21 (q, J=7.04 Hz, 2H), 0.83-0.91 (m, 2H). m/z (ES, +ve) 281.0, 283.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:17]([CH:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[OH:24])=[N:18][C:19]([CH3:22])=[CH:20][CH:21]=1.C(N(CC)CC)C.[C:38](OC(=O)C)(=[O:40])[CH3:39].O>C(Cl)(Cl)Cl.CN(C)C1C=CN=CC=1>[C:38]([O:24][CH:23]([C:17]1[C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:21][CH:20]=[C:19]([CH3:22])[N:18]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:40])[CH3:39]
Reactant: COc1cc2nccc(Oc3ccc(C)nc3C(O)c3ccccc3)c2cc1OC
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1cc2nccc(Oc3ccc(C)nc3C(OC(C)=O)c3ccccc3)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
[3-(6,7-Dimethoxy-quinolin-4-yloxy)-6-methyl-pyridin-2-yl]-phenyl-methanol (47 mg) (compound 217) was dissolved in chloroform (7 ml) to prepare a solution. Triethylamine (1 ml), acetic anhydride (0.8 ml), and 4-dimethylaminopyridine (20 mg) were added to the solution, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was purified by thin layer chromatography using chloroform-acetone to give the title compound (48 mg, yield 89%).
Reaction SMILES: O[C:2]1([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N:22]3[C:30]4[CH:29]=[C:28]([C:31]5[CH:32]=[N:33][N:34]([CH3:36])[CH:35]=5)[N:27]=[CH:26][C:25]=4[CH:24]=[N:23]3)[N:17]=2)[CH2:8][CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4][CH2:3]1.C(N(S(F)(F)[F:43])CC)C>C(Cl)Cl>[F:43][C:2]1([C:16]2[N:17]=[C:18]([N:22]3[C:30]4[CH:29]=[C:28]([C:31]5[CH:32]=[N:33][N:34]([CH3:36])[CH:35]=5)[N:27]=[CH:26][C:25]=4[CH:24]=[N:23]3)[CH:19]=[CH:20][CH:21]=2)[CH2:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1
Reactant: Cn1cc(-c2cc3c(cn2)cnn3-c2cccc(C3(O)CCCN(C(=O)OC(C)(C)C)CC3)n2)cn1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: Cn1cc(-c2cc3c(cn2)cnn3-c2cccc(C3(F)CCCNCC3)n2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 110.7 %

Procedure:
To a solution of tert-butyl 4-hydroxy-4-(6-(6-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)azepane-1-carboxylate (150 mg, 0.3 mmol) in DCM (5 mL) was added diethylaminosulfur trifluoride (DAST, 0.12 mL, 0.9 mmol). The mixture was stirred at room temperature for 1 hour, which was monitored by LCMS. After completion of the reaction, it was concentrated under reduced pressure to afford 1-(6-(4-fluoroazepan-4-yl)pyridin-2-yl)-6-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine as a light yellow oil (130 mg, 87%). MS (ESI) m/z: 493 [M+H]+.
Reaction SMILES: CC([O-])=O.[Na+].[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][C:16](O)([CH:19]([C:26]([OH:28])=[O:27])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]>CC(OC(C)=O)=O>[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][C:16](=[C:19]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:26]([OH:28])=[O:27])[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(C(C(=O)O)c2ccccc2)CC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(=C(C(=O)O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92 %

Procedure:
A mixture of NaOAc (16.3 g, 0.20 mol) and 4-hydroxy-4-(1-carboxy-1-phenyl-methyl)piperidine-1-carboxylic acid tert-butyl ester (33.3 g, 0.099 mol) were dissolved in Ac2O (110 mL) in a sealed tube and allowed to stir at rt for 4 h. The mixture was then heated at 70° C. for 16 h, after which the volatiles were removed in vacuo. The residue was subsequently diluted with EtOAc and 300 mL of 1M NaOH was added. This mixture was stirred for 2 h and then the pH was adjusted to 2 using conc. HCl. The mixture was extracted with EtOAc (×3) and the combined organic layers were washed (brine), dried (Na2SO4) and evaporated to give an oil, which was triturated with hexane to give the title compound (28.9 g, 87%) as a colorless solid:
Reaction SMILES: [F:1][C:2]1[CH:22]=[C:21]([C:23]#[C:24][Si](C)(C)C)[CH:20]=[CH:19][C:3]=1[NH:4][C:5]1[C:6]([C:12]([NH:14][CH2:15][CH2:16][CH2:17][OH:18])=[O:13])=[CH:7][NH:8][C:9](=[O:11])[CH:10]=1.C([O-])([O-])=O.[K+].[K+]>CO.C1COCC1>[C:23]([C:21]1[CH:20]=[CH:19][C:3]([NH:4][C:5]2[C:6]([C:12]([NH:14][CH2:15][CH2:16][CH2:17][OH:18])=[O:13])=[CH:7][NH:8][C:9](=[O:11])[CH:10]=2)=[C:2]([F:1])[CH:22]=1)#[CH:24]
Reactant: C[Si](C)(C)C#Cc1ccc(Nc2cc(=O)[nH]cc2C(=O)NCCCO)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: C#Cc1ccc(Nc2cc(=O)[nH]cc2C(=O)NCCCO)c(F)c1
Yield: 68 %

Procedure:
4-{2-Fluoro-4-[(trimethylsilyl)ethynyl]anilino}-N-(3-hydroxypropyl)-6-oxo-1,6-dihydro-3-pyridinecarboxamide was reacted with K2CO3 in MeOH/THF as for example 12, step B. The resulting crude product was purified by column chromatography on silica gel (10% MeOH/CH2Cl2 as eluant) to give 4-(4-ethynyl-2-fluoroanilino)-N-(3-hydroxypropyl)-6-oxo-1,6-dihydro-3-pyridinecarboxamide as a pale yellow solid (68%), m.p. (EtOAc/MeOH) 249-252° C. 1H NMR [(CD3)2SO, 400 MHz] δ 11.42 (br s, 1H), 10.44 (s, 1H), 8.46 (s, 1H), 7.93 (s, 1H), 7.49 (t, J=8.5 Hz, 1H), 7.45 (dd, J=11.4, 1.9 Hz, 1H), 7.33 (dd, J=8.3, 1.3 Hz, 1H), 5.63 (s, 1H), 4.43 (t, J=5.2 Hz, 1H), 4.23 (s, 1H), 3.46 (q, J=5.9 Hz, 2H), 3.31-3.22 (m, 2H), 1.66 (pentet, J=6.7 Hz, 2H). Anal. Calcd for C17H16FN3O3: C, 62.0; H, 4.9; N, 12.8. Found: C, 62.0; H, 5.2; N, 12.8.
Reaction SMILES: Cl[Si:2]([CH3:5])([CH3:4])[CH3:3].C(N(CC)CC)C.[CH3:13][CH2:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)=[O:16].[I-].[Na+]>C(#N)C>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([C:15]([O:16][Si:2]([CH3:5])([CH3:4])[CH3:3])=[CH:14][CH3:13])=[CH:22][CH:21]=1
Reactant: C[Si](C)(C)Cl
Reactant: CCC(=O)c1ccc(Cl)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC=C(O[Si](C)(C)C)c1ccc(Cl)cc1
Reaction time: 15 h
Yield: 94.3 %

Procedure:
13.47 g of chlorotrimethylsilane are slowly added to 12.55 g of triethylamine, under a nitrogen atmosphere, at 20°±3° C. 16.86 g of 4-chloropropiophenone (endothermic mixture) and then a solution of 18.58 g of sodium iodide in 125 ml of acetonitrile are further added while maintaining the temperature at 18°±2° C. The mixture is then heated for 3 hours at 40°±5° C., the acetonitrile is removed under reduced pressure and 150 ml of toluene are added to the solid residue. 50 ml of solvent are distilled under reduced pressure to drive the residual acetonitrile off. The inorganic materials are extracted with 100 ml of iced water, the organic phase is washed with 100 ml of iced water and dried over magnesium sulfate. The toluene is removed under reduced pressure and complete removal of the solvents is performed for 15 hours at 60° C. under a pressure of 1 mbar to give 22.7 g of an oil. NMR run at 200 MHz (CDCl3) 0.13 ppm:s:9H 1.7 ppm:d:3H 5.28 ppm:q:1H 7.21-7.39 ppm:m:4H.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([NH2:9])[C:3]=1[NH2:10].O.O.[C:13](O)(=[O:17])[C:14](O)=[O:15]>Cl>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]2[C:3]=1[NH:10][C:13](=[O:17])[C:14](=[O:15])[NH:9]2
Reactant: Cc1ccc(N)c(N)c1C
Reactant: O=C(O)C(=O)O
Agent: Cl
Solvent: O
Product: Cc1ccc2[nH]c(=O)c(=O)[nH]c2c1C
Temperature: 100 °C

Procedure:
To a solution of 3,4-dimethyl-benzene-1,2-diamine (67.5 g, 496 mmol) in 5N HCl (250 mL) was added oxalic acid dihydrate (69.3 g, 550 mmol). The reaction mixture was heated to 100° C. under stirring. The reaction mixture was stirred for 8 hours and cooled to room temperature. The dark precipitate was filtered, washed, and dried.