Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[H-].[Na+].F[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=1[C:18]([F:21])([F:20])[F:19].C(=O)(O)[O-].[Na+]>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:10]=1[C:18]([F:19])([F:21])[F:20]
Reactant: O=[N+]([O-])c1ccc(F)c(C(F)(F)F)c1
Reactant: COCCO
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOc1ccc(N)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 75.3 %

Procedure:
2-Methoxyethanol (219 mg, 2.88 mmol) was dissolved in THF (6 mL), and sodium hydride (60%, 39 mg, 0.96 mmol) was added thereto. The mixture was stirred at room temperature for 10 minutes, and 2-fluoro-5-nitrobenzotrifluoride (200 mg, 0.96 mmol) was added thereto. The resulting mixture was heated at 60° C. for 5 hours. The reaction solution was poured in a saturated sodium bicarbonate solution and extracted with ethyl acetate and washed with saturated brine. To the organic layer, 10% palladium carbon (20 mg) and methanol (2 mL) were added. The resulting mixture was stirred under hydrogen atmosphere at atmospheric pressure at room temperature for 16 hours. The catalyst was removed by filtration, and the filtrate was concentrated. The residue was purified by silica-gel column chromatography (n-hexane:ethyl acetate=5:1) to give the desired material (170 mg, yield: 76%) as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([C:15]3=[CH:16][C:17]4[O:21][CH2:20][O:19][C:18]=4[CH:22]=[C:14]3[O:13][CH2:12]1)[C:5](=[O:11])[NH:6]2.BrC1C=CC=C2C=1[C:26]1([C:42]3=CC4OCOC=4C=[C:41]3[O:40][CH2:39]1)C(=O)N2CCCCC.O1C=CC(B(O)O)=C1.CN(C)C1N=CC(B(O)O)=CC=1>>[O:40]1[CH:41]=[CH:42][C:26]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[C:4]2([C:15]4=[CH:16][C:17]5[O:21][CH2:20][O:19][C:18]=5[CH:22]=[C:14]4[O:13][CH2:12]2)[C:5](=[O:11])[NH:6]3)=[CH:39]1
Reactant: O=C1Nc2cccc(Br)c2C12COc1cc3c(cc12)OCO3
Reactant: CCCCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2c(Br)cccc21
Agent: CN(C)c1ccc(B(O)O)cn1
Agent: OB(O)c1ccoc1
Product: O=C1Nc2cccc(-c3ccoc3)c2C12COc1cc3c(cc12)OCO3

Procedure:
Following the procedure as described in EXAMPLE 4, making variations using 4′-bromospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 4′-bromo-1′-pentylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and 3-furanboronic acid to replace [6-(dimethylamino)pyridin-3-yl]boronic acid, the title compound was obtained (66%) as a colorless solid: mp 270-272° C.; 1H NMR (300 MHz, CDCl3) δ 7.32 (t, 1H), 7.25 (d, 2H), 6.97 (d, 1H), 6.91 (d, 1H), 6.83 (s, 1H), 6.44 (s, 1H), 6.30 (s, 1H), 6.04 (d, 1H), 5.89 (dd, 2H), 4.68 (ABq, 2H); 13C NMR (75 MHz, CDCl3) δ 180.4, 156.2, 149.2, 142.9, 142.1, 141.2, 140.4, 131.3, 129.2, 128.5, 125.3, 122.6, 120.6, 111.0, 109.5, 102.9, 101.6, 94.0, 77.2, 59.0; MS (ES+) m/z 348.4 (M+1).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:35]=[CH:36][CH:37]=1)[CH2:6][N:7]([C@@H:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][CH2:26]1)[C:8]([C:10]1[CH:15]=[C:14]([C:16]([OH:18])=[O:17])[C:13]([C:19]([OH:21])=[O:20])=[CH:12][C:11]=1[C:22]([OH:24])=[O:23])=[O:9])=O.[CH:38]([O:41][NH2:42])([CH3:40])[CH3:39]>>[CH:38]([O:41][N:42]=[CH:1][C:3]1[CH:4]=[C:5]([CH:35]=[CH:36][CH:37]=1)[CH2:6][N:7]([C@@H:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][CH2:26]1)[C:8]([C:10]1[CH:15]=[C:14]([C:16]([OH:18])=[O:17])[C:13]([C:19]([OH:21])=[O:20])=[CH:12][C:11]=1[C:22]([OH:24])=[O:23])=[O:9])([CH3:40])[CH3:39]
Reactant: O=Cc1cccc(CN(C(=O)c2cc(C(=O)O)c(C(=O)O)cc2C(=O)O)[C@H]2CCCc3ccccc32)c1
Reactant: CC(C)ON
Product: CC(C)ON=Cc1cccc(CN(C(=O)c2cc(C(=O)O)c(C(=O)O)cc2C(=O)O)[C@H]2CCCc3ccccc32)c1

Procedure:
The product from Example 76E and O-isopropylhydroxylamine were processed as described in Example 76F to provide the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[C:7]([F:17])[C:8]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)#[N:2].Cl[C:22]1[CH:23]=[C:24]([CH:29]=[CH:30][N:31]=1)[C:25]([O:27][CH3:28])=[O:26].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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>[C:1]([C:3]1[CH:4]=[C:5]([C:22]2[CH:23]=[C:24]([CH:29]=[CH:30][N:31]=2)[C:25]([O:27][CH3:28])=[O:26])[CH:6]=[C:7]([F:17])[C:8]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)#[N:2]
Reactant: N#Cc1cc(B(O)O)cc(F)c1OCc1ccccc1
Reactant: COC(=O)c1ccnc(Cl)c1
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: Cc1ccccc1
Product: COC(=O)c1ccnc(-c2cc(F)c(OCc3ccccc3)c(C#N)c2)c1

Procedure:
(3-Cyano-4-benzyloxy-5-fluorophenyl)boronic acid and methyl 2-chloroisonicotinate were dissolved in a mixed solution of toluene and a 2M aqueous sodium carbonate solution, followed by heating under reflux for 3 hours in the presence of tetrakis(triphenylphosphine)palladium to obtain methyl 2-(3-cyano-4-benzyloxy-5-fluorophenyl)isonicotinate. F: 363.
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[C:8]12([C:18]([NH:20][NH2:21])=[O:19])[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([NH:21][NH:20][C:18]([C:8]12[CH2:17][CH:12]3[CH2:11][CH:10]([CH2:16][CH:14]([CH2:13]3)[CH2:15]1)[CH2:9]2)=[O:19])(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: NNC(=O)C12CC3CC(CC(C3)C1)C2
Reactant: CCCCC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCC(=O)NNC(=O)C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
Valeryl chloride (E) (0.981 mL, 8.1 mmol) was added dropwise to a solution of adamantane-1-carbohydrazide (F) (1.5 g, 7.72 mmol) and triethylamine (1.18 mL, 8.49 mmol) in methylene chloride (30 mL) at room temperature, and the mixture stirred at room temperature for 3.5 h. A solution of 10% NaHCO3 (15 mL) was added and the mixture stirred rapidly for 1.5 h. The mixture was extracted with methylene chloride (3×) and the combined extracts washed with water, dried (MgSO4) and concentrated in vacuo to give N′-pentanoyladamantane-1-carbohydrazide (G). 1H NMR (CDCl3): δ 0.94 (t, 3H); 1.38 (m, 2H); 1.75 (m, 8H); 1.93 (d, 6H); 2.08 (s, 3H); 2.29 (t, 2H); 8.47 (d, 1H); 8.7 (d, 1H).
Reaction SMILES: [Na].Cl.[NH2:3][C:4]([NH2:6])=[NH:5].[Cl:7][C:8]1[C:13]([C:14](=O)/[CH:15]=[CH:16]/N(C)C)=[CH:12][CH:11]=[CH:10][N:9]=1>CO>[Cl:7][C:8]1[C:13]([C:14]2[CH:15]=[CH:16][N:3]=[C:4]([NH2:6])[N:5]=2)=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: N=C(N)N
Reactant: CN(C)/C=C/C(=O)c1cccnc1Cl
Agent: Cl
Agent: [Na]
Solvent: CO
Product: Nc1nccc(-c2cccnc2Cl)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In an argon purged 500 mL round bottom flask placed in an isopropanol bath, was added sodium metal (3.40 g, 148 mmol) slowly to methanol (180 mL). The mixture was stirred at RT for about 30 minutes. To this was added guanidine hydrochloride (12.0 mL, 182 mmol) and the mixture was stirred at RT for 30 minutes, followed by addition of (E)-1-(2-chloropyridin-3-yl)-3-(dimethylamino)prop-2-en-1-one (12.0 g, 57.0 mmol), attached air condenser, moved reaction to an oil bath, where it was heated to about 50° C. for 24 h. Approximately half of the methanol was evaporated under reduced pressure and the solids were filtered under vacuum, then washed with saturated NaHCO3 and H2O, air dried to yield 4-(2-chloropyridin-3-yl)pyrimidin-2-amine as off white solid. MS m/z=207 [M+1]+. Calc'd for C9H7ClN4: 206.63.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][OH:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][CH2:24][C:23]2[CH:26]=[CH:27][C:20]([F:19])=[CH:21][CH:22]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Reactant: Fc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CCOCc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.6 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)-4-(2-hydroxyethyl)piperidine (195 mg, 0.85 mmol) in THF (5 mL) was added sodium hydride (60% dispersion in oil, 41 mg, 1.02 mmol, 1.2 equiv.). After stirring at room temperature for 2 h, 4-fluorobenzyl bromide (127 μL, 1.02 mmol, 1.2 equiv.) was added. The reaction mixture was allowed to stand overnight. After quenching with H2O, the phases were separated, and the aqueous layer was extracted with EtOAc. The combined organic layer was washed with brine and dried over Na2SO4. After the solvent was removed, the residue was purified by CC (SiO2, hexane/EtOAc 4:1) to afford 1-(tert-butoxycarbonyl)-4-[2-(4-fluorobenzyloxy)ethyl]piperidine (257 mg, 90%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.28 (dd, 2H, J=8.0 Hz, J=5.2 Hz), 7.01 (t, 2H, J=8.4 Hz), 4.61 (s, 2H), 4.05 (d, 2H, J=12.8 Hz), 3.48 (t, 2H, J=6.0 Hz), 2.66 (t, 2H, J=12.4 Hz), 1.55 (m, 5H), 1.44 (s, 9H), 1.10 (m, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:8]([C:15]2[C:24]3[C:19](=[CH:20][C:21]([OH:25])=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[C:9]2[CH2:14][CH2:13][CH2:12][N:10]2[N:11]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:33][CH2:34][O:35][CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][O:37]1>CN(C=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:8]([C:15]2[C:24]3[C:19](=[CH:20][C:21]([O:25][CH2:33][CH2:34][O:35][CH:36]4[CH2:41][CH2:40][CH2:39][CH2:38][O:37]4)=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[C:9]2[CH2:14][CH2:13][CH2:12][N:10]2[N:11]=1
Reactant: BrCCOC1CCCCO1
Reactant: Oc1ccc2c(-c3c(-c4ccccn4)nn4c3CCC4)ccnc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: c1ccc(-c2nn3c(c2-c2ccnc4cc(OCCOC5CCCCO5)ccc24)CCC3)nc1
Yield: 81 %

Procedure:
Heat 4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-ol (376 mg, 1.146 mmol), cesium carbonate (826 mg, 2.54 mmol), and 2-(2-bromoethoxy)tetrahydro-2H-pyran (380 μL, 2.52 mmol) in DMF (5 mL) at 120° C. for 4 hours. Quench the reaction with saturated sodium chloride and then extract with chloroform. Dry the organic layer over sodium sulfate and concentrate in vacuo. Purify the reaction mixture on a silica gel column eluting with dichloromethane to 10% methanol in dichloromethane to give the desired subtitled intermediate as a yellow oil (424 mg, 81%). MS ES+ m/e 457.0 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]([CH3:16])[CH:13]=[CH:14][N:15]=3)[S:10][C:3]=12.[CH3:17][C:18]1[NH:19][C:20]2[C:25]([CH:26]=1)=[CH:24][C:23]([NH2:27])=[CH:22][CH:21]=2.ClC(Cl)C>C(O)(C)(C)C>[CH3:16][N:12]1[CH:13]=[CH:14][N:15]=[C:11]1[C:9]1[S:10][C:3]2[C:4](=[N:5][CH:6]=[CH:7][C:2]=2[NH:27][C:23]2[CH:24]=[C:25]3[C:20](=[CH:21][CH:22]=2)[NH:19][C:18]([CH3:17])=[CH:26]3)[CH:8]=1
Reactant: Cc1cc2cc(N)ccc2[nH]1
Reactant: Cn1ccnc1-c1cc2nccc(Cl)c2s1
Solvent: CC(C)(C)O
Solvent: CC(Cl)Cl
Product: Cc1cc2cc(Nc3ccnc4cc(-c5nccn5C)sc34)ccc2[nH]1
Yield: 68.9 %

Procedure:
7-Chloro-2-(1-methyl-1H-imidazol-2-yl)-thieno[3,2-b]pyridine (1.0 g, 4.0 mmol) and 2-methyl-5-aminoindole (732 mg, 5.0 mmol) were dissolved in 7 mL of t-butyl alcohol and 7 mL of dichloroethane and the solution was heated to 85° C. After allowing the reaction to go dry overnight the reaction mixture was cooled and absorbed onto silica gel. Chromatography of the residue with 20% methanol:methylene chloride afforded 991 mg (69%) of [2-(1-methyl-1H-imidazol-2-yl)-thieno[3,2-b]pyridin-7-yl]-(2-methyl-1H-indol-5-yl)-amine. 1H NMR (400 MHz, CD3OD) δ8.26 (d, 1H), 7.95 (s, 1H), 7.62 (s, 1H), 7.48 (m, 2H), 7.39 (d, 1H), 7.04 (m, 2H), 6.20 (s, 1H), 3.33 (s, 3H), 2.43 (s, 3H). LC-MS: 360 (MH+); HPLC RT: 4.15 min.
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[C:16]([C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:15][CH:14]=[CH:13][N:12]=1.[CH:32]1([S:35](Cl)(=[O:37])=[O:36])[CH2:34][CH2:33]1.N1C=CC=CC=1>ClCCl>[F:1][C:2]1[C:3]([NH:10][C:11]2[C:16]([C:17]3[N:25]=[CH:24][N:23]=[C:22]4[C:18]=3[N:19]=[CH:20][N:21]4[CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:4]([F:9])[CH:5]=[CH:6][C:7]=1[NH:8][S:35]([CH:32]1[CH2:34][CH2:33]1)(=[O:37])=[O:36]
Reactant: O=S(=O)(Cl)C1CC1
Reactant: Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F)C1CC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
The 2,6-difluoro-N1-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)benzene-1,3-diamine (20 mg, 0.047 mmol) prepared at Step 9 was added and dissolved into dichloromethane solvent. cyclopropansulfonyl chloride (10 mg, 0.052 mmol) and pyridine (8 uL, 0.094 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that 24 mg of the target compound, N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)9H-purin-6-yl)pyridin-2-ylamino)phenyl)cyclopropansulfonamide (percentage yield: 96%), was obtained.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](Cl)[C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)[C:5]1=[O:27])(=O)C.[CH3:28][N:29]([CH2:31][C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1)[CH3:30].[OH-].[Na+]>CN(C=O)C.CO>[CH3:30][N:29]([CH2:31][C:32]1[CH:38]=[CH:37][C:35]([NH:36]/[C:16](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=3)/[C:17]2[CH:18]=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[CH:21][CH:22]=2)=[CH:34][CH:33]=1)[CH3:28]
Reactant: CC(=O)N1C(=O)C(=C(Cl)c2ccc([N+](=O)[O-])cc2)c2cc([N+](=O)[O-])ccc21
Reactant: CN(C)Cc1ccc(N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: CN(C)Cc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccc([N+](=O)[O-])cc2)cc1

Procedure:
Prepared analogously to Example 2 from 1-acetyl-3-[1-chloro-1-(4-nitrophenyl)-methylidene)-5-nitro-2-indolinone and 4-dimethylaminomethyl-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: CS([C:4]1[N:19]=[C:7]2[CH:8]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[CH:10]=[C:11]([NH2:12])[N:6]2[N:5]=1)=O.[N:20]12[CH2:30][CH2:29][CH2:28][N:27]=C1CCCCC2.C(OC(=O)C)C.CO>N1C=CC=N1>[N:20]1([C:4]2[N:19]=[C:7]3[CH:8]=[C:9]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=4)[CH:10]=[C:11]([NH2:12])[N:6]3[N:5]=2)[CH:30]=[CH:29][CH:28]=[N:27]1
Reactant: C1CCC2=NCCCN2CC1
Reactant: CS(=O)c1nc2cc(-c3ccccn3)cc(N)n2n1
Agent: c1cn[nH]c1
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1cc(-c2ccccn2)cc2nc(-n3cccn3)nn12
Temperature: 120 °C
Reaction time: 8 h
Yield: 23.4 %

Procedure:
A mixture of 0.50 g (0.002 mol) 2-methanesulfinyl-7-pyridin-2-yl-[1,2,4]triazolo[1,5-a]pyridin-5-ylamine and 0.33 ml (0.002 mol) 1,8-diazabicyclo[5.4.0]undec-7-en in 12.5 g molten pyrazole as solvent was stirred overnight at 120° C. Destillation of the solvent and chromatography on silicagel with ethylacetate/methanol 95/5 gave 0.13 g (26%) 2-pyrazol-1-yl-7-pyridin-2-yl-[1,2,4]triazolo[1,5-a]pyridin-5-ylamine as a white solid, MS m/e (%):278 (M+H+,100).
Reaction SMILES: [OH:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:8]=2)[CH:3]1[N:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][C@@H:16]1[CH3:28].[H-].[Na+].[CH3:31]I>C1COCC1>[CH3:31][O:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]([F:14])([F:12])[F:13])[CH:8]=2)[CH:3]1[N:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][C@@H:16]1[CH3:28]
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1C1c2ccc(C(F)(F)F)cc2CC1O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1Cc2cc(C(F)(F)F)ccc2C1N1CCN(C(=O)OC(C)(C)C)C[C@@H]1C
Reaction time: 0.17 h

Procedure:
To a solution of tert-butyl (3S)-4-[2-hydroxy-5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-3-methylpiperazine-1-carboxylate (isomer 1 from step C in Example 9) (50 mg, 0.1 mmol) in THF (2 mL) at 0° C. was added NaH (8 mg, 60% in oil, 0.2 mmol). After being stirred for 10 min, MeI (28 mg, 0.2 mmol) was added. The mixture was stirred at ambient temperature for 1 h and quenched with aqueous NH4Cl. The resulting solution was extracted with EtOAc twice. The extracts were washed with brine, dried (MgSO4), filtered and concentrated to give the crude product. LC/MS calculated for C21H29F3N2O3: (M+H)+ 415. found 415.2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[N:16][C:17]([NH:20][C:21]3[N:22]=[CH:23][C:24]4[C:30]([CH3:31])=[C:29](Br)[C:28](=[O:33])[N:27]([CH:34]5[CH2:38][CH2:37][CH2:36][CH2:35]5)[C:25]=4[N:26]=3)=[CH:18][CH:19]=2)[CH2:10][C:9]1([CH3:40])[CH3:39])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:46]([O:48][CH2:49][CH3:50])=[CH2:47])CCC>C1(C)C=CC=CC=1.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>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[N:16][C:17]([NH:20][C:21]3[N:22]=[CH:23][C:24]4[C:30]([CH3:31])=[C:29]([C:46]([O:48][CH2:49][CH3:50])=[CH2:47])[C:28](=[O:33])[N:27]([CH:34]5[CH2:38][CH2:37][CH2:36][CH2:35]5)[C:25]=4[N:26]=3)=[CH:18][CH:19]=2)[CH2:10][C:9]1([CH3:40])[CH3:39])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)C(C)(C)C4)cn3)ncc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=C(OCC)c1c(C)c2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)C(C)(C)C4)cn3)nc2n(C2CCCC2)c1=O
Yield: 99.7 %

Procedure:
4-[6-(6-Bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-2,2-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (0.412 g, 0.673 mmol), tetrakis(triphenylphosphine)palladium (0.093 g, 0.081 mmol) and tributyl-(1-ethoxy-vinyl)-stannane (0.379 g, 1.05 mmol) were dissolved in toluene (3 mL) and slowly brought to reflux for 1 hour. The solvent was evaporated and the solid was redissolved in dichloromethane (8 mL) and purified by silica gel chromatography to give 4-{6-[8-cyclopentyl-6-(1-ethoxy-vinyl)-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-pyridin-3-yl}-2,2-dimethyl-piperazine-1-carboxylic acid tert-butyl ester as a yellow solid (0.405 g, 99.0%). 1H NMR δ(400 MHz, CDCl3) 8.73 (s, 1H), 8.15 (d, J=9.0 Hz, 1H), 8.00 (s, 1H), 7.85 (d, J=2.9 Hz, 1H), 7.18 (m, 1H), 5.90 (m, 1H), 4.52 (d, J=2.4 Hz, 1H), 4.18 (d, J=2.4 Hz, 1H), 3.93 (q, J=7.1 Hz, 2H), 3.80 (m, 2H), 3.38 (m, 2H), 3.26 (s, 2H), 2.41 (s, 3H), 2.35 (m, 2H), 2.06 (m, 2H), 1.85 (m, 2H), 1.64 (m, 2H), 1.49 (s, 9H), 1.45 (s, 6H), 1.36 (t, J=7.1 Hz, 3H).
Reaction SMILES: [I-].[CH3:2][S+](C)C.[H-].[Na+].[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=1>CS(C)=O.O>[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([CH3:2])[CH2:16][O:17]2)=[CH:11][CH:10]=1
Reactant: CC(=O)c1ccc(F)cc1
Reactant: C[S+](C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC1(c2ccc(F)cc2)CO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The title compound was prepared by following general procedure 3. To a solution of trimethylsulfonium iodide (3.5 g, 17.15 mmol, 1.2 equiv.) in DMSO (30 mL) was added sodium hydride 50%-55% dispersion in oil (0.97 g, 22.2mmol, 1.5 equiv.) portionwise over 5 min. and stirred for 1 h at RT. A solution of 1-(4-fluorophenyl) ethanone (2 g, 14.47 mmol, 1 equiv.) in DMSO (10 mL) was added to the reaction mixture dropwise over 20 min. and stirred at RT for 4 h. The progress of the reaction was checked by TLC and the reaction mixture was poured in 100 mL water and extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with water (2×150 mL), followed by brine. The organic layer was dried over sodium sulfate and evaporated to dryness to yield a brown oil (2.2 g). 1H NMR (d6-acetone) was consistent with the structure. Product Rf 0.8 (ethyl acetate: hexane 10:90)
Reaction SMILES: Br[CH:2]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:13][C:14]([C:16]1[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=1)=[O:15]>>[C:14]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH:2]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:18][CH:17]=1)(=[O:15])[CH3:13]
Reactant: CCOC(=O)C(Br)C(=O)OCC
Reactant: CC(=O)c1ccc(O)cc1
Product: CCOC(=O)C(Oc1ccc(C(C)=O)cc1)C(=O)OCC

Procedure:
Diethyl bromomalonate was reacted with 4-hydroxyacetophenone to give diethyl 4-acetylphenoxymalonate by the procedure described for the preparation of isopropyl 4-acetylphenoxyacetate.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([NH:9][C:10]([NH:12][CH2:13][CH3:14])=[O:11])[S:8][C:4]=2[CH:3]=1.C(N(CC)CC)C.[C:24]1([C:30]#[CH:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:24]1([C:30]#[C:31][C:2]2[CH:16]=[CH:15][C:5]3[N:6]=[C:7]([NH:9][C:10]([NH:12][CH2:13][CH3:14])=[O:11])[S:8][C:4]=3[CH:3]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: C#Cc1ccccc1
Reactant: CCNC(=O)Nc1nc2ccc(Br)cc2s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCNC(=O)Nc1nc2ccc(C#Cc3ccccc3)cc2s1
Yield: 8 %

Procedure:
A mixture of 1-(6-bromo-2-benzothiazolyl)-3-ethylurea, Pd(PPh3)2Cl2, triethylamine, and phenylacetylene in 1 mL of anhydrous DMF was reacted according to the procedure of Example 213 to give 0.008 g (8%) of the desired compound. LC/MS 322 (M+1); LC retention time 3.65 min.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=O)[O-:24])=[CH:16][CH:15]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1)[CH3:2].[F:26][C:27]1[CH:32]=[CH:31][C:30]([S:33]([NH2:36])(=[O:35])=[O:34])=[CH:29][CH:28]=1>>[F:26][C:27]1[CH:28]=[CH:29][C:30]([S:33]([NH:36][C:23]([NH:22][CH2:21][CH2:20][C:17]2[CH:16]=[CH:15][C:14]([N:4]3[CH:5]=[C:6]([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)[N:7]=[C:3]3[CH2:1][CH3:2])=[CH:19][CH:18]=2)=[O:24])(=[O:34])=[O:35])=[CH:31][CH:32]=1
Reactant: NS(=O)(=O)c1ccc(F)cc1
Reactant: CCc1nc(-c2ccccc2)cn1-c1ccc(CCNC(=O)[O-])cc1
Product: CCc1nc(-c2ccccc2)cn1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(F)cc2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 18 from 2-[4-(2-ethyl-4-phenyl-1H-imidazol-1-yl)phenyl]ethylcarbamate and 4-fluorobenzenesulfonamide. MS (ESI) m/z 493 [M+H]+, 491 [M−H]−, 1H-NMR (CDCl3) δ 1.23 (3H, t, J=7.5 Hz), 2.68 (2H, q, J=7.7 Hz), 2.87 (2H, t, J=7.0 Hz), 3.42-3.60 (2H, m), 6.46 (1H, br), 7.16-7.28 (7H, m), 7.37 (2H, t, J=7.3 Hz), 7.76 2H, d, J=7.1 Hz), 7.85-7.91 (2H, m).