Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[C:5]#[N:6].[CH:11](I)([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12])[C:5]#[N:6]
Reactant: CC(C)I
Reactant: N#Cc1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)Oc1ccc(C#N)cc1F
Temperature: 25 °C

Procedure:
5.0 g 3-Fluoro-4-hydroxy-benzonitrile, 7.3 mL isopropyl iodide and 6.05 g potassium carbonate were placed in 54 mL acetone and heated to reflux where the reaction was maintained for 24 h. After this time, the mixture was cooled to ambient temperature and concentrated under reduced pressure. The material that remained was partitioned between ethyl acetate and water and the aqueous phase was removed and extracted with additional ethyl acetate. The combined organics were dried, filtered and the solvent was removed from the filtrate under reduced pressure to give the title compound that was used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:12]([F:15])([F:14])[F:13])[C:7]([C:10]#[N:11])=[N:8][CH:9]=1)([O-])=O>C(O)(=O)C.[Fe]>[NH2:1][C:4]1[CH:5]=[C:6]([C:12]([F:15])([F:13])[F:14])[C:7]([C:10]#[N:11])=[N:8][CH:9]=1
Reactant: N#Cc1ncc([N+](=O)[O-])cc1C(F)(F)F
Agent: [Fe]
Solvent: CC(=O)O
Product: N#Cc1ncc(N)cc1C(F)(F)F
Yield: 91 %

Procedure:
A mixture of 5-nitro-3-(trifluoromethyl)pyridine-2-carbonitrile 22 and iron powder in acetic acid is heated. 5-amino-3-(trifluoromethyl)pyridine-2-carbonitrile, 8 is obtained in a yield of 91%.
Reaction SMILES: [CH3:1][CH:2]1[CH2:9][C@H:8]2[C@H:4]([CH2:5][NH:6][C@@H:7]2[CH2:10][NH:11][C:12]([C:14]2[N:21]3[C:17]([S:18][CH:19]=[CH:20]3)=[N:16][C:15]=2[CH3:22])=[O:13])[CH2:3]1.[F:23][C:24]1[CH:25]=[C:26]([C:30]2[S:34][C:33]([CH3:35])=[N:32][C:31]=2[C:36](O)=[O:37])[CH:27]=[CH:28][CH:29]=1>>[F:23][C:24]1[CH:25]=[C:26]([C:30]2[S:34][C:33]([CH3:35])=[N:32][C:31]=2[C:36]([N:6]2[CH2:5][C@H:4]3[C@H:8]([CH2:9][CH:2]([CH3:1])[CH2:3]3)[C@H:7]2[CH2:10][NH:11][C:12]([C:14]2[N:21]3[C:17]([S:18][CH:19]=[CH:20]3)=[N:16][C:15]=2[CH3:22])=[O:13])=[O:37])[CH:27]=[CH:28][CH:29]=1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2CC(C)C[C@@H]21
Reactant: Cc1nc(C(=O)O)c(-c2cccc(F)c2)s1
Product: Cc1nc(C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid-[(1S,2S,5R)-7-methyl-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with 5-(3-fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29]Br)=[CH:23][CH:22]=1>>[F:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][N:17]2[CH2:18][CH2:19][CH:14]([C:11]3[CH:12]=[CH:13][C:8]([O:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:9][CH:10]=3)[CH2:15][CH2:16]2)=[CH:23][CH:22]=1
Reactant: c1ccc(Oc2ccc(C3CCNCC3)cc2)cc1
Reactant: Fc1ccc(OCCBr)cc1
Product: Fc1ccc(OCCN2CCC(c3ccc(Oc4ccccc4)cc3)CC2)cc1

Procedure:
The same procedure was followed as in Example 11 using the compound (9) synthesized in Example 2 and 2-(4-fluorophenyl)oxyethyl bromide to produce the above.
Reaction SMILES: C1(COC([NH:11][CH2:12][CH2:13][C:14]2[S:15][C:16]([CH2:19][CH2:20][NH:21]C(OCC3C=CC=CC=3)=O)=[CH:17][CH:18]=2)=O)C=CC=CC=1>[Pd]>[NH2:11][CH2:12][CH2:13][C:14]1[S:15][C:16]([CH2:19][CH2:20][NH2:21])=[CH:17][CH:18]=1
Reactant: O=C(NCCc1ccc(CCNC(=O)OCc2ccccc2)s1)OCc1ccccc1
Agent: [Pd]
Product: NCCc1ccc(CCN)s1
Yield: 152.5 %

Procedure:
(Phenylmethoxy)N-[2-(5-{2-[(phenylmethoxy)carbonylamino]ethyl}(2-thienyl))ethyl]carboxamide (1.6 g, 3.6 mmol) and 10% palladium on carbon (1.0 g, 62 mole %) were combined and hydrogenation was carried out in a manner analogous to the procedure described in example 6 to provide the intermediate title compound, 2-[5-(2-aminoethyl)-2-thienyl]ethylamine, (0.935 g, 55%) as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([NH2:15])[N:9]=2)=[CH:6][C:5]([CH3:16])=[CH:4][N:3]=1.[NH:17]1[C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([NH2:26])[C:20]=2[CH:19]=[N:18]1>>[NH2:15][C:10]1[N:11]=[C:12]([CH3:14])[N:13]=[C:8]([C:7]2[C:2]([NH:26][C:21]3[C:20]4[CH:19]=[N:18][NH:17][C:25]=4[CH:24]=[CH:23][CH:22]=3)=[N:3][CH:4]=[C:5]([CH3:16])[CH:6]=2)[N:9]=1
Reactant: Nc1cccc2[nH]ncc12
Reactant: Cc1cnc(Cl)c(-c2nc(C)nc(N)n2)c1
Product: Cc1cnc(Nc2cccc3[nH]ncc23)c(-c2nc(C)nc(N)n2)c1

Procedure:
The experimental procedure for this compound was the same as Example 22, Step 2 using 4-(2-chloro-5-methylpyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine and 1H-indazol-4-amine. LCMS (API-ES) m/z 333 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 13.08 (d, J=2.35 Hz, 1H); 12.12 (br. s., 1H); 8.64 (br. s., 1H); 8.28 (dd, J=3.81, 2.05 Hz, 1H); 8.14 (d, J=5.28 Hz, 2H); 7.74 (br. s., 2H); 7.31 (d, J=7.63 Hz, 1H); 7.32 (br. s., 1H); 7.13 (d, J=12.91 Hz, 1H); 3.32 (d, J=1.37 Hz, 6H).
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:7]=[CH:8][C:9]([O:12][C:13]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:14]=2[C:15]([O:17][CH3:18])=[O:16])=[N:10][CH:11]=1.[F:24][B-](F)(F)F.[H+]>O>[Cl:23][C:20]1[CH:21]=[CH:22][C:13]([O:12][C:9]2[CH:8]=[CH:7][C:6]([F:24])=[CH:11][N:10]=2)=[C:14]([CH:19]=1)[C:15]([O:17][CH3:18])=[O:16]
Reactant: F[B-](F)(F)F
Reactant: COC(=O)c1cc(Cl)ccc1Oc1ccc(N)cn1
Agent: O=N[O-]
Agent: [H+]
Agent: [Na+]
Solvent: O
Product: COC(=O)c1cc(Cl)ccc1Oc1ccc(F)cn1
Temperature: 140 °C
Reaction time: 5 h
Yield: 42 %

Procedure:
To a solution of sodium nitrite (224 mg, 3.25 mmol) in water (5 mL) was added methyl 2-[(5-aminopyridin-2-yl)oxy]-5-chlorobenzoate (907 mg, 3.25 mmol) and 48% tetrafluoroboric acid in water (5 mL) at 0° C. The reaction mixture was stirred for 5 h. The resulting precipitate was collected by filtration and dried under reduced pressure at room temperature. To the solids of tetrafluoroborate were added chlorobenzene (5 mL) and the mixture was heated at 140° C. for 40 min. The reaction mixture was diluted with ethyl acetate. The solution was washed with brine and concentrated. The residue was purified by flush column chromatography on silica gel eluting with hexane/ethyl acetate (8/1) to afford 382 mg (42%) of the title compound: 1H-NMR (CDCl3) δ 7.98 (1H, d, J=2.8 Hz), 7.90 (1H, d, J=3.1 Hz), 7.59–7.41 (2H, m), 7.14 (1H, d, J=8.6 Hz), 6.99 (1H, dd, J=8.9, 3.5 Hz), 3.72 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=3)[CH:10]([CH2:25][NH2:26])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:27][S:28]([NH:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=1)(=[O:30])=[O:29]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=3)[CH:10]([CH2:25][NH:26][C:36](=[O:37])[C:35]3[CH:39]=[CH:40][C:32]([NH:31][S:28]([CH3:27])(=[O:30])=[O:29])=[CH:33][CH:34]=3)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CN2CCN(c3cccc(Cl)c3)CC2CN)cc1OC
Reactant: CS(=O)(=O)Nc1ccc(C(=O)Cl)cc1
Product: COc1ccc(CN2CCN(c3cccc(Cl)c3)CC2CNC(=O)c2ccc(NS(C)(=O)=O)cc2)cc1OC

Procedure:
In a manner similar to Preparation 3, react 4-(3-chlorophenyl)-1-[(3,4-dimethoxyphenyl)methyl]-2-piperazinemethanamine(3.0 g, 7.9 mmol) with 4-[(methylsulfonyl)amino]benzoyl chloride (2.4 g, 10mmol) to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:21]2[CH:31]=[CH:30][C:24]([C:25]([N:27]([CH3:29])[CH3:28])=[O:26])=[CH:23][CH:22]=2)=[N:6][C:7]=1[C:8]1[O:9][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19]Br)=[CH:15][CH:14]=2)=[N:11][N:12]=1.[C:32]([O-:35])(=[O:34])[CH3:33].[K+].Cl>CN(C=O)C>[C:32]([O:35][CH2:19][C:16]1[CH:17]=[CH:18][C:13]([C:10]2[O:9][C:8]([C:7]3[C:2]([NH2:1])=[N:3][CH:4]=[C:5]([C:21]4[CH:22]=[CH:23][C:24]([C:25](=[O:26])[N:27]([CH3:29])[CH3:28])=[CH:30][CH:31]=4)[N:6]=3)=[N:12][N:11]=2)=[CH:14][CH:15]=1)(=[O:34])[CH3:33]
Reactant: CC(=O)[O-]
Reactant: CN(C)C(=O)c1ccc(-c2cnc(N)c(-c3nnc(-c4ccc(CBr)cc4)o3)n2)cc1
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)OCc1ccc(-c2nnc(-c3nc(-c4ccc(C(=O)N(C)C)cc4)cnc3N)o2)cc1
Temperature: 100 °C
Yield: 78.4 %

Procedure:
A mixture of 4-[5-amino-6-[5-[4-(bromomethyl)phenyl]-1,3,4-oxadiazol-2-yl]pyrazin-2-yl]-N,N-dimethyl-benzamide (200 mg, 0.4172 mmol) and potassium acetate (102.4 mg, 1.043 mmol) in DMF (5.714 mL) was heated at 100° C. for 4 h in a sealed microwave tube. The reaction mixture was cooled to room temperature and poured onto ice/water and acidified by HCl (1.043 mL of 1 M, 1.043 mmol). The mixture was extracted with ethyl acetate (3×10 mL) and the combined organic extracts washed with brine (3×10 mL). The extracts were dried over MgSO4 and concentrated under reduced pressure to give a yellow solid (150 mg, 74% yield); 1H NMR (400 MHz, DMSO) d 2.13 (s, 3H), 2.98-3.02 (m, 6H), 5.22 (s, 2H), 7.55 (d, 2H), 7.66 (d, 2H), 7.78 (br s, 2H), 8.16-8.19 (m, 4H) and 8.99 (s, 1H) ppm; MS (ES+) 459.18
Reaction SMILES: [C:1]([C:6]1[CH:14]=[C:10]([C:11]([OH:13])=O)[C:9]([OH:15])=[CH:8][CH:7]=1)([CH2:4][CH3:5])([CH3:3])[CH3:2].[CH3:16][C:17]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:20][C:18]=1[NH2:19].P(Cl)(Cl)Cl>C1(C)C(C)=CC=CC=1>[C:1]([C:6]1[CH:14]=[C:10]([C:11]([NH:19][C:18]2[CH:20]=[CH:21][C:22]([N+:24]([O-:26])=[O:25])=[CH:23][C:17]=2[CH3:16])=[O:13])[C:9]([OH:15])=[CH:8][CH:7]=1)([CH2:4][CH3:5])([CH3:2])[CH3:3]
Reactant: CCC(C)(C)c1ccc(O)c(C(=O)O)c1
Reactant: Cc1cc([N+](=O)[O-])ccc1N
Solvent: Cc1ccccc1C
Solvent: ClP(Cl)Cl
Product: CCC(C)(C)c1ccc(O)c(C(=O)Nc2ccc([N+](=O)[O-])cc2C)c1
Temperature: 70 °C
Yield: 55 %

Procedure:
A mixture of 10.4 g of 5-tert-amylsalicylic acid and 7.6 g of 2-methyl-4-nitroaniline in 100 ml of xylene is heated at 70° C and to the mixture is added a solution of 2.6 g of phosphorus trichloride in 10 ml of xylene. The whole mixture is refluxed for two and a half hours. The hot reaction solution is decanted. The supernatant solution is cooled on an ice bath. The crystalline precipitate is collected by filtration. Recrystallization from methanol gives 9.4 g of the title compound as pale yellow crystals, melting at 150°-151° C.
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[CH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH2:14]([O:21][C:22](Cl)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>ClCCl>[CH2:14]([O:21][C:22]([N:1]1[CH2:2][CH:3]=[CH:4][CH2:5][CH2:6]1)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C1=CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CC=CCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 1,2,3,6-tetrahydropyridine (5.0 g) in dichloromethane (200 mL) was cooled to 0° C. and treated with triethylamine (10.1 mL) followed by benzylchloroformate (10.3 mL). The reaction mixture was stirred for 1 hour at 0° C., diluted with dichloromethane, washed (dilute hydrochloric acid, sodium bicarbonate solution), dried and evaporated. The crude product was distilled to give the N-protected derivative (11.01 g); bp 160°-165° C. (26.7 Pa); NMR (CDCl3): 2.15 (broad, 2), 3.5 (t,2, J=6), 3.96 (m, 2), 5.15 (s, 2), 5.8 (2 broad peaks, 2), 7.4(m, 5); MS: m/z=218(M+1).
Reaction SMILES: NC(N)=O.[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][CH2:29][CH3:30])=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4CCN(C(OCC)=O)CC4)[N:32]=[CH:33][C:14]=13)[CH2:6]2.[CH3:45][N:46]1[CH2:51][CH2:50][N:49]([C:52]2[N:57]=CC(N)=[CH:54][CH:53]=2)[CH2:48][CH2:47]1.NC1C=CC=CC=1>>[CH:9]12[O:12][CH:5]([CH2:11][CH2:10]1)[CH2:6][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][C:29]4[CH:30]=[N:57][C:52]([N:49]5[CH2:48][CH2:47][N:46]([CH3:45])[CH2:51][CH2:50]5)=[CH:53][CH:54]=4)=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH3:34])[N:32]=[CH:33][C:14]=13)[CH2:8]2
Reactant: CN1CCN(c2ccc(N)cn2)CC1
Reactant: CCNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(C(=O)OCC)CC4)c3n2)cc1
Agent: NC(N)=O
Solvent: Nc1ccccc1
Product: CN1CCN(c2ccc(NC(=O)Nc3ccc(-c4nc(N5CC6CCC(C5)O6)c5cnn(C)c5n4)cc3)cn2)CC1

Procedure:
A urea formation procedure similar to that used for the synthesis of ethyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-ethylureido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate is used, utilizing 6-(4-methylpiperazino)-3-pyridinamine as the aniline component. (16%, MS=555.3 (M+H))
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=[CH:9][CH3:10])=[C:6]([F:11])[CH:5]=[CH:4][C:3]=1[CH:12]1[O:16][CH2:15][CH2:14][O:13]1>CO.[Pd]>[Cl:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([F:11])[CH:5]=[CH:4][C:3]=1[CH:12]([O:16][CH3:15])[O:13][CH3:14]
Reactant: CC=Cc1c(F)ccc(C2OCCO2)c1Cl
Agent: [Pd]
Solvent: CO
Product: CCCc1c(F)ccc(C(OC)OC)c1Cl
Reaction time: 12 h
Yield: 93.5 %

Procedure:
To a solution of the obtained 2-{2-chloro-4-fluoro-3-[prop-1-en-1-yl]phenyl}-1,3-dioxolane (1.41 g) in methanol (20 ml) was added finely shredded palladium-fibroin (200 mg), and the mixture was vigorously stirred under a hydrogen atmosphere for 12 hr. The reaction mixture was filtered by suction through a glass filter with a layer of celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate=30:1→3:1) to give the title compound as a colorless oil (yield: 1.34 g).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:19][CH3:20])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].[N:21]([O-])=[O:22].[Na+]>C(O)=O>[Cl:1][CH2:2][CH2:3][N:4]([N:21]=[O:22])[C:5]([N:7]([CH2:19][CH3:20])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: O=N[O-]
Reactant: CCN(C(=O)NCCCl)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: [Na+]
Solvent: O=CO
Product: CCN(C(=O)N(CCCl)N=O)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reaction time: 1 h
Yield: 30.5 %

Procedure:
6.0 g of 1-(2-chloroethyl)-3-ethyl-3-D-glucopyranosylurea are dissolved in 15 ml of formic acid, and 4.0 g of sodium nitrite are added gradually thereto at 0° to 5° C. for one hour under stirring. The mixture is further stirred at the same temperature for 20 minutes. 100 ml of ether-hexane(1:1) are added to the reaction mixture, and the resultant oil is collected therefrom. Said oil is washed with ether. Then, 100 ml of methylene chloride-methanol(5:1) are added to said oil, and insoluble materials are removed by filtration. The filtrate is evaporated to remove solvent, and the residue obtained is purified by silica gel chromatography (Solvent: chloroform-ethyl acetate-methanol (2:1:1)). 2.0 g of 1-(2-chloroethyl)-1-nitroso-3-ethyl-3-D-glucopyranosylurea are thereby obtained as pale yellow caramel.
Reaction SMILES: [F:1][C:2]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH2:12][OH:13])[N:9]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[F:21])[C:8](=[O:22])[CH:7]=1.[Cl:28]N1C(=O)CCC1=O>C(#N)C>[Cl:28][C:7]1[C:8](=[O:22])[N:9]([C:14]2[C:15]([F:21])=[CH:16][CH:17]=[CH:18][C:19]=2[F:20])[C:10]([CH2:12][OH:13])=[CH:11][C:6]=1[O:5][CH2:4][C:3]1[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:2]=1[F:1]
Reactant: O=c1cc(OCc2ccc(F)cc2F)cc(CO)n1-c1c(F)cccc1F
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: O=c1c(Cl)c(OCc2ccc(F)cc2F)cc(CO)n1-c1c(F)cccc1F
Reaction time: 1 h

Procedure:
The title compound was prepared by taking 4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-6-(hydroxymethyl)pyridin-2(1H)-one (1.5 g, 3.9 mmol) in acetonitrile (15 mL) and adding to that N-chlorosuccinimide (580 mg, 4.3 mmol). The reaction was stirred at rt for 3 h afterwhich a small amount of additional N-chlorosuccinimide (50 mg, 0.4 mmol) was added to the reaction. Stirring was continued for 1 h. The reaction mixture was filtered through a fritted funnel to obtain the crude material. 1H NMR (400 MHz, DMSO-d6) δ 7.69-7.61 (m, 2H), 7.37-7.31 (m, 3H), 7.17 (dt, J=8.8, 2.0 Hz, 1H), 6.80 (s, 1H), 5.70 (t, J=6.0 Hz, 1H), 5.38 (s, 2H), 4.01 (d, J=6.0 Hz, 2H); ES-HRMS m/z 414.0515 (M+H calcd for C19H13ClF4NO3, requires 414.0520).
Reaction SMILES: [O:1]=[C:2]1[CH2:8][CH:7]2[N:9]([C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]([C:20]#[N:21])=[CH:12][CH:11]=3)[CH:4]([CH2:5][CH2:6]2)[CH2:3]1.[CH3:22][Si]([N-][Si](C)(C)C)(C)C.[Li+].IC>C1COCC1>[CH3:22][CH:8]1[C:2](=[O:1])[CH2:3][CH:4]2[N:9]([C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]([C:20]#[N:21])=[CH:12][CH:11]=3)[CH:7]1[CH2:6][CH2:5]2
Reactant: N#Cc1ccc(N2C3CCC2CC(=O)C3)c2ccccc12
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CC1C(=O)CC2CCC1N2c1ccc(C#N)c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19.8 %

Procedure:
To 156AF03-217 (552 mg, 2 mmol) in THF (20 mL) under argon atmosphere at −78° C. was added dropwise lithium bis(trimethylsilyl)amide (2.6 mL, 2.6 mmol, 1 M in THF). After 30 min at −78° C., iodomethane (2.0 mL) was added over 1 min and the reaction was allowed to warm to rt overnight. Partitioning of the reaction mixture between ethyl acetate (2×500 mL) and water (500 mL), drying of the combined organic phases over Na2SO4, filtration, removing of volatiles in vacuo and purification by preparative TLC (ethyl acetate/n-heptane 1:4, 5× eluted) afforded the title compound (115 mg, 20%) as a thick oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15](CC3C=CC(OC)=CC=3OC)[C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[Cl:32][C:33]1[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[CH:35][C:34]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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>[Cl:32][C:33]1[CH:38]=[C:37]([C:39]([F:40])([F:41])[F:42])[CH:36]=[CH:35][C:34]=1[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([NH:15][C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:13])=[O:14])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1Cl
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Cl)ncnc3c2)c(OC)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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=S(=O)(Nc1nccs1)c1ccc2c(-c3ccc(C(F)(F)F)cc3Cl)ncnc2c1
Reaction time: 2 h
Yield: 23.1 %

Procedure:
To a mixture of 4-chloro-N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)quinazoline-7-sulfonamide (Intermediate KKKK; 0.07 g, 0.147 mmol), (2-chloro-4-(trifluoromethyl)phenyl)boronic acid (0.049 mg, 0.220 mmol) and potassium carbonate (0.101 g, 0.734 mmol) in Dioxane (Solvent Ratio: 3, Solvent Volume: 0.734 ml) and Water (Solvent Ratio: 1.000, Solvent Volume: 0.245 ml) was added Pd (PPh3)4 (17 mg, 0.015 mmol), degassed with nitrogen and irradiated in microwave at 100° C. for 1 h. The aqueous layer was discarded and the reaction mixture was filtered through SPE and concentrated. To this was then added DCM (1 ml) and TFA (1 ml) and the reaction was stirred for 2 h. The crude mixture was purified using reverse phase HPLC to obtain 4-(2-chloro-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)quinazoline-7-sulfonamide (16 mg, 23% yield) as white solid. m/z (ESI) 470.0 (M+H)+.
Reaction SMILES: Cl[CH:2]([CH3:14])[C:3](=[O:13])[C:4]#[C:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.[I-].[NH2:16][N+:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1CCN2C(=NCCC2)CC1>C(#N)C>[F:12][C:9]1[CH:10]=[CH:11][C:6]([C:5]2[C:4]([C:3](=[O:13])[CH2:2][CH3:14])=[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][N:17]3[N:16]=2)=[CH:7][CH:8]=1
Reactant: N[n+]1ccccc1
Reactant: CC(Cl)C(=O)C#Cc1ccc(F)cc1
Agent: [I-]
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCC(=O)c1c(-c2ccc(F)cc2)nn2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 2 %

Procedure:
To a mixture of 8.7 g (38 mmol) of 4-chloro-1-(4-fluorophenyl)pent-1-yn-3-one and 10 g (45 mmol) of N-aminopyridinium iodide in 140 ml of acetonitrile was added dropwise 11 g of DBU in 50 ml of acetonitrile at 0° C. for 20 minutes under a nitrogen atmosphere. The reaction was then stirred at RT overnight. After evaporation of the solvent, the crude mixture was purified on an Al2O3 column, and the desired product recrystallized from ethyl acetate-hexane to obtain 200 mg of 1-(2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl)propan-1-one. Compound 1070.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH2:5].[Cl:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=1[Cl:15])[CH2:10]Cl>C1COCC1>[NH2:1][CH2:2][CH2:3][CH2:4][NH:5][CH2:10][C:9]1[CH:12]=[CH:13][C:14]([Cl:15])=[C:7]([Cl:6])[CH:8]=1
Reactant: ClCc1ccc(Cl)c(Cl)c1
Reactant: NCCCN
Solvent: C1CCOC1
Product: NCCCNCc1ccc(Cl)c(Cl)c1
Reaction time: 0.25 h

Procedure:
To 1,3-diaminopropane (42 ml) in dry THF (200 ml) at 60° C. was added dropwise a solution of 3,4-dichlorobenzylchloride (13.9 ml, 100 mmol) in 90 ml dry THF over 3 h. The mixture was kept at 60° C. for an additional 15 min and then kept at 25° C. for 3 days. The precipitate was removed by filtration and the mother liquor concentrated in vacuo. The residue was partitioned between water and t-butyl methyl ether (TBME). To the organic layer was added aq. HCl (2 M) and the mixture was filtered. The layers were separated and NaOH was added to the aqueous layer with stirring. The resulting mixture was extracted with TBME and the organic extract was dried (Na2CO3), filtered, and the solvent evaporated to give the title compound as a slightly cloudy oil, (18.2 g, 78%). δH (CDCl3) 1.20 (br, s, ca. 3H), 1.58-1.71 (m, 2H), 2.67 (t, J=6.9, 2H), 2.78 (t, J=6.8, 2H), 3.74 (s, 2H), 7.15 (dd, J=8.2, 2.0, 1H), 7.37 (d, J=8.2, 1H), 7.43 (d, J=1.9, 1H); MS (ES+) 233 (MH+, 13%), 159 (100).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][C:12]1[N:17]=[CH:16][C:15]([CH2:18][OH:19])=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl.O>[CH3:11][C:12]1[CH:13]=[CH:14][C:15]([CH:18]=[O:19])=[CH:16][N:17]=1
Reactant: Cc1ccc(CO)cn1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1ccc(C=O)cn1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 85 %

Procedure:
To a solution of oxalyl chloride (2 M in dichloromethane, 9.34 mL, 18.68 mmol) in 30 mL dichloromethane at −60° C. under argon, dimethyl sulfoxide (3.1 g, 2.81 mL, 39.63 mmol) was added over 20 min. The mixture was stirred at −60° C. for 20 min before a solution of (6-methylpyridin-3-yl)methanol in 8 mL dichloromethane was added over 20 min. The reaction mixture was stirred for 20 min, and then triethylamine (8.02 g, 11.05 mL, 79.25 mmol) was added over 10 min. The reaction mixture was allowed to warm up to room temperature and 48 mL water was added. The mixture was extracted with dichloromethane and the combined extracts were dried (Na2SO4), filtered and concentrated. The crude product was purified by automated silica gel chromatography (eluted with ethyl acetate-hexanes) to isolate 1.67 g (85%) of the title compound as a light brown oil. HPLC: retention time=0.19 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][C:9]12[CH2:18][CH:13]3[CH2:14][CH:15]([CH2:17][CH:11]([CH:12]3[OH:19])[CH2:10]1)[CH2:16]2)([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][C:9]12[CH2:18][CH:13]3[CH2:14][CH:15]([CH2:17][CH:11]([C:12]3=[O:19])[CH2:10]1)[CH2:16]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC12CC3CC(C1)C(O)C(C3)C2
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC12CC3CC(C1)C(=O)C(C3)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.2 %

Procedure:
To a solution of (4-Hydroxy-adamantan-1-ylmethyl)-carbamic acid tert-butyl ester (1B) (2.81 g, 10 mmol) in 200 mL of DCM was added Dess martin periodinane (5.08 g, 12 mmol) at one portion at rt. The mixture was stirred at rt overnight and was quenched by 20 mL of NH4Cl aq (Sat'd) solution. The mixture was extracted by DCM (5 mL×3) and the combined DCM layers were dried over Na2SO4. Solvent was remove under vacuum and the residue was purified by silica gel chromatography (Hexane:EtOAc 2:1(v/v)) to give the title compounds (3B) (2.52 g, 90%). LC-MS (ESR): m/z=280 (M+H)+.