Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([NH2:14])[CH:12]=2)[NH:7][N:6]=1.[F:15][C:16]1[C:24]([NH:25][S:26]([CH2:29][CH2:30][CH3:31])(=[O:28])=[O:27])=[CH:23][CH:22]=[C:21]([F:32])[C:17]=1[C:18](O)=[O:19].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.CCOC(C)=O>[F:15][C:16]1[C:24]([NH:25][S:26]([CH2:29][CH2:30][CH3:31])(=[O:27])=[O:28])=[CH:23][CH:22]=[C:21]([F:32])[C:17]=1[C:18]([NH:14][C:11]1[CH:12]=[C:13]2[C:5]([O:4][CH2:3][CH2:2][F:1])=[N:6][NH:7][C:8]2=[N:9][CH:10]=1)=[O:19]
Reactant: Nc1cnc2[nH]nc(OCCF)c2c1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)O)c1F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]nc(OCCF)c3c2)c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 3-(2-fluoroethoxy)-1H-pyrazolo[3,4-b]pyridin-5-amine (0.020 g, 0.10 mmol), 2,6-difluoro-3-(propylsulfonamido)benzoic acid (0.031 g, 0.11 mmol), EDCI (0.021 g, 0.11 mmol), and HOBt (0.017 g, 0.11 mmol) in DMF (6 mL) was stirred at room temperature for 1 hour. The reaction mixture was diluted with EtOAc and washed with saturated aqueous NH4Cl, saturated aqueous NaHCO3 and brine. The organic layer was dried over MgSO4 and concentrated under reduced pressure to give 2,6-difluoro-N-(3-(2-fluoroethoxy)-1H-pyrazolo[3,4-b]pyridin-5-yl)-3-(propylsulfonamido)benzamide. The crude material was purified by silica gel flash column chromatography (5% 7N NH3-MeOH in CH2Cl2) to afford 2,6-difluoro-N-(3-(2-fluoroethoxy)-1H-pyrazolo[3,4-b]pyridin-5-yl)-3-(propylsulfonamido)benzamide (41 mg, 88% yield). LRMS (ACPI pos) m/e 458.1 (M+1). 1H-NMR (400 MHz, d6-DMSO) δ 12.68 (s, 1H), 11.12 (s, 1H), 9.73 (br s, 1H), 8.58 (d, 1H), 8.54 (d, 1H), 7.55 (q, 1H), 7.27 (t, 1H), 4.90 (m, 1H), 4.78 (m, 1H), 4.63 (m, 1H), 4.55 (m, 1H), 3.12 (t, 2H), 1.76 (m, 2H), 0.99 (t, 3H); 19F NMR (376 MHz, DMSO) δ−117.3, −122.6, −223.1.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=1.[CH3:12][Mg]Br.C(OCC)C>O1CCCC1>[NH2:1][C:2]1[C:7]([CH:8]([OH:9])[CH3:12])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=1
Reactant: CSc1ncc(C=O)c(N)n1
Reactant: C[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: CSc1ncc(C(C)O)c(N)n1
Reaction time: 8 h
Yield: 96 %

Procedure:
To a suspension of 5.0 g (29 mmol) 4-amino-2-methylsulfanyl-pyrimidine-5-carboxaldehyde (Example 3) in 150 mL of tetrahydrofuran, cooled by an ice bath, is added during 20 minutes. 23.2 mL of a 3.0 M methylmagnesium bromide solution in diethyl ether (69.4 mmol). After 1 hour at 0° C. another 23.2 mL of the 3.0 M methylmagnesium bromide solution is added, and the suspension is allowed to come to room temperature and stirred overnight. The reaction is quenched with 100 mL of saturated aqueous ammonium chloride, and partitioned between water and ethyl acetate. The organic layer is dried (magnesium sulfate) and concentrated to give 5.24 g (96%) of the product, mp 140-142° C.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[C:19](=O)[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][CH:23]=1.O.[NH2:32][NH2:33]>CN(C=O)C>[C:28]([C:25]1[CH:26]=[CH:27][C:22]([CH2:21][CH2:20][C:19]2[C:3]3[C:4](=[O:18])[N:5]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:6]4[N:7]=[CH:8][CH:9]=[CH:10][C:11]=4[C:2]=3[NH:33][N:32]=2)=[CH:23][CH:24]=1)#[N:29]
Reactant: N#Cc1ccc(CCC(=O)c2c(O)c3cccnc3n(-c3ccccc3)c2=O)cc1
Reactant: NN
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(CCc2n[nH]c3c2c(=O)n(-c2ccccc2)c2ncccc32)cc1
Yield: 90 %

Procedure:
To a suspension of 4-hydroxy-3-[1-oxo-3-(4-cyanophenyl)propyl]-1-phenyl-1,8-naphthyridin-2 (1H)-one (270 mg, 0.69 mmol, prepared in Synthetic Example 8) in DMF (5 ml) was added hydrazine monohydrate (80%, 102 μl, 2.55 mmol, 3.7 eq.), and the mixture was treated in the same manner as in Example 9 to give 3-[2-(4-cyanophenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (243 mg, 90%).
Reaction SMILES: [CH2:1]([O:8][C:9]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[C:19]C3C=CC(CC(OC)=O)=CC=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:31].[Na+]>C(O)C.O1CCCC1>[CH2:1]([O:8][C:9]1([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[C:17][C:5]3[CH:6]=[CH:7][C:2]([C:1]([OH:8])=[O:31])=[CH:3][CH:4]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)Cc1ccc(C#Cc2ccc(C3(OCc4ccccc4)CC3)cc2)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(C#Cc2ccc(C3(OCc4ccccc4)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
Using General Procedure I; a solution of methyl {4-[4-(1-benzyloxycyclopropyl)-phenylethynyl]-phenyl}-acetate (Compound 76, 45.0 mg, 0.11 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with NaOH (80.0 mg, 2.0 mmols, 2.0 mL of a 1N aqueous solution) and stirred overnight at room temperature. Work-up afforded 35.0 mg (81%) of the title compound as a pale-yellow solid.
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])[CH2:9][NH:8][CH2:7][C:6]2=[O:15].[CH:16]([O:19][C:20]1[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][C:21]=1[C:22](O)=[O:23])([CH3:18])[CH3:17]>>[CH:16]([O:19][C:20]1[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][C:21]=1[C:22]([N:8]1[CH2:7][C:6](=[O:15])[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:9]1)=[O:23])([CH3:18])[CH3:17]
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: COc1cc2c(cc1OC)C(=O)CNC2
Product: COc1cc2c(cc1OC)C(=O)CN(C(=O)c1cc(S(C)(=O)=O)ccc1OC(C)C)C2

Procedure:
Prepared in analogy to example 1.1 from 6,7-dimethoxy-2,3-dihydro-1H-isoquinolin-4-one (CA [206763-75-9]) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.1). MS (m/e): 448.3 (M+H+).
Reaction SMILES: [C:1]([C:3](=[CH:10][CH:11]([CH3:13])[CH3:12])[CH2:4][C:5]([O:7]CC)=[O:6])#[N:2].CO.[OH-].[K+]>O>[C:1]([C:3](=[CH:10][CH:11]([CH3:13])[CH3:12])[CH2:4][C:5]([OH:7])=[O:6])#[N:2]
Reactant: CCOC(=O)CC(C#N)=CC(C)C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)C=C(C#N)CC(=O)O
Temperature: 55 °C
Reaction time: 5 h

Procedure:
A glass liner is charged with ethyl 3-cyano-5-methylhex-3-enoate (starting material prepared above), methanol (100 mL), and water (18 mL). Potassium hydroxide is added with stirring. A liner is placed in a 600 mL PARR hydrogenation vessel. The vessel is purged with nitrogen and then with hydrogen via charging to 60 psi and releasing the pressure on 5 cycles. The vessel is heated to 55° C. A solution of [(R,R)-MeDuPHOS]Rh(COD)+BF4− in deoxygenated methanol (18.0 mg in 20 mL) is added via syringe. The vessel is again purged with hydrogen and then pressurized to 60 psi with stirring. Periodically, hydrogen is added to maintain the pressure between 50 to 60 psi. Hydrogen uptake ceases after 5 hours. After an additional 1 hour, the mixture is cooled to room temperature, and the pressure is released. The mixture is transferred to a flask, and the solvent is removed in vacuo to give the product. A small sample is removed and converted to (S)-3-cyano-5-methylhexanoic acid by reaction with 1N hydrochloric acid. GC analysis shows 98.7% conversion to the desired cyano alkanoic salt with 96.6% e.e S isomer.
Reaction SMILES: FC(F)(F)C(O)=O.[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][C:21]1=[O:26])(=[O:19])=[O:18].[CH2:27]([O:34][C:35]([NH:37][C:38]1[N:46]=[CH:45][N:44]=[C:43]2[C:39]=1[N:40]=[CH:41][N:42]2[CH2:47][C:48](O)=[O:49])=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17]([N:20]1[CH2:25][CH2:24][N:23]([C:48](=[O:49])[CH2:47][N:42]2[CH:41]=[N:40][C:39]3[C:43]2=[N:44][CH:45]=[N:46][C:38]=3[NH:37][C:35]([O:34][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:36])[CH2:22][C:21]1=[O:26])(=[O:19])=[O:18]
Reactant: O=C(O)Cn1cnc2c(NC(=O)OCc3ccccc3)ncnc21
Reactant: O=C1CNCCN1S(=O)(=O)c1nc2ccccc2s1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ncnc2c1ncn2CC(=O)N1CCN(S(=O)(=O)c2nc3ccccc3s2)C(=O)C1)OCc1ccccc1

Procedure:
The title compound was synthesized by the reaction of 1-(benzothiazole-2-sulfonyl)-piperazin-2-one trifluoroacetic acid salt with [6-N-(benzyloxycarbonyl)-adenine-9-yl]-acetic acid as per the procedure of Example 52. 1H-NMR (500 MHz; DMSO-d6) δ 10.81 (brs, 1H), 8.60 (d, 1H), 8.36 (m, 1H), 8.28 (m, 2H), 7.73 (m, 2H), 7.46 (d, 2H), 7.40 (t, 2H), 7.34 (t, 1H), 5.41 (s, 1.2H), 5.29 (s, 0.8H), 5.23 (s, 2H), 4.57 (s, 0.8H), 4.28 (s, 2.4H), 4.09 (m, 2.0H), 3.88 (t, 0.8H).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30]([OH:32])=O)[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[CH3:63][O:64][C:65]1[CH:71]=[C:70]([S:72]([N:75]2[CH2:80][CH2:79][O:78][CH2:77][CH2:76]2)(=[O:74])=[O:73])[CH:69]=[CH:68][C:66]=1[NH2:67]>>[CH3:63][O:64][C:65]1[CH:71]=[C:70]([S:72]([N:75]2[CH2:80][CH2:79][O:78][CH2:77][CH2:76]2)(=[O:73])=[O:74])[CH:69]=[CH:68][C:66]=1[NH:67][C:30]([CH:20]1[NH:19][CH:18]([CH2:33][C:34]([CH3:35])([CH3:36])[CH3:37])[C:17]2([C:12]3[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=3)[NH:15][C:16]2=[O:38])[CH:21]1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=1[F:29])=[O:32]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Reactant: COc1cc(S(=O)(=O)N2CCOCC2)ccc1N
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(S(=O)(=O)N2CCOCC2)ccc1NC(=O)C1NC(CC(C)(C)C)C2(C(=O)Nc3cc(Cl)ccc32)C1c1cccc(Cl)c1F
Yield: 8.1 %

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.4 g, 0.69 mmol), was reacted with diisopropylethylamine (0.46 g, 3.6 mmol), diphenylphosphinic chloride (0.34 g, 1.4 mmol), then reacted with 2-methoxy-4-(morpholinosulfonyl)aniline (Matrix) (0.29 g, 1.1 mmol) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid [2-methoxy-4-(morpholine-4-sulfonyl)-phenyl]-amide as a white solid (Yield 0.04 g, 8%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]([C:11](=[O:42])[NH:12][C@H:13]([CH2:33][O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:14](=[O:32])[N:15]1[CH2:20][CH2:19][N:18]2[C:21](=[O:24])[CH2:22][CH2:23][C:17]2([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[CH2:16]1)([CH3:10])[CH3:9])(C)(C)C.Cl>CCOCC>[NH2:7][C:8]([CH3:10])([CH3:9])[C:11]([NH:12][C@H:13]([CH2:33][O:34][CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:14](=[O:32])[N:15]1[CH2:20][CH2:19][N:18]2[C:21](=[O:24])[CH2:22][CH2:23][C:17]2([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[CH2:16]1)=[O:42]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@H](COCc1ccccc1)C(=O)N1CCN2C(=O)CCC2(Cc2ccccn2)C1
Agent: Cl
Solvent: CCOCC
Product: CC(C)(N)C(=O)N[C@H](COCc1ccccc1)C(=O)N1CCN2C(=O)CCC2(Cc2ccccn2)C1

Procedure:
Compound of Example 202, Step E (12 mg, 0.020 mmol) was deprotected as described in General Procedure C to provide, after trituration with ether, Example 202, Step F as its HCl salt (5 mg, 50%): +APcI MS (M+1)+ 494; 1H NMR (400 MHz, CD3OD) δ: 8.90-7.15 (arom, series of m, 9 H), 5.31 (m, 0.5H), 5.15 (m, 0.5H), 2.86 (d, 0.5H), 2.77 (d, 0.5H), 1,60 (Me, m, 6H).
Reaction SMILES: [O:1]([CH2:8][CH:9]([OH:12])[CH2:10][Cl:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:14]([O:16][CH2:17][CH2:18][Cl:19])=[O:15]>>[C:14](=[O:15])([O:12][CH:9]([CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:10][Cl:11])[O:16][CH2:17][CH2:18][Cl:19]
Reactant: OC(CCl)COc1ccccc1
Reactant: O=C(Cl)OCCCl
Product: O=C(OCCCl)OC(CCl)COc1ccccc1

Procedure:
By reacting 3-phenoxy-1-chloro-2-propanol with 2-chloroethyl chloroformate according to conventional chloroformate ester reaction procedures, 2-chloroethyl 3-phenoxy-1-chloro-2-propyl carbonate is obtained. When the latter compound is heated in the presence of a phosphonium or ammonium salt catalyst as shown in the foregoing examples, phenyl glycidyl ether is produced as the principal epoxide product.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[N:5]=[C:4]([CH3:11])[C:3]=1[CH2:12][CH2:13]Cl.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>C(O)C>[CH2:15]([N:22]1[C:2]2[N:7]3[N:8]=[CH:9][N:10]=[C:6]3[N:5]=[C:4]([CH3:11])[C:3]=2[CH2:12][CH2:13]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCc1ccccc1
Reactant: Cc1nc2ncnn2c(Cl)c1CCCl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1nc2ncnn2c2c1CCN2Cc1ccccc1

Procedure:
A mixture of 2g of 7-chloro-6-(2-chloroethyl)-5-methyl-s-triazolo[1,5-a]pyrimidine, 0.94g of benzylamine, 3 ml of triethylamine and 20 ml of ethanol was stirred under reflux for 1 hour. The reaction mixture was then concentrated under reduced pressure and the residue was washed with water. The crystals thus obtained were recrystallized from ethanol to give 1.4g of colorless prisms of m.p. 170.5° - 172° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][C@@H:10]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[N:19]2[N:23]=[CH:22][CH:21]=[N:20]2)[CH3:11])[C:5]([NH2:8])=[N:6][CH:7]=1.[F:24][C:25]1[C:30]([F:31])=[C:29](B(O)O)[CH:28]=[CH:27][N:26]=1.[F-].[Cs+]>CO.O>[F:24][C:25]1[C:30]([F:31])=[C:29]([C:2]2[CH:7]=[N:6][C:5]([NH2:8])=[C:4]([O:9][C@@H:10]([C:12]3[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=3[N:19]3[N:23]=[CH:22][CH:21]=[N:20]3)[CH3:11])[CH:3]=2)[CH:28]=[CH:27][N:26]=1
Reactant: OB(O)c1ccnc(F)c1F
Reactant: C[C@@H](Oc1cc(Br)cnc1N)c1cc(F)ccc1-n1nccn1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: CO
Product: C[C@@H](Oc1cc(-c2ccnc(F)c2F)cnc1N)c1cc(F)ccc1-n1nccn1
Temperature: 80 °C
Yield: 79.8 %

Procedure:
5-Bromo-3-[(R)-1-(5-fluoro-2-[1,2,3]triazol-2-yl-phenyl)-ethoxy]-pyridin-2-ylamine (example 45) (200 mg, 0.529 mmol, 1.0 eq) and 2,3-difluoropyridin-4-ylboronic acid (168 mg, 1.06 mmol, 2.0 eq) were dissolved in MeOH (5 mL), followed by the addition of freshly prepared aqueous solution of CsF (563 mg, 3.5 mmol, 7 eq) in water (3.34 mL) and Pd-132 (64 mg, 0.09 mmol, 0.17 eq), then degassed for three times. The mixture was heated up to 80° C. for overnight. LCMS showed >80% conversion to desired product, and ˜10% of des-bromation of example 45. The reaction mixture was filtered. The filtrate was concentrated and purified via a Biotage silica gel cartridge to provide the title compound (174 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:3]=1[NH:4][C:5]1[C:6]([CH2:10]O)=[CH:7][S:8][CH:9]=1.[ClH:17]>>[Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:3]=1[NH:4][C:5]1[C:6]([CH2:10][Cl:17])=[CH:7][S:8][CH:9]=1
Reactant: Cl
Reactant: OCc1cscc1Nc1c(Cl)cccc1Cl
Product: ClCc1cscc1Nc1c(Cl)cccc1Cl
Reaction time: 8 h

Procedure:
27.4 g (0.1 mole) of 4-(2,6-dichloroanilino)-3-thiophenmethanol are dissolved in 800 ml of concentrated aqueous hydrochloric acid, and the solution is left to stand for eight hours, poured onto ice and extracted with toluene. The organic phase is washed with sodium bicarbonate solution, dried and concentrated. Recrystallization of the residue from petroleum ether gives 3-(2,6-dichloroanilino)-4-chloromethylthiophen (m. 89° to 92°).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[C:11]([O-])(=[S:13])[CH3:12].[K+]>CC(C)=O>[C:11]([CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4])(=[S:13])[CH3:12]
Reactant: CC([O-])=S
Reactant: O=C(CCl)c1ccccc1
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=S)CC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Chloroacetophenone in acetone (3.10 g, 200 ml) was added potassium thioacetate (2.80 g, 1.2 equivalents) and the reaction mixture was stirred overnight at RT. The salt precipitate was filtered off and the filtrate was concentrated. The residue was purified by flash chromatography on silica gel to give 2.04 g of α-thioacetyl acetophenone as orange reddish oil. 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 7.98–8.02 (2 H, m) 7.60 (1 H, t, J=7.48 Hz) 7.48 (2 H, t, J=7.78 Hz) 4.40 (2 H, s) 2.41 (3 H, s). MS [ESI, MNa+] m/z calcd for C10H10O2SNa 217.04, found 217.16.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([Cl:11])[C:8]([CH:12]2[CH2:14][CH2:13]2)=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[OH:15][CH2:16][CH2:17][CH2:18][C:19](=[O:21])[CH3:20].[H-].[Na+]>CN(C=O)C>[Cl:11][C:9]1[C:8]([CH:12]2[CH2:14][CH2:13]2)=[CH:7][C:3]([C:4]([NH2:6])=[O:5])=[C:2]([O:15][CH2:16][CH2:17][CH2:18][C:19](=[O:21])[CH3:20])[N:10]=1
Reactant: CC(=O)CCCO
Reactant: NC(=O)c1cc(C2CC2)c(Cl)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)CCCOc1nc(Cl)c(C2CC2)cc1C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.5 %

Procedure:
To a mixture of 2,6-dichloro-5-cyclopropylnicotinamide (2.00 g, 8.66 mmol) and 5-hydroxypentan-2-one (883 mg, 8.66 mmol) in DMF (30 mL) was added and NaH (416 mg, 10.4 mmol) in portions at 0° C. The mixture was stirred at r.t. overnight, quenched by water, extracted by EtOAc. The separated organics was dried, concentrated and purified by column chromatography (Petroleum ether:EtOAc=10:1˜1:1) to give 6-chloro-5-cyclopropyl-2-(4-oxopentyloxy)nicotinamide (500 mg, 19.4%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:14]#[CH:15])[C:11]=1[O:12][CH3:13])[C:6](O)=[O:7])#[N:2].C1(C)C=CC=CC=1.C(Cl)(=O)C([Cl:26])=O>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:14]#[CH:15])[C:11]=1[O:12][CH3:13])[C:6]([Cl:26])=[O:7])#[N:2]
Reactant: C#Cc1cc(C(=O)O)cc(C#N)c1OC
Reactant: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: C#Cc1cc(C(=O)Cl)cc(C#N)c1OC
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To 3-cyano-5-ethynyl-4-methoxybenzoic acid (610 mg), toluene (6 mL), N,N-dimethylformamide (1 droplet) and oxalyl chloride (0.32 mL) were added to the solution under ice cooling, and the mixture was stirred at room temperature for 1.5 hours. The solvent was distilled off under reduced pressure and the obtained residue was azeotroped with toluene and used for the synthesis of (c).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[N:25][C:26]=1[N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)=[C:5]([CH3:19])[C:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)=[N:7]2.Cl[C:37]1[CH:42]=[C:41]([CH3:43])[N:40]=[C:39]([NH2:44])[N:38]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>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.O>[NH2:44][C:39]1[N:38]=[C:37]([C:23]2[CH:22]=[C:21]([NH:20][C:4]3[C:3]4[C:8](=[CH:9][C:10]([F:12])=[CH:11][C:2]=4[F:1])[N:7]=[C:6]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=4)[C:5]=3[CH3:19])[C:26]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[N:25][CH:24]=2)[CH:42]=[C:41]([CH3:43])[N:40]=1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Nc1cc(B(O)O)cnc1N1CCOCC1
Reactant: Cc1cc(Cl)nc(N)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(-c2cnc(N3CCOCC3)c(Nc3c(C)c(-c4ccccn4)nc4cc(F)cc(F)c34)c2)nc(N)n1
Temperature: 120 °C

Procedure:
A solution of 5-(5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-ylamino)-6-morpholinopyridin-3-ylboronic acid (0.026 mmol, described herein), 4-chloro-6-methylpyrimidin-2-amine (3.7 mg, 0.026 mmol), sodium carbonate (8.18 mg, 0.077 mmol), dichlorobis(triphenylphosphine)palladium(ii) (1.8 mg, 2.57 μmol), 1,4-dioxane (560 μL) and water (140 μL) heated in a microwave at 120° C. for 60 min. The reaction was then cooled to rt and partitioned between EtOAc and water. The organic layer was dried (magnesium sulfate) and concentrated, and chromatography afforded N-(5-(2-amino-6-methyl-4-pyrimidinyl)-2-(4-morpholinyl)-3-pyridinyl)-5,7-difluoro-3-methyl-2-(2-pyridinyl)-4-quinolinamine as a yellow solid. 1H NMR (400 MHz, chloroform-d) δ ppm 8.72-8.81 (1H, m), 8.52-8.61 (1H, m), 7.85-7.96 (2H, m), 7.61-7.71 (1H, m), 7.52-7.61 (1H, m), 7.47-7.52 (1H, m), 7.41 (1H, m), 7.03 (1H, m), 6.84-6.93 (1H, m), 5.22 (2H, br. s.), 3.94 (4H, br. s.), 3.45-3.73 (2H, m), 3.00-3.40 (2H, br. s.), 2.33-2.52 (3H, m), 2.15-2.29 (3H, m). Mass Spectrum (ESI) m/e=541.0 (M+1).
Reaction SMILES: [C:1]1([C:7](=[O:12])[C:8](=[N:10][OH:11])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]1([CH3:21])[CH:18]=[CH:17][C:16]([CH:19]=O)=[CH:15][CH:14]=1.Cl>C(O)(=O)C>[CH3:9][C:8]1[N+:10]([O-:11])=[C:21]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[O:12][C:7]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: CC(=NO)C(=O)c1ccccc1
Agent: Cl
Solvent: CC(=O)O
Product: Cc1ccc(-c2oc(-c3ccccc3)c(C)[n+]2[O-])cc1

Procedure:
12.5 g of 1-phenyl-1,2-propanedione-2-oxime and 10 ml of p-tolualdehyde are added to 50 ml of glacial acetic acid, and HCl gas is introduced for 30 minutes, with ice-cooling. The product is precipitated as the hydrochloride by addition of methyl tert-butyl ether and filtered off with suction, and the precipitate is washed with methyl tert-butyl ether. The precipitate is suspended in water and the pH is made alkaline using ammonia. The mixture is extracted three times with in each case 200 ml of dichloromethane, the combined organic phases are dried over MgSO4 and the solvent is then removed under reduced pressure. This gives 6.4 g of 4-methyl-5-phenyl-2-p-tolyloxazole 3-oxide as a white solid. C17H15NO2 (265.31), MS (ESI)=266 (M+H+).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7](Cl)=[O:8].[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH3:18].[Cl-].[Al+3].[Cl-].[Cl-]>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([C:15]1[CH:14]=[CH:13][C:12]([O:17][CH3:18])=[C:11]([Cl:10])[CH:16]=1)=[O:8]
Reactant: COc1ccccc1Cl
Reactant: O=C(Cl)CCCCCBr
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc(C(=O)CCCCCBr)cc1Cl
Yield: 32.8 %

Procedure:
6-Bromohexanoyl chloride (2.0 g), 2-chloroanisole (1.17 g) and aluminum chloride (1.12 g) were reacted and treated in the same manner as in Preparation Example 105 to give 0.86 g of 6-bromo-1-(3-chloro-4-methoxyphenyl)-1-hexanone.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:34])=[C:4]([C:8]2[N:9]=[C:10]([C:20]3([CH3:33])[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]3)[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([Cl:19])[N:14]=2)[CH:5]=[CH:6][CH:7]=1.[F:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[C:37]=1[S:43](Cl)(=[O:45])=[O:44]>N1C=CC=CC=1>[Cl:19][C:15]1[N:14]=[C:13]([C:12]2[S:11][C:10]([C:20]3([CH3:33])[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])[CH2:22][CH2:21]3)=[N:9][C:8]=2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][S:43]([C:37]3[C:38]([F:42])=[CH:39][CH:40]=[CH:41][C:36]=3[F:35])(=[O:45])=[O:44])[C:3]=2[F:34])[CH:18]=[CH:17][N:16]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C)(c2nc(-c3cccc(N)c3F)c(-c3ccnc(Cl)n3)s2)CC1
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(C)(c2nc(-c3cccc(NS(=O)(=O)c4c(F)cccc4F)c3F)c(-c3ccnc(Cl)n3)s2)CC1
Reaction time: 5 h
Yield: 81.5 %

Procedure:
To a solution of 1,1-dimethylethyl 4-[4-(3-amino-2-fluorophenyl)-5-(2-chloro-4-pyrimidinyl)-1,3-thiazol-2-yl]-4-methyl-1-piperidinecarboxylate (200 mg, 0.397 mmol) in pyridine (2 mL) was added 2,6-difluorobenzenesulfonyl chloride (130 mg, 0.612 mmol) and the reaction mixture was stirred for 5 h. The reaction mixture was quenched with water (5 mL) and extracted with EtOAc (3×). The extract was dried, filtered and concentrated. The residue was purified using column chromatography (40 to 100% EtOAc/hexane) to obtain the title compound (220 mg). MS (ESI): 680.4 [M+1]+.