Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[N:7]([C:9]1[C:14]2[N:15]=[CH:16][N:17]([CH3:18])[C:13]=2[C:12](I)=[C:11]([NH2:20])[N:10]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[C:22]([CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)#[CH:23].C(NC(C)C)(C)C.CN(C)C=O>C(OCC)(=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.[Cu]I>[NH2:20][C:11]1[N:10]=[C:9]([N:7]([CH3:8])[C:6](=[O:21])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:14]2[N:15]=[CH:16][N:17]([CH3:18])[C:13]=2[C:12]=1[C:23]#[C:22][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: C#CC1CCCCC1
Reactant: CN(C(=O)OC(C)(C)C)c1nc(N)c(I)c2c1ncn2C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: CN(C(=O)OC(C)(C)C)c1nc(N)c(C#CC2CCCCC2)c2c1ncn2C
Temperature: 95 °C

Procedure:
A1.12 tert-Butyl-6-amino-7-iodo-1-methyl-1H-imidazo[4,5-c]pyridin-4-yl(methyl)carbamate (1.0 g, 2.48 mmol), dichlorobis(triphenylphosphine)palladium (75 mg, 0.11 mmol), ethynylcyclohexane (0.3 g, 2.8 mmol), CuI (25 mg, 0.13 mmol), and diisopropylamine (5 mL) were added to N,N-dimethylformamide (7 mL). The reaction mixture was heated at 95° C. (in preheated oil bath) for 60 min. Additional ethynylcyclohexane (0.3 g, 2.8 mmol) was added to the reaction mixture and heated for another 60 min. The reaction was cooled and diluted with ethyl acetate and washed several times with water. The solvent removed under reduced pressure and the residue was chromatographed on a silica gel column (50%-70% ethyl acetate/hexane) to give 400 mg of C32.1 as a yellow solid. LCMS B: Ret time 3.15 min, (M+H)+=384.41.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[CH:12]=[C:11](B3OC(C)(C)C(C)(C)O3)[CH:10]=[CH:9][C:8]2=[O:22])=[C:4]([F:25])[CH:3]=1.Br[C:27]1[CH:35]=[CH:34][C:30]2[S:31][CH:32]=[CH:33][C:29]=2[CH:28]=1>>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[CH:12]=[C:11]([C:27]3[CH:35]=[CH:34][C:30]4[S:31][CH:32]=[CH:33][C:29]=4[CH:28]=3)[CH:10]=[CH:9][C:8]2=[O:22])=[C:4]([F:25])[CH:3]=1
Reactant: CC1(C)OB(c2ccc(=O)n(Cc3ccc(Cl)cc3F)c2)OC1(C)C
Reactant: Brc1ccc2sccc2c1
Product: O=c1ccc(-c2ccc3sccc3c2)cn1Cc1ccc(Cl)cc1F
Yield: 5.9 %

Procedure:
According to Scheme 17 Step 2: The title compound was prepared from 1-(4-chloro-2-fluorobenzyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (1 eq, 1.26 mmol, 0.40 g) and 5-bromobenzo[b]thiophene (1.5 eq, 0.29 mmol, 0.06 g) according to the procedure described for Example 1 Step 2. The crude product was purified by flash chromatography over silica gel (AIT Flashsmart prepacked column 25 g SiO2) using CH2Cl2/AcOEt 90/10 and by crystallization with diisopropyl ether/pentane to afford the title compound (17 μmol, 6.4 mg, 9%) as a white solid.
Reaction SMILES: [C:1]1([N:7]=[N+:8]=[N-:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]([C:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH:18]=1)#[C:11][CH3:12]>C1(C)C=CC=CC=1>[C:1]1([N:7]2[C:11]([CH3:12])=[C:10]([C:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH:14]=3)[N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC#CC1=CCN(C(=O)OC(C)(C)C)CC1
Reactant: [N-]=[N+]=Nc1ccccc1
Solvent: Cc1ccccc1
Product: Cc1c(C2=CCN(C(=O)OC(C)(C)C)CC2)nnn1-c1ccccc1
Temperature: 120 °C
Yield: 3.1 %

Procedure:
The above-prepared phenyl azide (214 mg) and 200 mg of tert-butyl 4-(1-propynyl)-1,2,3,6-tetrahydropyridine-1-carboxylate prepared in 3) were dissolved in 3 ml of toluene and the solution was stirred at 120° C. for one night. The resulting solution was cooled down to room temperature, the solvent was evaporated in vacuo and the resulting residue was purified by a preparative thin-layer silica gel chromatography (hexane:ethyl acetate=2:1) to give 9.4 mg of the title compound as a white solid.
Reaction SMILES: [N:1]([CH2:4][CH:5]([C:7]1[CH:8]=[C:9]([C:13](=[O:34])[C:14](=[C:25]2[NH:29][C:28]3[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=3[NH:26]2)[C:15]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=2)=[O:16])[CH:10]=[CH:11][CH:12]=1)[OH:6])=[N+]=[N-].[H][H]>[C].[Pd].C(OCC)(=O)C>[NH2:1][CH2:4][CH:5]([C:7]1[CH:8]=[C:9]([C:13](=[O:34])[C:14](=[C:25]2[NH:29][C:28]3[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=3[NH:26]2)[C:15]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=2)=[O:16])[CH:10]=[CH:11][CH:12]=1)[OH:6]
Reactant: [H][H]
Reactant: [N-]=[N+]=NCC(O)c1cccc(C(=O)C(C(=O)c2cc(F)cc(F)c2)=C2Nc3ccccc3N2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: NCC(O)c1cccc(C(=O)C(C(=O)c2cc(F)cc(F)c2)=C2Nc3ccccc3N2)c1
Yield: 47 %

Procedure:
A 568 mg portion of 1-[3-(2-azido-1-hydroxyethyl)phenyl]-3-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)propane-1,3-dione and 120 mg of 10% palladium-carbon were added to 50 ml of ethyl acetate and stirred at room temperature for 8.5 hours under ordinary pressure and in an atmosphere of hydrogen. This was filtered through celite, concentrated, mixed with diethyl ether and then extracted with water. By concentrating the water layer, 250 mg (47%) of 1-[3-(2-amino-1-hydroxyethyl)phenyl]-3-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)propane-1,3-dione (Example 14-1) was obtained as a yellow solid. FA: 436
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([N:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][CH:20]([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)=[N:7][C:6]=12.O.[F:24][C:25]1[C:30](B(O)O)=[CH:29][CH:28]=[CH:27][N:26]=1.C(=O)([O-])[O-].[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2].O>[F:24][C:25]1[C:30]([C:2]2[CH:3]=[N:4][N:5]3[CH:10]=[CH:9][C:8]([N:11]4[CH2:16][CH2:15][N:14]([C:17]([O:19][CH:20]([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]4)=[N:7][C:6]=23)=[CH:29][CH:28]=[CH:27][N:26]=1
Reactant: OB(O)c1cccnc1F
Reactant: CC(C)OC(=O)N1CCN(c2ccn3ncc(Br)c3n2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Solvent: O
Product: CC(C)OC(=O)N1CCN(c2ccn3ncc(-c4cccnc4F)c3n2)CC1
Temperature: 25 °C
Yield: 21.3 %

Procedure:
Isopropyl 4-(3-bromopyrazolo[1,5-a]pyrimidin-5-yl)piperazine-1-carboxylate (4 g, 10.86 mmol), 2-fluoropyridine-3-boronic acid hydrate (3.44 g, 21.7 mmol), potassium carbonate (4.5 g, 32.6 mmol), Pd(OAc)2 (24 mg, 0.1086 mmol), and x-Phos (146 mg, 0.217 mmol) were taken up in dioxane and water under nitrogen and stirred at 80° C. for 2 hours. Reaction then cooled to room temperature, filtered through celited plug with ethyl acetate. Reduced in vacuo and run through an isco silica column with hexane:ethyl acetate 75-100%. Product plus desbromo co elute, reduced in vacuo. Product recrystallized 3 times from IPAC, washed with heptanes dried to get 889 mg product. 1H NMR (400 MHz, DMSO-d6) δ 8.95 (t, J=2.15 Hz, 1H), 8.78 (d, J=7.83 Hz, 1H), 8.29 (d, J=4.29 Hz, 1H), 8.00 (d, J=4.80 Hz, 1H), 7.43 (dt, J=2.40, 4.99 Hz, 1H), 6.85 (d, J=7.83 Hz, 1H), 4.78-4.87 (m, 1H), 3.73-3.83 (m, 4H), 3.48-3.58 (m, 4H), 3.31 (s, 1H), 1.22 (d, J=6.06 Hz, 6H) LRMS (ESI) m/z 385 [(M+H)]+, calc'd for C19H21FN6O2: 384.42.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[N:18]([CH3:33])[CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=4)[N:21]=3)[CH2:13][CH2:12]2)[N:5]=[CH:4][N:3]=1.NC1C(C#N)=C(N2CCC(C3N(C[CH2:66][N:67]([CH2:69][CH2:70][O:71][CH3:72])[CH3:68])C=C(C4C=CC(F)=C(C(F)(F)F)C=4)N=3)CC2)N=CN=1>>[NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[N:18]([CH2:33][CH2:66][N:67]([CH2:69][CH2:70][O:71][CH3:72])[CH3:68])[CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=4)[N:21]=3)[CH2:13][CH2:12]2)[N:5]=[CH:4][N:3]=1
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C(N)=O)CC1
Reactant: COCCN(C)CCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C#N)CC1
Product: COCCN(C)CCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C(N)=O)CC1

Procedure:
The title compound was prepared in an analogous manner as 4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamide using 4-Amino-6-[4-(4-(4-fluoro-3-trifluoromethyl-phenyl)-1-{2-[(2-methoxy-ethyl)-methyl-amino]-ethyl}-1H-imidazol-2-yl)-piperidin-1-yl]-pyrimidine-5-carbonitrile instead of 4-amino-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidine-5-carbonitrile. LC-MS: (M+1=565, obsd.=565).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[CH2:5].C(=O)(O)[O-].[Na+].[Cl:15][CH2:16][C:17](=[O:22])[C:18](Cl)=[N:19][OH:20]>C1(C)C=CC=CC=1>[Cl:15][CH2:16][C:17]([C:18]1[CH2:5][CH:4]([C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[F:1])[O:20][N:19]=1)=[O:22]
Reactant: O=C(CCl)C(Cl)=NO
Reactant: C=Cc1ccccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C(CCl)C1=NOC(c2ccccc2F)C1
Temperature: 55 °C
Reaction time: 2 h
Yield: 85.3 %

Procedure:
To a suspension of 2-fluorostyrene (2.78 g, 22.8 mmol) and sodium bicarbonate (2.88 g, 34.2 mmol) in anhydrous toluene (15 mL) heated at 55° C. was added 3-chloro-N-hydroxy-2-oxo-propanimidoyl chloride (1.78 g, 11.4 mmol). After 2 h at 55° C., the reaction mixture was cooled, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel using 10% ethyl acetate in hexanes as eluant to provide the title compound as a yellow solid (2.35 g) melting at 42-44° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]=[CH2:17])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].B.C1C[O:22]CC1.O.C([O-])([O-])=O.C([O-])([O-])=O.OO.OO.OO.[Na+].[Na+].[Na+].[Na+]>C1COCC1>[OH:22][CH2:17][CH2:16][C:12]1[C:9]2[C:10]([CH3:11])=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[O:7][C:8]=2[CH:15]=[CH:14][CH:13]=1
Reactant: C1CCOC1
Reactant: C=Cc1cccc2oc(C(=O)OCC)c(C)c12
Agent: B
Agent: O=C([O-])[O-]
Agent: OO
Solvent: O
Product: CCOC(=O)c1oc2cccc(CCO)c2c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.6 %

Procedure:
To a solution of 0.35 g (1.5 mmol) of 3-methyl-4-vinyl-1-benzofuran-2-carboxylate (Example 87, Step 1) in 3 mL of THF, cooled in an ice bath, was added 1 mL (1 mmol) of borane-THF complex (1.0M solution in THF). The reaction was stirred at room temperature for 2 hours. The reaction was cooled in an ice bath and 1.5 mL of water was added. Next 0.61 g of sodium percarbonate was added in one portion. The reaction was heated at ˜50° C. for 1 hour, then cooled to room temperature. Water was added and the resulting mixture was extracted with ethyl acetate. The organic layer washed with water and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexane/ethyl acetate (2:1) to provide 0.20 g of ethyl 4-(2-hydroxyethyl)-3-methyl-1-benzofuran-2-carboxylate. Yield 54%. m.p. 88-90° C.; MS 249.1 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7](OC2C=C3C(=CC=2)OC(C2C=CC=CC=2)CC3)=[N:8][CH:9]=1)([O-:3])=[O:2].[F:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=1[CH:35]1[CH2:44][CH2:43][C:42]2[C:37](=[CH:38][CH:39]=[C:40]([OH:45])[CH:41]=2)[O:36]1>>[F:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=1[CH:35]1[CH2:44][CH2:43][C:42]2[C:37](=[CH:38][CH:39]=[C:40]([O:45][C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=3)[CH:41]=2)[O:36]1
Reactant: Oc1ccc2c(c1)CCC(c1cc(F)ccc1F)O2
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Product: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2cc(F)ccc2F)O3)nc1

Procedure:
2-[2-(2,5-Difluorophenyl)chroman-6-yloxy]-5-nitropyridine was prepared as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) starting from 100 mg of 2-(2,5-difluorophenyl)chroman-6-ol. The product was recrystallised from 2-propanol. 1H NMR (400 MHz, CDCl3) δ: 9.07 (dd, 1H, J 2.8, 0.4 Hz), 8.47 (dd, 1H, J 9.1, 2.8 Hz), 7.26 (m, 1H), 7.05-6.91 (m, 6H), 5.35 (dd, 1H, J 10.3, 1.5 Hz), 3.04 (ddd, 1H, J −16.9, 11.7, 6.0 Hz), 2.82 (ddd, 1H, J −16.9, 5.2, 3.0 Hz), 2.29 (m, 1H), 2.01 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.[C:10](Cl)(=[O:12])[CH3:11].O>CN(C)C1C=CC=CC=1>[C:10]([NH:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)Cl
Reactant: Cc1cc(Br)cnc1N
Solvent: CN(C)c1ccccc1
Solvent: O
Product: CC(=O)Nc1ncc(Br)cc1C
Temperature: 70 °C
Reaction time: 3 h
Yield: 32.7 %

Procedure:
To a solution of 2-amino-5-bromo-3-methylpyridine (300 mg) in N,N-dimethylaniline (486 mg) was added acetyl chloride (138 mg), and the mixture was stirred for 3 hours at 70° C. The reaction mixture was poured into water, and extracted with ethyl acetate. The extract was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography (chloroform) to give 2-acetamido-5-bromo-3-methylpyridine (120 mg).
Reaction SMILES: C(N(CC)CC)C.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.FC(F)(F)C(O)=O.C([O:32][C:33]([C:35]1[CH:36]=[N:37][NH:38][C:39]=1[N:40]1[C:44](=[O:45])[NH:43][C:42]([CH:46]([NH:61][C:62]2[CH:67]=[CH:66][C:65]([C:68](=[NH:70])[NH2:69])=[CH:64][CH:63]=2)[C:47]2[CH:52]=[C:51]([O:53][CH3:54])[CH:50]=[C:49]([O:55][CH2:56][CH2:57][CH2:58][OH:59])[C:48]=2[F:60])=[N:41]1)=[O:34])C.CN(C=O)C>CN(C)C1C=CN=CC=1.C(#N)C>[C:68]([C:65]1[CH:64]=[CH:63][C:62]([NH:61][CH:46]([C:47]2[CH:52]=[C:51]([O:53][CH3:54])[CH:50]=[C:49]([O:55][CH2:56][CH2:57][CH2:58][OH:59])[C:48]=2[F:60])[C:42]2[NH:43][C:44](=[O:45])[N:40]([C:39]3[NH:38][N:37]=[CH:36][C:35]=3[C:33]([OH:34])=[O:32])[N:41]=2)=[CH:67][CH:66]=1)(=[NH:69])[NH2:70]
Reactant: CCOC(=O)c1cn[nH]c1-n1nc(C(Nc2ccc(C(=N)N)cc2)c2cc(OC)cc(OCCCO)c2F)[nH]c1=O
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: COc1cc(OCCCO)c(F)c(C(Nc2ccc(C(=N)N)cc2)c2nn(-c3[nH]ncc3C(=O)O)c(=O)[nH]2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.7 %

Procedure:
After adding 38 μl of triethylamine, 0.3 mg of 4-dimethylaminopyridine and 46 mg of di-t-butyl dicarbonate to a solution of 55 mg of 5-(3-{(4-carbamimidoylphenylamino)-[2-fluoro-3-(3-hydroxypropoxy)-5-methoxyphenyl]methyl}-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl)-1H-pyrazole-4-carboxylic acid ethyl ester trifluoroacetate in 6 ml of an acetonitrile:DMF=2:1 mixed solvent, the mixture was stirred at room temperature for 15 hours. The solvent was removed under reduced pressure, and then 1 ml of methanol and 1 ml of a 1N aqueous sodium hydroxide solution were added and the mixture was stirred at room temperature for 8 hours. After adding 5 ml of a methanol:water:acetic acid=1:1:1 mixed solvent to the reaction mixture, it was stirred and heated at 50° C. for 15 hours. The mixture was cooled and then directly purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% acetic acid) to give 16 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[OH:13][C:14]1([CH3:21])[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClC(Cl)C>[OH:13][C:14]1([CH3:21])[CH2:19][CH2:18][CH:17]([NH:1][C:2]2[C:3]([CH3:12])=[C:4]([CH:9]=[CH:10][CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])[CH2:16][CH2:15]1
Reactant: COC(=O)c1cccc(N)c1C
Reactant: CC1(O)CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: COC(=O)c1cccc(NC2CCC(C)(O)CC2)c1C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of methyl 3-amino-2-methylbenzoate (1.5 g, 9.1 mmol) and 4-hydroxy-4-methylcyclohexanone (1.51 ml, 11.8 mmol) in 10 ml of dichloroethane was added acetic acid (3.2 mL, 55 mmol) and the reaction mixture stirred at room temperature for 20 minutes. The reaction mixture was cooled to 0° C. and sodium triacetoxyborohydride (5.78 g, 27.3 mmol) was added and the mixture stirred at room temperature overnight. The reaction mixture was neutralized with sat. NaHCO3, extracted with DCM, dried over Na2SO4, concentrated under reduced pressure, and purified by silica gel column chromatography to afford the title compound which was carried forward as a mixture of cis and trans isomers (1.4 g, 56%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:4]=1[NH2:5].[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[BH4-].[Na+]>O.C(O)C.C(O)(=O)C>[CH2:12]([NH:5][C:4]1[CH:6]=[CH:7][C:8]([O:10][CH3:11])=[CH:9][C:3]=1[O:2][CH3:1])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COc1ccc(N)c(OC)c1
Reactant: O=Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(NCc2ccccc2)c(OC)c1
Temperature: 40 °C
Reaction time: 1 h
Yield: 84.2 %

Procedure:
Into 150 ml of ethanol, 30.6 g of 2,4-dimethoxyaniline and 21.2 g of benzaldehyde were dissolved, and 2 g of acetic acid was added. The mixture was reacted at a temperature of from 50° to 60° C. for 4 hours. The reaction solution was poured into 500 ml of water and extracted with 300 ml of toluene. The toluene solution was separated by liquid separation, then washed with water and concentrated to dryness. The oily product thereby obtained was dissolved into 150 ml of ethanol, and 11.3 g of sodium boro-hydride was added in 2 hours at a temperature of from 30° to 40° C. and reacted therewith. Further, the mixture was stirred for one hour at a temperature of 40° C. The reaction mixture was poured into 1 liter of water and extracted with 500 ml of toluene. The toluene layer was washed with water, concentrated and purified by distillation under reduced pressure, whereby 40.9 g of N-benzyl-2,4-dimethoxyaniline was obtained. The product was a liquid having a boiling point of from 166° to 168° C./2 mmHg.
Reaction SMILES: Br[C:2]1[C:25](=[O:26])[N:24]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:5]2[N:6]=[C:7]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]4)=[CH:13][N:12]=3)[N:8]=[CH:9][C:4]=2[C:3]=1[CH3:32].C1(C)C=CC=CC=1.C([Sn](CCCC)(CCCC)[C:45]([O:47][CH2:48][CH3:49])=[CH2:46])CCC>C(Cl)(Cl)Cl.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:27]1([N:24]2[C:5]3[N:6]=[C:7]([NH:10][C:11]4[CH:16]=[CH:15][C:14]([N:17]5[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]5)=[CH:13][N:12]=4)[N:8]=[CH:9][C:4]=3[C:3]([CH3:32])=[C:2]([C:45]([O:47][CH2:48][CH3:49])=[CH2:46])[C:25]2=[O:26])[CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(Nc3ccc(N4CCN(C)CC4)cn3)ncc12
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: C=C(OCC)c1c(C)c2cnc(Nc3ccc(N4CCN(C)CC4)cn3)nc2n(C2CCCC2)c1=O
Temperature: 110 °C
Reaction time: 12 h
Yield: 90.6 %

Procedure:
A 6-dram vial was charged with 6-bromo-8-cyclopentyl-5-methyl-2-[5-(4-methyl-piperazin-1-yl)-pyridin-2-ylamino]-8H-pyrido[2,3-d]pyrimidin-7-one (266 mg, 0.53 mmol) and tetrakis(triphenylphosphine) palladium(0) (61 mg, 0.053 mmol) and the atmosphere replaced with argon. Toluene (5 ml) was added followed by tributyl-(1-ethoxy-vinyl)-stannane (289 mg, 0.80 mmol). The vial was heated to 110° C. and stirred for 12 h. The reaction mixture was diluted with chloroform (25 ml) and adsorbed onto silica gel. Chromatographic purification on silica gel (chloroform/2-propanol+1% TEA gradient) gave the 8-cyclopentyl-6-(1-ethoxy-vinyl)-5-methyl-2-[5-(4-methyl-piperazin-1-yl)-pyridin-2-ylamino]-8H-pyrido[2,3-d]pyrimidin-7-one (237 mg, 0.48 mmol). MS (APCI+) 490 (M+1, 100).
Reaction SMILES: [N:1]([C@H:4]([CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:5][OH:6])=[N+:2]=[N-:3].N1C=CC=CC=1.[O:31](S(C(F)(F)F)(=O)=O)[S:32]([C:35]([F:38])([F:37])[F:36])(=O)=[O:33]>C(Cl)Cl>[F:36][C:35]([F:38])([F:37])[S:32]([O:6][CH2:5][C@H:4]([N:1]=[N+:2]=[N-:3])[CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])(=[O:33])=[O:31]
Reactant: CCCCCCCCCCCCCCCCOC[C@H](CO)N=[N+]=[N-]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCOC[C@H](COS(=O)(=O)C(F)(F)F)N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-2-azido-3-(hexadecyloxy)propan-1-ol (1 eq) and pyridine (4 eq) in DCM (0.1 M) at 0° C., was added Tf2O (2 eq). The reaction was stirred at 0° C. for 1 hour and quenched by H2O. The aqueous phase was extracted with DCM. The combined organic phases were washed with H2O, and the aqueous phase was back extracted with DCM. The combined organic phases were washed with saturated NaHCO3 and brine, dried over anhydrous Na2SO4 and concentrated en vaccuo. The resulting crude was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-10% EtOAc/Hex to give (R)-2-azido-3-(hexadecyloxy)propyl trifluoromethanesulfonate.
Reaction SMILES: CS[C:3]1[N:4]=[N:5][C:6]([C:21]#[N:22])=[C:7]([N:9]2[CH2:14][CH:13]=[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)[N:8]=1.[CH2:23]([CH2:25][NH2:26])[OH:24]>O1CCOCC1>[OH:24][CH2:23][CH2:25][NH:26][C:3]1[N:4]=[N:5][C:6]([C:21]#[N:22])=[C:7]([N:9]2[CH2:14][CH:13]=[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)[N:8]=1
Reactant: CSc1nnc(C#N)c(N2CC=C(c3ccccc3)CC2)n1
Reactant: NCCO
Solvent: C1COCCO1
Product: N#Cc1nnc(NCCO)nc1N1CC=C(c2ccccc2)CC1
Temperature: 120 °C
Reaction time: 8 h
Yield: 47.6 %

Procedure:
A mixture of 68 mg (0.21 mmol) of 3-methylsulfanyl-5-(4-phenyl-3,6-dihydro-2H-pyridin-1-yl)-[1,2,4]triazine-6-carbonitrile and 14.5 mg (0.23 mmol) ethanolamine in 1 ml of dioxane was stirred at 120° C. overnight. For the working-up, the solution was evaporated under reduced pressure and the residue was chromatographed on silica gel with a 90:10:0.1 mixture of dichloromethane, methanol, and ammonium hydroxide as the eluent. There were obtained 35 mg (0.10 mmol, 50% of theory) of 3-(2-hydroxy-ethylamino)-5-(4-phenyl-3,6-dihydro-2H-pyridin-1-yl)-[1,2,4]triazine-6-carbonitrile as an amorphous, white solid; MS: 323 (M+H)+;
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:17])[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].C(O)(=O)C(C)(C)C.C(=O)([O-])[O-].[Na+].[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:12]1[C:13]2[C:7]3[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=3[O:1][C:8]=2[C:9]([NH:14][C:15](=[O:17])[CH3:16])=[CH:10][CH:11]=1
Reactant: CC(=O)Nc1ccccc1Oc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)C(=O)O
Product: CC(=O)Nc1cccc2c1oc1ccccc12
Temperature: 105 °C
Yield: 75.7 %

Procedure:
The mixture of N-(2-phenoxyphenyl)acetamide (120 g, 528 mmol), potassium carbonate (7.30 g, 52.8 mmol), palladium acetate (11.85 g, 52.8 mmol) and pivalic acid (539 g, 5280 mmol) was prepared and heated at 105° C. (inner temperature) under air for two days. GC-MS showed 60% product. The reaction was stirred at 115° C. (inner temperature) for another night. The reaction was then cooled to room temperature and neutralized by saturated sodium carbonate solution, which was then extracted by EtOAc three times. The extraction was concentrated to give the crude product N-(dibenzo[b,d]furan-4-yl)acetamide (90 g, 76% yield) as brown solid.