Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([O:27]C)=[O:26])=[CH:19][CH:18]=3)[CH:10]=2)=[C:4]([CH3:29])[CH:3]=1.[OH-].[Na+]>CO.O1CCCC1>[OH:1][C:2]1[CH:3]=[C:4]([CH3:29])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][C:17]3[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[CH:21][CH:22]=3)[CH:10]=2)=[C:6]([CH3:8])[CH:7]=1
Reactant: COC(=O)CCc1ccc(OCc2cccc(-c3c(C)cc(O)cc3C)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(O)cc(C)c1-c1cccc(COc2ccc(CCC(=O)O)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.1 %

Procedure:
To a solution of methyl 3-[4-[(4′-hydroxy-2′,6′-dimethylbiphenyl-3-yl)methoxy]phenyl]propanoate (0.18 g, 0.46 mmol) in methanol (2 mL) and tetrahydrofuran (4 mL) was added 1 N aqueous sodium hydroxide solution (0.91 mL) and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated and the residue was diluted with ethyl acetate, washed with 1 N hydrochloric acid and saturated brine, dried and concentrated under reduced pressure. The residue was crystallized from hexane/ethyl acetate=4/1 to give the title compound (0.13 g, yield 74%) as colorless crystals.
Reaction SMILES: [C:1](Cl)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH2:19]([NH2:23])[CH2:20][CH2:21][CH3:22]>C(OCC)C>[CH2:19]([NH:23][C:1](=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:20][CH2:21][CH3:22]
Reactant: CCCCN
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCC(=O)NCCCC

Procedure:
An amount of 137.4 g of palmitoyl chloride in 100 ml of ethyl ether was added, under stirring at room temperature, to 80.5 g of n-butylamine in 700 ml of ethyl ether. Stirring was continued under gentle reflux for one hour. The precipitate was filtered off and thoroughly washed with water. The reaction product was recrystallized from ethanol giving 148.4 g of the title compound, melting point 74°-76° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]=[N:11][C:12]1[CH:22]=[CH:21][C:15]([N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:14][CH:13]=1.[CH2:23]=[N:24]O.N1C(C)=CC=CC=1C.[N+](C1C=CC=CC=1)([O-])=O>[Cu]I>[C:23]([C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]=[N:11][C:12]1[CH:22]=[CH:21][C:15]([N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:14][CH:13]=1)#[N:24]
Reactant: C=NO
Reactant: CCN(CC)c1ccc(N=Nc2c(C)cc(Br)cc2Br)cc1
Agent: [Cu]I
Solvent: O=[N+]([O-])c1ccccc1
Solvent: Cc1cccc(C)n1
Product: CCN(CC)c1ccc(N=Nc2c(C)cc(Br)cc2C#N)cc1
Temperature: 95 °C
Yield: 15.1 %

Procedure:
A stirred mixture of 4-(2',4'-dibromo-6'-methylphenylazo)-N,N-diethylaniline (4.25 parts), copper (I) iodide (2.0 parts), formaldoxime trimer (1.75 parts), 2,6-lutidine (2.15 parts), and nitrobenzene (150 parts) was heated to 95° C. for 6 hours when thin layer chromatography showed reaction to be complete. The mixture was cooled, filtered and the nitrobenzene was removed by steam distillation. Crystallisation of the solid product from ethanol gave 4-(2'-cyano-4'-bromo-6'-methylphenylazo)-N,N-diethylaniline (Found: C, 58.2; H, 5.4; Br, 21.7; N, 15.2. C18H19BrN4 requires C, 58.2; H, 5.15; Br, 21.55; N, 15.1%).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2].[C:24]1([CH3:34])[C:25]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:27]=[CH:28][CH:29]=1.C(N(CC)C(C)C)(C)C>O1CCCC1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][S:30]([C:25]3[C:24]([CH3:34])=[CH:29][CH:28]=[CH:27][CH:26]=3)(=[O:32])=[O:31])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
Reactant: Cc1ccccc1S(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)N1c2ccc(NS(=O)(=O)c3ccccc3C)cc2C(C)(c2ccccc2)CC1(C)C

Procedure:
Sulfonylation of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) with -toluenesulfonyl chloride (12 mg) and N,N-diisopropylethylamine (22 l) in tetrahydrofuran (25 ml) was performed according to the acylation method described in example 6.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]2.CC1(C)COB([C:23]2[CH:24]=[C:25]([CH:34]=[CH:35][CH:36]=2)[O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)OC1>>[N:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[CH2:27][O:26][C:25]1[CH:34]=[C:35]([C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]3)[CH:36]=[CH:23][CH:24]=1
Reactant: CC1(C)COB(c2cccc(OCc3ccccn3)c2)OC1
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2n1
Product: FC(F)(F)c1ccc2c(-c3cccc(OCc4ccccn4)c3)ccnc2n1
Yield: 42.9 %

Procedure:
5-Chloro-2-trifluoromethyl[1,8]naphthyridine (50 mg, 0.22 mmol) was coupled to 2-[3-(5,5-dimethyl[1,3,2]dioxaborinan-2-yl)phenoxymethyl]pyridine (83 mg, 0.28 mmol) as described in Example 7 part g), affording 5-[3-(pyridin-2-ylmethoxy)phenyl]-2-trifluoromethyl[1,8]naphthyridine (36 mg, 34%). δH (360 MHz, CDCl3) 5.28 (2H, s), 7.07-7.11 (2H, m), 7.20 (1H, dd, J 2.1 and 8.4), 7.23-7.30 (1H, m), 7.47-7.56 (3H, m), 7.73-7.78 (2H, m), 8.50 (1H, d, J 8.8), 8.61 (1H, d, J 4.6), 9.26 (1H, d, J 4.6). m/z (ES+) 382 [MH]+.
Reaction SMILES: [NH2:1][C:2]1[C:3](=O)[N:4]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[C:9]=2[CH3:17])[NH:6][N:7]=1.S(Cl)([Cl:21])=O>>[Cl:21][C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[C:9]=2[CH3:17])[N:6]=[N:7][C:2]=1[NH2:1]
Reactant: O=S(Cl)Cl
Reactant: Cc1c(-c2nc(=O)c(N)n[nH]2)cccc1[N+](=O)[O-]
Product: Cc1c(-c2nnc(N)c(Cl)n2)cccc1[N+](=O)[O-]
Yield: 102.7 %

Procedure:
A suspension of 6-amino-3-(2-methyl-3-nitrophenyl)-1,2,4-triazin-5(2H)-one (0.95 g, 3.38 mmol) in thionyl chloride (180 mL, 2466 mmol) was heated at reflux for 4 hr, after which period the mixture became a clear solution. The volatiles were removed under vacuum. The residue was dissolved in ice-cold ethyl acetate (250 mL), washed with water (2×60 mL), saturated NaHCO3 solution (60 mL), and brine (60 mL). The organic solution was dried over anhydrous MgSO4 and concentrated under vacuum to dryness to provide the desired product, 5-chloro-3-(2-methyl-3-nitrophenyl)-1,2,4-triazin-6-amine (0.97 g, 3.47 mmol, 77% yield over two steps), as a yellow solid.
Reaction SMILES: [N:1]1([C:5]2[O:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([N+:17]([O-])=O)[CH:11]=3)[N:6]=2)[CH2:4][CH2:3][CH2:2]1.O.O.Cl[Sn]Cl>C(O)C>[N:1]1([C:5]2[O:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([CH:11]=3)[NH2:17])[N:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(-c2noc(N3CCC3)n2)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Cc1ccc(-c2noc(N3CCC3)n2)cc1N
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 64.6 %

Procedure:
To a stirred solution of 5-(azetidin-1-yl)-3-(4-methyl-3-nitrophenyl)-1,2,4-oxadiazole (108) (1.4 g, 5.38 mmol) in ethanol (25 mL) was added SnCl2.2H2O (6.07 g, 26.90 mmol). The resulting solution was stirred for 20 min at reflux then cooled to room temperature and concentrated under vacuum. The residue was poured into saturated sodium hydroxide (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (3×250 mL), dried over anhydrous sodium sulfate, concentrated under vacuum and purified by flash chromatography (PE/EA=10:1) to afford 5-(5-(azetidin-1-yl)-1,2,4-oxadiazol-3-yl)-2-methylaniline (109) (0.8 g, 65% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 7.28-7.36 (m, 2H), 7.12 (d, J=7.8 Hz, 1H), 4.32 (t, J=7.5 Hz, 4H), 3.69 (brs, 2H), 2.47-2.57 (m, 2H), 2.21 (s, 3H). MS m/z 231.1 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:21][C:22]1[CH:23]=[N:24][CH:25]=[C:26]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:27]=1)=[C:5]([CH3:20])[C:6]([N:13]1[CH2:18][CH2:17][NH:16][C@H:15]([CH3:19])[CH2:14]1)=[N:7]2.[CH3:34][N:35]=[C:36]=[O:37]>>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:21][C:22]1[CH:23]=[N:24][CH:25]=[C:26]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:27]=1)=[C:5]([CH3:20])[C:6]([N:13]1[CH2:18][CH2:17][N:16]([C:36]([NH:35][CH3:34])=[O:37])[C@H:15]([CH3:19])[CH2:14]1)=[N:7]2
Reactant: Cc1c(N2CCN[C@H](C)C2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1
Reactant: CN=C=O
Product: CNC(=O)N1CCN(c2nc3cc(F)cc(F)c3c(Nc3cncc(N4CCOCC4)c3)c2C)C[C@H]1C

Procedure:
Prepared according to Procedure N using (R)-5,7-difluoro-3-methyl-2-(3-methylpiperazin-1-yl)-N-(5-morpholinopyridin-3-yl)quinolin-4-amine (50.0 mg, 0.11 mmol) and methylisocyanate to give (R)-4-(5,7-difluoro-3-methyl-4-(5-morpholinopyridin-3-ylamino)quinolin-2-yl)-N,2-dimethylpiperazine-1-carboxamide. 1H NMR (CDCl3) δ ppm 7.93 (1H, d, J=2.5 Hz), 7.68 (1H, d, J=2.3 Hz), 7.27-7.33 (1H, m), 6.92 (1H, d, J=12.7 Hz), 6.79 (1H, ddd, J=13.8, 8.8, 2.6 Hz), 6.58 (1H, t, J=2.3 Hz), 4.58 (1H, q, J=4.3 Hz), 4.16-4.29 (1H, m), 3.78-3.92 (5H, m), 3.68-3.78 (1H, m), 3.54-3.64 (1H, m), 3.36 (1H, td, J=12.4, 3.3 Hz), 3.11-3.25 (5H, m), 2.95 (1H, td, J=12.4, 3.4 Hz), 2.85 (3H, d, J=4.5 Hz), 2.09 (3H, s), 1.30 (3H, d, J=6.7 Hz). Mass Spectrum (ESI) m/e=512.3 (M+1).
Reaction SMILES: C(OC([NH:8][CH:9]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=1)[C:10]([NH:12][C:13]1([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:15][CH2:14]1)=[O:11])=O)(C)(C)C.[ClH:31]>ClCCl.O1CCOCC1>[ClH:31].[NH2:8][CH:9]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:29])[F:30])[CH:22]=1)[C:10]([NH:12][C:13]1([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:14][CH2:15]1)=[O:11]
Reactant: CCOC(=O)C1(NC(=O)C(NC(=O)OC(C)(C)C)c2cccc(C(F)(F)F)c2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOC(=O)C1(NC(=O)C(N)c2cccc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
262 mg (0.61 mmol) of the compound of Example 17A were dissolved in 4 ml of dichloromethane, and 4 ml of a 4N solution of hydrogen chloride in dioxane were added. The solution was stirred at RT for 3 h and then freed from the volatile components on a rotary evaporator. The residue was dried under high vacuum. This gave 223 mg (quant.) of the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:38])=[C:23]([C:25]4[N:26]=[CH:27][C:28]5[C:33]([CH:34]=4)=[C:32]([Cl:35])[C:31]([F:36])=[CH:30][C:29]=5[F:37])[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:39]>C(Cl)Cl.CCOCC>[ClH:35].[ClH:39].[ClH:35].[Cl:35][C:32]1[C:31]([F:36])=[CH:30][C:29]([F:37])=[C:28]2[C:33]=1[CH:34]=[C:25]([C:23]1[C:22]([NH2:38])=[N:21][CH:20]=[C:19]([C:17]3[CH:16]=[N:15][N:14]([CH:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)[CH:18]=3)[CH:24]=1)[N:26]=[CH:27]2
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(-c4cc5c(Cl)c(F)cc(F)c5cn4)c3)cn2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1cc2c(Cl)c(F)cc(F)c2cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-{4-[6-Amino-5-(5-chloro-6,8-difluoroisoquinolin-3-yl)-pyridin-3-yl]-pyrazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester (0.0311 mmol) was dissolved in DCM (4.4 ml), and 1.0 M of HCl in Et2O (8.8 ml) was added. The mixture was stirred at rt for 16 h. After that time, solvent was removed in vacuo to give the title compound as a yellow powder. 1H NMR (400 MHz, DMSO-d6): δ=2.14-2.30 (m, 4H), 3.03-3.18 (m, 2H), 3.36-3.42 (m, 2H), 4.50-4.60 (m, 1H), 4.97 (brs, 2H), 8.07 (t, J=10.0 Hz, 1H), 8.14 (s, 1H), 8.49 (s, 1H), 8.53 (d, J=2.4 Hz, 1H), 8.63 (d, J=0.8 Hz, 1H), 8.81 (d, J=2.4 Hz, 1H), 9.14 (brs, 1H), 9.31 (brs, 1H), 9.66 (s, 1H). MS(ES+): m/z=440.84/442.79 (82/32) [MH+]. HPLC: tR=1.89 min (ZQ3, polar—5 min).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1[O:13][C:14]2[C:19]([C:20](=[O:22])[CH:21]=1)=[C:18]([O:23]C)[CH:17]=[C:16]([O:25]C)[C:15]=2[C@@H:27]1[CH2:31][CH2:30][N:29]([CH3:32])[C@H:28]1[CH2:33][OH:34].Cl.N1C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>CO>[Cl:1][C:2]1[C:7]([C:8]([F:9])([F:11])[F:10])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1[O:13][C:14]2[C:19]([C:20](=[O:22])[CH:21]=1)=[C:18]([OH:23])[CH:17]=[C:16]([OH:25])[C:15]=2[C@@H:27]1[CH2:31][CH2:30][N:29]([CH3:32])[C@H:28]1[CH2:33][OH:34]
Reactant: COc1cc(OC)c2c(=O)cc(-c3cccc(C(F)(F)F)c3Cl)oc2c1[C@@H]1CCN(C)[C@H]1CO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CO
Product: CN1CC[C@@H](c2c(O)cc(O)c3c(=O)cc(-c4cccc(C(F)(F)F)c4Cl)oc23)[C@@H]1CO
Temperature: 180 °C

Procedure:
A mixture of compound of example 40 (0.560 g, 1.12 mmol) and pyridine hydrochloride (0.700 g, 6.05 mmol) was heated at 180° C. for a period of 2.5 hours. The reaction mixture was diluted with methanol (60 mL) and basified with solid Na2CO3 to pH 10. The reaction mixture was filtered, and washed with methanol. The organic layer was concentrated and the residue purified by column chromatography using 0.01% ammonia and 4.5% methanol in chloroform as eluent to afford the title compound.
Reaction SMILES: O=[C:2]([CH3:15])[CH2:3][S:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([OH:14])=[O:13])[CH:8]=[CH:9][CH:10]=1.Cl.[F:17][C:18]1[CH:19]=[C:20]([NH:24]N)[CH:21]=[CH:22][CH:23]=1>CC(O)(C)C>[F:17][C:18]1[CH:19]=[C:20]2[C:21]([C:3]([S:4][C:5]3[CH:6]=[C:7]([CH2:11][C:12]([OH:14])=[O:13])[CH:8]=[CH:9][CH:10]=3)=[C:2]([CH3:15])[NH:24]2)=[CH:22][CH:23]=1
Reactant: NNc1cccc(F)c1
Reactant: CC(=O)CSc1cccc(CC(=O)O)c1
Agent: Cl
Solvent: CC(C)(C)O
Product: Cc1[nH]c2cc(F)ccc2c1Sc1cccc(CC(=O)O)c1
Temperature: 70 °C
Reaction time: 1.5 h

Procedure:
[3-(2-Oxo-propylsulfanyl)-phenyl]-acetic acid (0.500 g, 2.2 mmol) and 3-fluorophenylhydrazine hydrochloride (0.400 g, 2.45 mmol) were dissolved in t-BuOH (10 mL). The reaction was stirred at 70° C. for 1.5 hours then submitted to aqueous workup. Purification by preparatory HPLC (10-100% ACN in H2O) afforded a 5:3 mixture of separable regioisomers of which the title compound was the major component.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:6][CH:5]=1.C(N(CC)CC)C.[Cl:24][CH2:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:27]>C(O)C>[ClH:3].[ClH:24].[Cl:3][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([CH2:25][C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:27])[CH2:11][CH2:10]2)=[CH:6][CH:5]=1
Reactant: Clc1ccc(CN2CCNCC2)cc1
Reactant: O=C(CCl)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(CN1CCN(Cc2ccc(Cl)cc2)CC1)c1ccccc1
Yield: 129.4 %

Procedure:
A mixture of N-(4-chlorobenzyl)piperazine dihydrochloride (5 g, 20 mmol), triethylamine (5.58 ml, 40 mmol) and 2-chloro-1-phenylethanone (4.08 g, 26 mmol) in 40 ml of anhydrous ethanol was refluxed for 8 hours, and then treated according to general preparation 2 to give 5.2 g of compound (IV-3), yield 59.51%, mp 256-258° C. M+ 328.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:12]([C:14]3[S:15][C:16]([CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)=[CH:17][CH:18]=3)=[O:13])=[CH:6][C:5]=12.CN1CCOCC1.[CH:32]([O:35][C:36](Cl)=[O:37])([CH3:34])[CH3:33]>ClCCl>[CH3:33][CH:32]([O:35][C:36]([N:22]1[CH2:23][CH2:24][CH:19]([C:16]2[S:15][C:14]([C:12](=[O:13])[NH:11][CH2:10][C:7]3[CH:8]=[CH:9][N:4]4[CH:3]=[CH:2][N:1]=[C:5]4[CH:6]=3)=[CH:18][CH:17]=2)[CH2:20][CH2:21]1)=[O:37])[CH3:34]
Reactant: CC(C)OC(=O)Cl
Reactant: O=C(NCc1ccn2ccnc2c1)c1ccc(C2CCNCC2)s1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)OC(=O)N1CCC(c2ccc(C(=O)NCc3ccn4ccnc4c3)s2)CC1

Procedure:
To a suspension N-(imidazo[1,2-a]pyridin-7-ylmethyl)-5-(piperidin-4-yl)thiophene-2-carboxamide (0.103 g, 0.249 mmol) in dichloromethane (2 ml) was added N-methylmorpholine (0.110 ml, 0.997 mmol) followed by isopropylchloroformate (0.374 ml, 0.374 mmol). A second portion of isopropylchloroformate (0.4 ml) was added and after 1 hour the mixture was directly purified by normal phase chromatography to give the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 9.05 (t, J=6.0 Hz, 1H), 8.51 (d, J=7.0 Hz, 1H), 7.92 (s, 1H), 7.68 (d, J=3.8 Hz, 1H), 7.56 (d, J=1.2 Hz, 1H), 7.40 (d, J=1.4 Hz, 1H), 6.96 (d, J=3.8 Hz, 1H), 6.88 (dd, J=7.0, 1.7 Hz, 1H), 4.78 (hept, J=6.2 Hz, 1H), 4.47 (d, J=5.9 Hz, 2H), 4.05 (d, J=12.9 Hz, 2H), 3.10-2.97 (m, 1H), 2.98-2.81 (m, 2H), 2.01-1.88 (m, 2H), 1.57-1.38 (m, 2H), 1.19 (d, J=6.2 Hz, 6H); MS (ESI(+)) m/e 427 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][NH2:15])=[CH:9][CH:8]=2)=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19].CS[C:24]1[NH:25][CH:26]=[C:27]([CH2:31][C:32]2[CH:37]=[CH:36][N:35]=[N:34][CH:33]=2)[C:28](=[O:30])[N:29]=1>C(O)C>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][NH:15][C:24]3[NH:25][CH:26]=[C:27]([CH2:31][C:32]4[CH:37]=[CH:36][N:35]=[N:34][CH:33]=4)[C:28](=[O:30])[N:29]=3)=[CH:9][CH:8]=2)=[CH:4][C:3]=1[C:18]([F:19])([F:20])[F:21]
Reactant: CSc1nc(=O)c(Cc2ccnnc2)c[nH]1
Reactant: NCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Solvent: CCO
Product: O=c1nc(NCCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)[nH]cc1Cc1ccnnc1
Temperature: 150 °C
Reaction time: 8 h
Yield: 42.6 %

Procedure:
2-[4-(4-chloro-3-trifluoromethyl-phenoxy)-phenyl]-ethylamine (0.317 mmol, 1.00 eq) and 2-methylsulfanyl-5-pyridazin-4-ylmethyl-1H-pyrimidin-4-one (0.341 mmol, 1.01 eq) were dissolved in dry ethanol (300 μL) and stirred at 150° C. overnight. Solvent was evaporated and crude product was purified on Biotage SP1 Snap Si 10; 15 ml/min in the gradient of MeOH in DCM: 0-7% in 15 CV. The appropriate fractions were combined and evaporated in vacuo to give the required product 2-{2-[4-(4-chloro-3-trifluoromethyl-phenoxy)-phenyl]ethylamino}-5-pyridazin-4-ylmethyl-1H-pyrimidin-4-one (0.135 mmol, yield: 43%, UPLC-MS/UV:[M+H]+=502.30; rt: 1.07 mins; purity: 95%). 1H NMR (300 MHz; CDCl3) δ/ppm 1.42 (s, 1H), 2.89 (t, J=7.33, 2H), 3.55-3.60 (m, 2H), 3.62 (s, 2H), 6.99 (dd, J=8.40, J=10.08, 2H), 7.01 (dd, J=9.07 J=3.02, 1H), 7.16-7.28 (m, 3H), 7.35-7.42 (m, 2H), 7.62-7.70 (m, 1H), 8.94 (dd, J=5.42, J=0.95, 1H), 9.09-9.12 (m, 1H)
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][C:15]=1[O:22][CH3:23].[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH2:36][C:37]#[N:38])[CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33].CC(C)([O-])C.[K+].Cl>COC(C)(C)C.O>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:21]=[CH:20][C:17](/[CH:18]=[C:36](/[C:28]2[CH:29]=[C:30]([O:34][CH3:35])[C:31]([O:32][CH3:33])=[C:26]([O:25][CH3:24])[CH:27]=2)\[C:37]#[N:38])=[CH:16][C:15]=1[O:22][CH3:23]
Reactant: COc1cc(C=O)ccc1OCCCCCCCCCCCO
Reactant: COc1cc(CC#N)cc(OC)c1OC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: COC(C)(C)C
Product: COc1cc(/C=C(\C#N)c2cc(OC)c(OC)c(OC)c2)ccc1OCCCCCCCCCCCO
Temperature: 54 °C
Reaction time: 18 h
Yield: 75.5 %

Procedure:
7.1 g (22 mmol) of 4-[(11-hydroxyundecyl)oxy]-3-methoxybenzaldehyde, 5.0 g (24 mmol) of (3,4,5-trimethoxyphenyl)acetonitrile are dissolved in 50 mL of tert-butyl methyl ether. 0.49 g of potassium tert-butoxide are added under stirring and the mixture is heated to 54° C. After 18 h at 54° C., the reaction mixture is poured on 75 mL icy water under stirring. The pH is adjusted to 7 with 25% HCl. After 1 h stirring, the precipitate is filtered off, washed with water and dried at 40° C. under vacuum. 8.5 g of (2Z)-3-{4-[(11-hydroxyundecyl)oxy]-3-methoxyphenyl}-2-(3,4,5-trimethoxyphenyl)prop-2-enenitrile are obtained as a yellow solid (76% yield). This material proves chromatographically homogenous and displays spectral characteristics consistent with its assigned structure.
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([C:21]3[C:32](=[O:33])[N:31]([CH3:34])[C:24]4[N:25]=[C:26](SC)[N:27]=[CH:28][C:23]=4[CH:22]=3)[CH:15]=2)=[O:12])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:35][NH2:36].C1COCC1>>[C:1]([N:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([C:21]3[C:32](=[O:33])[N:31]([CH3:34])[C:24]4[N:25]=[C:26]([NH:36][CH3:35])[N:27]=[CH:28][C:23]=4[CH:22]=3)[CH:15]=2)=[O:12])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN
Reactant: CSc1ncc2cc(-c3cc(NC(=O)Nc4cnn(C(C)(C)C)c4)ccc3C)c(=O)n(C)c2n1
Solvent: C1CCOC1
Product: CNc1ncc2cc(-c3cc(NC(=O)Nc4cnn(C(C)(C)C)c4)ccc3C)c(=O)n(C)c2n1
Yield: 80 %

Procedure:
Using general method D, Example B30 (150 mg, 0.585 mmol) and Example A44 (165 mg, 0.585 mmol) were combined to give the intermediate sulfide, 1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(4-methyl-3-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (56 mg, 24% yield). Using a procedure analogous to Example A1, the sulfide (56 mg, 0.117 mmol) was combined with 2.0N methylamine in THF (0.59 mL, 1.173 mmol) to afford the desired product, 1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(4-methyl-3-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (43 mg, 80% yield). 1H NMR (300 MHz, DMSO-d6), δ 1.22 (s, 9H), 2.06 (s, 3H), 2.90 (s, 3H), 3.53-3.60 (m, 3H), 6.01 (s, 1H), 7.14-7.16 (d, 1H), 7.27-7.29 (d, 1H), 7.34 (s, 1H), 7.67 (s, 1H), 7.68-7.81 (m, 1H), 8.60-8.65 (m, 1H), 8.74 (s, 1H), 10.06 (s, 1H); MS (ESI) m/z: 461.2 (M+H+).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[CH:33]=[CH:32][CH:31]=[CH:30][C:22]=4[O:23][CH:24]([CH2:27][CH2:28][CH3:29])[C:25]#[N:26])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[N-:34]=[N+:35]=[N-:36].[Na+].[Cl-].[NH4+].O>CN(C)C=O>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[CH:33]=[CH:32][CH:31]=[CH:30][C:22]=4[O:23][CH:24]([C:25]4[NH:36][N:35]=[N:34][N:26]=4)[CH2:27][CH2:28][CH3:29])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCC(C#N)Oc1ccccc1COc1ccc2oc(-c3nc(C(C)(C)C)cs3)cc2c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCC(Oc1ccccc1COc1ccc2oc(-c3nc(C(C)(C)C)cs3)cc2c1)c1nnn[nH]1
Temperature: 120 °C
Reaction time: 3 h
Yield: 85.1 %

Procedure:
2-{2-{[2-(4-tert-Butylthiazol-2-yl)benzofuran-5-yloxy]methyl}phenoxy}pentanenitrile (430 mg) was dissolved in dimethylformamide (5 ml), and sodium azide (364 mg) and ammonium chloride (0.3 g) were added. The mixture was stirred at 120° C. for three hours. The reaction mixture was cooled and poured into water and extracted with ethyl acetate. The aqueous layer was extracted with ethyl acetate again and the combined organic layer was washed with brine and dried over magnesium sulfate. After concentration, the crude product was purified on a silica gel column (15 g) eluting with a mixed solvent of methylene chloride and methanol (2% vol.) to give 2-(4-tert-butylthiazol-2-yl)-5-{2-[1-(1H-tetrazol-5-yl)butoxy]phenylmethoxy}benzofuran (400 mg).
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH2:18]Cl)[C:14]([NH2:17])=[N:15][CH:16]=1.Cl>C1COCC1>[Cl:10][C:11]1[CH:12]=[C:13]([CH2:18][O:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:14]([NH2:17])=[N:15][CH:16]=1
Reactant: Nc1ncc(Cl)cc1CCl
Reactant: Oc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1ncc(Cl)cc1COc1ccccc1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
Sodium hydride (80% in oil, 124 mg, 4.1 mmol) was added portionwise to a solution of phenol (290 mg, 3.1 mmol) in anhydrous THF (15 ml). 5-Chloro-3-(chloromethyl)-2-pyridinamine.HCl (R. Herbert, D. G. Wibberley, J. Chem. Soc., 1969, 1504) (300 mg, 1.4 mmol) was then added and the reaction stirred at 50° C. for 3 h. After removal of THF in vacuo, the residue was partioned between diethyl ether and 1N NaOH. The aqueous phase was removed, extracted with diethyl ether and the combined organics washed with saturated brine, dried over MgSO4 and concentrated to an oil which upon triturating with hexane gave the title compound as a white solid (265 mg, 1.1 mmol):