Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[F:10][CH2:11][CH2:12]Cl.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[F:10][CH2:11][CH2:12][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: FCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCCF)cc1
Temperature: 25 °C
Yield: 99.4 %

Procedure:
4-Hydroxybenzaldehyde (26.0 g), 20.7 g of 1-fluoro-2-chloroethane and 42.4 g of anhydrous potassium carbonate were added to 100 ml of dimethylformamide, and reacted at 130° C. for 5 hours. After the reaction, the reaction mixture was cooled to room temperature, poured into water, and then extracted with toluene. The toluene layer was washed with water, and dried over anhydrous sodium sulfate. Toluene was evaporated under reduced pressure to give 35.6 g of crude 4-(2-fluoroethoxy)benzaldehyde.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[C:8]([NH2:13])[CH:7]=[C:6]([Cl:14])[N:5]=1.[NH4+].[Cl-].[CH2:17]([OH:20])[CH2:18][OH:19]>>[NH2:13][C:8]1[CH:7]=[C:6]([Cl:14])[N:5]=[C:4]([O:19][CH2:18][CH2:17][OH:20])[C:9]=1[N+:10]([O-:12])=[O:11]
Reactant: OCCO
Reactant: Nc1cc(Cl)nc(Cl)c1[N+](=O)[O-]
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Product: Nc1cc(Cl)nc(OCCO)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of 60% sodium hydride in mineral oil (769 mg, 19.2 mmol) in ethylene glycol (10 mL) was added 2,6-dichloro-3-nitro-pyridin-4-ylamine (2.00 g, 9.62 mmol) slowly over 5 min. After stirring at room temperature for 16 h, the resulting mixture was treated with saturated NH4Cl (20 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with H2O (2×50 mL), brine (50 mL), and then dried over Na2SO4. The solvent was removed in vacuo and the resulting residue was triturated with hexanes. 2-(4-Amino-6-chloro-3-nitro-pyridin-2-yloxy)-ethanol was obtained as a light yellow solid (by filtration) and washed with hexanes. 1H-NMR (400 MHz, CD3OD) δ: 6.50 (s, 1H), 4.37-4.50 (m, 2H), 3.80-3.93 (m, 2H). Mass Spectrum (LCMS, ESI pos.) Calculated For C7H8ClN3O4: 234.0 (M+H). Measured: 234.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][CH2:14][C:15]3[S:16][C:17]([C:21]([OH:23])=O)=[C:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[N:6][CH:7]=1.[NH2:25][CH2:26][CH:27]1[CH2:29][CH2:28]1>>[CH:27]1([CH2:26][NH:25][C:21]([C:17]2[S:16][C:15]([CH2:14][CH2:13][C:12]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=4)=[N:9][O:10][C:11]=3[CH3:24])=[N:19][C:18]=2[CH3:20])=[O:23])[CH2:29][CH2:28]1
Reactant: NCC1CC1
Reactant: Cc1nc(CCc2c(-c3ccc(F)cn3)noc2C)sc1C(=O)O
Product: Cc1nc(CCc2c(-c3ccc(F)cn3)noc2C)sc1C(=O)NCC1CC1
Yield: 85 %

Procedure:
As described for example 31b, 2-{2-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-ethyl}-4-methyl-thiazole-5-carboxylic acid (69 mg, 0.20 mmol) was converted, using aminomethylcyclopropane instead of 4-aminotetrahydropyran, to the title compound (68 mg, 85%) which was obtained as an off white solid. MS: m/e=401.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:11](=[O:12])[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.Cl[CH2:14][C:15]1[N:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:18]2[CH:26]=[CH:27][CH:28]=[CH:29][C:17]=2[N:16]=1.C([O-])([O-])=O.[Cs+].[Cs+].[I-].[K+]>CN(C=O)C>[NH2:1][C:2]1[C:3]2[C:11](=[O:12])[CH:10]=[CH:9][N:8]([CH2:14][C:15]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18]4[CH:26]=[CH:27][CH:28]=[CH:29][C:17]=4[N:16]=3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1ncnc2[nH]ccc(=O)c12
Reactant: ClCc1nc2ccccc2n1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(=O)ccn2Cc1nc2ccccc2n1-c1ccccc1
Temperature: 130 °C
Reaction time: 3 h

Procedure:
A mixture of 4-amino-8H-pyrido[2,3-d]pyrimidin-5-one (35 mg, 0.214 mmol), 2-chloromethyl-1-phenyl-1H-benzoimidazole (52 mg, 0.214 mmol), Cs2CO3 (105 mg, 0.321 mmol) and potassium iodide (4 mg, 0.021 mmol) in DMF (1 mL) was stirred for 3 h in a sealed tube at 130° C. Volatiles were then removed under reduced pressure and the residue suspended in DCM and filtered. The filtrate was purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) and the resulting material was triturated with diethyl ether affording 111 as a pale yellow solid (28 mg, 36%). LCMS: RT 3.47 min [M+H]+ 369.1. 1H NMR (CDCl3, 400 MHz): δ 9.76 (1H, bs), 8.07 (1H, s), 7.82-7.77 (1H, m), 7.65 (1H, d, J=7.97 Hz), 7.50-7.44 (3H, m), 7.34-7.23 (4H, m), 7.14-7.09 (1H, m), 6.28 (1H, d, J=7.97), 5.86-5.78 (1H, m), 5.63 (2H, s)
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH:14]([CH3:15])[CH2:13][NH:12][C:11]3=[O:16])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.I[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][C:23]=1[CH3:24].N[C@@H]1CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH:14]([CH3:15])[CH2:13][N:12]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][C:23]=4[CH3:24])[C:11]3=[O:16])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CC1CNC(=O)N1c1ccc2ncsc2c1
Reactant: Cc1ccncc1I
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CC(C)N(c2ccc3ncsc3c2)C1=O
Yield: 23.9 %

Procedure:
1-Benzothiazol-6-yl-5-methyl-imidazolidin-2-one (I-203b: 150 mg, 0.644 mmol) was reacted with 3-iodo-4-methyl-pyridine (140.99 mg, 0.644 mmol), 1,4-dioxane (10 mL), copper iodide (12.27 mg, 0.0644 mmol), trans-1,2-diamino cyclohexane (27.43 mg, 0.193 mmol) and potassium phosphate (341 mg, 1.61 mmol) to afford the crude product. Purification by column chromatography on silica gel (1.5% MeOH in DCM) afforded 50 mg of the product (24.15% yield).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:20]([O:21][CH3:22])=[CH:19][C:13]2[CH:14]=[CH:15][C:16](=[O:18])[O:17][C:12]=2[CH:11]=1)(=O)=O.[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]([C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=2)[N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:26][CH:25]=1.C([O-])(=O)/C=C/C([O-])=O>CC(C)=O>[F:43][C:40]1[CH:39]=[CH:38][C:37]([CH:30]([C:27]2[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=2)[N:31]2[CH2:32][CH2:33][N:34]([CH2:6][CH2:7][CH2:8][O:9][C:10]3[C:20]([O:21][CH3:22])=[CH:19][C:13]4[CH:14]=[CH:15][C:16](=[O:18])[O:17][C:12]=4[CH:11]=3)[CH2:35][CH2:36]2)=[CH:42][CH:41]=1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Reactant: COc1cc2ccc(=O)oc2cc1OCCCOS(C)(=O)=O
Agent: O=C([O-])/C=C/C(=O)[O-]
Solvent: CC(C)=O
Product: COc1cc2ccc(=O)oc2cc1OCCCN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Yield: 76 %

Procedure:
Method B (36 h at 60° C.); starting materials: 7-[3-(methanesulfonyloxy)propoxy]-6-methoxy-2H-1-benzopyran-2-one (example 68) and 1-[bis(4-fluorophenyl)methyl]-piperazine; yield 76% Ol. Fumarate: method E; yield 82%; fusion point 200°-202° C. (from acetone).
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.CO.[Si:10]([O:27][C@@H:28]([CH2:32][CH2:33][S:34][CH3:35])[C:29]([OH:31])=[O:30])([C:23]([CH3:26])([CH3:25])[CH3:24])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(O)(=O)C>C1(C)C=CC=CC=1>[Si:10]([O:27][C@@H:28]([CH2:32][CH2:33][S:34][CH3:35])[C:29]([O:31][CH3:1])=[O:30])([C:23]([CH3:26])([CH3:25])[CH3:24])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CSCC[C@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COC(=O)[C@H](CCSC)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.7 %

Procedure:
Sodium thiomethoxide (0.187 g, 2.67 mmol) was added to (S)-3-(tert-butyldiphenylsilyloxy)dihydrofuran-2(3H)-one (CAS no. 220351-82-6: Klar, U.; Schwede, W.; Skuballa, W.; Buchmann, B.; Schirner, M. Ger. Offen. 1999 DE 19735575 A1) (0.826 g, 2.43 mmol) in DMF (2 mL) at 0° C. The resulting solution was stirred at room temperature for 16 hours. The reaction mixture was neutralised with 2M HCl and diluted with ethyl acetate. The organic layer was extracted with water (3×100 mL), the organic layer was dried (MgSO4) and evaporated to afford (S)-2-(tert-butyldiphenylsilyloxy)-4-(methylthio)butanoic acid (0.160 g, 16.98%) which was used without further purification. A solution of trimethylsilyldiazomethane (2M solution in ether, 0.412 ml, 0.82 mmol) was added dropwise to a stirred solution of methyl alcohol (0.167 ml, 4.12 mmol) and (S)-2-(tert-butyldiphenylsilyloxy)-4-(methylthio)butanoic acid (0.160 g, 0.41 mmol) in toluene (0.174 ml) over a period of 2 minutes. The resulting solution was stirred at ambient temperature for 2 hours. The reaction mixture was quenched with acetic acid (0.071 ml, 1.24 mmol) and stirred at ambient temperature for 10 minutes. The reaction mixture was evaporated. The residue was purified by flash silica chromatography, eluting with 0 to 50% ethyl acetate in isohexane to afford the product (0.120 g, 72.4%). 1H NMR (400 MHz, CDCl3) δ 1.09 (9H, s), 1.94-2.05 (5H, m), 2.48-2.60 (2H, m), 3.47 (3H, s), 4.33-4.36 (1H, m), 7.34-7.45 (6H, m), 7.62-7.67 (4H, m); m/z (ES+) (M-Ph)-=325; HPLC tR=3.63 min
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17]O)=[CH:13][CH:12]=1.S(Cl)([Cl:21])=O>C(Cl)Cl>[Cl:21][CH2:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][C:2]2[S:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)=[CH:12][CH:13]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(Cc2nc3ccccc3s2)cc1
Solvent: ClCCl
Product: ClCc1ccc(Cc2nc3ccccc3s2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 117.2 %

Procedure:
To a solution of (4-benzothiazol-2-ylmethyl-phenyl)-methanol (2.1 g, 8.1 mmol) in CH2Cl2 (90 mL) was added thionyl chloride (0.65 mL, 8.9 mmol) and the mixture was stirred at rt for 4 h. The reaction mixture was concentrated to afford the title compound as a tan solid (2.6 g, 100%). MS (ESI): mass calcd. for C15H12ClNS, 273.04; m/z found, 274.0 [M+H]+. 1H NMR (500 MHz, CDCl3): 8.34 (d, J=8.2 Hz, 1H), 7.89 (d, J=8.2 Hz, 1H), 7.71-7.67 (m, 1H), 7.61-7.58 (m, 1H), 7.50-7.48 (m, 2H), 7.45-7.44 (m, 2H), 4.84 (s, 2H), 4.60 (s, 2H).
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[CH:10][CH:9]=2)[N:5]([C:17]2[CH:18]=[N:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)[N:4]=1.CCN(CC)CC.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>C(Cl)Cl>[CH3:33][S:34]([O:16][CH2:15][CH2:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[N:5]([C:17]3[CH:18]=[N:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=3)[N:4]=[C:3]([CH:2]([F:1])[F:25])[CH:7]=2)=[CH:9][CH:10]=1)(=[O:36])=[O:35]
Reactant: COc1ccc(-n2nc(C(F)F)cc2-c2ccc(CCO)cc2)cn1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(-n2nc(C(F)F)cc2-c2ccc(CCOS(C)(=O)=O)cc2)cn1
Reaction time: 1 h

Procedure:
To a solution of 2-{4-[3-(difluoromethyl)-1-(6-methoxy-3-pyridinyl)-1-H-pyrazol-5-yl]phenyl}ethanol (7.4 g) and Et3N (4.5 ml) in CH2Cl2 (75 ml) was added MsCl (2.5 ml) under ice-cooling. After stirring for 1 hour, the reaction mixture was quenched with water, separated. The aqueous layer was extracted with CH2Cl2 and combined organic layer was washed with water and brine, dried over MgSO4, filtered and evaporated under reduced pressure to give 10.5 g (quant) of 2-{4-[3-(difluoromethyl)-1-(6-methoxy-3-pyridinyl)-1-H-pyrazol-5-yl]phenyl}ethyl methanesulfonate as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7](Br)=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].[CH3:28][C:29]([CH3:33])([CH3:32])[C:30]#[CH:31]>CN(C=O)C.C(N(CC)CC)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:31]#[C:30][C:29]([CH3:33])([CH3:32])[CH3:28])=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4]
Reactant: C#CC(C)(C)C
Reactant: COC(=O)c1sc(Br)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](O)CC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](O)CC1
Reaction time: 16 h

Procedure:
To a solution of compounds 5-bromo-3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (500 mg, 1.09 mmol) and 3,3-Dimethyl-but-1-yne (385 mg, 4.69 mmol) in DMF (0.5 mL), triethylamine (1.06 mL) and tris(dibenzylideneacetone)dipalladium (0) (70 mg, 0.08 mmol) are added and the reaction mixture is stirred under reflux conditions for 16 h under a N2 atmosphere. DMF and triethylamine are removed under reduced pressure and the residue is partitioned between water and ethyl acetate. The organic layer is separated, dried (Na2SO4), concentrated and the residue is purified by column chromatography using ethyl acetate and hexane (1:2) as eluent to obtain 5-(3,3-dimethyl-but-1-ynyl)-3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester as a solid, 330 mg (66%).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][N:5]([CH2:7][C:8]2[CH:9]=NC(C)=N[CH:13]=2)[CH2:4][C@H:3]1[C:15]1[NH:16][C:17](=[O:30])[C:18]2[CH:23]=[N:22][N:21]([CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:19]=2[N:20]=1.C([BH3-])#N.[Na+].[F:35][C:36]1C=C(C=[C:42]([F:44])[CH:43]=1)C=O>>[F:35][C:36]1[CH:13]=[C:8]([CH:9]=[C:42]([F:44])[CH:43]=1)[CH2:7][N:5]1[CH2:6][C@@H:2]([CH3:1])[C@H:3]([C:15]2[NH:16][C:17](=[O:30])[C:18]3[CH:23]=[N:22][N:21]([CH:24]4[CH2:25][CH2:26][O:27][CH2:28][CH2:29]4)[C:19]=3[N:20]=2)[CH2:4]1
Reactant: O=Cc1cc(F)cc(F)c1
Reactant: Cc1ncc(CN2C[C@@H](C)[C@H](c3nc4c(cnn4C4CCOCC4)c(=O)[nH]3)C2)cn1
Agent: [BH3-]C#N
Agent: [Na+]
Product: C[C@@H]1CN(Cc2cc(F)cc(F)c2)C[C@H]1c1nc2c(cnn2C2CCOCC2)c(=O)[nH]1

Procedure:
Following the procedure for the preparation of 6-{(3S,4S)-4-methyl-1-[(2-methylpyrimidin-5-yl)methyl]pyrrolidin-3-yl}-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one but substituting sodium cyanoborohydride and 3,5-difluorobenzaldehyde provided the title compound. 400 MHz 1H NMR (CDCl3) δ 8.03 (s, 1H), 6.93-6.90 (m, 2H), 6.73-6.69 (m, 1H), 4.81-4.80 (m, 1H), 4.14-4.10 (m, 2H), 3.79-3.67 (m, 2H), 3.62-3.55 (m, 2H), 3.30-3.26 (m, 1H), 3.10-3.07 (m, 1H), 2.95-2.92 (m, 1H), 2.83-2.79 (m, 1H), 2.26-2.53 (m, 1H), 2.38-2.32 (m, 2H), 2.18-2.14 (m, 1H), 1.91-1.85 (m, 2H), 1.18 (d, J=7.1 Hz, 3H). MS: (M+H m/z 430.4).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:22][NH:23][CH2:24][CH2:25][CH2:26][N:27]([CH3:29])[CH3:28]>>[CH3:28][N:27]([CH3:29])[CH2:26][CH2:25][CH2:24][N:23]([CH3:22])[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccccc23)cc1
Reactant: CNCCCN(C)C
Product: COc1ccc(N(C)c2nc(N(C)CCCN(C)C)nc3ccccc23)cc1

Procedure:
The title compound was prepared from (2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (200 mg, 0.67 mmol) and N,N,N-trimethyl-1,3-propane diamine (116 mg, 1.0 mmol) by a procedure similar to Example 1 and was isolated as a brown oil (112 mg, 44%). 1H NMR (CDCl3) δ 7.5 (d, 1H), 7.4 (m, 1H), 7.15 (d, 2H), 6.9 (m, 3H), 6.6 (m, 1H), 3.81 (s, 3H), 3.78 (t, 2H), 3.5 (s, 3H), 3.48 (s, 3H), 3.3 (s, 3H), 2.4 (m, 2H), 2.2 (s, 3H), 1.8 (m, 2H); LC-MS (ESI+; 380 ([M+H]+)).
Reaction SMILES: O[CH2:2]/[C:3](/[C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1)=[C:4](/[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)=[CH:11][CH:10]=1)\[C:5]([NH:7][CH3:8])=[O:6].P(Br)(Br)Br.C([O-])(O)=O.[Na+]>CCOCC.C(Cl)Cl>[CH3:8][N:7]1[CH2:2][C:3]([C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)=[C:4]([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:16][C:17]3[CH:26]=[CH:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]=3)=[CH:13][CH:14]=2)[C:5]1=[O:6]
Reactant: CNC(=O)/C(=C(\CO)c1ccncc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Agent: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: CN1CC(c2ccncc2)=C(c2ccc(OCc3ccc4ccccc4n3)cc2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
To a solution of (Z)-4-hydroxy-N-methyl-3-(pyridin-4-yl)-2-(4-(quinolin-2-ylmethoxy)phenyl)-but-2-enamide (430 mg, 1.01 mmol) in Ether: DCM (20 mL; 1:1) was added PBr3 (0.114 mL, 1.21 mol) dropwise at 0° C. The reaction mixture was stirred at RT for 2 h. The reaction mixture was then diluted with DCM and basified with NaHCO3 solution. The organic layer was separated, washed with water, dried over Na2SO4 and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 1-methyl-4-(pyridin-4-yl)-3-(4-(quinolin-2-ylmethoxy)phenyl)-1H-pyrrol-2(5H)-one (350 mg, 85%) as a solid. 1H NMR (500 MHz, CD3OD): δ 8.81 (d, J=7.8 Hz, 2 H), 8.24-8.19 (m, 2 H), 8.11-7.94 (m, 3 H), 7.85-7.80 (m, 1 H), 7.59 (d, J=7.2 Hz, 2 H), 7.44 (s, 2 H), 7.21 (d, J=7.2 Hz, 2 H), 5.61 (s, 2 H), 3.38 (s, 2 H), 3.09 (s, 3 H). MS: M+H: m/z=408.2. HPLC: 89%, (Condition-B).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[O:12])[NH:8]2)=[CH:4][C:3]=1[O:19][CH:20]1[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]1.[CH3:29][N:30]([CH3:34])[C:31](Cl)=[O:32]>>[CH3:29][N:30]([CH3:34])[C:31]([N:16]1[CH2:17][CH2:18][N:13]([C:11]([C:7]2[NH:8][C:9]3[C:5]([CH:6]=2)=[CH:4][C:3]([O:19][CH:20]2[CH2:21][CH2:22][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:24][CH2:25]2)=[C:2]([Cl:1])[CH:10]=3)=[O:12])[CH2:14][CH2:15]1)=[O:32]
Reactant: CN(C)C(=O)Cl
Reactant: CC(C)N1CCC(Oc2cc3cc(C(=O)N4CCNCC4)[nH]c3cc2Cl)CC1
Product: CC(C)N1CCC(Oc2cc3cc(C(=O)N4CCN(C(=O)N(C)C)CC4)[nH]c3cc2Cl)CC1
Yield: 62 %

Procedure:
The title compound was synthesized in analogy to example 37, from [6-chloro-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-piperazin-1-yl-methanone (example 36), and dimethylcarbamoyl chloride, to afford the title compound as a light-yellow solid (62%).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:13][CH2:12][CH2:11][CH:10]([N:14]([C:30](=[O:32])[CH3:31])[CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)[C:9]2[CH:33]=[CH:34][C:35](Br)=[CH:36][C:8]1=2)=[O:6])([CH3:3])[CH3:2].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:74]([OH:81])[C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=1>C1(C)C=CC=CC=1.ClCCl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:30]([N:14]([CH2:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=1)[CH:10]1[CH2:11][CH2:12][CH2:13][N:7]([C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[O:6])[C:8]2[CH:36]=[C:35]([O:81][CH2:74][C:75]3[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=3)[CH:34]=[CH:33][C:9]1=2)(=[O:32])[CH3:31]
Reactant: OCc1ccccc1
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(Br)ccc21
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(OCc3ccccc3)ccc21
Yield: 51.6 %

Procedure:
Combine isopropyl-5-[acetyl-(3,5-bistrifluoromethylbenzyl)amino]-8-bromo-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (0.100 g, 0.168 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.0031 g, 0.0033 mmol), 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (0.0043 g, 0.010 mmol), cesium carbonate (0.082 g, 0.252 mmol) and benzyl alcohol (0.035 mL, 0.336 mmol) in toluene (0.67 mL) in a sealed tube and heat at 110° C. for 20 h. Dilute the cooled mixture with dichloromethane (50 mL) and filter through Celite. Remove the filtrate solvent under reduced pressure and first purify the residue using chromatography on silica gel, eluting with hexanes/ethyl acetate (60:40), to provide the title compound as a white solid (0.054 g, 52%): ESI MS 623 (M+H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1O.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.P(OCCCC)(OCCCC)OCCCC>O>[C:13]1([NH:12][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ccccc1
Reactant: Oc1ccc2ccccc2c1
Agent: CCCCOP(OCCCC)OCCCC
Solvent: O
Product: c1ccc(Nc2ccc3ccccc3c2)cc1
Reaction time: 5 h
Yield: 94 %

Procedure:
288 parts of β-naphthol, 250 parts of aniline and 9 parts of tributyl phosphite are mixed and fused at 130° C. At 190° C internal temperature, the reaction commences, with elimination of water. After 5 hours, the internal temperature has reached 235° C and 34 parts of water have distilled off. Thereafter, 412 parts of N-phenyl-β-naphthylamine, of melting point 100° - 102° C, distil, passing over at 230° C/15 mm Hg. This corresponds to a yield of 94% of theory.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][N:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=1)[CH2:6][C:7]([O:9][CH3:10])=[O:8].[CH2:19](Br)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]/[CH:27]=[CH:28]\[CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>>[CH3:10][O:9][C:7](=[O:8])[CH2:6][N:5]([CH2:4][C:3]([O:2][CH3:1])=[O:18])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]/[CH:27]=[CH:28]\[CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH:12]=1
Reactant: COC(=O)CN(CC(=O)OC)c1cccc(O)c1
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCBr
Product: CCCCC/C=C\C/C=C\CCCCCCCCOc1cccc(N(CC(=O)OC)CC(=O)OC)c1

Procedure:
Using this procedure, the reaction of N-(3-hydroxyphenyl-N-(2-methoxy-2-oxoethyl)glycine methyl ester with linoleyl bromide gave N-(2-methoxy-2-oxoethyl)-N-[3-[(9Z, 12Z)-(9,12-octadecadienyl]oxy]phenyl]glycine methyl ester as an oil. The structure was confirmed by nmr and mass spectra.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[NH:14][N:13]=2)=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(-c2n[nH]c3c2CCNCC3)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 59, Step C, 0.1 mmol) in CH2Cl2 (5 mL) was added TFA (1 mL). The mixture was stirred at RT for 16 h. After concentration, the intermediate 3-(4-chloro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene was obtained. The intermediate (0.1 mmol) was converted to the title compound (16 mg) according to the procedure described in Example 165 using 3,4-dimethoxy-benzaldehyde (0.2 mmol) in place of formaldehyde. MS (ESI): exact mass calculated for C22H24ClN3O2, 397.16. found, m/z 398.2 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.38-7.35 (br m, 4H), 7.91 (d, J=1.8 Hz, 1H), 6.82-6.80 (dd, J=8.1, 1.8 Hz, 1H), 6.76-6.74 (d, J=8.1 Hz, 1H), 3.83-3.80 (s, 6H), 2.84-2.82 (m, 4H), 2.71-2.69 (m, 4H).