Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1[C@@H](C(C)C)N=[C:6]([O:12][CH3:13])[C@H:7]([CH2:9][O:10][CH3:11])[N:8]=1.[C:17](Cl)([O:19][CH2:20][CH:21]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]2[C:22]1=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18].C([O-])(O)=[O:36].[Na+]>O1CCOCC1.O.C(Cl)(Cl)Cl>[CH:32]1[C:33]2[CH:21]([CH2:20][O:19][C:17]([NH:8][C@@H:7]([CH2:9][O:10][CH3:11])[C:6]([O:12][CH3:13])=[O:36])=[O:18])[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:28]=2[CH:29]=[CH:30][CH:31]=1
Reactant: O=C([O-])O
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: COC[C@@H]1N=C(OC)[C@@H](C(C)C)N=C1OC
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: C1COCCO1
Product: COC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (2R,5S)-3,6-dimethoxy-5-(methoxymethyl)-2-isopropyl-2,5-dihydropyrazine (2.1 g, 9.2 mmol) in dioxane (18 ml ) 1M HCl (18.4 ml ), 18.4 mmol) was added and the mixture stirred at ambient temperature overnight. The volatile components were evaporated, the residue redissolved in dioxane and again evaporated. The crude residue was dissolved dioxane and FmocCl (5.71 g, 2.21 mmol) was added. After 2 minutes 1M NaHCO3 (44.2 ml, 44.2 mmol) was added. After 15 minutes the mixture was diluted with water (50 ml) and CHCl3 (100 ml). The layers were separated and the aqueous phase extracted with CHCl3 (2×75 ml). The combined organic layer was dried (Na2SO4), concentrated and purified by flash chromatography (silica gel; hexane: ethyl acetate 2:1).
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[S:10][CH:11]=1.[C:16]1([CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][CH:27]([CH:30]=[O:31])[CH2:26][CH2:25]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CCCCCC.C(OCC)C>[C:16]1([CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][CH:27]([CH:30]([C:7]3[C:8]4[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=4[S:10][CH:11]=3)[OH:31])[CH2:26][CH2:25]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=CC1CCN(CCc2ccccc2)CC1
Reactant: Brc1csc2ccccc12
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: OC(c1csc2ccccc12)C1CCN(CCc2ccccc2)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Dissolve n-butyllithium (9.4 mL of a 2.5M solution in hexane, 23.46 mmol) in anhydrous ethyl ether (100 mL), place under an argon atmosphere and cool to -78° C. Add, by dropwise addition, a solution of 3-bromobenzo[b]thiophene (5.0 g, 23.46 mmol) in anhydrous ethyl ether (50 mL). Stir at -78° C. for 30 minutes then add, by dropwise addition, a solution of 1-(2-phenylethyl)-4-piperidinecarboxaldehyde (5.10 g, 23.46 mmol) in anhydrous ethyl ether (50 mL). Stir for 5 hours at -78° C., remove the ice bath and stir for an additional 1 hour. Quench with saturated ammonium chloride (150 mL) and stir overnight. Separate the organic phase and extract the aqueous phase with ethyl ether and methylene chloride. Combine the organic phases, dry (MgSO4) and evaporate the solvent in vacuo. Purify by recrystallization (isopropanol) to give the title compound as an off-white solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]([C:11]2[N:16]=[C:15]([O:17][CH3:18])[N:14]=[C:13]([NH:19][CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[CH:12]=2)[CH:7]=[CH:8][C:9]=1[F:10].C(N(CC)CC)C.[CH3:37][O:38][CH2:39][C:40](Cl)=[O:41]>C(Cl)Cl>[F:10][C:9]1[CH:8]=[CH:7][C:6]([C:11]2[CH:12]=[C:13]([NH:19][CH2:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=3)[N:14]=[C:15]([O:17][CH3:18])[N:16]=2)=[CH:5][C:4]=1[CH2:3][NH:2][C:40](=[O:41])[CH2:39][O:38][CH3:37]
Reactant: COc1ccc(CCNc2cc(-c3ccc(F)c(CN)c3)nc(OC)n2)cc1
Reactant: COCC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCC(=O)NCc1cc(-c2cc(NCCc3ccc(OC)cc3)nc(OC)n2)ccc1F
Reaction time: 15 h

Procedure:
A solution of [6-(3-aminomethyl-4-fluoro-phenyl)-2-methoxy-pyrimidin-4-yl]-[2-(4-methoxy-phenyl)-ethyl]-amine [200 mg, 0.52 mmol, see example 27] and triethylamine (264 mg, 2.61 mmol) in DCM (5 mL) is treated with methoxyacetyl chloride (114 mg, 1.1 mmol) at 0° C. After 15 hours at 4° C. in a refrigerator, the mixture is quenched with water (10 mL) filtered through Chem-Elut. The filtrate is concentrated, and subjected to chromatography on silica gel eluting with 10% MeOH in DCM to give N-(2-fluoro-5-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-2-methoxy-acetamide, which is treated with saturated solution of hydrogen chloride in EtOAc followed by lyophilization to afford N-(2-Fluoro-5-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-2-methoxy-acetamide hydrochloride [190 mg, 74%, Example 28]. LCMS: RT=2.35 minutes, MS: 455 (M+H). IC50=9 nM
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([F:11])([F:10])[F:9].C(N(CC)CC)C.[CH2:19]([C:21]1[N:22]([CH2:34][C:35]#[CH:36])[C:23]2[C:32]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[N:26]=[CH:25][C:24]=2[N:33]=1)[CH3:20]>CN(C=O)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.C(Cl)(Cl)Cl.[Pd].[Pd].[Cu]I>[CH2:19]([C:21]1[N:22]([CH2:34][C:35]#[C:36][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]([F:11])([F:10])[F:9])[C:23]2[C:32]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[N:26]=[CH:25][C:24]=2[N:33]=1)[CH3:20]
Reactant: C#CCn1c(CC)nc2cnc3ccccc3c21
Reactant: FC(F)(F)c1ccccc1I
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCc1nc2cnc3ccccc3c2n1CC#Cc1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (64.5 mg, 0.03 eq.), 2-iodobenzotrifluoride (321 μL, 1.1 eq.), triethylamine (869 μL, 3.0 eq.), and copper (I) iodide (23.7 mg, 0.06 eq.) were added sequentially to a solution of 2-ethyl-1-(2-propynyl)-1H-imidazo[4,5-c]quinoline (489 mg, 2.08 mmol, 1.0 eq.) in DMF (10.6 mL). The reaction mixture was stirred at ambient temperature for 18 hours and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel eluting with 3/97 methanol/chloroform) to provide 0.13 g of 2-ethyl-1-[3-(2-trifluoromethylphenyl)-2-propynyl]-1H-imidazo[4,5-c]quinoline as a light yellow solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10])(=O)[NH2:2].P(Cl)(Cl)(Cl)=O.Cl.[H][H]>C(O)C.[Pd]>[NH2:2][CH2:1][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10]
Reactant: [H][H]
Reactant: NC(=O)c1cncc(C(=O)O)c1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: O=P(Cl)(Cl)Cl
Product: NCc1cncc(C(=O)O)c1
Temperature: 100 °C

Procedure:
A mixture of 5-carbamoyl-nicotinic acid (compound F3) (5.00 g) and phosphorus oxychloride (50 mL, 0.55 mol) is heated to 100° C. for 5 h. After usual workup the crude product is dissolved in ethanol acidified with hydrochloric acid and hydrogenated with the use of Pd/C (1.00 g, 5% Pd) at 4 bar hydrogen pressure for 16 h. After filtration of the catalyst, the mixture is evaporated, and the residue is treated with ethanol and extracted several times with chloroform.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12]O[C:10]=1[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[CH2:19]([CH2:21][NH2:22])[OH:20].Cl>C(O)C.C(OCC)C.O>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:22]([CH2:21][CH2:19][OH:20])[C:10]=1[CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1occc(=O)c1OCc1ccccc1
Reactant: NCCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: CCO
Product: Cc1c(OCc2ccccc2)c(=O)ccn1CCO
Yield: 44.94 %

Procedure:
A solution of the product from (1) in ethanol:water (300 ml:300 ml) containing 5% aqueous sodium hydroxide (2 ml) was treated with ethanolamine (17 ml) and then refluxed for 18 hours with rapid stirring. The resultant solution was cooled and adjusted to pH 1 with concentrated hydrochloric acid. The solid which formed on cooling was extracted with hot absolute ethanol and the precipitate obtained on cooling was taken up in diethylether, the solution being filtered and evaporated to dryness by rotary evaporation to give the title compound in 44.94% yield, m.p. 191.5°-193° C.
Reaction SMILES: [CH2:1]([C@@H:4]([CH2:7][CH2:8][CH2:9][CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:5][OH:6])[CH:2]=[CH2:3].C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl>[CH3:26][S:27]([O:6][CH2:5][C@@H:4]([CH2:1][CH:2]=[CH2:3])[CH2:7][CH2:8][CH2:9][CH2:10][O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: C=CC[C@H](CO)CCCCOCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC[C@@H](CCCCOCc1ccccc1)COS(C)(=O)=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of (-)-2(R)-allyl-6-(benzyloxy)-hexan-1-ol (5.0 g, 20 mmol) in methylene chloride (85 ml) at 0° C. is added triethylamine (4.6 ml, 33 mmol) followed by methanesulfonyl chloride. The mixture is allowed to stir at 0° C. for 2 hours and then quenched using saturated sodium bicarbonate solution. The organic layer is separated, dried, filtered and evaporated to give (-)-2(R)-allyl-6-(benzyloxy)hexan-1-yl methanesulfonate (mesylate ester) which is used as is.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.[C:18]([O:22][C:23]([NH:25][C@@H:26]([C:32]([OH:34])=O)[CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:24])([CH3:21])([CH3:20])[CH3:19].C(Cl)CCl.Cl.[CH3:40][O:41][C:42](=[O:50])[C@H:43]([CH2:45][C:46]([CH3:49])([CH3:48])[CH3:47])[NH2:44]>ClCCl>[CH3:40][O:41][C:42](=[O:50])[C@H:43]([CH2:45][C:46]([CH3:48])([CH3:47])[CH3:49])[NH:44][C:32](=[O:34])[C@@H:26]([CH2:27][C:28]([CH3:29])([CH3:30])[CH3:31])[NH:25][C:23]([O:22][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:24]
Reactant: CC(C)(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)[C@@H](N)CC(C)(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: COC(=O)[C@H](CC(C)(C)C)NC(=O)[C@@H](CC(C)(C)C)NC(=O)OC(C)(C)C

Procedure:
HOBt (3 equivalents, 39.4 g, 292 mmol), N-methylmorpholine (3 equivalents, 32.1 ml, 291.8 mmol), N-tert-butoxycarbonyl-3-tert-butyl-D-alanine (Example 6A, 1.0 equivalent, 97.3 mmol), EDC (2 equivalents, 37.3 g, 194.6 mmol) and again N-methylmorpholine (2 equivalents, 21.4 ml, 194.5 mmol) are added successively at −20° C. to a solution of 3-tert-butyl-L-alanine methyl ester hydrochloride (1.1 equivalents, 21 g, 107 mmol) in dichloromethane p.a. (1.4 l). The reaction mixture warms slowly (about 12 h) to RT, whereby complete conversion of the amine component is observed by means of HPLC. The reaction mixture is then washed with a saturated aqueous sodium hydrogen carbonate solution (300 ml), 5% aqueous citric acid (2×500 ml), a saturated aqueous sodium hydrogen carbonate solution (500 ml) and a saturated sodium chloride solution. The reaction mixture is dried over sodium sulfate and filtered. The mixture is concentrated to dryness in vacuo and then dried further under high vacuum. 36 g (96% of theory) of the title compound are obtained, which is reacted without further purification.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].O.[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([O:17][OH:18])=[O:16])[CH:10]=1.[Cl:19][CH:20]([CH2:24][CH3:25])[C:21](Cl)=[O:22]>C(Cl)(Cl)Cl>[Cl:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[C:15]([O:17][O:18][C:21](=[O:22])[CH:20]([Cl:19])[CH2:24][CH3:25])=[O:16]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCC(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCC(Cl)C(=O)OOC(=O)c1cccc(Cl)c1
Temperature: -2 °C
Yield: 97.7 %

Procedure:
To 6.4 g. (0.06 moles) anhydrous sodium carbonate in 60 cc. H2O was added 10.2 g. (0.05 moles) of m-chloroperbenzoic acid of 84.35% purity. The stirred mixture was chilled to -2° C. and 8.5 g. (0.06 moles) 2-chlorobutyryl chloride in 30 cc. chloroform was added over 17 minutes. After a total reaction time of 60 minutes, the reaction was worked up as in Example I and gave 15.2 g. product. Product A.O. analysis: theory, 5.77; found, 5.15; 89.30% pure; 97.7% yield.
Reaction SMILES: F[CH2:2][O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1C=O.Cl.[F:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][NH2:21])=[CH:16][CH:15]=1.[C:22](=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1.ClCCl>[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:9]3[C:10](=[CH:11][C:4]([O:3][CH3:2])=[CH:5][CH:8]=3)[CH:22]=[N:21]2)=[CH:16][CH:15]=1
Reactant: NNc1ccc(F)cc1
Reactant: O=Cc1ccccc1OCF
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: COc1ccc2c(cnn2-c2ccc(F)cc2)c1
Temperature: 150 °C

Procedure:
A mixture of 2-fluoromethoxybenzaldehyde (2.1 mmol, 320 mg), 4-fluorophenylhydrazine hydrochloride (2.1 mmol, 340 mg) and cesium carbonate (3 mmol, 2.0 g) in NMP (6 ml) was heated in a microwave reactor (300 W, 20 min, 150° C.). After cooling to r.t. the reaction mixture was diluted with dichloromethane (20 ml) and washed with 1M HCl, and sat. NaHCO3. The organic layer was dried over Na2SO4, concentrated, and purified by flash chromatography on silica gel (heptane-ethyl acetate).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[CH:15][N:14]([C:17]4[S:18][C:19]([C:29]([NH2:31])=[O:30])=[C:20]([C:22]5[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=5)[N:21]=4)[C:13]=3[CH:32]=2)[CH2:4][CH2:3]1.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)N=N1)C.F[P-](F)(F)(F)(F)F.[CH2:56]([N:58]([CH2:61][CH3:62])[CH2:59][CH3:60])C.[C:63]([O:67]C(NC(C)(C)C(O)=O)=O)(C)(C)[CH3:64]>C(OCC)(=O)C.CN(C)C=O>[C:29]([C:19]1[S:18][C:17]([N:14]2[C:13]3[CH:32]=[C:9]([CH2:8][N:5]4[CH2:4][CH2:3][CH:2]([NH:1][C:63]([CH:64]5[CH2:62][CH2:61][N:58]([CH3:56])[CH2:59][CH2:60]5)=[O:67])[CH2:7][CH2:6]4)[CH:10]=[CH:11][C:12]=3[N:16]=[CH:15]2)=[N:21][C:20]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=1)(=[O:30])[NH2:31]
Reactant: CCN(CC)CC
Reactant: NC(=O)c1sc(-n2cnc3ccc(CN4CCC(N)CC4)cc32)nc1-c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Agent: CN(C)C(N(C)C)=[N+]1N=Nc2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1CCC(C(=O)NC2CCN(Cc3ccc4ncn(-c5nc(-c6cccc(Cl)c6)c(C(N)=O)s5)c4c3)CC2)CC1
Reaction time: 0.25 h
Yield: 54.8 %

Procedure:
A mixture of 0.360 g (0.77 mmole) of 2-[6-(4-amino-piperidin-1-ylmethyl)-benzoimidazol-1-yl]-4-(3-chloro-phenyl)-thiazole-5-carboxylic acid amide (I.13), 5 mL of dimethylformamide, 0.441 g (1.16 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium, 3-oxide, hexafluorophosphate(1-) (1:1), 0.311 g (3.08 mmole) of triethylamine was stirred for 15 minutes, then 0.236 g (1.16 mmole) of 2-tert-butoxycarbonylamino-2-methyl-propionic acid was added. After 3 hours, the mixture was taken up in 100 mL of ethyl acetate, washed twice with 100 mL of water, and then once with 100 mL of brine. The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-(methanol-ammonium hydroxide, (92.8:0.3)) (gradient 100:0-0:100) to give 0.250 g of 1-methyl-piperidine-4-carboxylic acid (1-{3-[5-carbamoyl-4-(3-chloro-phenyl)-thiazol-2-yl]-3H-benzoimidazol-5-ylmethyl}-piperidin-4-yl)-amide (I.15) as an off white solid. MH+/Z=652
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.CN(C)C=O.[NH2:25][C:26]1[CH:27]=[C:28]([CH:45]=[CH:46][CH:47]=1)[O:29][C:30]1[CH:42]=[CH:41][C:33]2[N:34]=[C:35]([NH:37][C:38](=[O:40])[CH3:39])[S:36][C:32]=2[C:31]=1[C:43]#[N:44]>O1CCCC1.C(OCC)(=O)C>[C:38]([NH:37][C:35]1[S:36][C:32]2[C:31]([C:43]#[N:44])=[C:30]([O:29][C:28]3[CH:27]=[C:26]([NH:25][C:9](=[O:11])[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=4)([CH3:13])[CH3:12])[CH:47]=[CH:46][CH:45]=3)[CH:42]=[CH:41][C:33]=2[N:34]=1)(=[O:40])[CH3:39]
Reactant: CC(=O)Nc1nc2ccc(Oc3cccc(N)c3)c(C#N)c2s1
Reactant: CC(C)(C(=O)O)c1cccc(Br)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(=O)Nc1nc2ccc(Oc3cccc(NC(=O)C(C)(C)c4cccc(Br)c4)c3)c(C#N)c2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.4 %

Procedure:
To a solution of 2-(3-bromophenyl)-2-methylpropionic acid (89 mg, 0.361 mmol) in tetrahydrofuran (1 mL) were added oxalyl chloride (40 μL, 0.466 mmol) and N,N-dimethylformamide (10 μL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in N,N-dimethylacetamide (1 mL). N-[6-(3-Aminophenoxy)-7-cyano-1,3-benzothiazol-2-yl]acetamide (100 mg, 0.308 mmol) produced in Example 12(ii) was added to the solution, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate (12 mL), washed successively with 5% aqueous sodium hydrogen carbonate solution (6 mL) and saturated brine (6 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=30/70→80/20), and the obtained solution was concentrated under reduced pressure. The residue was crystallized from ethanol to give the title compound (136 mg, 81%) as a white powder.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[C:16]2[C:7](=[CH:8][C:9]3[CH2:10][CH2:11][CH:12]([CH3:21])[N:13]([CH2:17][CH:18]4CC4)[C:14]=3[CH:15]=2)[NH:6][C:5](=[O:22])[CH:4]=1.C(=O)C>>[F:24][C:2]([F:1])([F:23])[C:3]1[C:16]2[C:7](=[CH:8][C:9]3[CH2:10][CH2:11][CH:12]([CH3:21])[N:13]([CH2:17][CH3:18])[C:14]=3[CH:15]=2)[NH:6][C:5](=[O:22])[CH:4]=1
Reactant: CC1CCc2cc3[nH]c(=O)cc(C(F)(F)F)c3cc2N1CC1CC1
Agent: CC=O
Product: CCN1c2cc3c(C(F)(F)F)cc(=O)[nH]c3cc2CCC1C

Procedure:
This compound was prepared in a similar fashion as that described in Example 84 from Compound 187 (Structure 33 of Scheme VI, where R1=methyl, n=1) and acetaldehyde. 1H NMR (400 MHz, CDCl3) 11.19 (br. s, 1H), 7.11 (s, 1H), 7.00 (s, 1H), 6.80 (s, 1H), 3.55 (m, 1H), 3.47–3.32 (m, 2H), 2.93–2.80 (m, 2H), 1.93–1.79 (m, 2H), 1.22 (t, 3H, J=7.0), 1.18 (d, 3H, J=6.4).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[OH:10].C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20].O>ClCCl>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[O:10][S:19]([CH3:18])(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: OC1Cc2ccccc2C1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1Cc2ccccc2C1
Reaction time: 1.5 h

Procedure:
To a solution of 2-indanol (4 g) and triethylamine (5.8 ml) in dichloromethane (40 ml) was added dropwise with stirring methanesulfonylchloride (2.8 ml) in an ice-bath. The mixture was then stirred for 1.5 hours. The reaction mixture was added to a mixture of water and dichloromethane. The organic layer was taken and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure to give methanesulfonic acid indan-2-yl ester (6.29 g).
Reaction SMILES: F[C:2]1[N:33]=[CH:32][CH:31]=[CH:30][C:3]=1[C:4]([C:6]1[N:7]=[C:8]([N:16]2[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18][CH2:17]2)[C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:5].[OH-].[NH4+:35]>>[NH2:35][C:2]1[N:33]=[CH:32][CH:31]=[CH:30][C:3]=1[C:4]([C:6]1[N:7]=[C:8]([N:16]2[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18][CH2:17]2)[C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:5]
Reactant: CC(C)(C)OC(=O)N1CCCN(c2nc(C(=O)c3cccnc3F)cc3ccccc23)CC1
Reactant: [NH4+]
Agent: [OH-]
Product: CC(C)(C)OC(=O)N1CCCN(c2nc(C(=O)c3cccnc3N)cc3ccccc23)CC1
Temperature: 110 °C
Yield: 24 %

Procedure:
A microwave vial was charged with tert-butyl 4-(3-(2-fluoronicotinoyl)isoquinolin-1-yl)-1,4-diazepane-1-carboxylate (78 mg, 0.17 mmol) and a saturated aqueous solution of ammonium hydroxide (2 ml). The reaction mixture was heated under microwave irradiation at 110° C. for 25 minutes. The mixture was cooled down to room temperature, partitioned between ethyl acetate and water. The organic phase was dried over magnesium sulfate, filtered and evaporated to dryness. The residue was purified on silica gel by flash column chromatography to afford the title compound as a yellow solid (18 mg, 24% yield).
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:13])[NH:6]2.Br[CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1>>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:13])[N:6]2[CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1
Reactant: Cc1cc2c(Cl)c(C#N)ccc2[nH]1
Reactant: Fc1ccc(OCCBr)cc1
Product: Cc1cc2c(Cl)c(C#N)ccc2n1CCOc1ccc(F)cc1

Procedure:
Synthesized as described in Example 4 from 4-chloro-2-methyl-1H-indole-5-carbonitrile and 1-[(2-bromoethyl)oxy]-4-fluorobenzene: 1H NMR (400 MHz, DMSO-d6) δ 7.88 (d, J=1.1 Hz, 1 H), 7.78 (d, J=8.7 Hz, 1 H), 7.53 (dd, J=8.5, 1.5 Hz, 1 H), 7.10-6.98 (m, 2 H), 6.84-6.76 (m, 2 H), 4.63 (t, J=5.0 Hz, 2 H), 4.22 (t, J=5.0 Hz, 2 H), 2.49 (s, 3 H); MS (ES) m/z 329 (M+1).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[Cl:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][NH2:12])=[CH:9][CH:8]=1.C(N(CC)CC)C>ClCCl>[Cl:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][NH:12][C:1](=[O:4])[CH:2]=[CH2:3])=[CH:9][CH:8]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)NCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Acryloyl chloride (86.9 g) was added dropwise with stirring to a solution of 4-chlorobenzylamine (135.8 g) and triethylamine (133.5 ml) in dichloromethane (500 ml) at -15 to -20° C., under nitrogen. After the addition the mixture was stirred at ambient temperature for 2.5 hours. The mixture was washed with dilute aqueous sodium hydroxide solution and then with water. The dichloromethane solution was dried and evaporated under reduced pressure. The solid residue was recrystallised from ethyl acetate to give N-(4-chlorobenzyl)acrylamide, m.p. 103°-104° C.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][O:8][C:9](=[O:19])[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18].Br[CH2:21][CH2:22][CH2:23][CH2:24]/[CH:25]=[CH:26]/[C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1>CN(C)C=O>[CH3:7][O:8][C:9](=[O:19])[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH2:21][CH2:22][CH2:23][CH2:24]/[CH:25]=[CH:26]/[C:27]1[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=1
Reactant: COC(=O)CCc1ccccc1O
Reactant: COc1ccc(/C=C/CCCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)CCc1ccccc1OCCCC/C=C/c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.3 %

Procedure:
651 mg of cesium carbonate is added to a solution of 180 mg of 3-(2-hydroxyphenyl)-propionic acid methyl ester and 272 mg of (1E)-6-bromo-1-(4-methoxyphenyl)-1-hexene in 2 ml of dimethylformamide and the suspension is stirred for 16 hours at room temperature. The reaction mixture is filtered, the filtration residue is washed with dichloromethane, the filtrate concentrated by evaporation and the residue chromatographed on silica gel with hexane. 255 mg of 3-[2-[6-(4-methoxyphenyl)(5E)-5-hexenyloxy]-phenyl]-propionic acid methyl ester is obtained as oil.