Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[C:10]2[CH2:23][C@:22]3([CH3:36])[C@@H:24]([CH3:35])[CH2:25][CH2:26][C@H:27]4[C:28]([CH3:34])([CH3:33])[C@@H:29]([OH:32])[CH2:30][CH2:31][C@@:21]34[O:20][C:11]=2[C:12]2[CH:13]([OH:19])[NH:14][C:15](=[O:18])[C:16]=2[CH:17]=1)C1C=CC=CC=1.C(OCC)(=O)C>C1COCC1.[C].[Pd]>[OH:19][CH:13]1[C:12]2[C:11]3[O:20][C@@:21]45[CH2:31][CH2:30][C@H:29]([OH:32])[C:28]([CH3:34])([CH3:33])[C@@H:27]4[CH2:26][CH2:25][C@H:24]([CH3:35])[C@@:22]5([CH3:36])[CH2:23][C:10]=3[C:9]([OH:8])=[CH:17][C:16]=2[C:15](=[O:18])[NH:14]1
Reactant: C[C@H]1CC[C@H]2C(C)(C)[C@@H](O)CC[C@]23Oc2c(c(OCc4ccccc4)cc4c2C(O)NC4=O)C[C@]13C
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@H]1CC[C@H]2C(C)(C)[C@@H](O)CC[C@]23Oc2c(c(O)cc4c2C(O)NC4=O)C[C@]13C
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.1 %

Procedure:
To the above Compound (29a) (100 mg, 0.20 mmol) dissolved in 5.0 ml of THF and 2.0 ml of ethyl acetate was added 45 mg of 10% palladium-carbon, and the mixture stirred at room temperature for 3 hours under hydrogen atmosphere. The palladium-carbon was filtered off, and the filtrate concentrated under reduced pressure. The residue was then purified by a silica gel column chromatography (silica gel 5.2 g; ethyl acetate) to give 78 mg (96%) of Compound (30a).
Reaction SMILES: Cl.[CH3:2][O:3][N:4]1[C:9](=[O:10])[C:8]2[CH2:11][NH:12][CH2:13][CH2:14][C:7]=2[NH:6][C:5]1=[O:15].C(N(CC)CC)C.[Cl:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1.O>C(Cl)Cl>[Cl:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([N:12]2[CH2:13][CH2:14][C:7]3[NH:6][C:5](=[O:15])[N:4]([O:3][CH3:2])[C:9](=[O:10])[C:8]=3[CH2:11]2)=[O:29])=[CH:26][CH:25]=1
Reactant: COn1c(=O)[nH]c2c(c1=O)CNCC2
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COn1c(=O)[nH]c2c(c1=O)CN(C(=O)c1ccc(Cl)cc1)CC2

Procedure:
3-Methoxy-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-dione hydrochloride (790 mg) was suspended in methylene chloride, and triethylamine (1.17 ml) and 4-chlorobenzoyl chloride (0.43 ml) were added under ice cooling and the resultant mixture was stirred at the same temperature for 1.5 hours. To the reaction solution, water was added and the resultant mixture was concentrated. To the residue, diethyl ether was added and insoluble matter was obtained by filtration. The titled compound (684 mg) was obtained as a white powder. The resultant compound was used in a next reaction without further purifying.
Reaction SMILES: Br[CH2:2][CH:3]1[O:20][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH:4]1[CH3:21])[NH:11][C:10](=[O:16])[C:9]([CH:17]([CH3:19])[CH3:18])=[CH:8]3.[N-:22]=[N+:23]=[N-:24].[Na+].C(OCC)(=O)C.O>CN(C)C=O>[N:22]([CH2:2][CH:3]1[O:20][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH:4]1[CH3:21])[NH:11][C:10](=[O:16])[C:9]([CH:17]([CH3:19])[CH3:18])=[CH:8]3)=[N+:23]=[N-:24]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc2c(c3cc(C(C)C)c(=O)[nH]c13)OC(CBr)C2C
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc2c(c3cc(C(C)C)c(=O)[nH]c13)OC(CN=[N+]=[N-])C2C
Temperature: 150 °C
Reaction time: 3 h
Yield: 74.1 %

Procedure:
The compound obtained in Example 327 (1.97 g, 5.62 mmol) was dissolved in dimethylformamide (25 ml). To the resultant solution, sodium azide (2.2 g, 33.84 mmol) was added, and the mixture was stirred at 150° C. for 3 hours. After the mixture was cooled, ethyl acetate-water was added for phase separation. The organic phase was washed with water, and saturated aqueous sodium chloride solution in this order, and dried. The solvent was distilled off under reduced pressure, and the residue was washed with hexane. 1.3 g of the title compound was obtained (78%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C@H:16]([CH2:22][OH:23])[CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])[CH2:12][CH:13]([CH3:15])[CH3:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[N:24]1([C:30]([NH:32][CH:33]([CH2:37][C:38]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[CH:41]=[CH:40][CH:39]=2)[C:34](O)=[O:35])=[O:31])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:12][CH:13]([CH3:15])[CH3:14])[C@H:16]([CH2:22][OH:23])[CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:34]([C@@H:33]([NH:32][C:30]([N:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)=[O:31])[CH2:37][C:38]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[CH:41]=[CH:40][CH:39]=2)=[O:35])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(C)CN([C@H](CO)CCCCN)S(=O)(=O)c1ccc(N)cc1
Reactant: O=C(O)C(Cc1cccc2ccccc12)NC(=O)N1CCOCC1
Product: CC(C)CN([C@H](CO)CCCCNC(=O)[C@H](Cc1cccc2ccccc12)NC(=O)N1CCOCC1)S(=O)(=O)c1ccc(N)cc1
Yield: 32 %

Procedure:
This material was prepared from (1S)-4-amino-N-(5-amino-1-hydroxymethyl-pentyl)-N-isobutyl-benzenesulfonamide (XII) (example 28, step D) as described in general procedure B using 2-[(morpholine-4-carbonyl)-amino]-3-naphthalen-1-yl-propionic acid (step A). The final product was obtained in 32% yield (33 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][C:10]2[NH:14][N:13]=[C:12]([CH:15]3[CH2:17][CH2:16]3)[CH:11]=2)[N:3]=1.[OH:18][C@@H:19]1[CH2:23][NH:22][C@H:21]([C:24]([NH:26][C:27]2[S:28][CH:29]=[CH:30][N:31]=2)=[O:25])[CH2:20]1.ClC1N=C(NC2NN=C(C3CC3)C=2)N=C(N2CCC[C@@]2(C)C(NC2C=NC(F)=CC=2)=O)N=1>>[Cl:8][C:6]1[N:5]=[C:4]([NH:9][C:10]2[CH:11]=[C:12]([CH:15]3[CH2:17][CH2:16]3)[NH:13][N:14]=2)[N:3]=[C:2]([N:22]2[CH2:23][C@@H:19]([OH:18])[CH2:20][C@H:21]2[C:24]([NH:26][C:27]2[S:28][CH:29]=[CH:30][N:31]=2)=[O:25])[N:7]=1
Reactant: O=C(Nc1nccs1)[C@@H]1C[C@H](O)CN1
Reactant: Clc1nc(Cl)nc(Nc2cc(C3CC3)n[nH]2)n1
Agent: C[C@@]1(C(=O)Nc2ccc(F)nc2)CCCN1c1nc(Cl)nc(Nc2cc(C3CC3)n[nH]2)n1
Product: O=C(Nc1nccs1)[C@@H]1C[C@H](O)CN1c1nc(Cl)nc(Nc2cc(C3CC3)[nH]n2)n1

Procedure:
88B was prepared from 1A and 88A as described for 1C. LC/MS [M+H]+: 448/450; Ret time (Method F): 2.34 min.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O-:9])=[O:8].[CH3:10]O>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8]
Reactant: CO
Reactant: O=C([O-])CCCCCBr
Product: COC(=O)CCCCCBr
Temperature: 25 °C
Reaction time: 18 h
Yield: 93 %

Procedure:
To a 2 liter round bottom flask, charge with 99.7 g (0.511 mol) of 6-bromohexanoate (Aldrich Chemi(al Co., Milwaukee, Wis.) and 1 liter of methanol, was bubbled hydrogen chloride gas for 1-2 minutes. The mixture was stirred at 20-30° C. for 18 h and then concentrated via rotary evaporation. The residue was diluted with 500 mL of diethyl ether and washed with 150 mL of de-ionized water, 200 mL of saturated sodium bicarbonate, and then once again with 200 mL of de-ionized water. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated via rotary evaporation. The residue was distiled under vacuum to afford 99.6 g of the product (1) as a colorless oil (93%): b.P.=93-96° C. at 3 mm Hg: 1H NMR (d6-DMSO) d 3.57 (3H, s), 3.51 (2H, t), 2.30 (2H, t), 1.78 (2H, pentet) and 1.62-1.28 (4H, mr) ppm.
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([NH:12]N)=[CH:8][CH:7]=1)(=[O:5])=[O:4].[N:14]12[CH2:22][CH2:21][CH:18]([CH2:19][CH2:20]1)[C:17](=O)[CH2:16][CH2:15]2.Cl.O1CCOCC1>C(O)(=O)C>[CH3:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]2[NH:12][C:17]3[CH:18]4[CH2:21][CH2:22][N:14]([CH2:15][C:16]=3[C:8]=2[CH:7]=1)[CH2:20][CH2:19]4)(=[O:5])=[O:4]
Reactant: CS(=O)(=O)c1ccc(NN)cc1
Reactant: O=C1CCN2CCC1CC2
Agent: Cl
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc2[nH]c3c(c2c1)CN1CCC3CC1
Temperature: 80 °C

Procedure:
A mixture of (4-(methylsulfonyl)phenyl)hydrazine hydrochloride (1105 mg, 5.0 mmol; Acros), 1-azabicyclo[3.2.2]nonan-4-one (696 mg, 5.0 mmol; Example 2A), 4 N HCl in dioxane (2.5 mL, 10.0 mmol; Aldrich), and acetic acid (15 mL) was heated to 80° C. overnight (16 hours), then cooled to room temperature. The solvent was removed, and the residue was basified with 5 N sodium hydroxide and extracted with ethyl acetate (3×50 mL). The combined organic phases were concentrated in vacuo and purified by reverse-phase HPLC [Waters XBridge RP18 column, 5 μm, 30×100 mm, flow rate 40 mL/minute, 20-99% gradient of methanol in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide) over 20 minutes] to afford the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 2.05-2.14 (m, 4H), 3.02-3.15 (m, 6H), 3.20-3.28 (m, 2H), 4.29 (s, 2H), 7.47 (d, J=8 Hz, 1H), 7.57-7.62 (m, 1H), 7.95 (d, J=1 Hz, 1H); MS (DCI/NH3) m/z 291 (M+H)+.
Reaction SMILES: Cl.[C:2]([NH2:5])(=O)[CH3:3].[CH3:6][O:7][CH:8]([O:16]C)[C:9]([C:12](OC)=O)=[CH:10][O-].[Na+].C[N:20](C)C=O>>[CH3:3][C:2]1[N:5]=[CH:12][C:9]([C:8]([O:7][CH3:6])=[O:16])=[CH:10][N:20]=1
Reactant: CC(N)=O
Reactant: COC(=O)C(=C[O-])C(OC)OC
Reactant: CN(C)C=O
Agent: Cl
Agent: [Na+]
Product: COC(=O)c1cnc(C)nc1
Temperature: 100 °C

Procedure:
N-(4-chlorophenyl)-N-{(2S,4R)-2-methyl-1-[(2-methylpyrimidin-5-yl)carbonyl]-1,2,3,4-tetrahydroquinolin-4-yl}acetamide was prepared following general procedure H, substituting 2-methylpyrimidine-5-carbonyl chloride for 6-trifluoromethyl nicotinyl chloride. (2-methylpyrimidine-5-carbonyl chloride was prepared in four steps. To a solution of 3,3-dimethoxypropionate in ethylene glycol dimethyl ether was added sodium hydride at 0° C., then methyl formate. The reaction mixture was warmed up to 50° C. for 30 m. and then stirred at room temperature for 20 h. Anhydrous diethyl ether was added and the precipitate was filtered to give sodium 2-(dimethoxymethyl)-3-methoxy-3-oxoprop-1-en-1-olate. To a solution of acetamide hydrochloride in dimethylformamide was added preformed sodium 2-(dimethoxymethyl)-3-methoxy-3-oxoprop-1-en-1-olate. Reaction mixture was heated to 100° C. for 1 h. to give methyl 2-methylpyrimidine-5-carboxylate. Hydrolysis of the ester with sodium hydroxide gave 2-methylpyrimidine-5-carboxylic acid. Subsequent treatment of this carboxylic acid with oxalyl chloride and catalytic DMF afforded 2-methylpyrimidine-5-carbonyl chloride in decent yield). The rest of the procedures were followed as indicated in general procedure H to afford N-(4-chlorophenyl)-N-{(2S,4R)-2-methyl-1-[(2-methylpyrimidin-5-yl)carbonyl]-1,2,3,4-tetrahydroquinolin-4-yl}acetamide.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:12]([C:22]([NH2:24])=O)[N:11]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[C:10]=1[C:33]([NH2:35])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+].C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[CH2:15]([O:14][C:13]1[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:10]([C:33]#[N:35])[N:11]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[C:12]=1[C:22]#[N:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COc1ccc(-n2c(C(N)=O)c(OCc3ccccc3)c(OCc3ccccc3)c2C(N)=O)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(-n2c(C#N)c(OCc3ccccc3)c(OCc3ccccc3)c2C#N)cc1
Temperature: 25 °C
Yield: 97 %

Procedure:
To a stirred solution of 3,4-bis(benzyloxy)-1-(4-methoxyphenyl)-1H-pyrrole-2,5-dicarboxamide (13) [prepared using the same procedure as Example A step (ii) using ammonium chloride] (267 mg, 0.57 mmol) and triethylamine (710 μL, 5.10 mmol) in DCM (8 mL) at 0° C. was added trifluoroacetic anhydride (240 μL, 1.70 mmol) and the reaction allowed to warm to RT over 30 min. The reaction mixture was partitioned between DCM (50 mL) and 1 M HCl (aq.) (30 mL), the organic was washed with 1 M HCl (aq.) (20 mL), sat. NaHCO3 (aq.) (30 mL), and brine (20 mL), dried (MgSO4), filtered and volatiles removed in vacuo to afford a yellow solid. The crude residue was purified by silica gel chromatography (40 g, 0-50% EtOAc in isohexane) to afford 3,4-bis(benzyloxy)-1-(4-methoxyphenyl)-1H-pyrrole-2,5-dicarbonitrile (14) (240 mg, 97%) as a pale yellow solid: 1H NMR (400 MHz, DMSO-d6) δ: 7.47-7.27 (m, 10H), 7.30-7.20 (m, 2H), 7.05-6.91 (m, 2H), 5.26 (s, 4H), 3.79 (s, 3H).
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:24][C:25]4[CH:26]=[N:27][C:28]([O:32][CH3:33])=[C:29]([F:31])[CH:30]=4)=[N:18][CH:19]=[C:20]([CH:23]=3)[CH:21]=[O:22])[N:10]=2)=CC=1.C(O)(C(F)(F)F)=O.S(O)(C(F)(F)F)(=O)=O>C(Cl)Cl>[NH2:8][C:9]1[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]2[C:17]([NH:24][C:25]3[CH:26]=[N:27][C:28]([O:32][CH3:33])=[C:29]([F:31])[CH:30]=3)=[N:18][CH:19]=[C:20]([CH:23]=2)[CH:21]=[O:22])[N:10]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C=O)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ncc(Nc2ncc(C=O)cc2-c2nc(C)nc(N)n2)cc1F
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
A solution of 5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)nicotinaldehyde (380 mg, 0.638 mmol) in DCM (5 mL) was treated with TFA (6.0 mL, 78 mmol) and then TfOH (0.050 mL, 0.563 mmol). The solution was heated at 80° C. under a condenser. After 2.5 h, more TfOH (0.050 mL, 0.563 mmol) was added. After 24 h, the mixture was concentrated. The residue was azeotroped with toluene (10 mL) once. The mixture was suspended in 1:1 DMSO-water (5 mL each) and filtered. The resulting solid was then suspended in saturated NaHCO3 for several hours and filtered. The mother liquor was discarded. The resulting sludge was dissolved in hot DMSO and filtered. The filtrate was diluted with MeOH (2× v/v) and allowed to settle. The resulting suspension was filtered. The resulting solid was again dissolved in hot DMSO and diluted with MeOH. After 3 repetitions, the solid was about 95% pure product (50 mg). LCMS (ES, pos.): calcd for C16H14FN7O2: 355.1; found: 356.2 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 12.47 (br. s., 1H); 9.92 (s, 1H); 9.17 (br. s., 1H); 8.81 (br. s., 1H); 8.42 (br. s., 1H); 8.32 (d, J=13.11 Hz, 1H); 8.01 (br. s., 1H); 7.85 (d, J=0.78 Hz, 1H); 3.96 (s, 3H); 2.46 (br. s., 3H). 19F NMR (377 MHz, d6-DMSO) δ −139.31 (d, J=11.44 Hz, 1 F).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[N:9][C:10]3[N:11]([N:13]=[CH:14][C:15]=3[C:16]3[CH:17]=[C:18]([C:21]([NH:23][CH2:24][C:25]([F:28])([F:27])[F:26])=[O:22])[S:19][CH:20]=3)[CH:12]=2)[CH:4]=[N:3]1.S(Cl)([Cl:31])=O>CN(C=O)C>[Cl:31][C:20]1[S:19][C:18]([C:21]([NH:23][CH2:24][C:25]([F:27])([F:28])[F:26])=[O:22])=[CH:17][C:16]=1[C:15]1[CH:14]=[N:13][N:11]2[CH:12]=[C:7]([C:5]3[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=3)[CH:8]=[N:9][C:10]=12
Reactant: O=S(Cl)Cl
Reactant: Cn1cc(-c2cnc3c(-c4csc(C(=O)NCC(F)(F)F)c4)cnn3c2)cn1
Solvent: CN(C)C=O
Product: Cn1cc(-c2cnc3c(-c4cc(C(=O)NCC(F)(F)F)sc4Cl)cnn3c2)cn1
Temperature: 80 °C
Yield: 51.8 %

Procedure:
4-[6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-3-yl]-N-(2,2,2-trifluoroethyl)thiophene-2-carboxamide (107 mg, 0.263 mmol) was taken up in thionyl chloride (2 ml, 27.4 mmol) and heated at 80° C. overnight. Evaporated solvent under vacuum and took up in 3 ml DMF, purified reverse-phase 30-100% ACN/H2O w/0.1% TFA. Evaporated solvent under vacuum to yield 60 mgs pale yellow solid (51.7%). LRMS [M+H]=441.0
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:33]=1)[C:7]([NH:9][C:10]1[S:11][C:12]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:23][CH2:22]2)=[C:13]([C:15]2[S:16][CH:17]=[C:18]([Cl:20])[CH:19]=2)[N:14]=1)=[O:8].C(Cl)(Cl)Cl.[NH:39]1[CH2:49][CH2:48][CH:42]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:41][CH2:40]1>C1COCC1>[CH2:46]([O:45][C:43]([CH:42]1[CH2:48][CH2:49][N:39]([C:3]2[C:2]([Cl:1])=[CH:33][C:6]([C:7](=[O:8])[NH:9][C:10]3[S:11][C:12]([N:21]4[CH2:26][CH2:25][N:24]([CH:27]5[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]5)[CH2:23][CH2:22]4)=[C:13]([C:15]4[S:16][CH:17]=[C:18]([Cl:20])[CH:19]=4)[N:14]=3)=[CH:5][N:4]=2)[CH2:40][CH2:41]1)=[O:44])[CH3:47]
Reactant: CCOC(=O)C1CCNCC1
Reactant: O=C(Nc1nc(-c2cc(Cl)cs2)c(N2CCN(C3CCCCC3)CC2)s1)c1cnc(Cl)c(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CCOC(=O)C1CCN(c2ncc(C(=O)Nc3nc(-c4cc(Cl)cs4)c(N4CCN(C5CCCCC5)CC4)s3)cc2Cl)CC1
Reaction time: 5 h

Procedure:
To a solution of 750 mg of the compound of Example 5 in 10 ml of THF, 2.1 ml of ethyl isonipecotate was added at room temperature, the temperature was elevated to 50° C., and the mixture was stirred for 5 hours. To the reaction solution, chloroform was added, and the organic layer was washed with saturated aqueous NaHCO3 and brine and dried over sodium sulfate. After the evaporation of the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography (chloroform-MeOH=200:1˜100:1) to obtain 881 mg of 1-(3-chloro-5-{[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl)thiazol-2-yl]carbamoyl}-2-pyridyl)piperidine-4-carboxylic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]#[N:27])[CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]([C:15](=O)[CH2:16][CH2:17][CH3:18])[C:10](OCC)=[O:11].Cl.[C:29](=[NH:32])([NH2:31])[CH3:30].C[O-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:20]2[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:10](=[O:11])[NH:32][C:29]([CH3:30])=[N:31][C:15]=1[CH2:16][CH2:17][CH3:18]
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1Cl)C(=O)OCC
Reactant: CC(=N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1Cl
Yield: 73 %

Procedure:
To a suspension of 60% sodium hydride (0.40 g) in tetrahydrofuran (20 mL) was added dropwise a solution of ethyl butyrylacetate (2.13 g) in tetrahydrofuran (10 mL). After stirring for 30 min, 4′-(bromomethyl)-3′-chlorobiphenyl-2-carbonitrile (2.06 g) was added. The mixture was stirred at room temperature for 15 hr, and 1 M hydrochloric acid was added. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography to give ethyl 2-[(3-chloro-2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate. Then, a solution of the obtained ethyl 2-[(3-chloro-2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate, ethanimidamide hydrochloride (2.55 g), 28% sodium methoxide (7.80 g) in methanol (50 mL) was stirred overnight. The solvent was evaporated under reduced pressure, and saturated aqueous ammonium chloride solution was added to the residue. The precipitated solid was collected by filtration, and washed with water and diethyl ether to give the title compound (0.64 g, 73%) as a white solid.
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: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(Nc3ccc(N4CCN(C)CC4)cn3)ncc12
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
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: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][C:10]1[N:15]=[CH:14][C:13]([NH:16][C:17](=[O:21])[C@@H:18]([CH3:20])[NH2:19])=[CH:12][CH:11]=1.C(N(CC)CC)C.Cl[C:30](Cl)([O:32]C(=O)OC(Cl)(Cl)Cl)Cl.C([O-])(O)=O.[Na+]>ClCCl>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][C:10]1[N:15]=[CH:14][C:13]([N:16]2[C:17](=[O:21])[C@@H:18]([CH3:20])[NH:19][C:30]2=[O:32])=[CH:12][CH:11]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1cccc(Oc2ccc(NC(=O)[C@@H](C)N)cn2)c1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccc(Oc2ccc(N3C(=O)N[C@H](C)C3=O)cn2)c1C
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
N1-{6-[(2,3-dimethylphenyl)oxy]-3-pyridinyl}-D-alaninamide (Intermediate 40, 13 mg) was dissolved in dry dichloromethane (2 mL). The reaction mixture (under argon) was cooled down in an ice bath. Triethylamine (38.1 μl, 0.273 mmol) was added. Then a solution of triphosgene in dry dichloromethane (5.41 mg, 0.018 mmol, 0.40 equiv dissolved in 1 mL of DCM) was added dropwise. The reaction mixture was stirred at 0° C., under argon, during 10 min. A saturated aqueous solution of NaHCO3 was added (3 mL) and the aqueous layer was extracted with dichloromethane 4 times (4×4 mL). After drying over sodium sulphate, the solvents were removed under vacuum. The residue was purified by silica gel chromatography (Companion system, 4 g silica cartridge,) with a gradient cyclohexane/ethylacetate from 100:0 to 55:45 during 10 min and 55:45 during 20 min. This afforded the title compound (9 mg)
Reaction SMILES: C([O:8][C:9]1[CH:27]=[CH:26][C:12]([CH2:13][C:14]2[CH:18]=[C:17]([C:19]3[C:20]([NH2:25])=[N:21][CH:22]=[CH:23][CH:24]=3)[O:16][N:15]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.FC(F)(F)C(O)=O.C1(SC)C=CC=CC=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[NH2:25][C:20]1[C:19]([C:17]2[O:16][N:15]=[C:14]([CH2:13][C:12]3[CH:26]=[CH:27][C:9]([OH:8])=[CH:10][CH:11]=3)[CH:18]=2)=[CH:24][CH:23]=[CH:22][N:21]=1
Reactant: Nc1ncccc1-c1cc(Cc2ccc(OCc3ccccc3)cc2)no1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: CSc1ccccc1
Product: Nc1ncccc1-c1cc(Cc2ccc(O)cc2)no1
Reaction time: 2 h
Yield: 99.8 %

Procedure:
To a mixture of 3-(3-(4-benzyloxy-benzyl)-isoxazol-5-yl)-pyridin-2-ylamine (32 mg, 0.090 mmol) described in Example 1 and trifluoroacetic acid (1 mL) was added thioanisole (45 mg, 0.36 mmol) at room temperature, which was stirred for 2 hours at the same temperature. To a mixture of saturated aqueous sodium hydrogencarbonate solution and ethyl acetate was added the reaction mixture. The organic layer was separated and washed with saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=4:1) to obtain the title compound (24 mg, 100%).