Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.[CH3:43][C:44]1([CH3:51])[O:48][CH:47]([CH2:49]O)[CH2:46][O:45]1.[H-].[Na+]>O1CCCC1>[Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([O:37][CH2:49][CH:47]3[CH2:46][O:45][C:44]([CH3:51])([CH3:43])[O:48]3)=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Reactant: CC1(C)OCC(CO)O1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(C(=O)OCC2COC(C)(C)O2)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Yield: 27746624 %

Procedure:
In a manner similar to the method described in Example 7, chiral 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (100.8 mg, 0.164 mmol) was reacted with N,N′-carbonyldiimidazole (Aldrich, 67.8 mg, 0.406 mmol) and then a mixture of (2,2-Dimethyl-[1,3]dioxolan-4-yl)-methanol (Aldrich, 69.3 mg, 0.514 nmol) and sodium hydride (11.2 mg, 0.443 mmol) in tetrahydrofuran to give (2,2-dimethyl-1,3-dioxolan-4-yl)methyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate as a white lyophilized solid (104.2 mg, 87% yield). MS (ES+) m/z calcd. for C37H40Cl2F2N3O6 [(M+H)+]: 730. found: 730.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=2)[C:3]=1[CH2:22][C:23]([O:25][CH3:26])=[O:24].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:37]1[CH2:41]OC[CH2:38]1.ICCC>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=2)[C:3]=1[CH:22]([CH2:38][CH2:37][CH3:41])[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1cccc(C)c1)CCCC3
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCCI
Solvent: CN(C)C=O
Product: CCCC(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1cccc(C)c1)CCCC3
Yield: 72.5 %

Procedure:
This compound was prepared according to the procedure C from methyl [2-methyl-4-(m-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate (0.310 g; 0.87 mmol), LHMDS 1N in THF (0.96 mL; 0.96 mmol), 1-iodopropane (0.13 mL; 1.5 mmol) in DMF (3.5 mL) for 18 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (2-30%) in heptane furnished 0.257 g (73%) of the title compound as a yellow oil.
Reaction SMILES: [CH2:1]([OH:11])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl>[CH3:19][S:20]([O:11][CH2:1][CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCC/C=C\CCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCC/C=C\CCCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To a cooled solution (0° C.) of (Z)-dec-4-en-1-ol 9 (20 g, 128.0 mmol) and triethylamine (26.7 mL, 191.9 mmol) in anhydrous dichloromethane (200 mL) was slowly added methane sulfonyl chloride (14.9 mL, 191.9 mmol). The solution was stirred for 30 min at room temperature then diluted with dichloromethane (100 mL). The solution was washed with saturated sodium bicarbonate (3×150 mL) and then the combined aqueous washes were extracted with dichloromethane (150 mL). The combined dichloromethane extracts were dried on magnesium sulfate, filtered and concentrated in vacuo to dryness. The residue was filtered through a pad of silica (100% dichloromethane) to afford (Z)-dec-4-enyl methanesulfonate 2 as a yellow oil (28.5 g, 95%). Rf 0.5 (100% CH2Cl2).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[CH:7]=[CH:8][NH:9]2)=[N:4][CH:3]=1.C(#N)C.CN(C=O)C.C(Cl)(=O)C([Cl:24])=O.C(=O)(O)[O-].[Na+]>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[N:9][CH:8]=[CH:7][C:6]=2[Cl:24]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=c1cc[nH]c2cc(Br)cnc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: Clc1ccnc2cc(Br)cnc12
Temperature: 95 °C
Reaction time: 16 h
Yield: 14 %

Procedure:
5-((5-bromopyridin-3-ylamino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione. A 350 mL sealed tube was charged with 2,2-dimethyl-1,3-dioxane-4,6-dione (21.6 g, 150.0 mmol) and triethyl orthoformate (150 mL, 150.0 mmol). This was heated to 100° C., and stirred at this temperature for 2 hours. Reaction then cooled to 30° C. and 55-bromopyridin-3-amine (25.95 g, 150.0 mmol) added portion-wise. Reaction vessel resealed and mixture stirred at 100° C. for 3 hours. LC/MS shows completion. Reaction mixture was cooled to room temperature, diluted with hexane, filtered, and air dried to yield 5-((5-bromopyridin-3-ylamino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (41.5 g, 85% yield) as a yellow solid. MS [M+H]=327.0. Calc'd for C12H11BrN2O4=327.1. 2) 7-bromo-1,5-naphthyridin-4(1H)-one. A 500 mL round bottom flask equipped with a reflux condenser was charged with 5-((5-bromopyridin-3-ylamino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (10.5 g, 32.1 mmol) and diphenyl ether (84.5 mL, 32.1 mmol). This was heated to 250° C. in heating mantle and allowed to stay at this temperature for 1 hour. Reaction mixture was cooled to room temperature and diluted with 300 mL of Hexanes. This was heated to 60° C. and triturated in this system for 3 hrs to afford 7-bromo-1,5-naphthyridin-4(1H)-one (6.05 g, 84% yield) as a crude brown solid. This was used without further purification. MS[M+H]=227.0. Calc'd for C8H5BrN2O=225.0. 3) 3-bromo-8-chloro-1,5-naphthyridine. 7-bromo-1,5-naphthyridin-4(1H)-one (23.8 g, 105.8 mmol), acetonitrile (192 mL, 105.8 mmol), and DMF (2.05 mL, 26.5 mmol) were placed in a 3-necked round bottom flask set up with a reflux condenser. Argon bubbled through. Reaction mixture brought to reflux (˜95° C.). Oxalyl chloride (28.7 ml, 328.1 mmol) was added dropwise via addition funnel over 40 minutes and reaction allowed to stir at this temperature for 16 hrs. Reaction mixture cooled to 0° C. and basified to pH ˜8 with aqueous sodium bicarbonate solution. Product extracted with DCM (500 mL) three times. Organic layers combined, dried over sodium sulfate and concentrated to afford brown solid. This was purified by ISCO silica gel chromatography to afford 3-bromo-8-chloro-1,5-naphthyridine (3.6 g, 14% yield) as fluffy tan solid. MS[M+H]=245.0@. Calc'd for C8H4BrClN2=243.5.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:9]([CH3:11])[CH3:10])=[N:4][CH:5]=[N:6][C:7]=1Cl.Br[CH:13]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:14]([OH:16])=O.[CH2:25]([NH2:31])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>>[CH3:10][N:9]([CH3:11])[C:3]1[C:2]([NH:1][C:14](=[O:16])[CH:13]([NH:31][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:7]([NH:31][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[N:6]=[CH:5][N:4]=1
Reactant: CN(C)c1ncnc(Cl)c1N
Reactant: CCCCCCN
Reactant: CCCCCCCCC(Br)C(=O)O
Product: CCCCCCCCC(NCCCCCC)C(=O)Nc1c(NCCCCCC)ncnc1N(C)C

Procedure:
5-Amino-4-(dimethyl)amino-6-chloropyrimidine (prepared as described in Example 257) was coupled with 2-bromodecanoic acid using the procedure described in Example 249, followed by the addition of n-hexylamine as described in Example 250 to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:11]=[C:10]([CH:23]=O)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[Cl-:25].C[NH3+].[C:28]([BH3-])#[N:29].[Na+]>>[ClH:25].[CH3:28][NH:29][CH2:23][C:10]1[CH:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[N:12]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH:11]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(C=O)cc2-c2cccc(F)c2)cc1
Reactant: [BH3-]C#N
Reactant: [Cl-]
Agent: C[NH3+]
Agent: [Na+]
Product: CNCc1cc(-c2cccc(F)c2)n(S(=O)(=O)c2ccc(C)cc2)c1
Product: Cl
Yield: 68.6 %

Procedure:
Using 5-(3-fluorophenyl)-1-[(4-methylphenyl)sulfonyl]-1H-pyrrole-3-carbaldehyde (0.57 g), methylammonium chloride (1.38 g) and sodium cyanoborohydride (0.32 g), a procedure as in Example 4 was performed to give the title compound as white crystals (yield 0.45 g, 69%).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([C:12]2[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=2)[N:4]=1.C(N1C=CN=C1)([N:25]1[CH:29]=[CH:28]N=C1)=O.C(N)C>ClCCl.O1CCCC1>[CH2:29]([NH:25][C:16](=[O:17])[C:15]1[CH:19]=[CH:20][C:12]([N:5]2[C:6]3[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=3[C:3]([C:2]([F:1])([F:22])[F:21])=[N:4]2)=[CH:13][CH:14]=1)[CH3:28]
Reactant: O=C(O)c1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CCN
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCNC(=O)c1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1
Reaction time: 0.5 h
Yield: 74.1 %

Procedure:
A suspension of 4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzoic acid (310 mg, 1.0 mmol) in dichloromethane (5 ml) was treated with 1,1′-carbonyldiimidazole (162 mg, 1.0 mmol) at room temperature under argon. This mix was stirred for 30 minutes and then treated with a 2M solution of ethylamine in tetrahydrofuran (0.5 ml). The whole mix was stirred at room temperature for 2 hours. The reaction mixture was washed with saturated aqueous sodium bicarbonate. The organic layer was separated, dried over sodium sulphate and reduced to minimum volume by rotary evaporation to give a beige solid (250 mg) which was purified by column chromatography on a 5 g pre-packed silica column, eluting from 0-50% ethyl acetate in petroleum ether to give the title compound as a colourless solid (128 mg, 38%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.[OH:14][CH2:15][CH2:16][N:17]1[CH:21]=[C:20]([CH:22]=O)[CH:19]=[N:18]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[Cl:1][C:2]1[C:3]([N:8]2[CH2:9][CH2:10][N:11]([CH2:22][C:20]3[CH:19]=[N:18][N:17]([CH2:16][CH2:15][OH:14])[CH:21]=3)[CH2:12][CH2:13]2)=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: O=Cc1cnn(CCO)c1
Reactant: Clc1nccnc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: OCCn1cc(CN2CCN(c3nccnc3Cl)CC2)cn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 89.6 %

Procedure:
To a solution of 3′-chloro-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (0.789 g, 4.01 mmol) and 1-(2-hydroxy-ethyl)-1H-pyrazole-4-carbaldehyde (0.562 g, 4.01 mmol) in 1,2-dichloroethane (35 mL) add sodium triacetoxyborohydride (1.28 g, 6.02 mmol) and acetic acid (0.382 mL) and stir at room temperature for 20 hr. Add saturated aq. sodium bicarbonate, separate the layers, extract the aq. layer twice with DCM, dry (sodium sulfate), filter and concentrate. Purify using silica gel chromatography, eluting with 6:94 methanol (with 2 N ammonia): DCM to give 2-[4-(3′-chloro-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-ylmethyl)-pyrazol-1-yl]-ethanol as a yellow oil (1.16 g, 90%). MS (ES): m/z=323 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[C:9](=[O:20])[N:10]([CH3:19])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([CH3:18])[CH:12]=3)[CH:7]=1.[C:22](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:23]>C(Cl)Cl>[N:1]([C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[C:9](=[O:20])[N:10]([CH3:19])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([CH3:18])[CH:12]=3)[CH:7]=1)=[C:22]=[S:23]
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Reactant: Cc1cc2c(cn1)cc(-c1cc(N)ccc1C)c(=O)n2C
Solvent: ClCCl
Product: Cc1cc2c(cn1)cc(-c1cc(N=C=S)ccc1C)c(=O)n2C

Procedure:
To a solution of 3-(5-amino-2-methylphenyl)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one 15 (280 mg, 1 mmol) in DCM (5 mL) was added 1,1′-thiocarbonyldipyridin-2(1H)-one (233 mg, 1 mmol) at rt. The solvent was removed in vacuo after 1 h. The crude white solid of 3-(5-isothiocyanato-2-methylphenyl)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one 19 was used without further purification. 1H NMR (400 MHz, CDCl3) δ 8.64 (s, 1H), 7.18 (d, J=8.0 Hz, 1H), 7.09 (dd, J=2.4, 8.0 Hz, 1H), 7.05 (d, J=2 Hz, 1H), 7.04 (s, 1H), 3.66 (s, 3H), 2.64 (s, 3H), 2.16 (s, 3H). MS m/z 322.2 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]2[NH:8][N:9]=[CH:10][C:3]=12.O.[NH2:12][NH2:13].[CH2:14](O)C>>[NH:12]([C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH3:14])[N:9]=[CH:10][C:3]=12)[NH2:13]
Reactant: Clc1ncnc2[nH]ncc12
Reactant: NN
Reactant: CCO
Solvent: O
Product: Cn1ncc2c(NN)ncnc21

Procedure:
50 g. of 4-chloropyrazolo[3,4-d]pyrimidine are dissolved in 700 ml. of absoulute ethanol and 25 g. of hydrazine hydrate in 100 ml. of ethanol are slowly added dropwise with stirring. This is stirred for 13 hours at room temperature and the product formed is then filtered under suction, water is added and the product, 4-hydrazino-1-methylpyrazolo[3,4-d]pyrimidine, is crystallized from dimethylformamide as yellowish crystals, m.p. 231°.
Reaction SMILES: [CH3:1][CH:2]([NH:28][CH2:29][C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=1)[CH:3]([C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)[CH2:4][C:5]1[O:6][C:7]([C:10](=[O:18])[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:9]=1.C([O:43][CH:44]([C:60]([O-])=[O:61])[CH:45]([C:54]([O:56][CH:57]([CH3:59])[CH3:58])=[O:55])[CH2:46][CH2:47][C:48]([O:50][CH:51]([CH3:53])[CH3:52])=[O:49])(=O)C.CC(C)[O-].[Na+].O>C(O)(C)C>[OH:43][CH:44]([C:60](=[O:61])[N:28]([CH:2]([CH3:1])[CH:3]([C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)[CH2:4][C:5]1[O:6][C:7]([C:10](=[O:18])[NH:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:8][CH:9]=1)[CH2:29][C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=1)[CH:45]([C:54]([O:56][CH:57]([CH3:59])[CH3:58])=[O:55])[CH2:46][CH2:47][C:48]([O:50][CH:51]([CH3:53])[CH3:52])=[O:49]
Reactant: CC(NCc1ccc2ccccc2c1)C(Cc1ccc(C(=O)Nc2ccccc2)o1)c1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)OC(C(=O)[O-])C(CCC(=O)OC(C)C)C(=O)OC(C)C
Agent: CC(C)[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: CC(C)OC(=O)CCC(C(=O)OC(C)C)C(O)C(=O)N(Cc1ccc2ccccc2c1)C(C)C(Cc1ccc(C(=O)Nc2ccccc2)o1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
99 mg of isopropyl 5-acetoxy-4-isopropoxycarbonyl-5-[N-[(1RS,2RS)-1-methyl-2-(4-nitrophenyl)-3-{5-(phenylcarbamoyl)-2-furyl}propyl]-N-(2-naphthylmethyl)carbamoyl]pentanoate obtained by subjecting N-{(1RS,2RS)-1-methyl-2-(4-nitrophenyl)3-{5-(phenylcarbamoyl)-2-furyl}propyl]-2-naphthylmethylamine obtained in Example 23(1) and 2,4-diisopropyl 1-acetoxy-1,2,4-butanetricarboxylate obtained in Reference Example 5 to a condensation reaction in accordance with the method of Example 24(1), was dissolved in 3 ml of isopropanol, and 9.8 mg of sodium isopropoxide was added thereto, followed by stirring at room temperature for one hour. The reaction solution was poured into water and extracted with ethyl acetate. Then, the organic layer was dried over anhydrous magnesium sulfate. The drying agent was filtered off, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1) to obtain 43 mg (yield: 45%) of the above-identified compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:22])=[CH:4][C:5]([Cl:21])=[C:6]([C:8]2[C:9](=[O:20])[N:10]([CH3:19])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13](Cl)[CH:12]=3)[CH:7]=1.[CH3:23][O:24][C:25]1[CH:33]=[CH:32][C:28]([CH2:29][NH:30][CH3:31])=[CH:27][CH:26]=1>CCOCC>[CH3:23][O:24][C:25]1[CH:33]=[CH:32][C:28]([CH2:29][N:30]([CH3:31])[C:13]2[CH:12]=[C:11]3[C:16]([CH:17]=[C:8]([C:6]4[CH:7]=[C:2]([NH2:1])[C:3]([F:22])=[CH:4][C:5]=4[Cl:21])[C:9](=[O:20])[N:10]3[CH3:19])=[CH:15][N:14]=2)=[CH:27][CH:26]=1
Reactant: CNCc1ccc(OC)cc1
Reactant: Cn1c(=O)c(-c2cc(N)c(F)cc2Cl)cc2cnc(Cl)cc21
Solvent: CCOCC
Product: COc1ccc(CN(C)c2cc3c(cn2)cc(-c2cc(N)c(F)cc2Cl)c(=O)n3C)cc1
Temperature: 180 °C
Yield: 89 %

Procedure:
A mixture of 3-(5-amino-2-chloro-4-fluorophenyl)-7-chloro-1-methyl-1,6-naphthyridin-2(1H)-one (2.5 g, 7.4 mmol) and 4-methoxy-N-methylbenzylamine (4 mL) was heated to 180° C. under N2 for 3 h. After cooling, the reaction mixture was diluted with Et2O. The precipitate was filtered, washed with water, and dried to give 7-((4-methoxybenzyl)(methyl)amino)-3-(5-amino-2-chloro-4-fluorophenyl)-1-methyl-1,6-naphthyridin-2(1H)-one (3 g, 89% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.47 (s, 1H), 7.77 (s, 1H) 7.22 (m, 2H), 7.17 (d, J=8.0 Hz, 2H), 6.86 (d, J=8.4 Hz, 2H), 5.86 (d, J=9.6 Hz, 1H), 6.30 (s, 1H), 5.32 (s, 2H) 4.87 (s, 1H), 3.72 (s, 3H), 3.52 (s, 3H), 3.09 (s, 3H); MS (ESI) m/z: 453.2[M+H]+.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]([CH3:50])[C@H:19]([C:23]([NH:25][C@H:26]([C:30]([N:32]([C@@H:34]([C@@H:46]([CH3:49])[CH2:47][CH3:48])[C@H:35]([O:44][CH3:45])[CH2:36][C:37]([O:39]C(C)(C)C)=[O:38])[CH3:33])=[O:31])[CH:27]([CH3:29])[CH3:28])=[O:24])[CH:20]([CH3:22])[CH3:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>ClCCl.C1(C)C=CC=CC=1>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([N:18]([CH3:50])[C@H:19]([C:23]([NH:25][C@H:26]([C:30]([N:32]([C@@H:34]([C@@H:46]([CH3:49])[CH2:47][CH3:48])[C@H:35]([O:44][CH3:45])[CH2:36][C:37]([OH:39])=[O:38])[CH3:33])=[O:31])[CH:27]([CH3:29])[CH3:28])=[O:24])[CH:20]([CH3:22])[CH3:21])=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)OC(C)(C)C)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Reaction time: 6 h
Yield: 122 %

Procedure:
To #7 (32 g, 46 mmol, 1 eq.) in dichloromethane (160 mL, 0.29 M) was added drop-wise over 10 minutes trifluoroacetic acid (17.4 mL, 231 mmol, 5 eq.). After 6 hours, the same amount of trifluoroacetic acid was added and the reaction was continued for 18 hours. The reaction mixture was diluted with toluene (320 mL) and concentrated in vacuo to provide #8 (35.8 g, 97%) as a pinkish oil, which was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6), presumed to be a mixture of rotamers, characteristic signals: δ 7.90 (d, J=7.0 Hz, 2H), 7.62 (d, J=7.4 Hz, 2H), 7.41 (br dd, J=7.4, 7.0 Hz, 2H), 7.29-7.35 (m, 2H), 4.54-4.68 (br m, 1H), [4.09 (d, J=11 Hz) and 4.22 (d, J=10.9 Hz), total 1H], 3.74-3.84 (br m, 1H), 3.22 and 3.24 (2 br s, total 3H), 2.94 and 2.96 (2 br s, total 3H), 2.78 and 2.80 (2 br s, total 3H), 2.13-2.24 (m, 1H), 1.89-2.10 (br m, 2H), 1.70-1.81 (br m, 1H).
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:11].[CH3:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1)=[O:14].C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(P(C2C(OC3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=CC=3)=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[CH3:11][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[NH:21][C:18]1[CH:19]=[CH:20][C:15]([C:13](=[O:14])[CH3:12])=[CH:16][CH:17]=1
Reactant: Cc1cccc([N+](=O)[O-])c1Br
Reactant: CC(=O)c1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2Oc2ccccc2P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(Nc2c(C)cccc2[N+](=O)[O-])cc1
Yield: 84.7 %

Procedure:
In a flask under an argon atmosphere are consecutively placed 2.16 g of 2-bromo-3-nitrotoluene, 1.69 g of 4-aminoacetophenone (1.25 equivalents), 229 mg of dipalladium trisdibenzylideneacetone (0.025 equivalents), 269 mg of DPEPhos (0.05 equivalents) and 4.07 g of cesium carbonate (1.25 equivalents). The toluene is added at room temperature. The heterogeneous reaction medium is purged with argon and refluxed for hours. After returning to room temperature, water and ethyl acetate are added. After separation of the phases, the organic phase is washed with water and then with a saturated NaCl solution, dried on sodium sulphate, filtered and then dry evaporated. The obtained red oil is purified by chromatography on silica (ethyl acetate/cyclohexane:5/95 to 10/90) in order to provide 2.29 g of the expected compound as a red oil.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([F:29])=[C:8]([N:10]2[C:15]([CH3:16])=[CH:14][C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])=[C:12]([Cl:27])[C:11]2=[O:28])[CH:9]=1.[CH3:30][N:31](C)[C:32](Cl)=[O:33].[CH2:36](N(CC)CC)C.[NH4+].[Cl-]>O1CCCC1>[Cl:27][C:12]1[C:11](=[O:28])[N:10]([C:8]2[CH:9]=[C:4]([CH:5]=[CH:6][C:7]=2[F:29])[CH2:3][N:2]([CH3:36])[C:32]([NH:31][CH3:30])=[O:33])[C:15]([CH3:16])=[CH:14][C:13]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=1[F:26]
Reactant: CCN(CC)CC
Reactant: CN(C)C(=O)Cl
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Cl)c(=O)n1-c1cc(CN)ccc1F
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CNC(=O)N(C)Cc1ccc(F)c(-n2c(C)cc(OCc3ccc(F)cc3F)c(Cl)c2=O)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 91.2 %

Procedure:
A 10 mL round bottomed flask equipped with stirbar and nitrogen inlet was charged with 1-[5-(aminomethyl)-2-fluorophenyl]-3-chloro-4-[(2,4 difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one hydrochloride (250 mg, 0.56 mmol), dimethylcarbamyl chloride (52 μL, 0.56 mmol), triethylamine (195 μL, 1.4 mmol) and tetrahydrofuran (4.0 mL). After stirring at 25° C. for 5 min the reaction was completed by LC-MS. The reaction mixture was poured into a saturated aqueous NH4Cl solution. The aqueous mixture was extracted with ethyl acetate. The organic phase was dried with Na2SO4 and concentrated in vacuo to obtain the desired product (245 mg, 86%) as a white solid. 1H NMR (400 MHz, (CD3OD) δ 7.61 (q, J=7.9 and 6.7 Hz, 1H), 7.4 (m, 1H), 7.3 (d, J=9.3 Hz, 1H), 7.21 (m, 1H), 7.1 (m, 2H), 6.65 (s, 1H), 5.35 (s, 2H), 4.38 (s, 2H), 2.9 (s, 6H), 2.1 (s, 3H) ppm. ES-HRMS m/z 480.1269 (M+H calcd for C23H22ClF3N3O3 requires 480.1296).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([NH2:8])[CH:7]=1.[CH2:11]([O:13][C:14](=[O:19])[CH2:15][C:16](=O)[CH3:17])[CH3:12].C(O)(=O)C.[O-]S([O-])(=O)=O.[Ca+2]>C(O)C>[CH2:11]([O:13][C:14](=[O:19])[CH:15]=[C:16]([NH:8][C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[O:9][CH3:10])[CH3:17])[CH3:12]
Reactant: COc1ccc(F)cc1N
Reactant: CCOC(=O)CC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Ca+2]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C=C(C)Nc1cc(F)ccc1OC
Temperature: 25 °C

Procedure:
A suspension of 5-fluoro-2-methoxy-phenylamine (3.3 g, 23 mmol), 3-oxo-butyric acid ethyl ester (3.0 g, 23 mmol), acetic acid (120 μL), and Drierite® (12.0 g) in ethanol (20 mL) was heated to reflux for 5 d. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo and purified by flash chromatography on silica gel (elution with EA/hexane 1:3) to give crude 3-(5-fluoro-2-methoxy-phenylamino)-but-2-enoic acid ethyl ester.