Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[CH:12]=[CH:11]2)=[C:2]=[S:3].[CH:19]1([N:27](C)[CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][CH:33]([O:36][CH2:37][O:38][CH3:39])[CH2:32][CH2:31]2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.[CH:41](Cl)(Cl)Cl>>[CH3:39][O:38][CH2:37][O:36][CH:33]1[CH2:32][CH2:31][N:30]([CH2:29][CH2:28][N:27]([CH:4]([N:1]=[C:2]=[S:3])[CH2:5][CH2:6][O:7][C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[CH:12]=[CH:11]3)[CH2:19][CH:26]2[CH2:41][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)[CH2:35][CH2:34]1
Reactant: O=c1ccc2cc(OCCCN=C=S)ccc2[nH]1
Reactant: COCOC1CCN(CCN(C)C2CCCCCCC2)CC1
Reactant: ClC(Cl)Cl
Product: COCOC1CCN(CCN(CC2CCCCCCC2)C(CCOc2ccc3[nH]c(=O)ccc3c2)N=C=S)CC1

Procedure:
A solution of 0.22 g of 6-(3-isothiocyanato-propoxy)carbostyril and 0.3 g of 1-[2-(cyclooctyl-methylamino)ethyl]-4-methoxymethoxypiperidine in 30 ml of chloroform was stirred at room temperature for 5 hours. The solvent was removed by distillation under reduced pressure. The resulting residue was purified by a silica gel column chromatography (eluant: 3% methanol/dichloromethane) to obtain 0.36 g of 6-[3-{N-2-(4-methoxymethoxy-1-piperidinyl)ethyl-N-cyclooctylmethylamino}-thiocarbonylaminopropoxy]carbostyril.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=O)[CH2:3][CH2:4][C:5]([OH:7])=[O:6].C1(C)C(S(O)(=O)=O)=CC=CC=1.[CH2:22]([O:29][C:30](=[O:40])[C@H:31]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[NH2:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N1CCOCC1)C.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O.ClCCl>[CH2:22]([O:29][C:30](=[O:40])[C@H:31]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[NH:32][C:8](=[O:10])[C@H:2]([CH2:3][CH2:4][C:5](=[O:6])[OH:7])[NH2:1])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Reactant: N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N[C@@H](CCC(=O)O)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1

Procedure:
A solution of 0.52 g of pyro-L-glutamic acid, 1.72 g of L-phenylalanine benzyl ester toluenesulfonic acid and 0.55 mg of N-ethylmorpholine in 5 ml of dimethylformamide (DMF) and 20 ml of dichloromethane was cooled in an ice bath with stirring. A solution of 0.826 g of dicyclohexylcarbodiimide in 2 ml dichloromethane was added to the above reaction mixture. The reaction mixture was stirred in an ice water bath for 1 hour and then at room temperature overnight. Dicyclohexylurea was removed by filtration and the product was washed in ethyl acetate. Solvents of the combined filtrates were removed under reduced pressure with a rotary evaporator at 40° C. Ethyl acetate (25 ml) was added to the residue and the organic solution was washed until neutral. The organic phase was dried over anhydrous MgSO4, filtered and then the solvent was removed with a rotary evaporator. The material was crystalized from isopropanol and ether, yield: 1.01 g of white needles, m.p. 103°-104.5° C. The material was homogeneous on all TLC and electrophoresis systems.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[C:16]([F:20])[C:17](F)=[CH:18][C:11]=3[O:10][CH2:9]2)=[CH:5][CH:4]=1.[CH3:23][NH2:24].O>CS(C)=O>[CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[C:16]([F:20])[C:17]([NH:24][CH3:23])=[CH:18][C:11]=3[O:10][CH2:9]2)=[CH:5][CH:4]=1
Reactant: CN
Reactant: COc1ccc(CN2COc3cc(F)c(F)cc3C2=O)cc1
Solvent: CS(C)=O
Solvent: O
Product: CNc1cc2c(cc1F)C(=O)N(Cc1ccc(OC)cc1)CO2
Temperature: 120 °C
Yield: 85.4 %

Procedure:
To 3-(4-methoxybenzyl)6,7-difluor-2,3-dihydrobenzo[e][1,3]oxazin-4-one (1.15 g, 3.7 mmol) in dimethyl sulfoxide (10 mL) was added methyl amine (2.5 mL, 5 mmol, 2M solution in tetrahydrofuran) and the reaction heated to 120° C. for 1 hr. Water was added and product extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated to give 1 g (85%) of 3-(4-methoxybenzyl)6-fluoro-7-(methylamino)2,3-dihydrobenzo[e][1,3]oxazin-4-one. RP-HPLC: 2.82 min; ES-MS (M+H)+=318.0; 1H-NMR (DMSO-d6) δ (ppm): 7.6 (d, 1), 6.8 (d, 2), 6.4 (d, 1H), 5.0 (s, 2), 4.6 (s, 2), 3.7 (s, 3), 2.8 (s, 3).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C@:15]3([CH2:19][O:18][C:17]([NH2:20])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12](I)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.[N:22]1[CH:27]=[C:26](B(O)O)[CH:25]=[N:24][CH:23]=1.C1COCC1.C(=O)([O-])[O-].[K+].[K+]>O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C@:15]3([CH2:19][O:18][C:17]([NH2:20])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:26]4[CH:27]=[N:22][CH:23]=[N:24][CH:25]=4)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1
Reactant: OB(O)c1cncnc1
Reactant: NC1=N[C@@]2(CO1)c1cc(I)ccc1Oc1ncc(Br)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: NC1=N[C@@]2(CO1)c1cc(-c3cncnc3)ccc1Oc1ncc(Br)cc12
Temperature: 110 °C

Procedure:
A sealable tube was charged with (S)-3-bromo-7-iodo-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (2.000 g, 4.37 mmol), pd(ph3p)4 (0.504 g, 0.437 mmol), pyrimidin-5-ylboronic acid (0.568 g, 4.58 mmol) and THF (21.83 mL, 4.37 mmol). The mixture was flushed with Ar then a solution of potassium carbonate (1.5 M) (5.82 mL, 8.73 mmol) was added. The reaction was heated at 110° C. for 2 hours before being diluted with water 50 mL and poured into a separatory funnel containing ethyl acetate 50 mL. The layers were separated and the aqueous layer was extracted with ethyl acetate 3×100 mL. The aqeuous layer was then extracted with DCM (3×100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to provide a brown oil that was purified by silica gel chromatography (Redi-Sep pre-packed silica gel column (80 g), 0-10% methanol in methylenechloride with 0.1% ammonium hydroxide) to provide (S)-3-bromo-7-(pyrimidin-5-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine as a light yellow foam.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[S:11][S:12][C:13]([C:16]2[C:25]([O:26][Si](C(C)(C)C)(C)C)=[N:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][C:22]=3[O:34][CH3:35])[N:17]=2)=[CH:14][CH:15]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.C(O)(=O)C>[OH:8][CH2:9][C:10]1[S:11][S:12][C:13]([C:16]2[C:25]([OH:26])=[N:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][C:22]=3[O:34][CH3:35])[N:17]=2)=[CH:14][CH:15]=1
Reactant: COc1cccc2nc(C3=CC=C(CO[Si](C)(C)C(C)(C)C)SS3)c(O[Si](C)(C)C(C)(C)C)nc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1cccc2nc(C3=CC=C(CO)SS3)c(O)nc12
Reaction time: 3 h
Yield: 51.7 %

Procedure:
To a stirred solution of the 3-[(tert-butyldimethylsilyloxy)methyl]-6-[methyloxy[3-(tert-butyldimethylsilyloxy)quinoxalin-2-yl]]-1,2-dithiin obtained above (50 mg, 0.09 mmol) in 1 mL of THF was added a mixture of 1.2 mL of 1M tetrabutylammonium fluoride in THF and 0.7 mL of acetic acid. The reation mixture was stirred for 3 h until TLC analysis showed the reaction to be complete, and then concentrated in vacuo. The residue was partitioned between 20 mL of water and 30 mL of ethyl acetate. The organic phase was washed with dilute aqueous sodium bicarbonate, water, dried over sodium sulfate, and then evaporated to a small volume. The residue was purified by flash chromatography (ethyl acetate-hexane, 1:1) to yield 15 mg (51.7%) of the title compound. Further purification was accomplished by reverse phase HPLC (acetonitrile:water 1:1, PRP-1 column); 1H-NMR (CD3OD) 5.68 (d, J=8.0, 1 H), 7.47 (m, 2 H), 7.37 (m, 1 H), 6.66 (d, J=5.6, 1 H), 6.42 (d, J=6.0, 1 H), 5.16 (s, 2 H), 4.17 (s, 2 H); MS (EI) 319.1 (M+).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([CH:16]([NH2:24])[C:17]2[C:22]([Cl:23])=[N:21][CH:20]=[CH:19][N:18]=2)[CH:13]=[CH:14][CH:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.[CH3:34][S:35][C:36](=[O:38])Cl>ClCCl.CCOC(C)=O>[CH3:34][S:35][C:36](=[O:38])[NH:24][CH:16]([C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([O:9][CH2:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:11]=1)[C:17]1[C:22]([Cl:23])=[N:21][CH:20]=[CH:19][N:18]=1
Reactant: CSC(=O)Cl
Reactant: NC(c1cccc(OCc2ccccc2)c1)c1nccnc1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CSC(=O)NC(c1cccc(OCc2ccccc2)c1)c1nccnc1Cl
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a suspension of C-(3-benzyloxy-phenyl)-C-(3-chloro-pyrazin-2-yl)-methylamine hydrochloride salt (3.10 g, 0.00856 mol) in dichloromethane (30 mL) were added N,N-diisopropylethylamine (2.98 mL, 0.0171 mol) and carbonochloridothioic acid S-methyl ester (946 mg, 0.00856 mol) at 0° C. After 5 min, the mixture was warmed to rt and stirred overnight. The mixture was diluted with EtOAc (100 mL), washed with water (20 mL), sat. aq. NaHCO3 (2×30 mL), brine (30 mL), and dried over anhydrous sodium sulfate. The crude product was purified by silical gel chromatogrphy (Hex: EtOAc=70:30→60:40) to give the title compound as a white solid; 1H NMR (CDCl3, 400 MHz) δ 2.34 (s, 3H), 5.03 (s, 2H), 6.53 (d, J=6.8 Hz, 1H), 6.87-6.97 (m, 3H), 7.08 (d, J=7.7 Hz, 1H), 7.22 (d, J=7.7 Hz, 1H), 7.30-7.41 (m, 5H), 8.33 (d, J=2.4 Hz, 1H), 8.51 (d, J=2.4 Hz, 1H).
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[Cl:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[C:11]([O:18][CH2:19][CH:20]([F:22])[F:21])[N:10]=1>CO.C(Cl)Cl>[CH3:1][O:14][C:13](=[O:15])[C:12]1[CH:16]=[CH:17][C:9]([Cl:8])=[N:10][C:11]=1[O:18][CH2:19][CH:20]([F:21])[F:22]
Reactant: O=C(O)c1ccc(Cl)nc1OCC(F)F
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1ccc(Cl)nc1OCC(F)F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Trimethylsilyl diazomethane (2 M in hexane; 15.0 mL, 30.0 mmol) is added to a mixture of 6-chloro-2-(2,2-difluoro-ethoxy)-nicotinic acid (6.0 g, 25.3 mmol) in MeOH (50 mL) and DCM (100 mL). The reaction mixture is stirred at rt for 10 min, quenched with AcOH and concentrated. The residue is diluted with water and filtered. The filtercake is washed with water and dried at 40° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[S:13][C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1)[CH2:9][C:10]#[CH:11]>>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:11]#[C:10][CH2:9][CH2:8][C:12]1[S:13][C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1
Reactant: Brc1ccccn1
Reactant: C#CCCc1nc2ccccc2s1
Product: C(#Cc1ccccn1)CCc1nc2ccccc2s1
Yield: 45 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (127 mg, 0.80 mmol) and 2-(but-3-ynyl)benzo[d]thiazole (150 mg, 0.80 mmol). Reaction time: 1 day. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 96 mg (0.36 mmol, 45%) of 2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]thiazole as an orange solid (M.P.=98.5-99.4° C.).
Reaction SMILES: [OH-].[Na+].[CH:3]([NH:6][C:7]1[N:12]=[CH:11][C:10]([C:13]([O:15]C)=[O:14])=[CH:9][N:8]=1)([CH3:5])[CH3:4].O>CO>[CH:3]([NH:6][C:7]1[N:8]=[CH:9][C:10]([C:13]([OH:15])=[O:14])=[CH:11][N:12]=1)([CH3:5])[CH3:4]
Reactant: COC(=O)c1cnc(NC(C)C)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)Nc1ncc(C(=O)O)cn1
Temperature: 66 °C
Yield: 91.6 %

Procedure:
6 ml of a 1N solution of sodium hydroxide are added to a solution of 2-isopropylamino-5-methoxycarbonylpyrimidine (1 g; 5.12 mmol) in 33 ml of methanol. The mixture is refluxed (66° C.) for two hours. A minimum of water is added in order to dissolve the precipitate which forms; the methanol is evaporated under reduced pressure. The remaining solution is acidified at 0° C. with 2N hydrochloric acid. The precipitate obtained is filtered, washed with water and then dried to give 850 mg (92%) of acid.
Reaction SMILES: [C:1]([CH:3]([CH:7]1[C:11]([Cl:12])=[C:10](Cl)C(=O)O1)[C:4]([NH2:6])=[O:5])#[N:2].[NH2:15][CH2:16][C:17]1[CH:18]=[C:19]([S:23]([NH:26][CH3:27])(=[O:25])=[O:24])[CH:20]=[CH:21][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[ClH:12].[Cl:12][C:11]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1](=[NH:2])[N:15]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([S:23](=[O:25])(=[O:24])[NH:26][CH3:27])[CH:18]=2)[CH:10]=1
Reactant: CNS(=O)(=O)c1cccc(CN)c1
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CNS(=O)(=O)c1cccc(Cn2cc(Cl)cc(C(N)=O)c2=N)c1
Product: Cl
Temperature: 70 °C
Reaction time: 8 h
Yield: 32.6 %

Procedure:
(Step 2) To a suspension of 2-cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide (0.28 g) and 3-(aminomethyl)-N-methylbenzenesulfonamide obtained in Step 1 (0.36 g) in ethanol (10 ml) was added potassium carbonate (0.25 g) at room temperature, and the mixture was stirred overnight at 70° C. The reaction solution was filtered through celite. The solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=7:3→1:0). 4N Hydrochloride-ethyl acetate solution (1 ml) was added to the obtained yellow oil, and the precipitated crystals were collected by filtration, and recrystallized to give the title compound (76 mg).
Reaction SMILES: Cl.[C:2]1([CH2:12][C:13]([NH2:15])=[NH:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.O.[NH2:17]N.[C:19]([NH:22][CH:23]([CH3:31])[C:24](=O)[C:25](OCC)=[O:26])(=[O:21])[CH3:20]>>[C:2]1([CH2:12][C:13]2[NH:15][C:25](=[O:26])[C:24]([CH:23]([NH:22][C:19](=[O:21])[CH3:20])[CH3:31])=[N:17][N:14]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=O)C(C)NC(C)=O
Reactant: N=C(N)Cc1cccc2ccccc12
Reactant: NN
Agent: Cl
Solvent: O
Product: CC(=O)NC(C)c1nnc(Cc2cccc3ccccc23)[nH]c1=O

Procedure:
Analogously to Example 10A, 1.67 g (8.00 mmol) of 2-(1-naphthyl)ethanamidine hydrochloride are reacted with 401 mg (8.00 mmol) of hydrazine hydrate and 2.70 g (14.4 mmol) of ethyl 3-(acetylamino)-2-oxobutanoate to give N-{1-[3-(1-naphthylmethyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]ethyl}acetamide.
Reaction SMILES: C1(C)C=CC=CC=1.Br[C:9]1[CH:21]=[CH:20][C:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[C:11]([N+:22]([O-:24])=[O:23])[CH:10]=1.[Cl:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C(O)C>[Cl:25][C:26]1[CH:31]=[C:30]([C:9]2[CH:21]=[CH:20][C:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[C:11]([N+:22]([O-:24])=[O:23])[CH:10]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1[N+](=O)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(-c2cccc(Cl)c2)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 31.7 %

Procedure:
To 20 mL of toluene solution containing 2.0 g of tert-butyl 4-bromo-2-nitrobenzoate, 6.0 mL of ethanol, 3.0 mL of water, 1.2 g of 3-chlorophenylboronic acid, 1.7 g of sodium carbonate and 0.23 g of tetrakis(triphenylphosphine)palladium (0) were added sequentially, and the resulting mixture was heated to reflux under nitrogen atmosphere for 3 hours. Water was added after the reaction mixture was cooled to room temperature. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with a saturated sodium chloride aqueous solution, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [PSQ100B (spherical) manufactured by Fuji Silysia Chemical Ltd., eluent; hexane:ethyl acetate=10:1] to obtain 0.70 g of tert-butyl 4-(3-chlorophenyl)-2-nitrobenzoate as white solid.
Reaction SMILES: Br[C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:23])[C:8]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:9]=4[C:10]([CH3:16])([CH3:15])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.COC1C=C2C(CCC(=O)C2(C)C)=CC=1.Cl.[Cl:40]C1C=C(NN)C=CC=1>>[Cl:40][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:23])[C:8]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:9]=4[C:10]([CH3:16])([CH3:15])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)C(C)(C)c1[nH]c3cc(Br)ccc3c1C2=O
Reactant: NNc1cccc(Cl)c1
Agent: COc1ccc2c(c1)C(C)(C)C(=O)CC2
Agent: Cl
Product: COc1ccc2c(c1)C(C)(C)c1[nH]c3cc(Cl)ccc3c1C2=O

Procedure:
Under the same conditions as the method for synthesizing Compound A3-1 and Compound A4, the title compound was prepared as a crude product from Compound A2 and (3-chlorophenyl)-hydrazine hydrochloric acid salt.
Reaction SMILES: [Li]CCCC.[F:6][C:7]1[CH:8]=[C:9]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH:10]=[C:11]([F:13])[CH:12]=1.[C:23](=[O:25])=[O:24]>C1COCC1>[F:6][C:7]1[CH:8]=[C:9]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH:10]=[C:11]([F:13])[C:12]=1[C:23]([OH:25])=[O:24]
Reactant: Fc1ccc(COc2cc(F)cc(F)c2)cc1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)c1c(F)cc(OCc2ccc(F)cc2)cc1F
Temperature: 25 °C
Yield: 59 %

Procedure:
BuLi (1.6 M in hexane, 27.1 mL, 43.4 mmol) was added to a solution of 3,5-difluoro-(4-fluoro-benzyloxy)-benzene (10.5 g, 41.4 mmol) in dry THF at −78° C., under Argon, and the reaction mixture maintained at this temperature for 1 h whereupon carbon dioxide gas was bubbled into the solution over a 10 min period. The reaction mixture was then warmed up to room temperature and water added. The resulting mixture was extracted with diethyl ether. The aqueous phase was adjusted to pH 2 with HCl and extracted with ethyl acetate. The combined ethyl acetate layers were washed with HCl (0.1 N), then dried over sodium sulfate, filtered and evaporated to leave a white solid. This was triturated with pentane-diethyl ether to afford the title compound (6.8 g, 59%) as a white solid. MS: m/e=280.9 (M−H−).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[CH:10]=[C:11]([N:15]2[C:20]3[N:21]=[C:22]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([N:32]5[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]5)=[CH:28][C:27]=4[O:39][CH3:40])[N:23]=[CH:24][C:19]=3[CH:18]=[CH:17][C:16]2=[O:41])[CH:12]=[CH:13][CH:14]=1.CCN(C(C)C)C(C)C.[Cl:51][CH2:52][CH2:53][C:54](Cl)=[O:55]>C(Cl)Cl>[Cl:51][CH2:52][CH2:53][C:54]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N:15]2[C:20]3[N:21]=[C:22]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([N:32]5[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]5)=[CH:28][C:27]=4[O:39][CH3:40])[N:23]=[CH:24][C:19]=3[CH:18]=[CH:17][C:16]2=[O:41])[CH:10]=1)=[O:55]
Reactant: COc1cc(N2CCN(C)CC2)ccc1Nc1ncc2ccc(=O)n(-c3cccc(N)c3)c2n1
Reactant: O=C(Cl)CCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(N2CCN(C)CC2)ccc1Nc1ncc2ccc(=O)n(-c3cccc(NC(=O)CCCl)c3)c2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 22.7 %

Procedure:
8-(3-Aminophenyl)-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one (1b; 200 mg, 0.44 mmol) in DCM (5 mL) at 0° C. was treated with DIEA (0.19 mL, 1.09 mmol) and cooled in an ice bath at 0° C. The solution was then treated with 3-chloropropionyl chloride (Sigma Aldrich, St. Louis, Mo.; 0.042 mL, 0.44 mmol) dropwise over 10 min and stirred at 0° C. for 30 min then stirred at RT for 2 h. 3 more drops of 3-chloropropionyl chloride was added and the reaction stirred at RT overnight. The reaction mixture was then concentrated, treated with DMSO (8 mL) and purified on a Gilson preparatory HPLC (Gemini Phenomenex; 30×150 mm, 5μ, 10-95% 0.1% TFA/CH3CN in 0.1% TFA/water). The product containing fractions were concentrated under reduced pressure (rotary evaporator) and the resulting aqueous solution treated with a 10% solution of Na2CO3 and extracted with DCM (4×30 mL), dried over Na2SO4 and concentrated under vacuum overnight affording 3-chloro-N-(3-(2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)propanamide (57 mg, 0.10 mmol, 23% yield) as a yellow solid. m/z (ESI, +ve ion) 548.0 (M+H)+ in about 65% purity with the mass balance corresponding to the acrylamide. The material was used in the subsequent step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[C:5]([N:7]1[CH2:11][CH2:10][C:9]([C:12]2[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=2)[C:15]#N)=[N:8]1)=[O:6].CCOC(C)=O>CCO.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([C:5]([N:7]2[CH2:11][CH2:10][C:9]([C:12]3[CH:13]=[C:14]([CH3:15])[CH:17]=[CH:18][CH:19]=3)=[N:8]2)=[O:6])[CH:20]=[CH:21][CH:22]=1
Reactant: N#Cc1cccc(C2=NN(C(=O)c3cccc(F)c3)CC2)c1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cccc(C2=NN(C(=O)c3cccc(F)c3)CC2)c1
Yield: 35 %

Procedure:
3-[1-(3-Fluoro-benzoyl)-4,5-dihydro-1H-pyrazol-3-yl]-benzonitrile (88 mg, 0.30 mmol), dissolved in EtOH (10 mL) and EtOAc (10 mL) was passed through the H-cube equipped with a 10% Pd/C cartridge. Temperature 80° C., 50 bar, flow rate, 1 mL/min. LC-MS showed consumption of SM. The solvent was evaporated under pressure and the material was purified by chromatography using a 12 g silica cartridge eluting with heptane-EtOAc, gradient 0 to 50% EtOAc. Amount obtained: 30 mg, 0.11 mmol, 35% yield. LC-MS (ESI) m/e 283 (M+H). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.40 (s, 3H) 3.26-3.33 (m, 2 H) 4.27 (t, J=9.96 Hz, 2 H) 7.17-7.26 (m, 2 H) 7.32 (t, J=7.81 Hz, 1H) 7.43 (td, J=7.98, 5.81 Hz, 1H) 7.49-7.54 (m, 2 H) 7.73-7.84 (m, 2 H).
Reaction SMILES: Cl.[CH:2]1([C:8]2[CH:13]=[CH:12][N:11]([CH2:14][CH2:15][C:16]([CH3:31])([S:27]([CH3:30])(=[O:29])=[O:28])[C:17]([NH:19][O:20]C3CCCCO3)=[O:18])[C:10](=[O:32])[CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.CO>O1CCOCC1.ClCCl>[CH:2]1([C:8]2[CH:13]=[CH:12][N:11]([CH2:14][CH2:15][C:16]([CH3:31])([S:27]([CH3:30])(=[O:29])=[O:28])[C:17]([NH:19][OH:20])=[O:18])[C:10](=[O:32])[CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CC(CCn1ccc(C2CCCCC2)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: C1COCCO1
Product: CC(CCn1ccc(C2CCCCC2)cc1=O)(C(=O)NO)S(C)(=O)=O
Yield: 202.4 %

Procedure:
A 4.0 M solution of HCl in 1,4-dioxane (3.3 mL) was added slowly to a solution of the 4-(4-cyclohexyl-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (220 mg, 0.14 mmol) in dichloromethane (5 mL) followed by methanol (1 mL) at room temperature. The reaction was concentrated in vacuo and the title compound was purified using reverse phase chromatography (Gradient used with formic acid modifier(0.05%), 95:5 water:acetonitrile to 5:95 water:acetonitrile). Gradient time 6 minutes. Furnished a white solid (105 mg, 58.6%) MS (LC/MS) m/z 371.6 (M+1)