Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:6](=[CH:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)[S:5][C:4]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[N:3]1.[NH2:27][CH2:28][C@@H:29]([C:31]1[CH:32]=[CH:33][C:34]([OH:42])=[C:35]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH:36]=1)[OH:30]>>[OH:42][C:34]1[CH:33]=[CH:32][C:31]([C@@H:29]([OH:30])[CH2:28][NH:27][CH:17]2[CH2:18][CH2:19][N:14]([C:11]3[CH:10]=[CH:9][C:8]([CH:7]=[C:6]4[S:5][C:4]([N:21]5[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]5)=[N:3][C:2]4=[O:1])=[CH:13][CH:12]=3)[CH2:15][CH2:16]2)=[CH:36][C:35]=1[NH:37][S:38]([CH3:41])(=[O:40])=[O:39]
Reactant: O=C1CCN(c2ccc(C=C3SC(N4CCCCC4)=NC3=O)cc2)CC1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNC2CCN(c3ccc(C=C4SC(N5CCCCC5)=NC4=O)cc3)CC2)ccc1O

Procedure:
The title compound was prepared from 1-[4-(4-oxo-2-piperidin-1-yl-4H-thiazol-5-ylidenemethyl)-phenyl]-piperidin-4-one (which was obtained in Intermediate 25) and N-[5-(2-amino-(1R)-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Intermediate 10) according to the procedure of Example 1 as a pale yellowish solid; mp>120° C. (dec.); 1H NMR (300 MHz, DMSO-d6) δ 1.20-1.40 (m, 2 H), 1.55-1.75 (m, 6 H), 1.80-2.00 (m, 2 H), 2.60-3.00 (m, 5H), 2.92 (s, 3 H), 3.50-3.90 (m, 6 H), 4.49 (dd, J=8.0, 4.2 Hz, 1 H), 6.82 (d, J=8.5 Hz, 1 H), 6.95-7.07 (m, 3 H), 7.18 (d, J=2.0 Hz, 1 H), 7.45 (d, J=8.9 Hz, 2 H),7.50 (s, 1 H); MS (ES) m/z: 300.6 ((M+2 H)2+, 100%), 600.1 (MH+, 50%); HRMS Calcd. for C29H37N5O5S2 (MH+): 600.2314. Found: 600.2330.
Reaction SMILES: Cl.[OH:2][CH:3]([CH2:17][CH2:18][CH3:19])[CH2:4][NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([NH2:16])(=[O:15])=[O:14])=[CH:9][CH:8]=1.[C:20]([C:28]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:29]=1[C:30](O)=[O:31])(=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[Cl:37][C:35]1[CH:36]=[C:28]2[C:29](=[CH:33][CH:34]=1)[C:30](=[O:31])[N:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([S:13]([NH2:16])(=[O:14])=[O:15])=[CH:11][CH:12]=1)[C:4]([C:3](=[O:2])[CH2:17][CH2:18][CH3:19])=[C:20]2[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(O)c1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: CCCC(O)CNCc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Product: CCCC(=O)c1c(-c2ccccc2)c2cc(Cl)ccc2c(=O)n1Cc1ccc(S(N)(=O)=O)cc1

Procedure:
In the same manner as in Example 452, Step 2, the title compound was synthesized from 4-[(2-hydroxypentylamino)methyl]benzenesulfonamide hydrochloride and 2-benzoyl-4-chlorobenzoic acid.
Reaction SMILES: C(C1N(C)C=C(C=O)C=1)#N.NCC1N(C)C(C#N)=CC=1.[N:21]([CH2:24][C:25]1[CH:26]=[C:27]([C:31]#[N:32])[N:28]([CH3:30])[CH:29]=1)=[N+]=[N-]>>[NH2:21][CH2:24][C:25]1[CH:26]=[C:27]([C:31]#[N:32])[N:28]([CH3:30])[CH:29]=1
Reactant: Cn1cc(CN=[N+]=[N-])cc1C#N
Agent: Cn1c(C#N)ccc1CN
Agent: Cn1cc(C=O)cc1C#N
Product: Cn1cc(CN)cc1C#N

Procedure:
Starting from 5-Cyano-1-methylpyrrole-3-carbaldehyde; 4-aminomethyl-1-methylpyrrole-2-carbonitrile was synthesized analogously to the synthesis of 5-aminomethyl-1-methylpyrrole-2-carbonitrile. However, the 4-azidomethyl-1-methylpyrrole-2-carbonitrile was advantageously reduced in a Staudinger reaction (see S. Nagarajan et al. J. Org. Chem. 1987, 52, 5044-6).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I:19]N1C(=O)CCC1=O>CN(C)C=O>[C:1]1([C:7]2[C:12]([I:19])=[CH:11][CH:10]=[C:9]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCC(=O)N1I
Reactant: c1ccc(-c2cccc(N3CCOCC3)n2)cc1
Solvent: CN(C)C=O
Product: Ic1ccc(N2CCOCC2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.2 %

Procedure:
A solution of 750 mg of 2-phenyl-6-morpholinopyridine and 5 ml of N,N-dimethylformamide was stirred in an ice bath, and to the mixture was added 740 mg of N-iodosuccinimide, followed by stirring at room temperature overnight. Further, 70 mg of N-iodosuccinimide was added thereto, followed by stirring at room temperature for 5 hours. The reaction mixture was extracted by adding ethyl acetate, water and sodium sulfite thereto, and the organic phase was washed with water and brine, dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography using 5-10% ethyl acetate/hexane, to give 1.1 g of the target compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][O:10][C:9]1([CH3:22])[CH3:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].CO[C:25]([CH3:27])=[CH2:26].FC(F)(F)C(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][N:14]([CH:25]([CH3:27])[CH3:26])[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:11][O:10][C:9]1([CH3:22])[CH3:21])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=C(C)OC
Reactant: CC(C)(C)OC(=O)N1[C@@H](CNc2ccccc2)COC1(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)N(C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C)c1ccccc1
Temperature: 40 °C
Yield: 89 %

Procedure:
To a stirred solution of (S)-2,2-dimethyl-4-phenylaminomethyl-oxazolidine-3-carboxylic acid tert-butyl ester (650 mg) at r.t. in 1,2-dichloroethane (15 ml) under an argon atmosphere were added 2-methoxypropene (0.30 ml), trifluoroacetic acid (0.16 ml) and sodium triacetoxyborohydride (674 mg). The mixture was heated to 40° C. overnight. The mixture was cooled to r.t., directly adsorbed on silica gel and purified by chromatography (SiO2; gradient:cyclohexane->cyclohexane/EtOAc 7:3) to give (S)-4-[(isopropyl-phenyl-amino)-methyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (659 mg, 89%) as light yellow viscous oil. MS (ISP): 349.5 ([M+H]+)
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([CH3:12])[C:9]([F:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:14][O-:15].[Na+].O>C1COCC1>[F:13][C:9]1[C:10]([CH3:12])=[N:11][C:2]([O:15][CH3:14])=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: C[O-]
Reactant: COC(=O)c1cc(F)c(C)nc1Cl
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cc(F)c(C)nc1OC
Temperature: 60 °C
Reaction time: 6 h
Yield: 32 %

Procedure:
To a stirred solution of methyl 2-chloro-5-fluoro-6-methylnicotinate (18) (0.8 g, 3.92 mmol,) in THF (35 mL) was added sodium methanolate (0.42 g, 7.85 mmol) at 0° C. The mixture was stirred at 60° C. for 6 hours and cooled to room temperature. Then the mixture was poured into water and extracted with dichloromethane (2×50 mL). The combined organic layer was washed with water, brine and solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 10% ethyl acetate in hexane to give methyl 5-fluoro-2-methoxy-6-methylnicotinate (19) (250 mg, 32%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:11]2[CH2:16][CH2:15][C@:14]([CH2:23][CH3:24])([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:13][C:12]2=[O:25])[CH2:9][CH3:10])=[CH:4][CH:3]=1.Br[C:27]1[CH:28]=[CH:29][C:30](=[O:35])[N:31]([CH2:33][CH3:34])[CH:32]=1>>[CH2:23]([C@@:14]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:13][C:12](=[O:25])[N:11]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:27]3[CH:28]=[CH:29][C:30](=[O:35])[N:31]([CH2:33][CH3:34])[CH:32]=3)=[CH:3][CH:4]=2)[CH2:9][CH3:10])[CH2:16][CH2:15]1)[CH3:24]
Reactant: CC[C@@H](c1ccc(Br)cc1)N1CC[C@](CC)(c2ccccc2)OC1=O
Reactant: CCn1cc(Br)ccc1=O
Product: CC[C@@H](c1ccc(-c2ccc(=O)n(CC)c2)cc1)N1CC[C@](CC)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (R)-3-((S)-1-(4-bromophenyl)propyl)-6-ethyl-6-phenyl-1,3-oxazinan-2-one following procedures analogous to those described in Example 32 Method 2 Steps 3 and 4 using 5-bromo-1-ethylpyridin-2(1H)-one in Step 4. LC-MS Method 1 tR=1.68 min, m/z=445 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH:8]2[CH2:10][CH2:9]2)[N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)[N:3]=1.[NH2:18][C:19]1[CH:27]=[CH:26][C:22]([CH2:23][CH2:24][OH:25])=[CH:21][CH:20]=1>CN1C(=O)CCC1.O>[Cl:17][C:13]1[CH:12]=[C:11]([C:4]2[N:3]=[C:2]([NH:18][C:19]3[CH:27]=[CH:26][C:22]([CH2:23][CH2:24][OH:25])=[CH:21][CH:20]=3)[CH:7]=[C:6]([CH:8]3[CH2:10][CH2:9]3)[N:5]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ccc(CCO)cc1
Reactant: Clc1cccc(-c2nc(Cl)cc(C3CC3)n2)c1
Solvent: CN1CCCC1=O
Solvent: O
Product: OCCc1ccc(Nc2cc(C3CC3)nc(-c3cccc(Cl)c3)n2)cc1
Temperature: 120 °C
Yield: 72.6 %

Procedure:
A 10-mL microwave vial was charged with 4-chloro-2-(3-chlorophenyl)-6-cyclopropylpyrimidine (0.100 g, 0.38 mmol) and 4-aminophenethyl alcohol (0.103 g, 0.75 mmol) in NMP (3 mL). The resulting mixture was heated at 120° C. under microwave irradiation for 1 h. The reaction mixture was cooled, diluted with water (20 mL) affording a solid. The solid was isolated by filtration and purified by chromatography on silica using hexanes/ethyl acetate (10:0 to 1:1) as eluent to afford the title compound (0.101 g, 73%) as a white solid. MW=365.86. M.p. 124-126° C. 1H NMR (DMSO-d6, 500 MHz) δ 9.46 (s, 1H), 8.27-8.21 (m, 2H), 7.62-7.51 (m, 4H), 7.21 (d, J=8.5 Hz, 2H), 6.62 (s, 1H), 4.61 (br s, 1H), 3.60 (t, J=7.0 Hz, 2H), 2.70 (t, J=7.0 Hz, 2H), 2.06-1.99 (m, 1H), 1.11-1.06 (m, 2H), 1.02-0.95 (m, 2H); ESI MS m/z 366 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([NH2:25])=[C:21]([CH2:26][S:27]([C:30]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH:33]=[CH:32][CH:31]=3)(=[O:29])=[O:28])[CH:20]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:40]([O-])=O.[Na+].C(=O)(O)[O-].[Na+]>C1COCC1.Cl.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([CH2:17][O:18][C:19]2[CH:20]=[C:21]3[C:22](=[CH:23][CH:24]=2)[NH:25][N:40]=[C:26]3[S:27]([C:30]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:33]=[CH:32][CH:31]=2)(=[O:29])=[O:28])[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=N[O-]
Reactant: Nc1ccc(OCC2CCN(C(=O)OCc3ccccc3)CC2)cc1CS(=O)(=O)c1cccc2ccccc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(OCc1ccccc1)N1CCC(COc2ccc3[nH]nc(S(=O)(=O)c4cccc5ccccc45)c3c2)CC1

Procedure:
A mixture of 4-[4-amino-3-(1-naphthylsulfonylmethyl)phenoxymethyl]-piperidine-1-carboxylic acid benzyl ester (0.74 g, 1.36 mmoles) in THF and 4M HCl (10 mL), under nitrogen, at 3° C. was treated dropwise with a solution of sodium nitrite (0.09 g, 1.42 mmoles) in H2O, poured into a cold solution of saturated sodium bicarbonate and extracted with EtOAc. The extracts were combined, dried over Na2SO4 and concentrated under vacuum to afford the title compound as an off white solid (0.71 g, 1.29 mmoles).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.[C:7]1(=O)[O:12][C:10](=[O:11])[C:9]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:8]12.O>CN(C)C=O>[NH:4]1[CH:5]=[CH:6][C:2]([N:1]2[C:10](=[O:11])[C:9]3[C:8](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:7]2=[O:12])=[N:3]1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Nc1cc[nH]n1
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1c1cc[nH]n1
Temperature: 125 °C
Reaction time: 24 h
Yield: 72.9 %

Procedure:
To a stirred mixture of 3-aminopyrazole (5.00 g, 60.2 mmol) dissolved in N,N-dimethylformamide (75 mL) was added phthalic anhydride (8.91 g, 60.2 mmol). After addition was complete, the mixture was stirred at 125° C. for 24 h. Upon cooling to 25° C., water (100 mL) was added, which resulted in precipitation. The white suspension was cooled (−5° C.) and stirred for 30 min. Subsequent filtration, washing with water, and suction drying afforded 2-(1H-pyrazol-3-yl)-isoindole-1,3-dione (9.36 g, 73.0%) as a white solid: LR-ES-MS m/z calculated for C11H7N3O2 [M]+ 213, observed [M+H]+ 214.
Reaction SMILES: [ClH:1].[CH3:2][NH:3][C:4]([NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[NH:15][CH:14]=[N:13][C:12]=1[CH3:16])=[S:5].[CH3:17]O>>[ClH:1].[ClH:1].[CH3:2][NH:3][C:4](=[N:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[NH:15][CH:14]=[N:13][C:12]=1[CH3:16])[S:5][CH3:17]
Reactant: CNC(=S)NCCSCc1[nH]cnc1C
Reactant: CO
Agent: Cl
Product: CNC(=NCCSCc1[nH]cnc1C)SC

Procedure:
Dry hydrogen chloride gas was passed into a solution of N-methyl-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl] thiourea (73.2 g) in methanol (600 ml) and the mixture was refluxed for 5 hours. Concentration and re-evaporation with isopropyl alcohol afforded a crystalline solid which was recrystallised from isopropyl alcohol-ether to give N,S-dimethyl-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]isothiourea dihydrochloride (96.2 g) m.p. 191°-192° (isopropyl alcohol-ether).
Reaction SMILES: [N+](C1C=CC(O[C:11](=[O:24])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH:21]=[CH2:22])=[C:15]([Cl:23])[CH:14]=2)=CC=1)([O-])=O.Cl.[CH3:26][O:27][C:28](=[O:31])[CH2:29][NH2:30].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:26][O:27][C:28](=[O:31])[CH2:29][NH:30][C:11](=[O:24])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH:21]=[CH2:22])=[C:15]([Cl:23])[CH:14]=1
Reactant: C=CCOc1ccc(CC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1Cl
Reactant: COC(=O)CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: C=CCOc1ccc(CC(=O)NCC(=O)OC)cc1Cl
Temperature: 40 °C
Reaction time: 4 h

Procedure:
4-Allyloxy-3-chloro-phenylacetic acid p-nitrophenyl ester (3.69 g) was dissolved in chloroform (30 ml). To the solution was added glycine methyl ester hydrochloride (1.5 g) in dry chloroform (30 ml) containing dry triethylamine (1.4 ml), and the solution was stirred at 40° C. for 4 hrs.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][S:9]([CH3:12])(=[O:11])=[O:10])[N:3]=1.Br[CH2:14][CH2:15]Br>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2([S:9]([CH3:12])(=[O:11])=[O:10])[CH2:15][CH2:14]2)[N:3]=1
Reactant: BrCCBr
Reactant: CS(=O)(=O)Cc1cccc(Br)n1
Product: CS(=O)(=O)C1(c2cccc(Br)n2)CC1
Yield: 53 %

Procedure:
The title compound was prepared from 2-bromo-6-methanesulfonylmethyl-pyridine and 1,2-dibromoethane following a procedure analogous to that described in Step 3 for Intermediate 4. Yield: 53% of theory; LC (method 3): tR=2.56 min; Mass spectrum (ESI+): m/z=276/278 (Br) [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[C:12]([CH:16]=[O:17])[CH:11]=[C:10]([S:18]([NH2:21])(=[O:20])=[O:19])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:22]1([CH2:28][CH2:29][CH2:30][C:31](Cl)=[O:32])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[C:12]([CH:16]=[O:17])[CH:11]=[C:10]([S:18]([NH:21][C:31](=[O:32])[CH2:30][CH2:29][CH2:28][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:19])=[O:20])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1c(C=O)cc(S(N)(=O)=O)cc1-c1cccc(N)c1
Reactant: O=C(Cl)CCCc1ccccc1
Product: COc1c(C=O)cc(S(=O)(=O)NC(=O)CCCc2ccccc2)cc1-c1cccc(N)c1

Procedure:
Proceeding as in Reference 21, but substituting 3′-amino-5-formyl-6-methoxy-biphenyl-3-sulfonamide and 4-phenylbutyryl chloride, gave 3′-amino-5-formyl-6-methoxy-N-(4-phenylbutyryl)-biphenyl-3-sulfonamide.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:25])[C:8]2[CH:9]=[C:10]3[CH:21]=[C:20]([F:22])[C:19](F)=[C:18]([F:24])[C:11]3=[N:12][C:13]=2[N:14]([CH2:16][CH3:17])[CH:15]=1)=[O:5])[CH3:2].[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:25])[C:8]2[CH:9]=[C:10]3[CH:21]=[C:20]([F:22])[C:19]([N:30]4[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]4)=[C:18]([F:24])[C:11]3=[N:12][C:13]=2[N:14]([CH2:16][CH3:17])[CH:15]=1)=[O:5])[CH3:2]
Reactant: CN1CCNCC1
Reactant: CCOC(=O)c1cn(CC)c2nc3c(F)c(F)c(F)cc3cc2c1=O
Product: CCOC(=O)c1cn(CC)c2nc3c(F)c(N4CCN(C)CC4)c(F)cc3cc2c1=O
Yield: 63.9 %

Procedure:
The 3-ethoxycarbonyl-1-ethyl-7,9-difluoro-8-(4-methyl-1-piperazinyl)-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine was prepared under the conditions of Example 3 but starting from 1.4 g of 3-ethoxycarbonyl-1-ethyl-7,8,9-trifluoro-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine and 4 g of 1-methylpiperazine. 1.1 g of 3-ethoxycarbonyl-1-ethyl-7,9-difluoro-8-(4-methyl-1-piperazinyl)-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine are obtained in the form of a yellow solid melting at 206° C.
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([O:6][CH2:7][CH:8]=C)=[O:5].[C:11]1([CH2:17][C:18]([NH2:20])=[S:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(O)C>N1C=CC=CC=1>[CH2:17]([C:18]1[S:19][CH:2]=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[N:20]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C=CCOC(=O)C(=O)CBr
Reactant: NC(=S)Cc1ccccc1
Solvent: c1ccncc1
Solvent: CCO
Product: CCOC(=O)c1csc(Cc2ccccc2)n1

Procedure:
40 g of allyl bromopyruvate were progressively added to a mixture of 30.2 gof phenylthioacetamide, 120 ml of ethanol and 20 ml of pyridine and the mixture was refluxed for 16 hours. The mixture was evaporated to dryness under reduced pressure and the residue was added to a water-ether mixture.The mixture was stirred and the decanted aqueous phase was extracte with ether. The combined organic phases were evaporated to dryness and the residue was chromatographed over silica gel. Elution with a 7-3 hexane-ethyl acetate mixture yielded 22.5 g of ethyl 2-benzyl-thiazole-4-carboxylate melting at 78°-79° C.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([CH2:18][CH2:19][CH3:20])[C:7]2[O:12][C:11]([C:13](N)=[O:14])=[CH:10][C:9](=[O:16])[C:8]=2[CH:17]=1)[CH2:2][CH3:3].Br.C(=O)(O)[O-:23].[Na+].C(=O)(O)[O-]>C(O)(=O)C>[CH2:1]([C:4]1[CH:5]=[C:6]([CH2:18][CH2:19][CH3:20])[C:7]2[O:12][C:11]([C:13]([OH:23])=[O:14])=[CH:10][C:9](=[O:16])[C:8]=2[CH:17]=1)[CH2:2][CH3:3]
Reactant: O=C([O-])O
Reactant: CCCc1cc(CCC)c2oc(C(N)=O)cc(=O)c2c1
Agent: Br
Agent: [Na+]
Solvent: CC(=O)O
Product: CCCc1cc(CCC)c2oc(C(=O)O)cc(=O)c2c1

Procedure:
A mixture of 1.0 parts of 6,8-dipropyl-4-oxo-4H-1-benzopyran-2-carboxamide, 20 parts of glacial acetic acid, and 20 parts of a solution of hydrogen bromide (45% weight/volume) in glacial acetic acid was heated at reflux for 3 hours, then the organic layer with saturated sodium bicarbonate solution, followed by acidification of the bicarbonate layer, afforded 0.16 parts of 6,8-dipropyl-4-oxo-4H-1-benzopyran-2-carboxylic acid, melting point 183°-184° C (decomposition). The melting point, IR spectrum and thin layer chromotographic properties of this material were identical with those of the compound prepared in Example 8.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)(=[O:21])=[O:20])=[CH:15][C:14]=2[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)(=[O:21])=[O:20])=[CH:15][C:14]=2[C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)c1cc(S(=O)(=O)c2cccc(F)c2)ccc1-c1ccn(C(=O)OC(C)(C)C)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCOC(=O)c1cc(S(=O)(=O)c2cccc(F)c2)ccc1C1CCN(C(=O)OC(C)(C)C)C1
Yield: 99.9 %

Procedure:
3-[2-Ethoxycarbonyl-4-(3-fluoro-benzenesulfonyl)-phenyl]-pyrrole-1-carboxylic acid tert-butyl ester (288 mg, 0.608 mmol) was dissolved in 40 ml of MeOH. Pd(OH)2 (200 mg) was added and the mixture was placed in a Parr bomb and stirred under 200 psi of Hydrogen for 72 hours. The solution was filtered through Celite and the filtrate was concentrated under reduced pressure to give 290 mgs (quantitative) of 3-[2-Ethoxycarbonyl-4-(3-fluoro-benzenesulfonyl)-phenyl]-pyrrolidine-1-carboxylic acid tert-butyl ester as a white crystalline solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[CH2:13]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:14].C(N(C(C)C)CC)(C)C>C(#N)C>[CH2:13]([N:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[CH3:14]
Reactant: Oc1ccc(OCCCBr)cc1
Reactant: CCNc1ccccc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CCCOc1ccc(O)cc1)c1ccccc1
Temperature: 70 °C
Reaction time: 12 h
Yield: 30 %

Procedure:
Compound 10a (500 mg, 2.2 mmol) and N-ethylaniline (1 g, 5.5 mmol) were reacted in acetonitrile for 30 mins before diisopropylethylamine (284 mg, 2.2 mmol) was added dropwise. The reaction mixture was then heated and stirred at 70° C. for 12 hours. After cooling to room temperature, the solvent was evaporated and the residue was purified by silica gel column chromatography to provide the compound 10 (170 mg, 0.66 mmol, 24% yield) as a pale yellow solid. MS (ESI, positive) m/z calcd. for C17H21NO2 [M+H]+: 272.16, found: 272.00. 1H NMR (400 MHz, Chloroform-d) δ 7.25 (d, J=7.8 Hz, 2H), 6.88-6.66 (m, 7H), 3.99 (t, J=5.8 Hz, 2H), 3.53 (t, J=7.1 Hz, 2H), 3.41 (q, J=7.2 Hz, 2H), 2.08 (q, J=6.7 Hz, 2H), 1.19 (t, J=7.1 Hz, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:13]3[CH:18]4[CH2:19][CH2:20][N:15]([CH2:16][CH2:17]4)[CH:14]=3)=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-])=O.O.NN>CO.[Ni]>[N:15]12[CH2:16][CH2:17][CH:18]([CH2:19][CH2:20]1)[C:13]([C:8]1[C:7]3[C:11](=[CH:12][C:4]([NH2:1])=[CH:5][CH:6]=3)[NH:10][CH:9]=1)=[CH:14]2
Reactant: O=[N+]([O-])c1ccc2c(C3=CN4CCC3CC4)c[nH]c2c1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Product: Nc1ccc2c(C3=CN4CCC3CC4)c[nH]c2c1
Yield: 98.5 %

Procedure:
Compound 109 (0.4 g, 1.485 mmol) in dry methanol (10 mL) was treated with Ra—Ni (˜0.05 g) and hydrazine hydrate (0.46 mL, 1.029 mmol). The resulting mixture was placed in a pre-heated oil bath and refluxed for 2 min (until yellow colour disappears). The reaction was brought to room temperature, filtered through celite bed and washed with methanol (3×10 mL). The combined methanol layer was evaporated and crude was purified by column chromatography (2M NH3 in MeOH:CH2Cl2, 1:9) to obtain compound 110 (0.35 g, quantitative) as a foam. mp 65-67° C.; 1H NMR (DMSO-d6) δ 1.42-1.54 (m, 2H), 1.62-1.74 (m, 2H), 2.52-2.56 (m, 2H), 2.86-2.94 (m, 2H), 2.98-3.02 (m, 1H), 4.75 (s, 2H), 6.41 (dd, 1H, J=2.1, 8.4 Hz), 6.53 (d, 1H, J=1.8 Hz), 6.69 (s, 1H), 7.16 (d, 1H, J=2.4 Hz), 7.35 (d, 1H, J=8.4 Hz), 10.57 (s, 1H); ESI-MS (m/z, %): 240 (MH+, 100).
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:15]([N+:16]([O-])=O)=[CH:14][N:13]=[C:12]([C:19]4[CH:24]=[CH:23][C:22]([CH2:25][C:26]#[N:27])=[CH:21][CH:20]=4)[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.[NH4+].[Cl-].CCO>[Fe].O>[NH2:16][C:15]1[C:10]([NH:9][C:6]2[CH:5]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[NH:8][N:7]=2)=[N:11][C:12]([C:19]2[CH:20]=[CH:21][C:22]([CH2:25][C:26]#[N:27])=[CH:23][CH:24]=2)=[N:13][CH:14]=1
Reactant: N#CCc1ccc(-c2ncc([N+](=O)[O-])c(Nc3cc(C4CC4)[nH]n3)n2)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: N#CCc1ccc(-c2ncc(N)c(Nc3cc(C4CC4)[nH]n3)n2)cc1
Yield: 24.1 %

Procedure:
To a solid mixture of 2-(4-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-nitropyrimidin-2-yl)phenyl)acetonitrile 45 mg, 0.125 mmol, 1 equivalent) and NH4Cl (3.6 g, 1.375 mmol, 11 equiv) was added EtOH (4 ml) and H2O (2 mL). The reaction mixture was heated to reflux under nitrogen atmosphere and iron powder (25 mg, 0.438 mmol, 3.5 equiv.) was added. The resulting mixture was continued to reflux for 0.5 h. The mixture was filtered immediately with a hot filter under reduced pressure. EtOH and water were removed under reduce pressure. The residue was washed by water. The title compound 2-(4-(5-amino-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)phenyl) acetonitrile (Compound 92) (10 mg, 24.4%) was obtained. LC-MS (m/z)=332.1 [M+H]+; 1H NMR (400 MHz, DMSO-d6): δ 0.71 (s, 2H), 0.93 (s, 2H), 1.92 (s, 1H), 3.83 (s, 2H), 5.30 (s, 2H), 6.21 (s, 2H), 7.04 (s, 1H), 7.21 (d, J=6.0 Hz, 1H), 7.53 (s, 1H), 7.70 (s, 1H), 8.30 (s, 1H), 9.78 (s, 1H), 12.03 (s, 1H).