Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[C:17]3[CH:18]=[C:19]([C:22]([NH:24][C:25]4[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=4)=[O:23])[CH:20]=[CH:21][C:16]=3[O:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH3:34][C:35]1C=C(S(Cl)(=O)=O)C=C(C)C=1>>[CH2:34]([O:30][C:29](=[O:31])[C:28]1[CH:27]=[CH:26][C:25]([NH:24][C:22]([C:19]2[CH:20]=[CH:21][C:16]3[O:15][CH2:14][CH2:13][N:12]([S:9]([C:4]4[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[CH:3]=4)(=[O:11])=[O:10])[C:17]=3[CH:18]=2)=[O:23])=[CH:33][CH:32]=1)[CH3:35]
Reactant: Cc1cc(C)cc(S(=O)(=O)Cl)c1
Reactant: Cc1cc(C)cc(S(=O)(=O)N2CCOc3ccc(C(=O)Nc4ccc(C(=O)O)cc4)cc32)c1
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(C)cc(C)c2)CCO3)cc1

Procedure:
4-{[4-(3,5-Dimethyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoic acid, MS (ISP): m/e=466.5 (M−H), was prepared as described for example 14, steps 1 to 8. Step 7 was performed using 3,5-dimethyl-benzenesulfonyl chloride and yielded 4-{[4-(3,5-dimethyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoic acid ethyl ester, which was hydrolyzed in step 8.
Reaction SMILES: O[C@H:2]([C:22]1[CH:23]=[CH:24][C:25]2[O:30][C@H:29]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([O:38][CH2:39][C:40]4[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[CH:41]=4)=[CH:34][CH:33]=3)[CH:28]=[CH:27][C:26]=2[CH:47]=1)[C@H:3]([O:19][CH2:20][CH3:21])[C:4]([N:6]1[C@@H:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:9][O:8][C:7]1=[O:18])=[O:5].C([SiH](CC)CC)C>FC(F)(F)C(O)=O.CCOCC>[CH2:20]([O:19][C@H:3]([C:4]([N:6]1[C@@H:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:9][O:8][C:7]1=[O:18])=[O:5])[CH2:2][C:22]1[CH:23]=[CH:24][C:25]2[O:30][C@H:29]([CH2:31][C:32]3[CH:33]=[CH:34][C:35]([O:38][CH2:39][C:40]4[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[CH:41]=4)=[CH:36][CH:37]=3)[CH:28]=[CH:27][C:26]=2[CH:47]=1)[CH3:21]
Reactant: CCO[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)[C@H](O)c1ccc2c(c1)C=C[C@@H](Cc1ccc(OCc3cccc(F)c3)cc1)O2
Agent: CC[SiH](CC)CC
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: CCO[C@@H](Cc1ccc2c(c1)C=C[C@@H](Cc1ccc(OCc3cccc(F)c3)cc1)O2)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Yield: 48.3 %

Procedure:
(R)-6-{(1R,2S)-1-Hydroxy-2-ethoxy-3-[(S)-4-benzyl-2-oxo-3-oxazolidinyl]-3-oxopropyl}-2-[4-(3-fluorobenzyloxy)benzyl]-2H-benzopyran (80 mg, 0.13 mmol) was dissolved in trifluoroacetic acid (2 ml) and triethylsilane (0.20 ml) was added. After 30 minutes the solution was diluted with ether, washed with water (2×) and saturated sodium bicarbonate (2×), dried over magnesium sulfate and concentrated. The product was purified by flash-chromatography (hexanes/ethyl acetate, 2:1) and obtained as an oil (39 mg).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:20][NH:21][O:22][CH3:23]>C(OCC)(=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:21]([O:22][CH3:23])[CH3:20])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: CNOC
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CON(C)C(=O)c1ccc(Br)cc1
Reaction time: 1 h

Procedure:
A solution of 4-bromobenzoyl chloride (4.67 g, 21.3 mmol), diisopropylethylamine (3.78 mL, 46.8 mmol), and N,O-dimethylhydroxylamine (2.18 g, 22.3 mmol) in ethyl acetate (100 mL) was heated to 45° C. After 1 h, the reaction mixture was diluted with ethyl acetate (100 mL). The resulting solution was washed sequentially with water and saturated aqueous sodium chloride solution. The collected organic was dried over magnesium sulfate, filtered, and concentrated. Purification by flash column chromatography (hexanes→ethyl acetate in hexanes) provided producted as a tan solid (4.12 g, 79%). LCMS (ESI) m/z: 244.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH2:9]([O:11][C:12](=[O:25])[CH2:13][CH:14]1[C:19](=[O:20])[NH:18][C:17]2[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=2[S:15]1)[CH3:10].Br[CH2:27][C:28]([OH:30])=[O:29].Cl>C1COCC1.C(OCC)C>[C:28]([CH2:27][N:18]1[C:19](=[O:20])[CH:14]([CH2:13][C:12]([O:11][CH2:9][CH3:10])=[O:25])[S:15][C:16]2[CH:24]=[CH:23][CH:22]=[CH:21][C:17]1=2)([OH:30])=[O:29]
Reactant: O=C(O)CBr
Reactant: CCOC(=O)CC1Sc2ccccc2NC1=O
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)CC1Sc2ccccc2N(CC(=O)O)C1=O
Reaction time: 2 h
Yield: 50 %

Procedure:
To a solution of LDA (2M) in THF (3.26 mmol) in 2 mL of anhydrous THF at 0° C. and under nitrogen, a solution of (3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-2-yl)-acetic acid ethyl ester (1.62 mmol) in 4 mL of dry THF is added dropwise. The temperature of the reaction mixture is held at room temperature for 2 hours and then dropped to −78° C. A solution of 2-bromo acetic acid (1.64 mmol) in 2 mL of anhydrous THF is added and the temperature of the reaction is slowly let to rise to room temperature. HCl (1M) is added to reach pH=1. Ethyl ether is added and the phases are separated. The organic phase is dried on Na2SO4, the drying agent is filtered and the solvent evaporated. The crude product is purified by automated column chromatography (hexane/EtOAc) to give the product ethyl 2-(3,4-dihydro-4-(carboxymetyl)-3-oxo-2H-benzo[b][1,4]thiazin-2-yl)acetate. Yield: 50%. 1H NMR (400 MHz, CDCl3): δ 9.07 (bs, 1H), 7.38 (d, J=7.6 Hz, 1H), 7.27 (t, J=7.6 Hz, 1H), 7.07 (t, J=7.6 Hz, 1H), 6.93 (d, J=7.6 Hz, 1H), 4.69 (dd, 2H), 4.18 (dd, 2H), 3.99 (t, J=6.4 Hz, 1H), 3.04 (dd, J1=6.4 Hz, J2=16.8 Hz, 1H), 2.58 (dd, 1H), 1.26 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].O=S(Cl)Cl.[CH3:15]O>>[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:15])=[O:5]
Reactant: CO
Reactant: Nc1ccccc1C(=O)O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccccc1N
Yield: 93 %

Procedure:
To a stirred solution of 2-aminobenzoic acid (2.0 g, 14.59 mmol) in MeOH (70 mL) at 0° C. was added SOCl2 (7.4 g, 145.9 mmol) dropwise. The mixture was heated at reflux overnight and was then concentrated under reduced pressure. DCM and saturated aqueous NaHCO3 were added and the aqueous phase extracted with DCM. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated to afford methyl 2-aminobenzoate (2.05 g, 93%). LC-MS (ES-API); rt 8.46 min; m/z calculated for C8H9NO2[M+H]+ 152.0, found 152.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[N+:10]([C:13]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:14]=1[C:15](O)=[O:16])([O-:12])=[O:11].Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH:7][C:15](=[O:16])[C:14]2[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:13]=2[N+:10]([O-:12])=[O:11])=[CH:5][CH:4]=1
Reactant: Cc1ccc([N+](=O)[O-])c(C(=O)O)c1
Reactant: COc1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: COc1ccc(NC(=O)c2cc(C)ccc2[N+](=O)[O-])cc1
Reaction time: 12 h
Yield: 49.9 %

Procedure:
To a stirred solution of 4-methoxyaniline (1.4 g, 11 mmol) and 2-nitro-5-methylbenzoic acid (2.0 g, 11 mmol) in dimethylformamide (20 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.17 g, 16.5 mmol). After 12 h, the solvent was removed in vacuo. The residue was dissolved in ethyl acetate and washed twice with 1 M aqueous citric acid, once with water, twice with saturated aqueous sodium bicarbonate solution, once with water, and once with saturated aqueous sodium chloride solution. The organic phase was dried (magnesium sulfate), filtered, and concentrated in vacuo. The residue was triturated with diethyl ether, filtered, and dried in vacuo to give 1.57 g (50%) of the title compound as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH3:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([C:16]2[N:20]=[C:19]([C:21]3[CH:22]=[CH:23][C:24]([CH2:27]O)=[N:25][CH:26]=3)[O:18][N:17]=2)[N:3]=1.CS(Cl)(=O)=O.[CH2:34]([N:36](CC)[CH2:37][CH3:38])[CH3:35].N1CCCC1>C(Cl)Cl>[CH3:15][N:8]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:6]1[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([C:16]2[N:20]=[C:19]([C:21]3[CH:26]=[N:25][C:24]([CH2:27][N:36]4[CH2:37][CH2:38][CH2:35][CH2:34]4)=[CH:23][CH:22]=3)[O:18][N:17]=2)[N:5]=1
Reactant: CCN(CC)CC
Reactant: CN(c1ccccc1)c1nc(N)nc(-c2noc(-c3ccc(CO)nc3)n2)n1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: C1CCNC1
Product: CN(c1ccccc1)c1nc(N)nc(-c2noc(-c3ccc(CN4CCCC4)nc3)n2)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 44.1 %

Procedure:
To a solution of [5-(3-{4-amino-6-[methyl(phenyl)amino]-1,3,5-triazin-2-yl}-1,2,4-oxadiazol-5-yl)pyridin-2-yl]methanol (Intermediate 125, 50 mg, 132 μmol) in DCM (10 mL) was added methanesulfonyl chloride (11 μL, 139 μmol) and triethylamine (20 μL, 145 μmol). The reaction mixture was stirred for 90 min at room temperature under an inert atmosphere and then evaporated to dryness. The resulting solid was dissolved in DCM (10 mL), pyrrolidine (24 μL, 333 μmol) and triethylamine (46 μL, 333 μmol) and stirred for a further 3 h at room temperature. Incomplete reaction was observed so the reaction was heated at 35 C for a further 16 h. The reaction mixture was then washed with water (3×25 mL) and combined organics were dried over magnesium sulfate and evaporated to dryness. The resulting crude product was purified by silica chromatography (5% MeOH in DCM) to afford the title compound as a beige solid (25 mg, 45%).
Reaction SMILES: O=[C:2]1[NH:10][C:9]2[C:4](=[N:5][C:6]([C:11]3[CH:12]=[N:13][N:14]4[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][C:15]=34)=[N:7][CH:8]=2)[N:3]1[CH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.[CH3:28][N:29]1[CH:33]=[CH:32][N:31]=[C:30]1C=O>CC(O)=O.CC(N(C)C)=O>[CH3:28][N:29]1[CH:33]=[CH:32][N:31]=[C:30]1[C:2]1[N:3]([CH:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)[C:4]2[C:9]([N:10]=1)=[CH:8][N:7]=[C:6]([C:11]1[CH:12]=[N:13][N:14]3[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][C:15]=13)[N:5]=2
Reactant: N#Cc1ccn2ncc(-c3ncc4[nH]c(=O)n(C5CCOCC5)c4n3)c2c1
Reactant: Cn1ccnc1C=O
Solvent: CC(=O)N(C)C
Solvent: CC(=O)O
Product: Cn1ccnc1-c1nc2cnc(-c3cnn4ccc(C#N)cc34)nc2n1C1CCOCC1
Temperature: 140 °C
Reaction time: 19 h
Yield: 31 %

Procedure:
To a solution of the compound obtained in example 1 section d (100 mg, 0.30 mmol) in AcOH (0.025 mL) and DMA (2.5 mL), 1-methyl-1H-imidazole-2-carbaldehyde (46 mg, 0.42 mmol) was added. The reaction mixture was stirred in a sealed tube at 140° C. for 19 h. The crude mixture was quenched with H2O (10 mL), extracted with EtOAc (3×10 mL) and the combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated. The crude product thus obtained was chromatographed over silica gel using hexanes/EtOAc mixtures of increasing polarity as eluent, to afford 40 mg of the desired compound (31% yield).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[S:8][C:9]([NH:11][C:12](=[O:24])[C:13]3[CH:18]=[CH:17][C:16]([C:19]([CH3:23])([CH3:22])[CH2:20][OH:21])=[CH:15][CH:14]=3)=[N:10][C:5]2=[CH:4][CH:3]=1.[CH3:25][C:26]1[C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][NH:28][N:27]=1>>[OH:21][CH2:20][C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:12]([NH:11][C:9]2[S:8][C:6]3[C:5]([N:10]=2)=[CH:4][CH:3]=[C:2]([C:30]2[C:26]([CH3:25])=[N:27][NH:28][CH:29]=2)[N:7]=3)=[O:24])=[CH:14][CH:15]=1)([CH3:23])[CH3:22]
Reactant: Cc1n[nH]cc1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(CO)c1ccc(C(=O)Nc2nc3ccc(Br)nc3s2)cc1
Product: Cc1n[nH]cc1-c1ccc2nc(NC(=O)c3ccc(C(C)(C)CO)cc3)sc2n1
Yield: 20 %

Procedure:
The titled compound (yield=20%, white solid) was prepared using a procedure analogous to that described in connection with 9 (Example 9) except 2F (Example 2) and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole were used as starting materials. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.27 (s, 6H) 2.59 (br. s., 3H) 3.49 (br. s., 2H) 7.57 (d, J=8.34 Hz, 2H) 7.74 (d, J=8.59 Hz, 1H) 8.02 (br. s., 1H) 8.05-8.13 (m, 3H) 12.86 (s, 1H); ESI-MS: m/z 408.0 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[C:4](Cl)[N:3]=1.O.C(=O)(O)[O-].[Na+].[F:17][C:18]([F:29])([F:28])[C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>C(COC)OC>[F:17][C:18]([F:29])([F:28])[C:19]1[CH:24]=[CH:23][C:22]([C:2]2[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[C:4]([C:22]3[CH:23]=[CH:24][C:19]([C:18]([F:29])([F:28])[F:17])=[CH:20][CH:21]=3)[N:3]=2)=[CH:21][CH:20]=1
Reactant: N#Cc1cc(Cl)nc(Cl)c1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: N#Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Yield: 30 %

Procedure:
2-6-dichloropyridine-4-carbonitrile 24 (3.7 g, 21.35 mmol) was dissolved in 100 ml of dimethoxyethane. To the solution were added 70 ml of water, sodium bicarbonate (3 equiv., 5.38 g), [4-(trifluoromethyl)phenyl]boronic acid (2.4 equiv., 9.74 g) and the mixture was stirred at rt for 5′. The mixture was degassed and put under argon. A catalytic amount of tetrakispalladium was added and the mixture was heated at 100° C. overnight. The solvents were evaporated off and the residue was dissolved with ethyl acetate, washed with water and brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The crude was crystallized from ethyl acetate and petroleum ether to give 28A as a beige solid. (2.5 g, 30% yield)
Reaction SMILES: [CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([Cl:19])=[CH:14][CH:15]=2)[N:10]=[C:9]1[CH:20]([NH:24][CH2:25][CH:26]([O:29][CH3:30])[O:27][CH3:28])[CH:21]([CH3:23])[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([Cl:19])=[CH:14][CH:15]=2)[N:10]=[C:9]1[CH:20]([N:24]([CH2:25][CH:26]([O:27][CH3:28])[O:29][CH3:30])[C:31](=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH:21]([CH3:23])[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(CNC(c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1)C(C)C)OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(CN(C(=O)c1ccccc1)C(c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1)C(C)C)OC
Yield: 54.1 %

Procedure:
A solution of 3-benzyl-7-chloro-2-[1-(2,2-dimethoxy-ethylamino)-2-methyl-propyl]-3H-quinazolin-4-one (505 mg, 1.17 mmol), benzoyl chloride (247 mg, 1.76 mmol), and triethylamine (179 mg, 1.76 mmol) in methylene chloride (10 mL) was stirred at room temperature for 18 h. The reaction was washed sequentially with 0.5 N HCl, water. 5% NaHCO3, water, and brine. The organic layer was dried (Na2SO4) and concentrated to yield the title compound as an orange oil (338 mg, 54%). MS(ES+) m/e 534 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[CH3:8].[C:9]([C:13]1[N:14]([CH3:25])[S:15](=[O:24])(=[O:23])[C:16]2[CH:22]=[CH:21][S:20][C:17]=2[C:18]=1[OH:19])(OC)=[O:10]>>[CH3:7][C:4]1[C:3]([CH3:8])=[C:2]([NH:1][C:9]([C:13]2[N:14]([CH3:25])[S:15](=[O:24])(=[O:23])[C:16]3[CH:22]=[CH:21][S:20][C:17]=3[C:18]=2[OH:19])=[O:10])[O:6][N:5]=1
Reactant: Cc1noc(N)c1C
Reactant: COC(=O)C1=C(O)c2sccc2S(=O)(=O)N1C
Product: Cc1noc(NC(=O)C2=C(O)c3sccc3S(=O)(=O)N2C)c1C

Procedure:
By reacting 5-amino-3,4-dimethyl-isoxazole with 3-carbomethoxy-4-hydroxy-2-methyl-thieno[2,3-e]-1,2-thiazine 1,1-dioxide for 14 hours in a manner analogous to that described in Example 1, there is obtained N-(3,4-dimethyl-5-isoxazolyl)-4-hydroxy-2-methyl-2H-thieno[2,3-e]-1,2-thiazine-3-carboxamide 1,1-dioxide of decomposition point 206°-208° C. (recrystallization from benzene.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)=[O:4].C1N2CN3CN(C2)C[N:13]1C3.Cl>C(Cl)(Cl)Cl.C(O)C>[ClH:11].[NH2:13][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)=[O:4]
Reactant: O=C(CBr)c1cccc(Cl)c1
Reactant: C1N2CN3CN1CN(C2)C3
Agent: Cl
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: NCC(=O)c1cccc(Cl)c1
Temperature: 55 °C
Yield: 239.4 %

Procedure:
2-Bromo-1-(3-chlorophenyl)ethanone (2.0 g, 8.57 mmol) was added to a solution of hexamethylenetetramine (1.201 g, 8.57 mmol) in CHCl3 (60 mL), and the resulting mixture was heated at 55° C. for 1 hour. The mixture was cooled to room temperature, and the white precipitate was collected by filtration, washed with CHCl3, and dried in vacuo to afford 3.1 g. This white solid was suspended in a mixture of ethanol (50 mL) and hydrochloric acid (0.25 mL, 8.30 mmol) and heated at 105° C. for 1.5 hours. The mixture was cooled to 0° C., filtered and washed by ethanol (30 mL). The organic phase was concentrated to afford an HCl salt of the title compound (1.74 g) as a pale yellow solid. LC-MS (ES) m/z=170 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:16]#[N:17])([CH2:14][OH:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:18][S:19](Cl)(=[O:21])=[O:20]>O1CCCC1.C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:16]#[N:17])([CH2:14][O:15][S:19]([CH3:18])(=[O:21])=[O:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(CO)CC1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(C#N)(COS(C)(=O)=O)CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
After dissolving 537 mg of 1-(tert-butoxycarbonyl)-4-cyano-4-(hydroxymethyl)piperidine in 100 ml of tetrahydrofuran, 0.4 ml of triethylamine was added and the solution was cooled to 0° C. 0.2 ml of methanesulfonyl chloride was added and the mixture was stirred overnight at room temperature. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. After adding water to the residue, extraction was performed with ethyl acetate. The organic layer was washed with water and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (799 mg, 100% yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][S:8]([C:11]2[CH:12]=[C:13]([N+:17]([O-])=O)[CH:14]=[CH:15][CH:16]=2)(=[O:10])=[O:9])[CH:2]=1.CN(C)C=O>C(O)C.[Pd]>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][S:8]([C:11]2[CH:12]=[C:13]([NH2:17])[CH:14]=[CH:15][CH:16]=2)(=[O:10])=[O:9])[CH:2]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Nc2cccnc2)c1
Agent: [Pd]
Solvent: CCO
Solvent: CN(C)C=O
Product: Nc1cccc(S(=O)(=O)Nc2cccnc2)c1
Reaction time: 2 h
Yield: 98.3 %

Procedure:
To a solution of 3-(pyrid-3-ylaminosulphonyl)-nitrobenzene (4.279 g, 15.3 mmol) in ethanol (500 ml)/dimethylformamide (50 ml) was added 10% palladium catalyst on charcoal (1 g) and the reaction mixture was hydrogenated at atmospheric pressure for 2 hours. The reaction mixture was then filtered through kieselguhr before being evaporated under reduced pressure to give the product as a white solid (3.749 g, 98%) 7.3 (1H, q, 5 Hz); 7.15 (1H, t, J7 Hz); 6.95 (1H, s); 6.8 (1H, d, J7 Hz); 6.7 (1H, d, J7 Hz); 5.6 (2H, s)
Reaction SMILES: [F:1][C:2]1[C:3]([N:13]2[CH:17]=[CH:16][N:15]=[CH:14]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[CH:6]=[CH:5]2.N1C=CC=CC=1>C(O)(=O)C>[F:1][C:2]1[C:3]([N:13]2[CH:17]=[CH:16][N:15]=[CH:14]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([CH3:12])[CH2:6][CH2:5]2
Reactant: Cc1ccc2c(-n3ccnc3)c(F)ccc2n1
Solvent: c1ccncc1
Solvent: CC(=O)O
Product: CC1CCc2c(ccc(F)c2-n2ccnc2)N1

Procedure:
A solution of 10.2 g (44.9 mmole) of 6-fluoro-5-(imidazol-1-yl)-2-methylquinoline, 16.7 g (180 mmole) of pyridine:diborane complex (that commercially available from Aldrich) and 200 ml of glacial acetic acid was stirred for about 22 hours at about 20° C. The solution was evaporated to reduce its volume, then 100 ml of 10% hydrochloric acid was added in small portions. The solution was heated on a steam bath for another one hour, then cooled with an ice bath and basified (pH 9 to 10) with 10% aqueous sodium hydroxide. The solid was separated by filtration, washed with water, and dissolved in ethyl acetate and dried. Recrystallization from aqueous ethanol provided 6-fluoro-5-(imidazol-1-yl)-1,2,3,4-tetrahydro-2-methylquinoline, m.p. 162°-164° C. Analysis: Calculated for C13H14FN3 : %C, 67.5; %H, 6.1; %N, 18.2; Found: %C, 67.5; %H, 6.1; %N, 18.0.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([N:11]2[CH2:16][CH2:15][CH:14]([NH:17][C:18]3[C:23]([N+:24]([O-])=O)=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:13][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[H][H]>CO.[Pd]>[NH2:24][C:23]1[C:18]([NH:17][CH:14]2[CH2:15][CH2:16][N:11]([CH:8]3[CH2:9][CH2:10][N:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:6][CH2:7]3)[CH2:12][CH2:13]2)=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: [H][H]
Reactant: COC(=O)N1CCC(N2CCC(Nc3ncccc3[N+](=O)[O-])CC2)CC1
Agent: [Pd]
Solvent: CO
Product: COC(=O)N1CCC(N2CCC(Nc3ncccc3N)CC2)CC1

Procedure:
Seventy (70) mg of 2-[1-(1-methoxycarbonylpiperidin-4-yl)-piperidin-4-yl]amino-3-nitropyridine was dissolved in 5 ml of methanol, and to which 20 mg of 10% palladium/carbon catalyst was added to effect catalytic reduction at room temperature under atmospheric pressure of hydrogen. After filtering the catalyst off and drying the filtrate to solid, the resulting residue was purified by silica gel column chromatography (chloroform/methanol=95/5) to give 20 mg of 3-amino-2-[1-(1-methoxycarbonylpiperidin-4-yl)-piperidin-4-yl]aminopyridin.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH:9]1([O:14][C:15]2[C:16]([O:35][CH3:36])=[CH:17][CH:18]=[C:19]3[C:24]=2[NH:23][C:22](=[O:25])[CH:21]=[C:20]3[NH:26][C:27]2[C:32]([Cl:33])=[CH:31][N:30]=[CH:29][C:28]=2[Cl:34])[CH2:13][CH2:12][CH2:11][CH2:10]1.CN(C)C=O>O>[Br:1][C:21]1[C:22](=[O:25])[NH:23][C:24]2[C:19]([C:20]=1[NH:26][C:27]1[C:32]([Cl:33])=[CH:31][N:30]=[CH:29][C:28]=1[Cl:34])=[CH:18][CH:17]=[C:16]([O:35][CH3:36])[C:15]=2[O:14][CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OC1CCCC1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)c(Br)c(=O)[nH]c2c1OC1CCCC1
Reaction time: 4 h

Procedure:
N-Bromosuccinimide (0.104 g, 0.585 mmol) was added to a solution of 4-(3,5, -dichloropyridin-4-ylamino)-8-(cyclopentyloxy)-7-methoxyquinolin-2(1H)-one (0.246 g, 0.585 mmol, Example 1) and anhydrous dimethylformamide (3 mL) at 0° C. After 4 h at 0° C., the mixture was poured into water, and the precipitate was filtered. Saturated sodium thiosulfate solution (1 mL) was added to a solution of the filter cake and methanol (5 mL). After the dibromo intermediate was consumed, as monitored by LCMS, the mixture was diluted with water and extracted with ethyl acetate. The organic extract was dried, filtered, and concentrated to give 3-bromo-8-(cyclopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one: 1H NMR (400 MHz, DMSO-d6): δ 10.56 (s, 1H), 8.88 (br s, 1H), 8.42 (s, 2H), 7.62 (d, 1H), 7.04 (d, 1H), 4.98 (m, 1H), 3.89 (s, 3H), 1.84-1.51 (m, 8H); MS (ESI): 497.8.
Reaction SMILES: C[Al](C)C.[CH3:5][O:6][CH2:7][CH2:8][NH:9][CH2:10][CH2:11][O:12][CH3:13].[NH2:14][C:15]1[CH2:16][C:17]([C:33](OCC)=[O:34])=[CH:18][C:19]2[CH:25]=[CH:24][C:23]([C:26]([F:32])([F:31])[C:27]([F:30])([F:29])[F:28])=[CH:22][C:20]=2[N:21]=1>C1(C)C=CC=CC=1.ClCCCl>[NH2:14][C:15]1[CH2:16][C:17]([C:33]([N:9]([CH2:10][CH2:11][O:12][CH3:13])[CH2:8][CH2:7][O:6][CH3:5])=[O:34])=[CH:18][C:19]2[CH:25]=[CH:24][C:23]([C:26]([F:32])([F:31])[C:27]([F:28])([F:29])[F:30])=[CH:22][C:20]=2[N:21]=1
Reactant: COCCNCCOC
Reactant: CCOC(=O)C1=Cc2ccc(C(F)(F)C(F)(F)F)cc2N=C(N)C1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: ClCCCl
Product: COCCN(CCOC)C(=O)C1=Cc2ccc(C(F)(F)C(F)(F)F)cc2N=C(N)C1
Temperature: 75 °C

Procedure:
Trimethylaluminum (0.34 mL of a 2.0 M solution in toluene) was added to bis(2-methoxyethyl)amine (92 mg, 0.69 mmol) in DCE (3 mL). After 10 minutes solid (1E,4E)-ethyl 2-amino-8-(perfluoroethyl)-3H-benzo[b]azepine-4-carboxylate (80 mg, 0.23 mmol) was added and the vessel was sealed and heated to 75° C. for 16-20 hours. Upon cooling the reaction was quenched with saturated Rochelle's salt (2 mL) and after 20 minutes the mixture was partitioned between CH2Cl2 (50 mL) and brine (50 mL). The phases were separated and the aqueous was extracted with CH2Cl2 (2×20 mL). The combined organics were dried and concentrated. The crude material was purified via preparative TLC (2, 0.5 mm plates, eluting with 5-10% MeOH/CH2Cl2 with 4-6 drops of NH4OH). 1H NMR (CDCl3) δ 2.81 (s, 2H), 3.36 (s, 6H), 3.55-3.74 (m, 8H), 6.98 (s, 1H), 7.20 (d, 1H), 7.40 (d, 1H), 7.39 (s, 1H).