Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][C:3]1[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14](=[O:23])[C:15]3[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:22])[C:5]=2[O:6][C:7]=1[CH3:8].[NH:24]1[CH:28]=[CH:27][N:26]=[CH:25]1.C(N(CC)CC)C>ClCCCl>[ClH:1].[Cl:21][C:20]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:22])[C:15]=1[C:14]([NH:13][C:9]1[C:5]2[O:6][C:7]([CH3:8])=[C:3]([CH2:2][N:24]3[CH:28]=[CH:27][N:26]=[CH:25]3)[C:4]=2[CH:12]=[CH:11][CH:10]=1)=[O:23]
Reactant: Cc1oc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1CCl
Reactant: c1c[nH]cn1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: Cc1oc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1Cn1ccnc1
Product: Cl
Yield: 34.9 %

Procedure:
A mixture of 3-chloromethyl-7-(2,6-dichlorobenzoylamino)-2-methylbenzo[b]furan (150 mg), imidazole (33 mg) and triethylamine (62 mg) in 1,2-dichloroethane (1.5 ml) was refluxed for 3 hours. The reaction mixture was evaporated in vacuo and the residue was purified by column chromatography on silica gel. The obtained oil was crystallized from a mixture of ethyl acetate and diisopropyl ether and the crystalline was treated with ethanolic hydrogen chloride. The separated solid was collected and washed with ethanol to give 7-(2,6-dichlorobenzoylamino)-3-(imidazol-1-yl)methyl-2-methylbenzo[b]furan hydrochloride (62 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](O)=[CH:14][N:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C=O)C.S(Cl)([Cl:29])=O>>[ClH:29].[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([Cl:29])=[CH:14][N:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc2c(O)cnnc2cc1OCc1ccccc1
Solvent: CN(C)C=O
Product: COc1cc2c(Cl)cnnc2cc1OCc1ccccc1
Product: Cl

Procedure:
The starting material, 7-benzyloxy-4-chloro-6-methoxycinnoline hydrochloride, was obtained by heating a solution of 7-benzyloxy-4-hydroxy-6-methoxycinnoline (11 g, 39 mmol) in thionyl chloride (180 ml) containing DMF (1 ml) at reflux for 1 hour. After cooling, excess thionyl chloride was removed by evaporation and azeotroped with toluene. The residue was triturated with ether, filtered off, washed with ether and dried under vacuum to give 7-benzyloxy-4-chloro-6-methoxycinnoline hydrochloride as a cream solid (13.6 g, quantitative).
Reaction SMILES: [C:1]([C@@H:3](O)[C:4]1C=C[CH:7]=[C:6]([O:10][C:11]2[CH:16]=CC=C[CH:12]=2)[CH:5]=1)#N>O>[CH3:1][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH:6]([O:10][CH:11]([CH3:16])[CH3:12])([CH3:7])[CH3:5]
Reactant: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Solvent: O
Product: CC(C)OC(C)C
Product: CCCCCC
Temperature: 20 °C
Reaction time: 17 h

Procedure:
Using the procedure of Step A of Example 7, 1.9 g of (1R, trans) 2,2-dimethyl-3-(4',4'-dibromo-buta-1',3'-dienyl)-cyclopropane-1-carboxylic acid chloride and 6.11 g of (S)α-cyano-3-phenoxy-benzyl alcohol were stirred for 17 hours at 20° C. and the mixture was poured into 200 ml of water with stirring. The decanted aqueous phase was extracted with benzene and the organic phase was washed with 0.1 N hydrochloric acid and then with water, was dried and evaporated to dryness under reduced pressure to obtain 15.4 g of raw product. The latter was chromatographed twice over silica gel and was eluted first with a 9-1 hexane-ethyl acetate mixture and then with an 8-2 hexane-isopropyl ether mixture to obtain 4.4 g of product which was crystallized from a 1-1 hexane-isopropyl ether mixture to obtain 2.2 g of (S)α-cyano-3-phenoxy-benzyl (1R,trans) 2,2-dimethyl-3-(4',4'-dibromo-buta-1',3'-dienyl)-cyclopropane-1-carboxylate melting at 110° C. and having a specific rotation of [α]D20 =+116°±1° (c=1% in benzene).
Reaction SMILES: [CH3:1][O:2][C@H:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4]([OH:6])=[O:5]>CO>[CH:7]1([C@@H:3]([O:2][CH3:1])[C:4]([OH:6])=[O:5])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CO[C@@H](C(=O)O)c1ccccc1
Solvent: CO
Product: CO[C@@H](C(=O)O)C1CCCCC1
Reaction time: 1 h

Procedure:
An autoclave is charged with a solution of 1.00 g of (R)-α-methoxy-phenyl acetic acid in 20 ml methanol. 0.100 g of Nishimura catalyst are added and the mixture is hydrogenated at 4 bar and 20° C. for 1 hour. The mixture is filtered over Hyflo and the filtrate concentrated by evaporation to provide the title compound as a colourless oil. The crude material is used without further purification. Rf=0.84 (150:54:10:1 dichloromethane-methanol-water-acetic acid).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:22][C:23](=[O:28])[CH2:24][C:25](=O)[CH3:26])[CH:6]=[CH:7][C:8]=1[N:9]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])#[N:2].[NH3:29]>CO>[NH2:29]/[C:25](/[CH3:26])=[CH:24]\[C:23]([NH:22][C:5]1[CH:6]=[CH:7][C:8]([N:9]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[C:3]([C:1]#[N:2])[CH:4]=1)=[O:28]
Reactant: N
Reactant: CCCCCCN(CCCCCC)c1ccc(NC(=O)CC(C)=O)cc1C#N
Solvent: CO
Product: CCCCCCN(CCCCCC)c1ccc(NC(=O)/C=C(/C)N)cc1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
A mixture of N-(3-cyano-4-(dihexylamino)phenyl)-3-oxobutanamide (1.47 g, 3.81 mmol), MeOH (15 mL) and ammonia (15 mL) was stirred at rt overnight. The mixture was concentrated in vacuo to give the title compound as black oil (1.30 g, 88%).
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Li]CCCC.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=[O:26])[CH2:23][CH2:24][CH3:25])=[CH:18][CH:17]=1.[F:27][C:28]([F:37])([F:36])[C:29](N1C=CN=C1)=[O:30]>C1COCC1>[Br:15][C:16]1[CH:17]=[CH:18][C:19]([C:22](=[O:26])[CH:23]([CH2:24][CH3:25])[C:29](=[O:30])[C:28]([F:27])([F:36])[F:37])=[CH:20][CH:21]=1
Reactant: O=C(n1ccnc1)C(F)(F)F
Reactant: CCCC(=O)c1ccc(Br)cc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC(C(=O)c1ccc(Br)cc1)C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 68.7 %

Procedure:
To a solution of hexamethyldisilazane (4.92 g, 30.5 mmol) in THF (10 ml) was added dropwise n-BuLi (1.57 M hexane solution, 19.4 ml, 30.5 mmol) at −78° C. and the mixture was stirred at room temperature for 15 minutes. The mixture was cooled down to −78° C. again and 1-(4-bromophenyl)-1-butanone (5.77 g, 25.4 mmol) in THF (25 ml) was added dropwise over 15 min. The resulting mixture was stirred at −78° C. for 30 minutes, then allowed to warm up to 0° C. and stirred for 40 minutes. The solution was recooled down to −78° C. and N-trifluoroacetylimidazole (5.00 g, 30.5 mmol) was added. The mixture was stirred at −78° C. for 20 minutes, and at room temperature for 2 hours. The reaction was quenched with 2N HCl (30 ml). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (50 ml×2). The combined organic layer was washed with brine (50 ml), dried over Na2SO4, and concentrated in vacuo. The residue was chromatographed over silica gel with hexane/ethyl acetate (8:1 to 3:1) to give 5.64 g (69%) of the title compound as a oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([N:11]2[C:15]3[CH:16]=[C:17]([CH2:20][N:21]4[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]4)[CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)=[N:8][C:7]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:5])C.O1CCCC1.[OH-].[Li+]>O>[CH3:27][N:24]1[CH2:25][CH2:26][N:21]([CH2:20][C:17]2[CH:18]=[CH:19][C:14]3[N:13]=[CH:12][N:11]([C:9]4[S:10][C:6]([C:4]([OH:5])=[O:3])=[C:7]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[N:8]=4)[C:15]=3[CH:16]=2)[CH2:22][CH2:23]1
Reactant: CCOC(=O)c1sc(-n2cnc3ccc(CN4CCN(C)CC4)cc32)nc1-c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN1CCN(Cc2ccc3ncn(-c4nc(-c5ccccc5)c(C(=O)O)s4)c3c2)CC1
Yield: 64.8 %

Procedure:
To a mixture of 0.041 g (0.089 mmole) of 2-[6-(4-methyl-piperazin-1-ylmethyl)-benzoimidazol-1-yl]-4-phenyl-thiazole-5-carboxylic acid ethyl ester (I.1a), 1 mL of tetrahydrofuran and 1 mL of water was added 0.011 g of lithium hydroxide. The reaction mixture was heated to 60 degrees for 30 minutes and then concentrated under reduced pressure. The mixture was diluted with 5 mL of water and then extracted with 5 mL of ethyl acetate. The pH of the aqueous layer was adjusted to ca 7 by addition of 1M hydrochloric acid and then extracted with 5 mL of ethyl acetate. A precipitate formed in aqueous layer after extraction. The solid was collected by filtration and air dried to give 0.025 g of 2-[6-(4-methyl-piperazin-1-ylmethyl)-benzoimidazol-1-yl]-4-phenyl-thiazole-5-carboxylic acid (I.1b) as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:27][C@H:28]4[CH2:33][CH2:32][C@H:31]([CH3:34])[CH2:30][CH2:29]4)[C:15]([N:17]4[CH2:22][C:21](=[O:23])[NH:20][C@H:19]5[CH2:24][CH2:25][CH2:26][C@H:18]45)=[N:16][C:12]=3[CH:11]=[C:10]([C:35]#[N:36])[N:9]=2)[CH:5]=[N:6][CH:7]=1.[H-].[Na+].I[CH3:40]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:27][C@H:28]4[CH2:33][CH2:32][C@H:31]([CH3:34])[CH2:30][CH2:29]4)[C:15]([N:17]4[CH2:22][C:21](=[O:23])[N:20]([CH3:40])[C@H:19]5[CH2:24][CH2:25][CH2:26][C@H:18]45)=[N:16][C:12]=3[CH:11]=[C:10]([C:35]#[N:36])[N:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: C[C@H]1CC[C@H](Cn2c(N3CC(=O)N[C@H]4CCC[C@@H]43)nc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)CN(c2nc3cc(C#N)nc(-c4cncc(Cl)c4)c3n2C[C@H]2CC[C@H](C)CC2)[C@H]2CCC[C@@H]21
Reaction time: 1 h

Procedure:
4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(4aS,7aS)-3-oxooctahydro-1H-cyclopenta[b]pyrazin-1-yl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile (282 mg, 0.559 mmol) was taken up in DMF (5595 μl), and sodium hydride (22.38 mg, 0.559 mmol) and iodomethane (87 μl, 1.399 mmol) were added. The mixture was stirred for 1 hour, quenched via the addition of saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified via silica gel chromatography (0-20% MeOH/DCM) to afford 4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(4aS,7aS)-4-methyl-3-oxooctahydro-1H-cyclopenta[b]pyrazin-1-yl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile as a brown foam. MS ESI calc'd. for C28H32ClN7O [M+H]+ 518. found 518.
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[Cl:6][C:7]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:8]=1[O:9][CH2:10][CH:11]1[CH2:16][CH2:15][CH:14]=[CH:13][O:12]1.[Cl:22][CH2:23][CH:24]([OH:34])[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30](Cl)=[CH:29][CH:28]=1>C(OCC)C.C(N(CC)CC)C>[Cl:6][C:7]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:8]=1[O:9][CH2:10][C@@H:11]1[O:12][C@@H:13]([O:34][CH:24]([CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:3])[CH2:23][Cl:22])[CH2:14][CH2:15][CH2:16]1
Reactant: OC(CCl)CCc1ccc(Cl)cc1
Reactant: Clc1ccc(OCC2CCC=CO2)c(Cl)c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: ClCC(CCc1ccccc1Cl)O[C@H]1CCC[C@H](COc2ccc(Cl)cc2Cl)O1

Procedure:
2 Drops of phosphorus oxytrichloride were added to a solution of 282 mg of 2-(2,4-dichlorophenoxymethyl)-3,4-dihydro-2H-pyran and 286 mg of 1-chloro-4-(4-chlorophenyl)-2-butanol in 7 ml of diethyl ether, and the mixture was allowed to react at room temperature for 4 days. At the end of this time, 3 drops of triethylamine were added, the solvent was evaporated off and the residue was purified by column chromatography through silica gel eluted with a 30:5:1 by volume mixture of hexane, benzene and ethyl acetate, to give 441 mg of trans-6-(2,4-dichlorophenoxymethyl)-2-[1-chloro-4-(chlorophenyl)-2-butoxy]tetrahydropyran as a pale yellow liquid comprising a mixture of isomers in a ratio of about 1:1.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8]N2CCN(C)CC2)[CH2:4][CH2:3]1.C([Cl:19])(=O)C>CCOCC>[Cl-:19].[CH3:8][N:5]1[CH2:6][CH2:7][N+:2](=[CH2:1])[CH2:3][CH2:4]1
Reactant: CN1CCN(CN2CCN(C)CC2)CC1
Reactant: CC(=O)Cl
Solvent: CCOCC
Product: C=[N+]1CCN(C)CC1
Product: [Cl-]
Reaction time: 0.5 h

Procedure:
to bis(4-methylpiperazino)methane in ether is added an equimolecular amount of acetyl chloride. After stirring for 1/2 hour, the colorless solid which separates is recovered by filtration providing 4-methyl-1-methylenepiperazinium chloride which is used in the next example.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH3:11][C@H:12]1[O:17][C@@H:16]([CH3:18])[CH2:15][NH:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CC(OC)(C)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:14]2[CH2:13][CH:12]([CH3:11])[O:17][CH:16]([CH3:18])[CH2:15]2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: C[C@@H]1CNC[C@H](C)O1
Reactant: O=Cc1cc(Br)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Product: CC1CN(c2ccc(Br)cc2C=O)CC(C)O1
Temperature: 120 °C
Yield: 91.7 %

Procedure:
A mixture of 5-bromo-2-fluorobenzaldehyde (16.0 g, 78.6 mmol), cis-2,6-dimethylmorpholine (9.32 g, 80.9 mmol), and potassium carbonate (15.0 g, 108 mmol) in DMF (75 mL) is heated in a 120° C. oil bath for 14 hours. The mixture is diluted with MTBE (250 mL) and washed with water (4×200 mL). (Ethyl acetate is added as needed to maintain the homogeneity of the organic layer). The organics are filtered through a 1″ plug of silica gel and evaporated to give 21.5 g of brown solid. This material is approximately 90% pure as judged by HPLC and is used without further purification. 1H NMR (DMSO-d6) δ 10.11, 7.78, 7.75, 7.17, 3.77–3.86, 3.12, 2.56, 1.11.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[C:13]1([S:19]([N:22]2[C:26]3[N:27]=[CH:28][N:29]=[C:30]([Cl:31])[C:25]=3[CH:24]=[CH:23]2)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.IC>C1COCC1>[C:13]1([S:19]([N:22]2[C:26]3[N:27]=[CH:28][N:29]=[C:30]([Cl:31])[C:25]=3[CH:24]=[C:23]2[CH3:1])(=[O:21])=[O:20])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(Cl)ncnc21
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: Cc1cc2c(Cl)ncnc2n1S(=O)(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To flame-dried flask under N2 was charged 0.57 ml (4.07 mmol) of diisopropylamine and 5.0 mL of dry THF. The solution was cooled to −78° C. and 1.63 mL (4.08 mmol) of a 2.5 M solution of n-butyllithium in hexanes added. The resulting mixture was brought to 0° C. and stirred for 10 min. After cooling the mixture again to −78° C., a solution of 1.0 g (3.40 mmol) of crude product from Method C in 10 mL of dry THF was added over a 10 min period. The resulting mixture was stirred for 1 h, at which time, 0.28 mL (4.50 mmol) of iodomethane were added. The reaction mixture was stirred for 2 h, quenched with a saturated solution of NH4Cl and warmed to room temperature. The mixture was stirred for 5 min., diluted with water and extracted three times with ethyl acetate. The combined extracts were washed with brine, dried over MgSO4, filtered and evaporated in vacuo to obtain the title compound. LRMS: 308, 310 (M+2).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3=[N:10][CH:11]=[C:12]([C:14]([O:16]C)=[O:15])[CH:13]=[C:8]3[N:7]=[C:6]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH3:27])=[CH:21][CH:20]=2)[CH2:3][CH2:2]1.[OH-].[Na+]>C1COCC1.CO>[CH:1]1([CH2:4][N:5]2[C:9]3=[N:10][CH:11]=[C:12]([C:14]([OH:16])=[O:15])[CH:13]=[C:8]3[N:7]=[C:6]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH3:27])=[CH:21][CH:20]=2)[CH2:3][CH2:2]1
Reactant: CCOc1ccc(Cc2nc3cc(C(=O)OC)cnc3n2CC2CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCOc1ccc(Cc2nc3cc(C(=O)O)cnc3n2CC2CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 8 %

Procedure:
To a solution of methyl 3-(cyclopropylmethyl)-2-(4-ethoxybenzyl)-3H-imidazo[4,5-b]pyridine-6-carboxylate (260 mg, 0.71 mmol) in THF/MeOH (1:1, 6 ml) was added 1 N NaOH (3 ml, 3 mmol). The reaction mixture was stirred at room temperature for 3 h, and concentrated in vacuo. The residue was dissolved in H2O (10 ml), and acidified by adding 1 N HCl solution to pH5. The solid was collected (230 mg), and the filtrate was extracted with EtOAc (2×50 ml). The extracts were dried over Na2SO4 and concentrated in vacuo to afford an additional crop of product (20 mg). The desired acid was produced in quantitative yield.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:17]2[C@@H:12]([C:13]3[C:21]([OH:22])=[CH:20][CH:19]=[CH:18][C:14]=3[CH2:15][CH2:16]2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:24]1[N:25]=[N:26][C:27]([CH3:30])=[CH:28][CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN1CCCC1=O>C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[C@@H:17]2[C@@H:12]([C:13]3[C:21]([O:22][C:24]4[N:25]=[N:26][C:27]([CH3:30])=[CH:28][CH:29]=4)=[CH:20][CH:19]=[CH:18][C:14]=3[CH2:15][CH2:16]2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]2c3c(O)cccc3CC[C@@H]21
Reactant: Cc1ccc(Cl)nn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Cc1ccc(Oc2cccc3c2[C@H]2CCCN(C(=O)OC(C)(C)C)[C@H]2CC3)nn1
Temperature: 150 °C
Reaction time: 1.5 h

Procedure:
A mixture of cis-10-hydroxy-2,3,4a,5,6,10b-hexahydro-1H-benzo[f]quinoline-4-carboxylic acid tert-butyl ester (0.40 g), 3-chloro-6-methyl-pyridazine (0.13 g), cesium carbonate (0.35 g), and N-methylpyrrolidinone (5 mL) is stirred at 150° C. for 1.5 h. After cooling to room temperature, the mixture is diluted with ethyl acetate and washed with water and brine and dried (Na2SO4). The solvent is evaporated and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 3:1→1:2) to give the title compound. Yield: 0.14 g (impure); LC (method 1): tR=4.19 min; Mass spectrum (ESI+): m/z=396 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH3:11])=[O:9])=[C:4]([NH:14]S(C2C=CC=CC=2)(=O)=O)[CH:3]=1.Br[CH2:25][C:26]([C:28]1[CH:33]=[C:32]([C:34]([CH3:37])([CH3:36])[CH3:35])[CH:31]=[CH:30][N:29]=1)=[O:27]>>[CH3:11][O:10][C:8](=[O:9])[CH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:13][CH:12]=2)[NH:14][C:25]=1[C:26]([C:28]1[CH:33]=[C:32]([C:34]([CH3:37])([CH3:36])[CH3:35])[CH:31]=[CH:30][N:29]=1)=[O:27]
Reactant: CC(C)(C)c1ccnc(C(=O)CBr)c1
Reactant: COC(=O)/C=C/c1ccc(Cl)cc1NS(=O)(=O)c1ccccc1
Product: COC(=O)Cc1c(C(=O)c2cc(C(C)(C)C)ccn2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-4-chloro-2-(penylsulfonylamino)cinnamate (step 1 of Example 8, Method A) and 2-bromoacetyl-4-tert-butylpyridine*.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:12]([O:14][C:15]([CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:16])[CH3:13]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:20]2[CH2:21][CH2:22][CH:17]([C:15]([O:14][CH2:12][CH3:13])=[O:16])[CH2:18][CH2:19]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: CCOC(=O)C1CCNCC1
Solvent: ClCCl
Product: CCOC(=O)C1CCN(S(=O)(=O)c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-bromophenylsulphonyl chloride (7.68 g) in dichloromethane (100 ml) was added dropwise over a period of 30 minutes to a solution of 4-(ethoxycarbonyl)piperidine (4.71 g) in dichloromethane (50 ml) at 0° C. and under argon. The mixture was stirred overnight during which time it was allowed to warm to room temperature. The organic phase was washed with water, brine, dried and evaporated to give a solid. This solid was triturated in petroleum ether (bp 40-60° C.) to give 1-(4-bromophenylsulphonyl)-4-(ethoxycarbonyl)piperidine (l0.05 g), m.p. 137-133° C.
Reaction SMILES: N1(O[C:11]2[N:16]=[C:15]([N:17]3[CH2:22][CH2:21][CH:20]([CH2:23][NH:24]C(=O)OC(C)(C)C)[CH2:19][CH2:18]3)[C:14]([C:32](=[O:34])[NH2:33])=[CH:13][N:12]=2)C2C=CC=CC=2N=N1.[NH2:35][C:36]1[CH:41]=[CH:40][C:39]([N:42]2[CH2:47][CH2:46][N:45]([C:48](=[O:50])[CH3:49])[CH2:44][CH2:43]2)=[CH:38][CH:37]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[C:48]([N:45]1[CH2:44][CH2:43][N:42]([C:39]2[CH:40]=[CH:41][C:36]([NH:35][C:11]3[N:16]=[C:15]([N:17]4[CH2:18][CH2:19][CH:20]([CH2:23][NH2:24])[CH2:21][CH2:22]4)[C:14]([C:32]([NH2:33])=[O:34])=[CH:13][N:12]=3)=[CH:37][CH:38]=2)[CH2:47][CH2:46]1)(=[O:50])[CH3:49]
Reactant: CC(=O)N1CCN(c2ccc(N)cc2)CC1
Reactant: CC(C)(C)OC(=O)NCC1CCN(c2nc(On3nnc4ccccc43)ncc2C(N)=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Product: CC(=O)N1CCN(c2ccc(Nc3ncc(C(N)=O)c(N4CCC(CN)CC4)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 11.3 %

Procedure:
A mixture of tert-butyl (1-(2-(1H-benzo[d][1,2,3]triazol-1-yloxy)-5-carbamoylpyrimidin-4-yl)piperidin-4-yl)methylcarbamate (138 mg, 0.294 mmol), 1-(4-(4-aminophenyl)piperazin-1-yl)ethanone (84 mg, 0.38 mmol) and p-toluenesulfonic acid (56 mg, 0.294 mmol) in dioxane (4 mL) was stirred at 100° C. for 3 h. dioxane was removed in vacuo. The residue was dissolved in CH2C12 (5 mL) and TFA (5 mL). The solution was stirred at room temperature for 30 min. It was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (15 mg). MS 453.6 (M+H); UV 222.8, 263.8 nm.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:26]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[C:28](F)[CH:27]=2)[N:3]=1.CCO.CCN(C(C)C)C(C)C.[NH2:47][NH2:48]>CO>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:26]2[CH:27]=[C:28]3[C:29]([C:32]([NH2:33])=[N:47][NH:48]3)=[CH:30][CH:31]=2)[N:3]=1
Reactant: NN
Reactant: C[C@@H]1CC[C@H](C(=O)NCc2ccccc2F)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Solvent: CCO
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CC[C@H](C(=O)NCc2ccccc2F)CN1c1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Temperature: 110 °C
Reaction time: 8 h
Yield: 41.2 %

Procedure:
Into a sealable vial, (3S,6R)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-N-[(2-fluorophenyl)methyl]-6-methyl-3-piperidinecarboxamide (189 mg, 0.409 mmol), EtOH (5 mL), Hunig's base (0.071 ml, 0.409 mmol), and hydrazine anhydrous (0.077 mL, 2.452 mmol) were added, and the yellow suspension mixture was heated overnight at 110° C. in an oil bath. When the temperature of the reaction reached to 100° C., the solid in the mixture was all dissolved. After overnight, there was a yellow solution as well as a little amount of black colored solid formed. LCMS showed mainly product. CH3OH (5 mL) was added to the solution. The black solid was filtered from the yellow solution. Water (20 mL) was added to the yellow solution, and a solid was formed. The solid was filtered, washed by water, and dried in vacuum. The solid was recrystallized from CH3CN, and the solid was filtered, washed by CH3CN, and dried in vacuum to afford the title compound (80 mg) as a light yellow solid. LC-MS (ES) m/z=475 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.15 (d, J=6.8 Hz, 3H), 1.66 (m, 2H), 1.76 (m, 1H), 1.84 (m, 1H), 2.35 (m, 1H), 2.85 (m, 1H), 4.22-4.47 (m, 3H), 5.38 (s, 2H), 6.08 (s, 2H), 6.59 (s, 1H), 7.14-7.25 (m, 2H), 7.28-7.41 (m, 2H), 7.57 (m, 1H), 7.70 (d, J=8.3 Hz, 1H), 7.94 (s, 1H), 8.45-8.54 (m, 1H), 11.50 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[SH:7].[H-].[Na+].[Cl:10][C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=1F.CCOC(C)=O>C1COCC1>[Cl:10][C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=1[S:7][C:3]1[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Reactant: Cn1ccnc1S
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cn1ccnc1Sc1ccc([N+](=O)[O-])cc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.6 %

Procedure:
A solution of 1-methyl-1H-imidazole-2-thiol (1.14 g, 10 mmol) in THF (50 ml) under argon at 0° C. was treated with NaH (303 mg, 11.98 mmol). The mixture was warmed to rt. A solution of 2-chloro-1-fluoro-4-nitro-benzene (1.76 g, 10 mmol) in THF (50 ml) was added, and the mixture was stirred at 70° C. for 4 h, cooled to rt. Treated with EtOAc (100 ml), the mixture was washed with H2O (2×25 ml), 1N KOH (30 ml) and brine (20 ml), dried with Na2SO4. Removal of the solvent under reduced pressure gave a yellow solid. Recrystalization of the solid in CH2Cl2/hexanes gave 426A (2.31 g, 86%) as a slight yellowish solid. It has a retention time of 3.99 min (standard LC1 method, 8 min run). MS Found: (M+H)+=270.1