Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][CH:4]=[C:3]([OH:10])[CH:2]=1.Cl[CH2:12][CH2:13][C:14]([OH:16])=[O:15]>C(O)C.[OH-].[K+]>[N+:7]([C:6]1[CH:5]=[CH:4][C:3]([O:10][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:2][CH:1]=1)([O-:9])=[O:8]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: O=C(O)CCCl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCOc1ccc([N+](=O)[O-])cc1
Yield: 35.5 %

Procedure:
Dissolve p-nitrophenol (11 g, 100 mmol), 3-chloropropanoic acid (14 g, 100 mmol) in a mixture of ethanol (100 mL) and 20% aqueous KOH solution (100 mL). Heat to reflux for 2 hrs, then adjust pH=1-3, extract with EtOAc (300 mL×3), combine the organic layers and wash with brine (300 mL×2), dry over anhydrous Na2SO4. Concentrate under reduced pressure to give the crude product. Purification by chromatography (silica gel, EtOAc:PE=1:4) affords the title compound (7.5 g, 14.9%). MS: (M+1): 212.1.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][CH3:17])[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([NH:22][C:23]([C@@H:25]1[CH2:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:26]1)=[O:24])[CH2:19][CH2:20][CH3:21]>>[CH2:18]([NH:22][C:23]([C@@H:25]1[CH2:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:26]1[C:13](=[O:15])[C@@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH2:16][CH3:17])=[O:24])[CH2:19][CH2:20][CH3:21]
Reactant: CCCCNC(=O)[C@@H]1Cc2ccccc2N1
Reactant: CC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Product: CCCCNC(=O)[C@@H]1Cc2ccccc2N1C(=O)[C@H](CC)NC(=O)OCc1ccccc1

Procedure:
The process is performed as in Example 15 c), using 0.646 g (2.73 mmol) of N-benzyloxycarbonyl-2(S)-aminobutyric acid prepared as in Example 3 a) and 0.595 g (2.73 mmol) of the amide prepared in step b). An oil is obtained which is recrystallized from CCl4.
Reaction SMILES: [N:1]1([C:7]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][C:14]([O:18][C@H:19]2[CH2:23][CH2:22][NH:21][CH2:20]2)=[CH:13][CH:12]=3)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:25][CH:26]1[CH2:28][CH2:27]1>>[CH:26]1([CH2:25][N:21]2[CH2:22][CH2:23][C@H:19]([O:18][C:14]3[CH:15]=[C:16]4[C:11](=[CH:12][CH:13]=3)[NH:10][C:9]([C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)=[O:8])=[CH:17]4)[CH2:20]2)[CH2:28][CH2:27]1
Reactant: O=C(c1cc2cc(O[C@H]3CCNC3)ccc2[nH]1)N1CCOCC1
Reactant: BrCC1CC1
Product: O=C(c1cc2cc(O[C@H]3CCN(CC4CC4)C3)ccc2[nH]1)N1CCOCC1

Procedure:
According to the procedure described for the synthesis of [5-((S)-1-Isopropyl-pyrrolidin-3-yloxy)-1H-indol-2-yl]-morpholin-4-yl-methanone the title compound was synthesized from Morpholin-4-yl-[5-((S)-pyrrolidin-3-yloxy)-1H-indol-2-yl]-methanone and bromomethyl-cyclopropane. The title compound was obtained as light yellow solid. MS (m/e): 370.3 (MH+, 100%).
Reaction SMILES: [CH3:1][C:2](OC(C)=O)=[O:3].CCN(CC)CC.Cl.[NH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]1[C:26]2[B:27]([OH:34])[O:28][CH:29]([CH2:30][N+:31]([O-:33])=[O:32])[C:25]=2[CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[OH:34][B:27]1[C:26]2[C:21]([O:20][CH2:19][CH2:18][CH2:17][NH:16][C:2](=[O:3])[CH3:1])=[CH:22][CH:23]=[CH:24][C:25]=2[CH:29]([CH2:30][N+:31]([O-:33])=[O:32])[O:28]1
Reactant: CC(=O)OC(C)=O
Reactant: NCCCOc1cccc2c1B(O)OC2C[N+](=O)[O-]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCCCOc1cccc2c1B(O)OC2C[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ac2O (1.16 mL, 12.3 mmol) was added slowly to a solution of Et3N (2.33 mL, 16.5 mmol) and 7-(3-amino-propoxy)-3-nitromethyl-3H-benzo[c][1,2]oxaborol-1-ol hydrochloride (1.69 g, 76.5 mmol) in CH2Cl2 (50 mL) at 0° C. (bath temp). The reaction mixture was stirred at rt for 1 h and then quenched with H2O (50 mL). The mixture was extracted with CH2Cl2 and the organic fraction was dried (MgSO4) and concentrated in vacuo to give the title compound as a viscous liquid: yield 1.29 g (75%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:20]=[C:19]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=[CH:18]3)[C:12]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Br:27]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:27][C:20]1[C:19]2[C:13]([CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[C:12]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:11]=1[C:8]1[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CS(=O)(=O)c1ccc(-c2cc3cccccc-3c2-c2ccccc2)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CS(=O)(=O)c1ccc(-c2c(Br)c3cccccc-3c2-c2ccccc2)cc1
Temperature: 25 °C
Yield: 99.1 %

Procedure:
To a solution of 2-(4-methylsulfonylphenyl)-1-phenylazulene (0.43 g) in CCl4 (20.0 ml) was added N-bromosuccinimide (0.23 g) and α,α'-azobis(isobutyronitrile) (0.01 g), and the reaction mixture was heated under reflux for 1 hr. The mixture was cooled to room temperature and was filtered, and concentrated. The crude product was purified by SiO2 column chromatography (benzene/EtOAc, 20:1) to give the title compound (0.52 g) as green crystals; mp 172°-173° C.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH2:5][C:6]3[C:12]([C:13]4[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=4)=[N:11][N:10]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:7]=3[C:8]=2[CH:9]=1.[CH3:29][N:30]1[CH2:35][CH2:34][N:33]([C:36]2[CH:41]=[CH:40][C:39](B3OC(C)(C)C(C)(C)O3)=[CH:38][N:37]=2)[CH2:32][CH2:31]1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[C:6]3[CH2:5][C:4]4[S:3][C:2]([C:39]5[CH:38]=[N:37][C:36]([N:33]6[CH2:32][CH2:31][N:30]([CH3:29])[CH2:35][CH2:34]6)=[CH:41][CH:40]=5)=[CH:9][C:8]=4[C:7]=3[N:10]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[N:11]=2)=[CH:14][CH:15]=1
Reactant: COc1ccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sc(Br)cc2-3)cc1
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sc(-c4ccc(N5CCN(C)CC5)nc4)cc2-3)cc1
Temperature: 100 °C
Yield: 60 %

Procedure:
A mixture of the corresponding 2-Bromo-6-(4-methoxy-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.75 g, 1.5 mmol), 1-Methyl-4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-piperazine (0.5 g, 17 mmol), Na2CO3 (2 M, 3.6 mL), and Pd(PPh3)2Cl2 (110 mg, 0.15 mmol) in toluene/ethanol (1:1, 12 mL) was heated at 100° C. for 8 hr. The solution was cooled to room temperature and extracted with ethyl acetate. The target product was purified by gravity column chromatography (20% EtOAc in hexane) to give 6-(4-Methoxy-phenyl)-2-[6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene as orange solid in 60% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C[O-].[Na+].Br[CH:13]([C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=2)=[CH:20][CH:19]=1)[C:14]([O:16][CH3:17])=[O:15]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:13]([C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]3[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:32])=[O:33])=[CH:27][CH:26]=3)=[CH:20][CH:19]=2)[C:14]([O:16][CH3:17])=[O:15])=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)cc1
Reactant: COC(=O)C(Br)c1ccc(Oc2ccc(S(C)(=O)=O)cc2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(Oc1ccc(F)cc1)c1ccc(Oc2ccc(S(C)(=O)=O)cc2)cc1
Reaction time: 18 h
Yield: 50 %

Procedure:
To a solution of 2.7 g of p-fluorophenol in 20 ml of methanol was added 1.89 g of sodium methoxide. To the solution was added 7.98 g of methyl α-bromo-α-[p-(p-methylsulfonylphenoxy)phenyl]acetate in 40 ml of methanol. The mixture was refluxed and stirred for 18 hours, chilled and filtered to give 4.3 g of white crystals, mp 135°-137° C. Recrystallization from acetone-hexane gave the product as white crystals, mp 136°-138° C.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10](OS(C)(=O)=O)[CH2:9]1)=O)(C)(C)C.[OH:17][CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>>[OH:17][CH:18]1[CH2:23][CH2:22][N:21]([CH:10]2[CH2:9][NH:8][CH2:11]2)[CH2:20][CH2:19]1
Reactant: OC1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Product: OC1CCN(C2CNC2)CC1
Temperature: 110 °C

Procedure:
A mixture of 1-(t-butoxycarbonyl)-3-methanesulphonyloxyazetidine (see International Patent Application Publication no WO93/19059) (1.2 g, 4.78 mmol) and 4-hydroxypiperidine (2.89 g, 6 mol equivalent) was heated at 110° C. for sixteen hours. The mixture was cooled to room temperature and partitioned between ethyl acetate (100 ml) and 5% aqueous sodium bicarbonate solution (100 ml). The layers were separated and the aqueous phase was extracted with a further portion of ethyl acetate (100 ml). The combined organic layers were dried over anhydrous magnesium sulphate. The solution was filtered, the solvent removed from the filtrate under reduced pressure and the crude product purified by column chromatography using silica gel eluting with methanol:dichloromethane (1:9, by volume) to give 1-butoxycarbonyl)-3-(4-hydroxypiperidyl)azetidine (1.4 g). TLC Rf=0.3 (silica, methanol:dichloromethane, 1:9, by volume). 1H-NMR (CDCl3): δ=1.35-1.5(m,1OH), 1.55-1.65(m,2H), 1.9-2.1(m,4H), 2.6-2.7(m,2H), 3.0-3.1 (m,1H), 3.7-3.95(m,5H)ppm.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[C:5]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[N:4][N:3]=1.[NH2:20][CH:21]1[CH2:26][CH2:25][N:24]([CH2:27][C:28]2[CH:37]=[CH:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=2)[CH2:23][CH2:22]1>>[F:12][C:9]1[CH:10]=[C:11]2[C:6]([C:5]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)=[N:4][N:3]=[C:2]2[NH:20][CH:21]2[CH2:22][CH2:23][N:24]([CH2:27][C:28]3[CH:37]=[CH:36][C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH:29]=3)[CH2:25][CH2:26]2)=[CH:7][CH:8]=1
Reactant: Fc1ccc(-c2nnc(Cl)c3cc(F)ccc23)cc1
Reactant: NC1CCN(Cc2ccc3ccccc3c2)CC1
Product: Fc1ccc(-c2nnc(NC3CCN(Cc4ccc5ccccc5c4)CC3)c3cc(F)ccc23)cc1

Procedure:
This compound is obtained according to the procedure described in 1.4. by reacting 1-chloro-7-fluoro-4-(4-fluorophenyl)phthalazine with 4-amino-1-(naphthalen-2-ylmethyl)piperidine.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]2[N:8]=[CH:9][CH:10]=[N:11][C:12]=2[C:13]([C:16]2[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=2[Cl:27])=[CH:14][CH:15]=1)=[O:5])C.[NH2:28][C:29]1[N:34]=[CH:33][C:32]([CH2:35][N:36]2[CH2:41][CH2:40][NH:39][C:38](=[O:42])[CH2:37]2)=[CH:31][CH:30]=1.C[Al](C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.CO.C(Cl)Cl>[O:42]=[C:38]1[NH:39][CH2:40][CH2:41][N:36]([CH2:35][C:32]2[CH:31]=[CH:30][C:29]([NH:28][C:4]([C:6]3[C:7]4[N:8]=[CH:9][CH:10]=[N:11][C:12]=4[C:13]([C:16]4[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=4[Cl:27])=[CH:14][CH:15]=3)=[O:5])=[N:34][CH:33]=2)[CH2:37]1
Reactant: CCOC(=O)c1ccc(-c2c(F)c(OC)cc(OC)c2Cl)c2nccnc12
Reactant: Nc1ccc(CN2CCNC(=O)C2)cn1
Agent: C[Al](C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ccc(CN4CCNC(=O)C4)cn3)c3nccnc23)c1F
Temperature: 80 °C
Reaction time: 6 h

Procedure:
The title compound was prepared in analogy to the procedure described in Example 115 but using 8-(2-chloro-6-fluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step 144.1), 4-(6-amino-pyridin-3-ylmethyl)-piperazin-2-one (Step 103.1), 2 equiv of trimethyl aluminum, stirring the reaction mixture for 6 h at 80° C., pouring it onto a saturated aqueous solution of NaHCO3 and DCM. The title compound: ESI-MS: 551.0 [M+H]+; tR=3.59 min (System 1); TLC: Rf=0.13 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[N:3]=1.[CH3:13][N:14]([CH3:22])[C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][N:16]=1.C([O-])(=O)C.[Na+]>>[CH3:13][N:14]([CH3:22])[C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([CH3:12])[N:3]=2)=[CH:17][N:16]=1
Reactant: Cc1nc(Cl)c2ccccc2n1
Reactant: CN(C)c1ccc(N)cn1
Agent: CC(=O)[O-]
Agent: [Na+]
Product: Cc1nc(Nc2ccc(N(C)C)nc2)c2ccccc2n1

Procedure:
To a solution of 2-dimethylamino-5-nitropyridine (334 mg, 2 mmol) in 100 ml of methanol was added 5% Pd/C (100 mg, 0.94 mmol). The reaction mixture was hydrogenated under 45 psi at room temperature for 2 h, then it was filtered through a layer of celite (2.5 in d×2 in h) and washed with additional methanol (25 ml). The organic filtrate was concentrated to yield 200 mg (73%) of 2-dimethylamino-5-amino-pyridine as dark brown sticky solids. The title compound was prepared from 4-chloro-2-methyl-quinazoline (182.2 mg, 1.02 mmol), 2-dimethylamino-5-amino-pyridine (140 mg, 1.02 mmol) and sodium acetate (98.4 mg, 1.2 mmol) similar to example 20 to give 60 mg (21%) of paint yellow solids. 1H NMR (CDCl3): 8.43 (d, J=2.4 Hz, 1H), 7.95 (dd, J=2.7 Hz, J=9.3 Hz, 1H), 7.84-7.72 (m, 3H), 7.47 (t, J=8.1 Hz, 1H), 7.16 (brs, 1H), 6.61 (d, J=9.0 Hz, 1H), 3.12 (s, 6H), 2.65 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:29])[N:4]([CH2:18][C:19]2[CH:28]=[CH:27][CH:26]=[C:25]3[C:20]=2[CH:21]=[CH:22][N:23]=[CH:24]3)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].[BH3-]C#N.[Na+]>CC(O)=O.O.[OH-].[Na+]>[Cl:1][C:2]1[C:3](=[O:29])[N:4]([CH2:18][C:19]2[CH:28]=[CH:27][CH:26]=[C:25]3[C:20]=2[CH2:21][CH2:22][NH:23][CH2:24]3)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: O=c1c(Cl)c(OCc2ccc(F)cc2F)ccn1Cc1cccc2cnccc12
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: O=c1c(Cl)c(OCc2ccc(F)cc2F)ccn1Cc1cccc2c1CCNC2
Temperature: 0 °C
Reaction time: 2 h
Yield: 91.7 %

Procedure:
To a solution of 3-chloro-4-(2,4-difluorobenzyloxy)-1-isoquinolin-5-ylmethyl-1H-pyridin-2-one (Example 84) (0.14 g, 0.34 mmol) in AcOH (1.3 mL) was added NaCNBH3 (0.09 g, 1.4 mmol), and the reaction mixture was stirred for 2 h. The reaction mixture was cooled to 0° C., and diluted with water(10 mL) and 40% aqueous NaOH (10 mL), and the aqueous layer was washed with EtOAc (3×50 mL). The combined organics were washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, eluent 98:1.8:0.2 to 88:10.8:1.2 CH2Cl2/MeOH/NH3) provided 3-chloro-4-(2,4-difluoro-benzyloxy)-1-(1,2,3,4-tetrahydroisoquinolin-5-ylmethyl)-1H-pyridin-2-one as a white solid (0.13 g, 92%): mp 180-184° C.; 1H NMR (300 MHz, MeOD) δ 7.65-7.55 (m, 2H), 7.16-7.00 (m, 4H), 6.90-6.80 (m, 1H), 6.60 (d, J=8 Hz, 1H), 5.31 (s, 2H), 5.20 (s, 2H), 4.06 (s, 2H), 3.21 (t, J=6 Hz, 2H), 2.82 (t, J=6 Hz, 2H). ES HRMS m/z 417.1173 (M+H C22H20ClF2N2O2 requires 417.1176).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][NH:14][CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.[F:25][C:26]1([F:35])[CH2:31][CH2:30][CH:29]([C:32](O)=[O:33])[CH2:28][CH2:27]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][N:14]([C:32]([CH:29]3[CH2:30][CH2:31][C:26]([F:35])([F:25])[CH2:27][CH2:28]3)=[O:33])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: O=C(O)C1CCC(F)(F)CC1
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CNC[C@H]1c1ccc(Cl)cc1
Product: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCC(F)(F)CC2)C[C@H]1c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described for the synthesis of example 44 (step c), the title compound [(3S,4R)-4-(4-chloro-phenyl)-1-(4,4-difluoro-cyclohexanecarbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester was prepared from [(3S,4R)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester using 4,4-Difluoro-cyclohexanecarboxylic acid instead of 1-methylcyclopropane-1-carboxylic acid and was obtained as an off-white solid. MS m/e: 494.2 [M]+.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][N:5]=1)[NH2:3].CN(C)/[CH:14]=[CH:15]/[C:16]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)=O>COCCO>[CH3:24][C:21]1[CH:22]=[CH:23][C:18]([C:16]2[N:2]([C:4]3[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][N:5]=3)[N:3]=[CH:14][CH:15]=2)=[CH:19][CH:20]=1
Reactant: Cc1ccc(C(=O)/C=C/N(C)C)cc1
Reactant: N#Cc1ccnc(NN)c1
Agent: Cl
Solvent: COCCO
Product: Cc1ccc(-c2ccnn2-c2cc(C#N)ccn2)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 92.2 %

Procedure:
A mixture of 2-hydrazinylpyridine-4-carbonitrile hydrochloride salt (124 mg, 0.6 mmol, PREPARATION 3) and (2E)-3-(dimethylamino)-1-(4-methylphenyl)prop-2-en-1-one (95 mg, 0.5 mmol) in 2-methoxyethanol (3 mL) was stirred at 100° C. for 2 h. The reaction mixture was cooled, concentrated, and dissolved in EtOAc and then washed with water and brine. The organic phase was dried, concentrated, triturated with EA/PE (1:10, 5 mL), filtered, and dried to give the title compound (120 mg, 92%) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 2.38 (3H, s), 6.49 (1H, d, J=1.6 Hz), 7.16 (4H, s), 7.38 (1H, dd, J=5.2, 1.2 Hz), 7.76 (1H, d, J=1.2 Hz), 7.90 (1H, s,), 8.44(1H, d, J=5.2 Hz).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH:12]1([C:18](Cl)=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(N(CC)CC)C>O1CCCC1>[CH:12]1([C:18]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([F:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=2)=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: O=C(Cl)C1CCCCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)C1CCCCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
15.6 g (0.1 mol) of 4-fluoro-3-nitro-aniline and 17.9 g (0.11 mol) of cyclohexylcarboxylic acid chloride are dissolved in 250 ml tetrahydrofuran and after the addition of 12.1 g (0.12 mol) of triethylamine the mixture is stirred for 3 hours at ambient temperature. The solvent is distilled off, the residue is mixed with water and extracted with ethyl acetate. The combined organic extracts are dried over sodium sulphate and concentrated by evaporation.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C@@H:2]([CH2:4][C:5]([OH:7])=[O:6])[OH:3].C1(N=C=NC2CCCCC2)CCCCC1.[CH2:25](O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1>[CH2:25]([O:8][C:1](=[O:9])[C@@H:2]([CH2:4][C:5]([OH:7])=[O:6])[OH:3])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: OCc1ccccc1
Reactant: O=C(O)C[C@@H](O)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: O=C(O)C[C@@H](O)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 64 %

Procedure:
To a solution of D-malic acid (18.8 g., 140.2 mmole) in 150 ml. of freshly-distilled THF was added dicyclohexylcarbodiimide (DCC, 1.1 equiv.) and the mixture was stirred at room temperature for 45 minutes. The reaction mixture was filtered to remove the precipitate of dicyclohexylurea which formed. The precipitate was washed with two 50 ml. portions of THF and the washings were combined with the filtrate. To the combined filtrate and washings were added two equivalents of benzyl alcohol and the solution was stirred overnight at room temperature. The reaction mixture was evaporated to remove the solvent and the residual oil containing the monoester was dissolved in 100 ml. of ethyl acetate. The solution was extracted with three 50 ml. portions of a 10% solution of sodium carbonate in water and the extracts were combined, acidified to pH 2 and extracted with three 50 ml. portions of ethyl acetate. The extracts were combined, washed with 25 ml. of brine, dried over magnesium sulfate, filtered, and then evaporated to dryness to yield D-malic acid monobenzyl ester as an oil in 64% yield.
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[N:6][CH:7]=[CH:8][N:9]=2)[NH:4][C:3]1=[S:13].[OH-].[Na+].[Cl:16][C:17]1[CH:32]=[CH:31][C:20]([C:21]([C:23]2[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=2)=[O:22])=[CH:19][CH:18]=1>C(O)C.O>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]([C:23]2[CH:30]=[CH:29][C:26]([CH2:27][S:13][C:3]3[N:2]([CH3:1])[C:11](=[O:12])[C:10]4[C:5](=[N:6][CH:7]=[CH:8][N:9]=4)[N:4]=3)=[CH:25][CH:24]=2)=[O:22])=[CH:31][CH:32]=1
Reactant: Cn1c(=S)[nH]c2nccnc2c1=O
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cn1c(SCc2ccc(C(=O)c3ccc(Cl)cc3)cc2)nc2nccnc2c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 27.9 %

Procedure:
To a solution of 3-methylpteridin-4-one-2-thione, (194 mg) in ethanol (5 ml) were added 1N-aqueous sodium hydroxide solution (1.2 ml) and 4-(4-chlorobenzoyl) benzyl bromide (310 mg) and the mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. The solvent was then distilled off and the residue was purified by silica gel column chromatography (ethyl acetate) to provide the title compound as white powder (118 mg, 28%).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH3:11])[C:5]([CH:12]2[CH2:14][O:13]2)=[CH:4][CH:3]=1.[C:15]([N:22]1[CH2:27][CH2:26][NH:25][C@H:24]([CH2:28][OH:29])[CH2:23]1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]>C(O)C>[C:8]([C:7]1[C:6]([O:10][CH3:11])=[C:5]([CH:12]([OH:13])[CH2:14][N:25]2[CH2:26][CH2:27][N:22]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:23][C@H:24]2[CH2:28][OH:29])[CH:4]=[CH:3][C:2]=1[F:1])#[N:9]
Reactant: COc1c(C2CO2)ccc(F)c1C#N
Reactant: CC(C)(C)OC(=O)N1CCN[C@H](CO)C1
Solvent: CCO
Product: COc1c(C(O)CN2CCN(C(=O)OC(C)(C)C)C[C@H]2CO)ccc(F)c1C#N
Temperature: 150 °C

Procedure:
6-Fluoro-2-methoxy-3-(oxiran-2-yl)benzonitrile (1.4 g, 7.3 mmol) and (S)-4-N-BOC-2-hydroxymethylpiperazine (3.13 g, 14.5 mmol) were suspended in ethanol (15 mL) then heated in a microwave apparatus for 60 min at 150° C. The reaction mixture was cooled and evaporated to dryness. The residue was purified by chromatography through a 40 g Redi-sep column and eluting with 5% MeOH/95% EtOAc to yield the title compound: LC-MS: M+1=410;
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]2[CH2:13][CH2:14][CH:9]1[CH:10]([C:38]([OH:40])=O)[CH:11]2[NH:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]=[C:29]([CH3:37])[CH:28]=2)=[CH:21][CH:20]=1)(=[O:18])=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:41][OH:42]>>[OH:42][NH:41][C:38]([CH:10]1[CH:11]([NH:15][S:16]([C:19]2[CH:20]=[CH:21][C:22]([O:25][CH2:26][C:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]=[C:29]([CH3:37])[CH:28]=3)=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:12]2[N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH:9]1[CH2:14][CH2:13]2)=[O:40]
Reactant: Cc1cc(COc2ccc(S(=O)(=O)NC3C(C(=O)O)C4CCC3N4C(=O)OC(C)(C)C)cc2)c2ccccc2n1
Reactant: NO
Product: Cc1cc(COc2ccc(S(=O)(=O)NC3C(C(=O)NO)C4CCC3N4C(=O)OC(C)(C)C)cc2)c2ccccc2n1

Procedure:
According to the procedure of Example 24, Step 3, 0.15 g (0.26 mmol) of 3-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonylamino]-7-aza-bicyclo[2.2.1]heptane-2,7-dicarboxylic acid 7-tert-butyl ester and hydroxylamine gave tert-butyl 2-[(hydroxyamino)carbonyl]-3-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]-7-azabicyclo[2.2.1]heptane-7-carboxylate as an amorphous off yellow solid (0.0162 g, 14.7%) after Biotage Flash 40S chromatography, eluting with 5% methanol in ethyl acetate. MS: 583 (M+H)+