Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8](=S)[NH:7][C:6]=2[CH:17]=1.[NH2:18][CH2:19][CH2:20][C:21]1[N:25]=[CH:24][NH:23][CH:22]=1>C(OCCO)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8]([NH:18][CH2:19][CH2:20][C:21]3[NH:25][CH:24]=[N:23][CH:22]=3)=[N:7][C:6]=2[CH:17]=1
Reactant: NCCc1c[nH]cn1
Reactant: S=C1Nc2cc(Cl)ccc2Nc2ccccc21
Solvent: CCOCCO
Product: Clc1ccc2c(c1)N=C(NCCc1cnc[nH]1)c1ccccc1N2
Yield: 100.1 %

Procedure:
A solution of 5.8 g (0.022 mol) of 8-chloro-5,10-dihydro-dibenzo[b,e][1,4]diazepin-11-thione in 145 mL of 2-ethoxyethanol was treated with 4.94 g (0.044 mol) of histamine and heated at reflux overnight. The solvent was removed under reduced pressure and the residue taken up in EtOAc and washed three times with H2O, then saturated NaHCO3 solution, then saturated NaCl solution. Drying over MgSO4 and removal of the solvent under reduced pressure left the crude product as a yellow foam. This was dissolved in CH2Cl2 and slowly treated with hexane to give 7.44 g (99.2% yield) of the product as an amorphous yellow solid. The structure was confirmed by NMR and mass spectroscopy. (m+H)+ =338.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:12]2[CH:25]=[C:24]([CH2:26][CH3:27])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[N:16]=1>>[N:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:15]1[N:16]=[C:11]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)[C:12]2[CH:25]=[C:24]([CH2:26][CH3:27])[S:23][C:13]=2[N:14]=1
Reactant: CCc1cc2c(Cl)nc(-c3ccccn3)nc2s1
Reactant: NCc1ccc(F)cc1
Product: CCc1cc2c(NCc3ccc(F)cc3)nc(-c3ccccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 4-fluorobenzylamine with 4-chloro-2-(pyridin-2-yl)-6-ethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)4-(4-fluorobenzylamino)-6-ethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [F:1][CH:2](P(=O)(C1C=CC=CC=1)C1C=CC=CC=1)[F:3].C([N-]C(C)C)(C)C.[Li+].[O:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]1[O:32][C:33]1[CH:50]=[CH:49][C:48]2[C:47]3[C@H:38]([C@H:39]4[C@@:43]([CH2:45][CH:46]=3)([CH3:44])[C:42](=O)[CH2:41][CH2:40]4)[CH2:37][CH2:36][C:35]=2[CH:34]=1>O1CCCC1.C(OCC)(=O)C.O>[F:1][C:2]([F:3])=[C:36]1[CH2:37][CH2:38][C@H:39]2[C@H:40]3[C:47](=[CH:46][CH2:45][C@:43]12[CH3:44])[C:48]1[CH:35]=[CH:34][C:33]([O:32][CH:27]2[CH2:28][CH2:29][CH2:30][CH2:31][O:26]2)=[CH:50][C:49]=1[CH2:42][CH2:41]3
Reactant: O=P(c1ccccc1)(c1ccccc1)C(F)F
Reactant: C[C@]12CC=C3c4ccc(OC5CCCCO5)cc4CC[C@H]3[C@@H]1CCC2=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: C[C@]12CC=C3c4ccc(OC5CCCCO5)cc4CC[C@H]3[C@@H]1CCC2=C(F)F
Reaction time: 1 h
Yield: 42.6 %

Procedure:
A solution of 3.85 g of difluoromethyldiphenylphosphine oxide in 107 ml of tetrahydrofuran is slowly mixed with 7.6 ml of 2 M lithium diisopropylamide solution at a bath temperature of -50° C., and it is stirred for 1 hour. Then, a solution of 2.14 g of 3-tetrahydropyranyloxy-estra-1,3,5(10),9(11)-tetraen-17-one in 42 ml of tetrahydrofuran is slowly added, stirred for 15 minutes, slowly heated at a bath temperature of from -50° C. to 100° C. and refluxed for 2.5 hours. For working-up, it is diluted with ethyl acetate and water, suctioned off on Celite, rewashed with ethyl acetate, washed with water as well as with saturated sodium chloride solution, dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with hexane/ethyl acetate/triethylamine. 1.0 g of 17-difluoromethylene-3-tetrahydropyranyloxy-estra-1,3,5(10),9(11) -tetraene is obtained as a colorless oil, [α]D22 -+52.6° (c-0.5% in pyridine).
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[F:15][C:16]([F:38])([F:37])[C:17]1[CH:18]=[C:19]([N:23]2[CH2:28][CH2:27][CH:26]([C:29]([N:31]3[CH2:35][CH2:34][C@H:33]([NH2:36])[CH2:32]3)=[O:30])[CH2:25][CH2:24]2)[CH:20]=[CH:21][CH:22]=1.[OH:39][C:40]1([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][N:48]=2)[CH2:45][CH2:44][C:43](=O)[CH2:42][CH2:41]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CCOC(C)=O>[N:48]1[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=1[C:40]1([OH:39])[CH2:45][CH2:44][CH:43]([NH:36][C@H:33]2[CH2:34][CH2:35][N:31]([C:29]([CH:26]3[CH2:27][CH2:28][N:23]([C:19]4[CH:20]=[CH:21][CH:22]=[C:17]([C:16]([F:15])([F:37])[F:38])[CH:18]=4)[CH2:24][CH2:25]3)=[O:30])[CH2:32]2)[CH2:42][CH2:41]1
Reactant: O=C1CCC(O)(c2ccccn2)CC1
Reactant: N[C@H]1CCN(C(=O)C2CCN(c3cccc(C(F)(F)F)c3)CC2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(C1CCN(c2cccc(C(F)(F)F)c2)CC1)N1CC[C@H](NC2CCC(O)(c3ccccn3)CC2)C1
Reaction time: 8 h

Procedure:
(3S)-1-({1-[3-(Trifluoromethyl)phenyl]piperidin-4-yl}carbonyl)pyrrolidin-3-amine bis(trifluoroacetate) (110 mg, 0.20 mmol), 4-hydroxy-4-pyridin-2-yl-cyclohexanone (45 mg, 0.24 mmol), triethylamine (0.082 mL, 0.59 mmol), and sodium triacetoxyborohydride (83 mg, 0.39 mmol) were mixed in methylene chloride (6 mL). After being stirred overnight, the reaction mixture was diluted with EtOAc and washed with saturated Na2CO3. The aqueous layer was extracted with EtOAc three times. The combined organic layers were dried (MgSO4), concentrated and purified by silica gel column (EtOAc to 1% Et3N/EtOAc to 5% Et3N/EtOAc) to provide the title compound. LCMS (M+H)=517.2.
Reaction SMILES: [I:1][C:2]1[C:3](O)=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.O=P(Cl)(Cl)[Cl:14].P(Cl)(Cl)(Cl)(Cl)Cl>O>[Cl:14][C:3]1[C:2]([I:1])=[CH:7][C:6]([N+:8]([O-:10])=[O:9])=[CH:5][N:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cnc(O)c(I)c1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: O
Product: O=[N+]([O-])c1cnc(Cl)c(I)c1
Temperature: 140 °C
Yield: 68.4 %

Procedure:
A mixture of 3-iodo-5-nitropyridin-2-ol (37.60 mmol, 10 g), POCl3 (86.47 mmol, 7.94 ml) and PCl5 (48.87 mmol, 10.2 g) was heated at 140° C. for 45 minutes under argon atmosphere. The mixture was cooled at room temperature, poured slowly over iced-water and extracted with dichloromethane. The organic phase was washed with water, NaHCO3 aqueous solution and brine. The solvent was evaporated and the crude mixture was purified by chromatography over SiO2 eluting hexane/DCM mixtures affording 7.32 g (yield 69%) of the expected product.
Reaction SMILES: Cl.[CH3:2][C:3]1[O:4][C:5]2[C:14]3[CH:13]([CH2:15][CH2:16][NH2:17])[CH2:12][CH2:11][C:10]=3[CH:9]=[CH:8][C:6]=2[N:7]=1.C(N(CC)CC)C.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:2][C:3]1[O:4][C:5]2[C:14]3[CH:13]([CH2:15][CH2:16][NH:17][C:25](=[O:32])[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:12][CH2:11][C:10]=3[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1nc2ccc3c(c2o1)C(CCN)CC3
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1nc2ccc3c(c2o1)C(CCNC(=O)c1ccccc1)CC3
Reaction time: 0.25 h
Yield: 43.8 %

Procedure:
2-(2-Methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethanamine hydrochloride (100 mg, 0.396 mmol) and triethylamine (111 μL, 0.792 mmol) were dissolved in tetrahydrofuran (4 mL), benzoyl chloride (55.1 μL, 0.475 mmol) was added under ice-cooling, and the mixture was stirred for 15 min. To the reaction solution was added saturated aqueous sodium hydrogencarbonate solution, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=20/80→60/40) to give the title compound (55.6 mg, yield 44%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[CH2:5][NH:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([NH2:17])[CH:13]=2)[N:8]=1.[CH:22]1([NH:25][S:26](Cl)(=[O:28])=[O:27])[CH2:24][CH2:23]1>N1C=CC=CC=1>[CH:22]1([NH:25][S:26]([NH:17][C:12]2[CH:13]=[C:14]3[C:9](=[CH:10][CH:11]=2)[N:8]=[C:7]([NH:6][CH2:5][C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]=2[O:2][CH3:1])[CH:16]=[CH:15]3)(=[O:28])=[O:27])[CH2:24][CH2:23]1
Reactant: O=S(=O)(Cl)NC1CC1
Reactant: COc1ccccc1CNc1ccc2cc(N)ccc2n1
Solvent: c1ccncc1
Product: COc1ccccc1CNc1ccc2cc(NS(=O)(=O)NC3CC3)ccc2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N2-(2-Methoxy-benzyl)-quinoline-2,6-diamine (example 10, step B, 40 mg, 0.143 mmol) was dissolved in 1 mL pyridine. Cyclopropylsulfamoyl chloride (29 mg, 0.186 mmol) was added and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated off and the residue purified by flash chromatography on silica gel (heptane/ethyl acetate 90:10→34:66 gradient). The title compound was obtained as a yellow solid (22 mg, 39%), MS: m/e=397.5 (M+H+).
Reaction SMILES: [CH3:1][O:2][N:3]1[CH2:8][CH:7]=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH2:5][CH2:4]1>CO.[Pd]>[CH3:1][O:2][N:3]1[CH2:8][CH2:7][CH:6]([C:9]2[CH:10]=[CH:11][C:12]([NH2:15])=[CH:13][CH:14]=2)[CH2:5][CH2:4]1
Reactant: CON1CC=C(c2ccc(N)cc2)CC1
Agent: [Pd]
Solvent: CO
Product: CON1CCC(c2ccc(N)cc2)CC1
Yield: 92.1 %

Procedure:
A solution of 4-(1-methoxy-1,2,3,6-tetrahydro-pyridin-4-yl)-phenylamine (as prepared in previous step) (40.8 mg, 0.200 mmol) in MeOH (5 mL) was hydrogenated over 10% Pd/C (20.4 mg) at 20 psi for 1 h. The solution was filtered through a pad of Celite and concentrated to give 4-(1-methoxy-piperidin-4-yl)-phenylamine (38 mg, 92%) which was directly used in the next step without purification.
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1C(C2NC=CN=2)=CN=C(CCN)N=1.Cl[C:24]1[N:29]=[C:28]([NH:30][CH3:31])[C:27]([N+:32]([O-:34])=[O:33])=[CH:26][CH:25]=1.[Cl:35][C:36]1[CH:41]=[C:40]([Cl:42])[CH:39]=[CH:38][C:37]=1[C:43]1[C:48]([C:49]2[NH:50][CH:51]=[CH:52][N:53]=2)=[CH:47][N:46]=[C:45]([NH:54][CH2:55][CH2:56][NH:57]C2C=CC([N+]([O-])=O)=C(OC)N=2)[N:44]=1>>[Cl:35][C:36]1[CH:41]=[C:40]([Cl:42])[CH:39]=[CH:38][C:37]=1[C:43]1[C:48]([C:49]2[NH:53][CH:52]=[CH:51][N:50]=2)=[CH:47][N:46]=[C:45]([NH:54][CH2:55][CH2:56][NH:57][C:24]2[CH:25]=[CH:26][C:27]([N+:32]([O-:34])=[O:33])=[C:28]([NH:30][CH3:31])[N:29]=2)[N:44]=1
Reactant: COc1nc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]
Reactant: CNc1nc(Cl)ccc1[N+](=O)[O-]
Agent: NCCc1ncc(-c2ncc[nH]2)c(-c2ccc(Cl)cc2Cl)n1
Product: CNc1nc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]

Procedure:
[4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl](2-{[6-(methylamino)-5-nitro(2-pyridyl)]amino}ethyl)amine was prepared from [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-ylethylamine and 6-chloro-2-methylamino-3-nitro-pyridine in accordance with the procedure described above for the preparation of [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(6-methoxy-5-nitro(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: [CH2:1]([O:23][C:24]1[CH:25]=[C:26]([CH:31]=[C:32]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])[CH:33]=1)[C:27](OC)=[O:28])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].O1CCCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C>C(OCC)C>[CH2:35]([O:34][C:32]1[CH:31]=[C:26]([CH:25]=[C:24]([O:23][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:33]=1)[CH2:27][OH:28])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56]
Reactant: CCCCCCCCCCCCCCCCCCCCCCOc1cc(OCCCCCCCCCCCCCCCCCCCCCC)cc(C(=O)OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCCCCCCCOc1cc(CO)cc(OCCCCCCCCCCCCCCCCCCCCCC)c1
Temperature: 40 °C
Reaction time: 1 h
Yield: 88.2 %

Procedure:
Under an argon atmosphere, methyl [3,5-bis(docosyloxy)]benzoate (2.03 g, 2.59 mmol) was dissolved in dehydrating tetrahydrofuran (50 mL) and, under ice-cooling, lithium aluminum hydride (148 mg, 3.93 mmol) was added, and the mixture was stirred at 40° C. for 1 hr. Ethyl acetate was added dropwise to decompose unreacted lithium aluminum hydride. Diethyl ether was added, and the mixture was washed with aqueous hydrochloric acid. The organic layer was concentrated under reduced pressure, methanol was added to the concentrated solution, and the precipitated solid was collected by filtration. The obtained solid was dried under reduced pressure to give the title compound (1.73 g, 88.0%) as a white solid.
Reaction SMILES: CON(C)[C:4](=[O:22])[C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[N:7][C:6]=1[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH3:24][Mg]Cl>O1CCCC1>[C:16]1([NH:15][C:6]2[C:5]([C:4](=[O:22])[CH3:24])=[CH:10][CH:9]=[C:8]([C:11]([F:12])([F:13])[F:14])[N:7]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: C[Mg]Cl
Reactant: CON(C)C(=O)c1ccc(C(F)(F)F)nc1Nc1ccccc1
Solvent: C1CCOC1
Product: CC(=O)c1ccc(C(F)(F)F)nc1Nc1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 97.3 %

Procedure:
A solution of N-methoxy-N-methyl-2-phenylamino-6-trifluoromethyl-nicotinamide (5.10 g, 15.7 mmol) in tetrahydrofuran (100 mL) cooled to 0° C. was treated with a solution of 3 M methylmagnesium chloride (15.7 mL, 47.0 mmol). The reaction was then stirred at 0° C. for 90 min. At this time, the reaction was warmed to 25° C. and was quenched with water (150 mL). The reaction was then partitioned between ethyl acetate (250 mL) and water (250 mL). The aqueous layer was back extracted with ethyl acetate (2×150 mL). The combined organics were washed with a saturated aqueous sodium chloride solution (50 mL), filtered, rinsed with ethyl acetate and concentrated in vacuo. Flash chromatography (20%-40% ethyl acetate/hexanes) afforded 1-(2-phenylamino-6-trifluoromethyl-pyridin-3-yl)-ethanone (4.28 g, 97.4%) as a yellow solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[O:17][CH3:18])[N:13]=[CH:12][C:11]([C:19]#[N:20])=[C:10]2[NH:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[C:24]([Cl:29])[CH:23]=1.N1CCOCC1.[I-].[Na+].C(=O)(O)[O-].[Na+]>CN(C)C=O>[Cl:29][C:24]1[CH:23]=[C:22]([NH:21][C:10]2[C:9]3[C:14](=[CH:15][C:16]([O:17][CH3:18])=[C:7]([N:6]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[CH:8]=3)[N:13]=[CH:12][C:11]=2[C:19]#[N:20])[CH:27]=[CH:26][C:25]=1[F:28]
Reactant: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1NCCCCCl
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1COCCN1
Product: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1N1CCCC1
Temperature: 750 °C
Reaction time: 7 h

Procedure:
A mixture of 2.5 g of 6-(4-chlorobutylamino)-4-(3-chloro-4-fluorophenyamino)-7-methoxy-3-quinolinecarbonitrile, 7.54 g of morpholine, and 0.17 g of sodium iodide in 30 ml of dimethylformamide was stirred at 750° C. for 7 hrs. The mixture was poured into dilute sodium bicarbonate and solid was collected. This material was dissolved in ethylacetate. The solution was dried over magnesium sulfate. The solvent was removed and the residue was chromatographed on silica gel using ethyl acetate-methanol-triethylamine mixtures. A more polar component (0.54 g) was 4-(3-chloro-4-fluoro-phenylamino)-7-methoxy-6-(4-morpholin-4-yl-butylamino)-quinoline-3-carbonitrile; a less polar component (0.28 g) is the compound of this invention, 4-(3-chloro-4-fluoro-phenylamino)-7-methoxy-6-pyrrolidin-l-yl-quinoline-3-carbonitrile, obtained as a yellow solid: mass spectrum electrospray, m/e): M+H 397.4.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([N:11]2[CH2:15][C@H:14]([C:16](=[O:19])[CH2:17][CH3:18])[CH2:13][C:12]2=[O:20])[CH3:10])=[CH:5][CH:4]=1.[BH4-].[Na+]>C(O)C>[OH:19][CH:16]([C@H:14]1[CH2:15][N:11]([C@@H:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH3:10])[C:12](=[O:20])[CH2:13]1)[CH2:17][CH3:18]
Reactant: CCC(=O)[C@@H]1CC(=O)N([C@H](C)c2ccc(OC)cc2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCC(O)[C@@H]1CC(=O)N([C@H](C)c2ccc(OC)cc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed (4R)-1-[(1R)-1-(4-methoxyphenyl)ethyl]-4-propanoylpyrrolidin-2-one 1.22 (6 g, 21.79 mmol, 1.00 equiv), ethanol (60 mL), followed by the addition of NaBH4 (1.85 g, 48.68 mmol, 2.50 equiv) in several batches with stifling at 0° C. The resulting solution was stirred at room temperature for 2 h, quenched by the addition of 100 mL of water/ice, extracted with 3×200 mL of ethyl acetate. The organic layers were combined, washed with 2×200 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was washed with 1×100 mL of ether and the solids were collected by filtration to afford (4R)-4-(1-hydroxypropyl)-1-[(1R)-1-(4-methoxyphenyl)ethyl]pyrrolidin-2-one as a mixture of diastereomers. The diastereomers were separated by chiral HPLC (CHIRALPAK AD), and the earlier eluting diastereomer was collected to afford (R)-4-((R)-1-hydroxypropyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one 1.23. This compound is the later eluting diastereomer under RP-HPLC conditions (Gemini column, water/acetonitrile/TFA).
Reaction SMILES: [CH:1]([C:3]1[C:4]([CH3:20])=[C:5]([NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:7][CH:8]=1)=O.[N+:21]([CH2:24][CH3:25])([O-:23])=[O:22].C([O-])(=O)C.[NH4+]>>[CH3:20][C:4]1[C:3]([CH:1]=[C:24]([N+:21]([O-:23])=[O:22])[CH3:25])=[CH:8][CH:7]=[CH:6][C:5]=1[NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC[N+](=O)[O-]
Reactant: Cc1c(C=O)cccc1NC(=O)OCc1ccccc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: CC(=Cc1cccc(NC(=O)OCc2ccccc2)c1C)[N+](=O)[O-]
Yield: 53.2 %

Procedure:
A solution of benzyl (3-formyl-2-methylphenyl)carbamate (8.00 g, 29.7 mmol), nitroethane (10.7 ml, 149 mmol), and ammonium acetate (11.5 g, 149 mmol) was heated in an oil bath at 95° C. overnight. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with a mixture of dichloromethane (150 mL) and water (75 mL) and basified with solid sodium bicarbonate slowly. The organic layer was collected, and the aqueous layer was extracted with dichloromethane (2×100 mL). The combined organic layers were dried over anhydrous sodium sulfate. Concentration under reduced pressure followed by purification by flash silica gel chromatography using a mixture of ethyl acetate in hexane (20%-35%-50%-65%-75%) afforded benzyl (2-methyl-3-(2-nitroprop-1-en-1-yl)phenyl)carbamate (5.16 g, 15.8 mmol, 53% yield) as a pale yellow solid.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH:13]=[CH:12][C:11](=[O:14])[C:10]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[CH:9]2)[CH:3]=1.[B:25]1(B2OC(C)(C)C(C)(C)O2)[O:29]C(C)(C)C(C)(C)[O:26]1.CC([O-])=O.[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][O:15][C:10]2[C:11](=[O:14])[CH:12]=[CH:13][N:8]([C:4]3[CH:3]=[C:2]([B:25]([OH:29])[OH:26])[CH:7]=[CH:6][N:5]=3)[CH:9]=2)=[CH:18][CH:19]=1
Reactant: COc1ccc(COc2cn(-c3cc(I)ccn3)ccc2=O)cc1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: COc1ccc(COc2cn(-c3cc(B(O)O)ccn3)ccc2=O)cc1
Temperature: 100 °C

Procedure:
A mixture of 4′-iodo-3-[(4-methoxybenzyl)oxy]-4H-1,2′-bipyridin-4-one (5.6 g, 12.9 mmol), bis(pinacolato)diboron (4.91 g, 19.3 mmol), KOAc (2.53 g, 25.8 mmol), and Pd(dppf)Cl2 (0.6 g) in 1,4-dioxane (100 mL) was heated to 100° C. overnight. After cooling to room temperature, the reaction mixture was concentrated to give a residue which was purified by Prep-HPLC to give {3-[(4-methoxybenzyl)oxy]-4-oxo-4H-1,2′-bipyridin-4′-yl}boronic acid. 1H NMR (DMSO, 400 MHz) δ 8.61(s, 1H), 8.51 (d, J=4.4 Hz, 1H), 8.437 (dd, J=8.0, 2.0 Hz, 1H), 8.21 (d, J=2.4 Hz, 1H), 8.00 (s, 1H), 7.65 (d, J=4.8 Hz, 1H), 7.36 (d, J=8.4 Hz, 2H), 6.92 (d, J=8.4 Hz, 2H), 6.34(d, J=7.6 Hz, 1H), 4.98 (s, 2H), 3.72 (s, 3H). MS (M+H)+ 353.2.
Reaction SMILES: [C@@H:1]12[N:8]([C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)=[O:10])[CH2:7][C@@H:6]1[CH2:5][CH2:4][NH:3][CH2:2]2.C1(C2C=CC=CC=2)C=CC=CC=1C(N1C2C(CCNC2)C1)=O.Cl[C:45]1[N:50]=[C:49]([CH3:51])[CH:48]=[C:47]([CH3:52])[N:46]=1.ClC1C=NC2C(=CC=CC=2)N=1>>[CH3:52][C:47]1[CH:48]=[C:49]([CH3:51])[N:50]=[C:45]([N:3]2[CH2:4][CH2:5][C@@H:6]3[C@@H:1]([N:8]([C:9]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[C:17]4[S:18][CH:19]=[CH:20][CH:21]=4)=[O:10])[CH2:7]3)[CH2:2]2)[N:46]=1
Reactant: Cc1cc(C)nc(Cl)n1
Reactant: O=C(c1ccccc1-c1cccs1)N1C[C@@H]2CCNC[C@@H]21
Agent: Clc1cnc2ccccc2n1
Agent: O=C(c1ccccc1-c1ccccc1)N1CC2CCNCC21
Product: Cc1cc(C)nc(N2CC[C@H]3CN(C(=O)c4ccccc4-c4cccs4)[C@H]3C2)n1

Procedure:
The title compound was prepared in a manner analogous to Example 1, substituting (1R,6S) (3,8-diaza-bicyclo[4.2.0]oct-8-yl)-(2-thiophen-2-yl-phenyl)-methanone (Intermediate 7) for biphenyl-2-yl-(3,8-diaza-bicyclo[4.2.0]oct-8-yl)-methanone and 2-chloro-4,6-dimethyl-pyrimidine for 2-chloro quinoxaline. MS (ESI) mass calcd. for C23H24N4OS, 404.53; m/z found 405.2 [M+H]+. 1H NMR (CDCl3) 7.54-7.27 (m, 4H), 7.25-7.12 (m, 2H), 7.07 (dd, J=5.1, 3.6, 0.7H), 6.81-6.75 (m, 0.3H), 6.29 (d, J=17.6, 1H), 4.78-4.54 (m, 0.75H), 4.10-3.55 (m, 4.5H), 3.52-3.33 (m, 0.75H), 3.01-2.90 (m, 0.6H), 2.73-2.56 (m, 1H), 2.30 (d, J=23.8, 6H), 2.10-1.50 (m, 2.4H).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH3:10][S:11](Cl)(=[O:13])=[O:12].[OH:15][CH2:16][CH2:17][NH:18][S:19]([C:22]1[CH:27]=[CH:26][C:25]([I:28])=[CH:24][CH:23]=1)(=[O:21])=[O:20]>CCOC(C)=O>[CH3:10][S:11]([O:15][CH2:16][CH2:17][NH:18][S:19]([C:22]1[CH:27]=[CH:26][C:25]([I:28])=[CH:24][CH:23]=1)(=[O:21])=[O:20])(=[O:13])=[O:12]
Reactant: CS(=O)(=O)Cl
Reactant: O=S(=O)(NCCO)c1ccc(I)cc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)OCCNS(=O)(=O)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 45.3 %

Procedure:
Diisopropylethylamine (585 μl, 3.36 mmol) followed by methane sulphonyl chloride (260 μl, 3.36 mmol) was added to a stirred solution of N-(2-hydroxyethyl)-4-iodobenzenesulphonamide (Method 45; 1 g, 3.06 mmol) in EtOAc (25 ml) at 5° C., under nitrogen. The reaction was allowed to warm to ambient temperature and stirred for 24 hours. The reaction mixture was washed with 1M hydrochloric acid (3×25 ml), saturated aqueous sodium hydrogen carbonate solution (3×25 ml), brine (2×25 ml), an then dried. The volatiles were removed by evaporation and the residue purified by chromatography on silica, eluting with DCM/MeOH (100:0 increasing in polarity to 99:1) to give the title compound (562 mg, 45%) as a white solid. NMR: 3.08 (m, 2H), 3.12 (s, 3H), 4.08 (t, 2H), 7.55 (d, 2H), 7.98 (d, 2H), 8.03 (t, 1H); m/z 405.