Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[N:9]2[CH2:14][CH2:13][NH:12][C:11](=[O:15])[CH2:10]2)=[CH:4][CH:3]=1.Br[CH2:24][C:25]([O:27][CH3:28])=[O:26].[H-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[N:9]2[CH2:14][CH2:13][N:12]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[C:11](=[O:15])[CH2:10]2)=[CH:6][CH:7]=1
Reactant: O=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)CCN1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)CN1CCN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)CC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.2 %

Procedure:
To a solution of 4-(bis(4-chlorophenyl)methyl)piperazin-2-one (180 mg, 537 μmol) in 10 mL of dry THF was added methyl 2-bromoacetate (60 μl, 644 μmol), followed by sodium hydride, 60% dispersion in mineral oil (16 μl, 644 μmol). After stirring rt overnight, the solvent was evaporated to dryness and was directly submitted to column chromatography (SiO2, hexane to hexane/EtOAc=100:5 to 100:10 to 100:20 to 100:30) to give methyl 2-(4-(bis(4-chlorophenyl)methyl)-2-oxopiperazin-1-yl)acetate (160 mg) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[C:8]([CH2:13][NH:14][OH:15])=[C:7]([N:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]3=[O:22])[C:6]=2[CH:23]=1.C[Si]([N:28]=[C:29]=[O:30])(C)C.O.ClCCl>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([CH3:11])([CH3:12])[C:8]([CH2:13][N:14]([OH:15])[C:29]([NH2:28])=[O:30])=[C:7]([N:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]3=[O:22])[C:6]=2[CH:23]=1
Reactant: C[Si](C)(C)N=C=O
Reactant: CC1(C)Oc2ccc(Br)cc2C(n2ccccc2=O)=C1CNO
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC1(C)Oc2ccc(Br)cc2C(n2ccccc2=O)=C1CN(O)C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.7 %

Procedure:
To a solution of 6-bromo-2,2-dimethyl-3-(hydroxyamino)methyl-4-(2-oxo-1,2-dihydropyridin-1-yl)-2H-1-benzopyran (0.300 g, 0.0795 mol) in tetrahydrofuran was added dropwise trimethylsilyl isocyanate (0.22 ml, 0.18 g, 0.0016 mol) at room temperature under nitrogen. The reaction mixture was stirred overnight at room temperature. Water and dichloromethane were added. The organic layer was separated, dried and evaporated to give crude product which was chromatographed on silica gel, eluting with dichloromethane/methanol (90/10) to afford 0.24 g (72%) of 6-bromo-2,2-dimethyl-3-(N-hydroxyureido)methyl-4-(2-oxo-1,2-dihydropyridin-1-yl)-2H-1-benzopyran, m.p. 216° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH:5]=O.[CH3:11][S:12]([NH2:15])(=[O:14])=[O:13].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH2:5][NH:15][S:12]([CH3:11])(=[O:14])=[O:13]
Reactant: CS(N)(=O)=O
Reactant: O=Cc1cc(F)cc(Br)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CS(=O)(=O)NCc1cc(F)cc(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.9 %

Procedure:
Preparation of 3-bromo-5-fluorobenzaldehyde (XLIX) (2.03 g, 10.0 mmol) in DCE (50 mL) was added methanesulfonamide (1.43 g, 15.0 mmol) and TEA (2.79 mL, 20.0 mmol). The solution was stirred for a few minutes before NaBH(OAc)3 (3.00 g, 14.1 mmol) was added. The reaction was stirred at room temperature overnight. The solvent was removed under vacuum and the residue was partitioned between EtOAc and water. The organic layer was separated, dried over MgSO4 and evaporated under vacuum to give N-(3-bromo-5-fluorobenzyl)methanesulfonamide (L) as a clear oil (2.65 g, 9.39 mmol, 99% yield). ESIMS found C8H9BrFNO2S m/z 282 (M+H).
Reaction SMILES: [BH4-].[Na+].[C:3]([C:6]1[N:7]([C:17]2[N:18]=[CH:19][N:20]=[C:21]([NH2:24])[C:22]=2[N:23]=1)[C@@H:8]1[O:16][C@H:13]([CH2:14][OH:15])[C@@H:11]([OH:12])[C@H:9]1[OH:10])(=[O:5])[CH3:4].Cl>C1COCC1.CO.C(Cl)Cl>[OH:5][CH:3]([C:6]1[N:7]([C:17]2[N:18]=[CH:19][N:20]=[C:21]([NH2:24])[C:22]=2[N:23]=1)[C@@H:8]1[O:16][C@H:13]([CH2:14][OH:15])[C@@H:11]([OH:12])[C@H:9]1[OH:10])[CH3:4]
Reactant: CC(=O)c1nc2c(N)ncnc2n1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: CC(O)c1nc2c(N)ncnc2n1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
NaBH4 (0.19 g, 5.05 mmol) was added to a solution of 8-acetyladenosine (17l) (0.78 g, 2.52 mmol) in THF (35 ml) and MeOH (4 ml) under argon and the mixture stirred at room temperature for 18 h. The mixture was treated dropwise with 1 M HCl until neutral pH and the mixture applied on top of a flash chromatography column which was developed by 30% MeOH in CH2Cl2; yield 0.46 g (59%). The product was a mixture of the two alcohol epimers, ratio 1:1.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([C:10]3[CH:11]=[C:12]([CH:22]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:23]([O:25]CC)=[O:24])[CH:13]=[C:14]([Cl:21])[C:15]=3[O:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.CO.O.O[Li].O>C1COCC1>[S:1]1[C:5]2[CH:6]=[C:7]([C:10]3[CH:11]=[C:12]([CH:22]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:23]([OH:25])=[O:24])[CH:13]=[C:14]([Cl:21])[C:15]=3[O:16][CH2:17][CH:18]3[CH2:19][CH2:20]3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CCOC(=O)C(CC(C)C)c1cc(Cl)c(OCC2CC2)c(-c2ccc3ncsc3c2)c1
Agent: [Li]O
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CC(C(=O)O)c1cc(Cl)c(OCC2CC2)c(-c2ccc3ncsc3c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.6 %

Procedure:
To a stirred solution of ethyl 2-(3-(benzo[d]thiazol-6-yl)-5-chloro-4-(cyclopropylmethoxy)phenyl)-4-methylpentanoate (0.1 g, 0.218 mmol) in a mixture of THF (10 mL), methanol (10 mL) and water (5 mL) was added LiOH.H2O (45 mg, 1.090 mmol) at room temperature and the mixture was stirred at RT for 2 h. After complete consumption of starting material as monitored by TLC, the reaction mixture was diluted with water (10 mL) and acidified using 1 N HCl at 0° C. The aqueous layer was extracted with EtOAc (2×20 mL); combined organic extracts were washed with water (10 mL), brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude material was purified by column chromatography to afford 2-(3-(benzo[d]thiazol-6-yl)-5-chloro-4-(cyclopropylmethoxy)phenyl)-4-methylpentanoic acid (39 mg) as an off white solid. 1HNMR (500 MHz) (CDCl3): δ (ppm) 9.05 (s, 1H), 8.2 (m, 2H), 7.73 (m, 1H), 7.40 (s, 1H), 7.30 (s, 1H), 3.63 (t, 1H), 3.40 (d, 2H), 1.99 (m, 1H), 1.65 (m, 1H), 1.55 (m, 1H), 0.93 (m, 7H), 0.38 (d, 2H), −0.5 (d, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][C@@H:13]([CH3:23])[CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:9][CH:8]=[CH:7][CH:6]=2.Cl.[Cl:25][CH2:26][C:27](=N)OCC>ClCCCl>[Cl:25][CH2:26][C:27]1[N:12]([C@@H:13]([CH3:23])[CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1
Reactant: C[C@@H](CNC(=O)OC(C)(C)C)Nc1c(N)cnc2ccccc12
Reactant: CCOC(=N)CCl
Agent: Cl
Solvent: ClCCCl
Product: C[C@@H](CNC(=O)OC(C)(C)C)n1c(CCl)nc2cnc3ccccc3c21
Temperature: 60 °C
Yield: 46.6 %

Procedure:
tert-Butyl (2S)-2-[(3-aminoquinolin-4-yl)amino]propylcarbamate (4.60 g, 14.55 mmol) was dissolved in 150 mL of anhydrous 1,2-dichloroethane and the solution was stirred under N2. Ethyl 2-chloroethanimidoate hydrochloride (3.45 g, 21.8 mmol) was added and the reaction was heated to 60° C. for 24 hours. The reaction mixture was cooled and washed with saturated sodium bicarbonate solution (2×100 mL) followed by brine. The organic layer was dried over Na2SO4, filtered, and concentrated to give an orange solid. Chromatography (SiO2, 60-80% EtOAc/hexanes) gave tert-butyl (2S)-2-[2-(chloromethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propylcarbamate (2.54 g) as a tan solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:9][CH:8]=[C:7]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH:6]=2.Cl.N1C=C[CH:37]=[CH:36][CH:35]=1.C(OC)(OC)(OC)CC>C1(C)C=CC=CC=1>[CH2:26]([O:25][C:7]1[CH:8]=[CH:9][C:10]2[C:11]3[N:12]([CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:35]([CH2:36][CH3:37])=[N:1][C:2]=3[CH:3]=[N:4][C:5]=2[CH:6]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: c1ccncc1
Reactant: CC(C)(C)OC(=O)NCCCCNc1c(N)cnc2cc(OCc3ccccc3)ccc12
Agent: CCC(OC)(OC)OC
Agent: Cl
Solvent: Cc1ccccc1
Product: CCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CCCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 206.3 %

Procedure:
tert-Butyl [4-(3-amino-7-benzyloxyquinolin-4-ylamino)butyl]carbamate (20.7 g, 43.6 mmol) was dissolved in toluene (225 mL). Pyridine hydrochloride (2.03 g) and trimethyl orthopropionate (6.2 mL, 43.6 mmol) were added, and the mixture was heated at reflux for 3.25 hours. The reaction was allowed to cool to room temperature; a fine precipitate formed. The precipitate was isolated by filtration and washed with toluene. The off-white solid was allowed to dry for 2 hours under vacuum. The filtrate was evaporated, and the residue was dissolved in dichloromethane. The resulting solution was washed with water and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford a brown amorphous solid. The solids were combined to provide 17.2 g of tert-butyl [4-(7-benzyloxy-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]carbamate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:37]([F:40])([F:39])[F:38])[CH2:14][CH2:13][N:12]([C:15]3[N:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[C:18]([CH2:25][N:26]4C(=O)C5C(=CC=CC=5)C4=O)=[CH:17][N:16]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].O.NN>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:37]([F:38])([F:39])[F:40])[CH2:14][CH2:13][N:12]([C:15]3[N:20]=[C:19]([C:21]([F:23])([F:24])[F:22])[C:18]([CH2:25][NH2:26])=[CH:17][N:16]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8]
Reactant: O=C1c2ccccc2C(=O)N1Cc1cnc(N2CCC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)nc1C(F)(F)F
Agent: NN
Solvent: O
Solvent: CCO
Product: NCc1cnc(N2CCC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)nc1C(F)(F)F
Temperature: 80 °C

Procedure:
2-({2-[3-(3,4,5-Trichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]-4-(trifluoromethyl)pyrimidin-5-yl}methyl)-1H-isoindole-1,3(2H)-dione (2.35 g) was added to ethanol (50 ml), followed by addition of hydrazine hydrate (0.37 ml) at room temperature. The reaction mixture was heated at 80° C. for 6 hours. The solvent was distilled off under reduced pressure, and then t-butyl methyl ether was added. The undissolved solids were removed by filtration, and the target compound was (1.71 g) obtained as a crude product after concentration under reduced pressure.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([N+:16]([O-:18])=[O:17])=[N:11][CH:12]=[C:13](Cl)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[OH:32].CN(C=O)C>C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[C:10]([N+:16]([O-:18])=[O:17])=[N:11][CH:12]=[C:13]([O:32][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[Cl:25])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ncc(Cl)cc1OCc1ccccc1
Reactant: Oc1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ncc(Oc2ccccc2Cl)cc1OCc1ccccc1
Temperature: 100 °C
Yield: 54.1 %

Procedure:
A mixture of 3-(benzyloxy)-5-chloro-2-nitropyridine (1.00 g, 3.78 mmol), potassium carbonate (2.09 g, 15.1 mmol), 2-chlorophenol (1.46 g, 11.3 mmol) and DMF (16 mL) was heated at 100° C. for 2 hours. The reaction mixture was cooled, partitioned between a 1:1 mixture of ethyl acetate (60 mL) and ether and water (60 mL). The organic layer was washed with 2N NaOH (30 mL), water, and brine, dried, and concentrated. The residue was purified by MPLC (Biotage) eluting with 5:1 hexane:ethyl acetate to afford 3-(benzyloxy)-5-(2-chlorophenoxy)-2-nitropyridine (0.73 g, 54.2% yield) as a light yellow solid. 1H NMR (CDCl3) δ 5.16 (s, 2H), 6.90 (s, 1H), 7.09 (d, 1H), 7.28-7.37 (m, 7H), 7.52 (d, 1H), 7.72 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:15]([NH:17][CH2:18][C:19]2[C:20](=[O:27])[NH:21][C:22]([CH3:26])=[CH:23][C:24]=2[CH3:25])=[O:16])[C:5]2[C:6]([CH3:14])=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:40]=[CH:39][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:37][N:36]=2)[CH2:31][CH2:30]1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.O.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>[CH3:25][C:24]1[CH:23]=[C:22]([CH3:26])[NH:21][C:20](=[O:27])[C:19]=1[CH2:18][NH:17][C:15]([C:4]1[C:5]2[C:6]([CH3:14])=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=[C:2]([C:38]2[CH:37]=[N:36][C:35]([N:32]3[CH2:31][CH2:30][N:29]([CH3:28])[CH2:34][CH2:33]3)=[CH:40][CH:39]=2)[CH:3]=1)=[O:16]
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2c(C)cn3C(C)C)c(=O)[nH]1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(N4CCN(C)CC4)nc3)cc3c2c(C)cn3C(C)C)c(=O)[nH]1

Procedure:
To a stirred solution of 6-bromo-N-((1,2-dihydro-4,6-dimethyl-2-oxopyridin-3-yl)methyl)-1-isopropyl-3-methyl-1H-indole-4-carboxamide (2 g, 4.65 mmol) in DMF (100 mL) was added 1-methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine (1.55 g, 5.12 mmol) followed by a solution of sodium carbonate (1.23 g, 11.62 mmol) in water (10 mL) and the contents were degassed with argon for 30 min. After that PdCl2(PPh3)2 (326 mg, 0.464 mmol) was added and the contents again degassed with argon for 10 min. The reaction mixture was stirred at reflux for 3 h. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3×150 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to afford the crude product (2.8 g). The crude compound was purified by column chromatography over silica gel (100-200 mesh, eluent: 0-10% MeOH: DCM), and the obtained product was further triturated with diethyl ether (100 mL) to afford the title compound as an off white solid (1.2 g, 50%). 1H NMR (DMSO-d6, 400 MHz): δ 1.493 (d, J=6.4 Hz, 6H), 2.092 (s, 3H), 2.286 (s, 3H), 2.409 (s, 3H), 2.424 (s, 3H), 2.632 (s, 4H), 3.621 (s, 4H), 4.603-4.685 (m, 3H), 5.880 (s, 1H), 6.606 (d, J=8.8 Hz, 1H), 7.016 (s, 1H), 7.261 (s, 1H), 7.433 (s, 1H), 7.675-7.704 (dd, J=9 Hz, 2.4 Hz, 1H), 8.425 (d, J=2.0 Hz, 1H), 11.699 (brs, 1H); LCMS (ES+): 525.23 [M−H].
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][N:9]2S(C2C=CC=CC=2)(=O)=O)=[CH:5][CH:4]=1.[Li]CCCC.[CH:26](=[O:30])[CH:27]([CH3:29])[CH3:28]>C1COCC1>[CH3:28][CH:27]([CH3:29])[C:26]([C:8]1[NH:9][C:10]2[C:6]([CH:7]=1)=[CH:5][CH:4]=[C:3]([S:2][CH3:1])[CH:11]=2)=[O:30]
Reactant: CC(C)C=O
Reactant: CSc1ccc2ccn(S(=O)(=O)c3ccccc3)c2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CSc1ccc2cc(C(=O)C(C)C)[nH]c2c1
Reaction time: 0.5 h
Yield: 64.4 %

Procedure:
To a solution of 6-(methylthio)-1-(phenylsulfonyl)-1H-indole (890 mg, 2.93 mmol) in anhydrous THF (10 mL) at 0° C. under nitrogen was added n-BuLi (5.86 mL, 14.65 mmol, 2.5 M). After stirring for 30 min, isobutyraldehyde (1.05 g, 14.65 mmol) was added. The reaction mixture was stirred at 0° C. for 1 h and quenched with sat. aq NH4Cl (10 mL) at 0° C. and extracted with EtOAc (20 mL×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography on silica gel eluted with (petroleum ether/EtOAc 20:1) to give 2-methyl-1-(6-(methylthio)-1H-indol-2-yl)propan-1-one (440 mg, 64.28% yield) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([S:7](Cl)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[CH3:11][O:12][C:13]1[C:14]([NH2:20])=[N:15][CH:16]=[C:17]([CH3:19])[N:18]=1>>[CH3:1][C:2]1[S:6][C:5]([S:7]([NH:20][C:14]2[C:13]([O:12][CH3:11])=[N:18][C:17]([CH3:19])=[CH:16][N:15]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)s1
Reactant: COc1nc(C)cnc1N
Product: COc1nc(C)cnc1NS(=O)(=O)c1ccc(C)s1

Procedure:
Prepared by the method of Example 1 using 5-methylthiophenesulphonyl chloride and 3-methoxy-5-methyl-2-pyrazinamine.
Reaction SMILES: N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:25]I.[CH2:27]([O:29][C:30]([CH:32]1[C:36](=[O:37])[N:35]([C@H:38]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH3:39])[CH2:34][C@H:33]1[C:46]1([CH2:49]O)[CH2:48][CH2:47]1)=[O:31])[CH3:28]>ClCCl>[CH2:27]([O:29][C:30]([CH:32]1[C:36](=[O:37])[N:35]([C@H:38]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH3:39])[CH2:34][C@H:33]1[C:46]1([CH2:49][I:25])[CH2:48][CH2:47]1)=[O:31])[CH3:28]
Reactant: CCOC(=O)C1C(=O)N([C@@H](C)c2ccccc2)C[C@H]1C1(CO)CC1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)C1C(=O)N([C@@H](C)c2ccccc2)C[C@H]1C1(CI)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 87.5 %

Procedure:
Imidazole (708 mg, 10.40 mmol), triphenylphosphine (2.727 g, 10.40 mmol), and iodine (2.111 g, 8.32 mmol) were sequentially added to a solution of (3R)-3-[1-(hydroxymethyl)cyclopropan-1-yl]-5-oxo-1-[(1S)-1-phenylethyl]pyrrolidin-4-ylcarboxylic acid ethyl ester (1.378 g, 4.16 mmol) in dichloromethane (50 mL) at room temperature. The mixture was stirred at room temperature for 15 hours. The solvent was evaporated under reduced pressure. Then, the residue was dissolved in ethyl acetate (200 mL) and washed with water (50 mL×2) and brine (50 mL). After drying over anhydrous sodium sulfate and filtration, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:9→1:4→1:2) to give 1.606 g (88%) of the title compound as a pale yellow gummy solid.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:24])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([CH3:23])=[CH:8]2)=[O:4].[NH2:25][CH2:26][C:27]([OH:29])=[O:28].C[O-].[Na+]>>[CH2:15]([N:11]1[C:12]2[C:7](=[C:6]([OH:24])[C:5]([C:3]([NH:25][CH2:26][C:27]([OH:29])=[O:28])=[O:4])=[N:14][CH:13]=2)[CH:8]=[C:9]([CH3:23])[C:10]1=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)c1ncc2c(cc(C)c(=O)n2Cc2ccccc2)c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: Cc1cc2c(O)c(C(=O)NCC(=O)O)ncc2n(Cc2ccccc2)c1=O
Temperature: 25 °C
Yield: 69.1 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-3-methyl-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (125 mg, 0.39 mmol), glycine (1.94 g, 25.8 mmol) and NaOMe solution (39 mL, 19.3 mmol, 0.5M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was dissolved in saturated NaHCO3 and washed with ether. The aqueous layer was acidified to pH 2 with 4M HCl, and the resulting mixture was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated to give 99 mg of the title compound as an off-white solid. MS: (+) m/z 368.08 (M+1).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=O)[CH3:11])[N:5]=1)(=O)[CH3:2].[NH2:13][N:14]1[CH:18]=[CH:17][CH:16]=[CH:15]1>C1(C)C=CC=CC=1>[N:14]1([N:13]=[C:1]([C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=[N:13][N:14]3[CH:18]=[CH:17][CH:16]=[CH:15]3)[CH3:11])[N:5]=2)[CH3:2])[CH:18]=[CH:17][CH:16]=[CH:15]1
Reactant: CC(=O)c1cccc(C(C)=O)n1
Reactant: Nn1cccc1
Solvent: Cc1ccccc1
Product: CC(=Nn1cccc1)c1cccc(C(C)=Nn2cccc2)n1
Reaction time: 48 h

Procedure:
2,6-Diacetylpyridine (345 mg, 2.11 mmol) and 1-aminopyrrole (400 mg, 4.87 mmol) were dissolved in 50 ml of toluene. To this solution, molecular sieves (4 Å) were added. After standing for 2 days at room temperature, the mixture was filtered. The solvent was removed in vacuo. The residue was crystallised from ethanol. Yield 350 mg (57%) of diimine 11.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:5]=1[O:13][CH3:14])[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=1[O:13][CH3:14])[CH3:2]
Reactant: CCOc1cc([N+](=O)[O-])ccc1OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOc1cc(N)ccc1OC
Yield: 98.4 %

Procedure:
A mixture of 2-ethoxy-1-methoxy-4-nitrobenzene (1.5 g, 7.6 mmol) and 5% Pd—C (0.3 g) in 30 mL of ethyl acetate was hydrogenated under 50 psi of hydrogen gas for 14 hours. The mixture was filtered through Celite and the filtrate was evaporated, providing 1.25 g of the product, in 98% yield: 1H NMR (CDCl3) δ 1.44 (t, J=7.0 Hz, 3H), 3.27 (br, 2H), 3.79 (s, 3H), 4.04 (q, J=7.0 Hz, 2H), 6.90 (d, J=8.9 Hz, 1H), 7.74 (d, J=2.5 Hz, 1H), 7.90 (dd, J=8.9 Hz, J=2.5 Hz, 1H).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][N:5]=1.[CH3:11]I>CN(C=O)C>[Br:10][C:7]1[CH:8]=[CH:9][C:4]([NH:3][CH3:11])=[N:5][CH:6]=1
Reactant: Nc1ccc(Br)cn1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNc1ccc(Br)cn1
Reaction time: 0.25 h
Yield: 32.1 %

Procedure:
To a suspension of NaH (60% dispersion in mineral oil, 0.44 g, 11 mmole) in dry DMF (40 mL) was added solid 2-amino-5-bromopyridine (1.73 g, 10 mmole) in portions over 5-10 min. Gas evolution was allowed to subside between additions. The resulting amber mixture was stirred for 15 min, then methyl iodide (0.61 mL, 10 mmole) was added all at once. The reaction mixture was stirred at RT overnight, then was concentrated in vacuo. The residue was diluted with 5% NH4Cl (30 mL) and the mixture was extracted with CH2Cl2. The combined organic extracts were washed with brine, dried (MgSO4), and concentrated. Flash chromatography on silica gel (3% MeOH/CH2Cl2) separated the products. 5-Bromo-2-(methylamino)pyridine (0.60 g, 32%) was obtained as a semisolid: TLC (3% MeOH/CH2Cl2) Rf 0.35; MS (ES) m/e 187 (M+H)+. 5-Bromo-2-(dimethylamino)pyridine (0.70 g, 34%) was obtained as a semisolid: TLC (3% MeOH/CH2Cl2) Rf 0.77; MS (ES) m/e 201 (M+H)+.
Reaction SMILES: [CH3:1][S:2][C:3]([CH3:8])([CH3:7])[CH:4]=[N:5][OH:6].[CH3:9][N:10]([S:14][C:15]([CH2:18][Cl:19])([CH3:17])[CH3:16])[C:11](Cl)=[O:12]>C(N(CC)CC)C>[CH3:9][N:10]([S:14][C:15]([CH2:18][Cl:19])([CH3:17])[CH3:16])[C:11]([O:6][N:5]=[CH:4][C:3]([S:2][CH3:1])([CH3:8])[CH3:7])=[O:12]
Reactant: CSC(C)(C)C=NO
Reactant: CN(SC(C)(C)CCl)C(=O)Cl
Solvent: CCN(CC)CC
Product: CSC(C)(C)C=NOC(=O)N(C)SC(C)(C)CCl

Procedure:
Prepared as in Example I by reacting 2-methylthio-2-methylpropionaldoxime with N-methyl-N-(2-chloromethyl-2-propanesulfenyl)carbamoyl chloride in the presence of triethylamine as an acid acceptor. The product was isolated as an oil.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[CH3:21][NH:22][C:23]([CH3:26])([CH3:25])[CH3:24].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.CCN(C(C)C)C(C)C>CN(C=O)C>[C:23]([N:22]([CH3:21])[C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])([CH3:26])([CH3:25])[CH3:24]
Reactant: CNC(C)(C)C
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CN(C(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)C(C)(C)C
Yield: 194 %

Procedure:
A solution of 6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)picolinic acid (10 mg, 35 μmol), N,2-dimethylpropan-2-amine (CAN 94896-77-2, 3.68 mg, 42.2 μmol), 1-hydroxybenzotriazole hydrate (11 mg, 70 μmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (12 mg, 70 μmol) and DIEA (18.2 mg, 24 μl, 141 μmol) in DMF (157 μL) was stirred for 2 d at ambient temperature. The reaction mixture was poured onto ice-water/1N HCl (20 mL), extracted with EtOAc (2×30 mL) and washed with ice-water/brine (20 mL). The organic layers were combined, dried over Na2SO4 and concentrated in vacuo to give 24 mg of a yellow oil which was purified by TLC (silica gel, Heptane/EtOAc 1:1, elution with DCM/EtOAc 1:1) to give the title compound (11 mg, 89%) as light yellow oil; MS (EI): m/e=354.5 [MH+].