Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][C:7](=O)[NH:6][C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[NH:3]1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:15].O>N1C=CC=CC=1>[CH3:1][CH:2]1[CH2:8][C:7](=[S:15])[NH:6][C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[NH:3]1
Reactant: CC1CC(=O)Nc2ccccc2N1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: O
Solvent: c1ccncc1
Product: CC1CC(=S)Nc2ccccc2N1
Yield: 83.2 %

Procedure:
A solution of 4-methyl-4,5-dihydro-1H-benzo[b][1,4]diazepin-2(3H)-one (220 mg, 1.25 mmol) and P2S5 (444 mg, 2.0 mmol) in pyridine (10 mL) was heated at 120° C. for 30 min. To the mixture, water (10 mL) was added, and then extracted with ethyl acetate (20 mL), dried with Na2SO4, concentrated and purified by CombiFlash (PE:EA=10:1) to give 4-methyl-4,5-dihydro-1H-benzo[b][1,4]diazepine-2(3H)-thione (200 mg, 83%). LRMS (M+H)+: 192 m/z.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:10]([N:12]1[C:20]2[C:15](=[CH:16][C:17]([CH2:21][NH:22][S:23]([C:26]3[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=3)(=[O:25])=[O:24])=[CH:18][CH:19]=2)[CH:14]=[N:13]1)[CH3:11]>>[Cl:1][C:2]1[C:3]([N:22]([CH2:21][C:17]2[CH:16]=[C:15]3[C:20](=[CH:19][CH:18]=2)[N:12]([CH2:10][CH3:11])[N:13]=[CH:14]3)[S:23]([C:26]2[CH:27]=[CH:28][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:34][CH:35]=2)(=[O:25])=[O:24])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Fc1ncc(Cl)cc1Cl
Reactant: CCn1ncc2cc(CNS(=O)(=O)c3ccc(C(=O)OC)cc3)ccc21
Product: CCn1ncc2cc(CN(c3ncc(Cl)cc3Cl)S(=O)(=O)c3ccc(C(=O)OC)cc3)ccc21

Procedure:
The titled compound was prepared according to the procedure described in step-2 of Example 1 from 3,5-dichloro-2-fluoropyridine and methyl 4-(N-((1-ethyl-1H-indazol-5-yl)methyl)sulfamoyl)benzoate (step-1 of Example 15).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:40]=[CH:41][C:42]=1[Cl:43])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C@H:13]2[CH2:39][O:38][C:16]3=[CH:17][C:18]4[CH2:19][C@@H:20]([C:35](O)=[O:36])[N:21]([C@H:25]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[CH2:26][CH2:27][CH3:28])[CH2:22][C:23]=4[CH:24]=[C:15]3[O:14]2)=[CH:9][CH:8]=1.Cl.C[O:46][C:47](=[O:65])[C@@H:48]([NH2:64])[CH2:49][C:50]1[CH:55]=[CH:54][C:53]([C:56]2[CH:61]=[CH:60][C:59]([C:62]#[N:63])=[CH:58][CH:57]=2)=[CH:52][CH:51]=1>>[C:62]([C:59]1[CH:58]=[CH:57][C:56]([C:53]2[CH:54]=[CH:55][C:50]([CH2:49][C@H:48]([NH:64][C:35]([C@@H:20]3[CH2:19][C:18]4[CH:17]=[C:16]5[O:38][CH2:39][C@H:13]([C:10]6[CH:9]=[CH:8][C:7]([O:6][CH2:5][C:4]7[CH:40]=[CH:41][C:42]([Cl:43])=[C:2]([Cl:1])[CH:3]=7)=[CH:12][CH:11]=6)[O:14][C:15]5=[CH:24][C:23]=4[CH2:22][N:21]3[C@H:25]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:26][CH2:27][CH3:28])=[O:36])[C:47]([OH:46])=[O:65])=[CH:51][CH:52]=2)=[CH:61][CH:60]=1)#[N:63]
Reactant: CCC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)O)OC[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccc(C#N)cc2)cc1
Agent: Cl
Product: CCC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)C(=O)O)OC[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3

Procedure:
The title compound was prepared from (3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-butyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid and (S)-2-amino-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester hydrochloride according to General Procedures L and B. LCMS (m/z): 868.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25](=[O:27])[NH2:26])=[CH:21][N:20]=3)[CH:14]=2)[CH2:9]1)=O)(C)(C)C.C(Cl)Cl.C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[K+].[K+]>C(Cl)(Cl)Cl>[CH2:9]1[C:10]2[C:15](=[CH:14][C:13]([O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([NH2:26])=[O:27])=[CH:21][N:20]=3)=[CH:12][CH:11]=2)[CH2:16][CH2:17][NH:8]1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(Oc3ccc(C(N)=O)cn3)ccc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CCNC3)nc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 99.7 %

Procedure:
Combine 6-(5-carbamoyl-pyridin-2-yloxy)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (4.0 g, 10.83 mmol), CH2Cl2 (100 mL), and TFA (25 mL). Stir at room temperature for 12 hours and add 1.0 M K2CO3 and CHCl3 to the reaction. Separate the organic layer, wash with brine, and dry over Na2SO4. Concentrate under reduced pressure and add mixture to 2, 10 g SCX columns, wash with MeOH, and elute with 1.0 N NH3 in MeOH. Concentrate to afford 2.91 g, 10.8 mmol (71% yield) of the title compound as a white foam: 1H NMR (500 MHz, DMSO-d6): 2.9-3.1 (2H, m), 3,2-3.5 (2H, m), 4.2-4.4 (2H, m), 6.9-7.2 (3H, m), 7.2-7.4 (1H, m), 7.4-7.6 (1H, m), 7.9-8.1 (1H, m), 8.2-8.4 (1H, m), 8.5-8.7 (1H, m), 8.2-9.4 (2H, m); MS m/z 269 (M+1).
Reaction SMILES: [CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5][C@H:4]1[CH3:16].[C:17]([OH:23])([C:19]([F:22])([F:21])[F:20])=[O:18]>C(Cl)Cl>[F:20][C:19]([F:22])([F:21])[C:17]([OH:23])=[O:18].[CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][NH:6][CH2:5][C@H:4]1[CH3:16]
Reactant: CO[C@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CO[C@H]1CCNC[C@H]1C

Procedure:
A solution of racemic (cis)-tert-butyl 4-methoxy-3-methylpiperidine-1-carboxylate (230 mg, 1.0 mmol) in DCM (2 mL) with TFA (0.23 mL, 3.01 mmol) was stirred at room temperature overnight. The reaction mixture was then concentrated to give racemic (cis)-4-methoxy-3-methylpiperidine 2,2,2-trifluoroacetate. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.27 (s, 3 H), 3.01-3.09 (m, 1 H), 2.93-3.00 (m, 1 H), 2.81-2.93 (m, 1 H), 2.69-2.77 (m, 1 H), 1.90-2.08 (m, 2 H), 1.57-1.67 (m, 1 H), 0.90 (d, J=7.1 Hz, 3 H).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C@:10]2([CH2:18][C@H:17]2[C:19]2[CH:27]=[C:26]3[C:22]([CH:23]=[N:24][N:25]3[CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:21][CH:20]=2)[C:9]1=[O:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS([O:40][C@@H:41](C1C=C2C(C=NN2CC2C=CC=CC=2)=CC=1)COS(C)(=O)=O)(=O)=O.C(N1C2C(=CC(OC)=CC=2)CC1=O)C1C=CC=CC=1>>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:40][CH3:41])=[CH:14][CH:15]=2)[C@:10]2([CH2:18][C@H:17]2[C:19]2[CH:27]=[C:26]3[C:22]([CH:23]=[N:24][N:25]3[CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:21][CH:20]=2)[C:9]1=[O:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OC[C@@H](OS(C)(=O)=O)c1ccc2cnn(Cc3ccccc3)c2c1
Reactant: O=C1N(Cc2ccccc2)c2ccccc2[C@]12C[C@H]2c1ccc2cnn(Cc3ccccc3)c2c1
Agent: COc1ccc2c(c1)CC(=O)N2Cc1ccccc1
Product: COc1ccc2c(c1)[C@]1(C[C@H]1c1ccc3cnn(Cc4ccccc4)c3c1)C(=O)N2Cc1ccccc1
Yield: 52 %

Procedure:
The title compound was prepared in a manner similar to the method of (1R,2S)-1′-benzyl-2-(1-benzyl-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indolin]-2′-one using (S)-1-(1-benzyl-1H-indazol-6-yl)ethane-1,2-diyl dimethanesulfonate (3.35 g, 7.90 mmol) and 1-benzyl-5-methoxyindolin-2-one (2.00 g, 7.90 mmol). The crude product was purified by silica gel chromatography (15-40% EtOAc in hexane) followed by trituration (EtOAc) to give the title compound as a white solid (1.97 g, 52%). 1H NMR (400 MHz, CDCl3) δ 8.01 (s, 1H), 7.64 (d, J=8.2 Hz, 1H), 7.36-7.23 (m, 10H), 7.14 (d, J=7.2 Hz, 2H), 6.94 (d, J=8.3 Hz, 1H), 6.63 (d, J=8.3 Hz, 1H), 6.53 (d, J=8.4 Hz, 1H), 5.61 (d, J=15.1 Hz, 1H), 5.54 (d, J=15.4 Hz, 1H), 5.37 (s, 1H), 5.07 (d, J=15.4 Hz, 1H), 4.95 (d, J=15.7 Hz, 1H), 3.51 (t, J=8.1 Hz, 1H), 3.18 (s, 3H), 2.32-2.29 (m, 1H), 2.09-2.00 (m, 1H). MS ESI 486.3 [M+H]+, calcd for [C32H27N3O2+H]+ 486.2.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=O)=O)=[CH:6][CH:5]=1.C(OCC)(=O)C>S(=O)(=O)(O)O.O.[Zn]>[F:15][C:2]([F:1])([F:14])[O:3][C:4]1[CH:5]=[CH:6][C:7]([SH:10])=[CH:8][CH:9]=1
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Agent: O=S(=O)(O)O
Agent: [Zn]
Solvent: O
Solvent: CCOC(C)=O
Product: FC(F)(F)Oc1ccc(S)cc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 47 %

Procedure:
Zinc powder (3.1 g) was added to a suspension of p-trifluoromethoxybenzenesulfonyl chloride (1.36 ml) in concentrated sulfuric acid (3.4 ml) and water (20 ml), and the suspension was stirred at 0° C. for 18 hours and heated under reflux for 6 hours. The mixture was added with ethyl acetate, washed with water, saturated aqueous solution of sodium hydrogen carbonate, and saturated brine, and then concentrated under reduced pressure to give p-trifluoromethoxybenzenethiol (0.73 g, 47%).
Reaction SMILES: ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.[O:15]([CH:23]1[CH2:27][CH:26]([OH:28])[CH:25]=[CH:24]1)[Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]>O1CCOCC1>[O:15]([CH:23]1[CH2:27][C:26](=[O:28])[CH:25]=[CH:24]1)[Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)OC1C=CC(O)C1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: CC(C)(C)[Si](C)(C)OC1C=CC(=O)C1
Temperature: 55 °C
Yield: 305.9 %

Procedure:
1.13 grams of 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) was dissolved in 15 milliliters of dioxane, to which was then added 660 milligrams of crude 4-t-butyldimethylsiloxycyclopent-2-en-1-ol (purity 74%), after which the mixture was heated at 55° C. for 16 hours with stirring. After completion of the reaction, the precipitate separating out was filtered off. When the filtrate was concentrated under reduced pressure, 2.0 grams of a crude product was obtained.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH2:15])[N:13]=[CH:14][C:9]=3[C:8]3[CH:16]=[CH:17][N:18]=[CH:19][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:21]1[CH:22]=[CH:23][C:24]([N:27]2[CH2:32][CH2:31][CH:30]([N:33]([CH3:35])[CH3:34])[CH2:29][CH2:28]2)=[N:25][CH:26]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:21]4[CH:26]=[N:25][C:24]([N:27]5[CH2:28][CH2:29][CH:30]([N:33]([CH3:35])[CH3:34])[CH2:31][CH2:32]5)=[CH:23][CH:22]=4)[N:13]=[CH:14][C:9]=3[C:8]3[CH:16]=[CH:17][N:18]=[CH:19][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN(C)C1CCN(c2ccc(Br)cn2)CC1
Reactant: Nc1ncc2c3ccncc3n(C3CCCC3)c2n1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: CN(C)C1CCN(c2ccc(Nc3ncc4c5ccncc5n(C5CCCC5)c4n3)cn2)CC1
Yield: 0 %

Procedure:
To a microwave reaction vessel were placed compound 4 (30 mg, 118 mmol), compound 91 (50 mg, 178 mmol), tris(dibenzylideneacetone)dipalladium(0) (5.4 mg, 5.9 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (8.6 mg, 15 mmol), and sodium tert-butoxide (34 mg, 355 mmol). 1,4-dioxane (4 mL) was added and the vessel was purged with N2 for 3 min, then capped and subjected to microwave irradiation for 2 h at 120° C. After removal of the volatiles, the residue was dissolved in methanol and filtered. The filtrate was subjected to reverse phase preparative HPLC (acetonitrile/water containing 0.1% TFA each, 40 min from 5 to 40%) to give ˜15 mg of compound 90 as a TFA salt. 1H NMR (400 MHz, CD3OD) δ 9.43 (1 H, s), 9.16 (1 H, s), 8.65 (1 H, d, J=2.3 Hz), 8.48-8.57 (2 H, m), 8.12 (1 H, dd, J=9.4, 2.3 Hz), 7.21 (1 H, d, J=9.4 Hz), 5.29-5.47 (1 H, m), 4.45 (2 H, d, J=13.7 Hz), 3.49-3.58 (1 H, m), 3.03-3.18 (2 H, m), 2.92 (6 H, s), 2.37-2.54 (2 H, m), 2.04-2.29 (6 H, m), 1.76-1.93 (4 H, m) ppm; LCMS-ESI (POS), M/Z, M+1: Found 457.3, Calculated 457.2.
Reaction SMILES: C([O:3][P:4]([CH2:9][N:10]1[C:19]2[C:14](=[CH:15][C:16]([N:23]3[CH:27]=[CH:26][N:25]=[CH:24]3)=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=2)[NH:13][C:12](=[O:28])[C:11]1=[O:29])(=[O:8])[O:5]CC)C>Cl>[N:23]1([C:16]2[CH:15]=[C:14]3[C:19](=[CH:18][C:17]=2[N+:20]([O-:22])=[O:21])[N:10]([CH2:9][P:4]([OH:5])(=[O:3])[OH:8])[C:11](=[O:29])[C:12](=[O:28])[NH:13]3)[CH:27]=[CH:26][N:25]=[CH:24]1
Reactant: CCOP(=O)(Cn1c(=O)c(=O)[nH]c2cc(-n3ccnc3)c([N+](=O)[O-])cc21)OCC
Agent: Cl
Product: O=c1[nH]c2cc(-n3ccnc3)c([N+](=O)[O-])cc2n(CP(=O)(O)O)c1=O

Procedure:
250 mg of [(6-(N-imidazolyl)-7-nitro-1,2,3,4-tetrahydro-2,3-dioxoquinoxalin-1-yl)methanephosphonic acid diethyl ester is heated in 3 ml of concentrated hydrochloric acid for 2.5 hours to 110° C. bath temperature. After concentration by evaporation, it is taken up in water, and the precipitated product is suctioned off. 100 mg of [6-(N-imidazolyl)-7-nitro-1,2,3,4-tetrahydro-2,3-dioxoquinoxalin-1-yl]methanephosphonic acid is obtained.
Reaction SMILES: [NH2:1][C@@H:2]1[C:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:15])([CH3:14])[C@H:3]1[OH:16].[CH3:17][S:18][C:19](SC)=[N:20][C:21]#[N:22]>N1C=CC=CC=1.C(OCC)(=O)C>[C:21]([N:20]=[C:19]([S:18][CH3:17])[NH:1][C@@H:2]1[C:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:14])([CH3:15])[C@H:3]1[OH:16])#[N:22]
Reactant: CSC(=NC#N)SC
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](N)[C@@H]1O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CSC(=NC#N)N[C@@H]1c2cc(C#N)ccc2OC(C)(C)[C@H]1O
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 63.6 %

Procedure:
A mixture of trans-4-amino-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (2.18 g) and dimethyl N-cyanoimidodithiocarbonate [(CH3S)2C=N--CN] (1.54 g) in dry pyridine (11 ml) was stirred at 80° C. for 2.5 hours, and under reflux for 2.5 hours. The reaction mixture was diluted with ethyl acetate (40 ml) and washed with 5% hydrochloric acid (30 ml×2). The organic layer was washed successively with water (30 ml), saturated aqueous sodium bicarbonate (30 ml) and brine (30 ml), dried over magnesium sulfate, and evaporated in vacuo. The residue was subjected to column chromatography on silica gel (70 g) and eluted with chloroform and a mixture of chloroform and methanol (50:1 and then 20:1). The fractions containing the object compound were combined and concentrated under reduced pressure. The residue was triturated with diisopropyl ether. The crystals were recrystallized from ethanol to give trans-4-(3-cyano-2-methyl-1-isothioureido)-3,4-dihydro- 3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (2.01 g).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[CH3:7][O:8][C:9](=[O:22])[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=1Br.[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl.[Na+].[Cl-]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(C)=O>[CH3:7][O:8][C:9](=[O:22])[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)COc1ccc([N+](=O)[O-])cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)COc1ccc([N+](=O)[O-])cc1-c1ccccc1
Reaction time: 1 h
Yield: 71.4 %

Procedure:
An aqueous Na2CO3 solution (2M, 3.79 mL) is added to a stirred solution of (2-bromo-4-nitro-phenoxy)-acetic acid methyl ester (1.06 g, 3.70 mmol), phenylboronic acid (450 mg, 3.72 mmol) and tetrakis(triphenylphosphine)palladium (0) (210 mg, 0.185 mmol) in 1,4-dioxane (10 mL) at ambient temperature under argon. The resultant mixture is heated at −95° C. for 24 hours. At ambient temperature, 5N HCl (3.8 mL) is added to the mixture, followed by the addition of EtOAc (50 mL) and saturated aqueous NaCl solution (15 mL). The organic layer is separated, dried over MgSO4, filtered and concentrated. The crude product is dissolved in MeOH (5 mL)/CH2Cl2 (20 mL) and the solution is treated dropwise with (trimethylsilyl)diazomethane (2M in hexane, 2.8 mL). After stirring for 1 hour, the mixture is concentrated and chromatographed on silica gel (gradient 50-75% CH2Cl2 in hexane) to give 760 mg (2.64 mmol, 71% yield) of the title compound as oil. ESIMS: m/z 288 (M+H)+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[CH:5]([CH2:7][OH:8])[NH2:6].S([O-])([O-])(=O)=O.[Na+].[Na+].C[O-].[Na+].[CH3:20][C:21]([CH3:23])=O>CO.[Pt](=O)=O>[CH3:2][O:3][C:4](=[O:9])[CH:5]([CH2:7][OH:8])[NH:6][CH:21]([CH3:23])[CH3:20]
Reactant: COC(=O)C(N)CO
Reactant: CC(C)=O
Agent: O=[Pt]=O
Agent: C[O-]
Agent: Cl
Solvent: CO
Product: COC(=O)C(CO)NC(C)C
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a slurry of 1 equivalent DL-serine methyl ester hydrochloride and 2 equivalents anhydrous sodium sulfate in methanol is added 1.05 equivalents sodium methoxide. The mixture is stirred at room temperature 5 minutes, after which 3 equivalents of acetone are added and the slurry is stirred overnight. The solids are removed by filtration and the excess acetone is removed from the filtrate under reduced pressure. Once the acetone is removed, platinum (IV) oxide (0.02 equivalents) is added. The slurry is stirred at room temperature 24 hours under a hydrogen atmosphere. The slurry is then filtered and the excess methanol is removed under reduced pressure. The residue is slurried in chloroform and filtered, and the filtrate is washed with dilute sodium bicarbonate, dried over anhydrous sodium sulfate, and filtered. Removal of chloroform under reduced pressure yields the desired product.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][NH2:13].[Cl:14][C:15]1[C:16](=[O:36])[N:17]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[CH:18]=[C:19]([CH2:25]Cl)[C:20]=1[C:21](OC)=[O:22]>CCO>[Cl:14][C:15]1[C:16](=[O:36])[N:17]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[CH:18]=[C:19]2[CH2:25][N:13]([CH2:12][CH2:11][C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]=3)[C:21](=[O:22])[C:20]=12
Reactant: NCCc1ccc2ccccc2n1
Reactant: COC(=O)c1c(CCl)cn(Cc2ccc(OC)cc2)c(=O)c1Cl
Solvent: CCO
Product: COc1ccc(Cn2cc3c(c(Cl)c2=O)C(=O)N(CCc2ccc4ccccc4n2)C3)cc1
Temperature: 100 °C
Yield: 53.4 %

Procedure:
A solution of 2-(quinolin-2-yl)ethanamine (48.4 mg, 0.281 mmol, see Example a1)), methyl 3-chloro-5-(chloromethyl)-1-(4-methoxybenzyl)-2-oxo-1,2-dihydropyridine-4-carboxylate (100 mg, 0.281 mmol) and TEA (0.117 ml, 0.842 mmol) were dissolved in EtOH (3.0 ml) in a 5 ml microwave reaction vial. The suspension was heated in a Biotage microwave at about 100° C. for about 20 min. After cooling, it was verified by LC-MS that the reaction was almost completed. The solution was concentrated to dryness and recrystallized from EtOH to give the title compound (69 mg, 0.150 mmol, 53.4% yield) as a yellow solid.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[CH2:16][NH2:17].C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[CH2:16][NH:17][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: NCc1cc(Cl)cc(Cl)c1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(F)cc1NCc1cc(Cl)cc(Cl)c1
Yield: 46 %

Procedure:
A mixture of 2,4-difluoronitrobenzene (5.0 mmol), 3,5-dichlorobenzylamine (5.0 mmol), N,N-diisopropylethylamine (10.0 mmol) and acetonitrile (25 mL) was heated at reflux for 18 h, cooled and concentrated in vacuo. The residue was dissolved in ethyl acetate; this solution was washed with water, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using 5% ethyl acetate in hexanes as eluent to yield the title compound as a yellowish solid (46%). 1H NMR (400 MHz, CDCl3): δ 9.28 (br s, 1H), 7.88 (m, 1H), 7.34 (s, 1H), 7.22 (s, 2H), 6.44 (m, 1H), 6.30 (dd, 1H), 4.43 (d, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:25][C:26]([CH3:32])=[CH:27][C:28]=1[C:29]([OH:31])=O)(=[O:12])=[O:11].[CH2:33]([N:35]([CH2:39][CH3:40])[CH2:36][CH2:37][NH2:38])[CH3:34]>>[CH2:33]([N:35]([CH2:39][CH3:40])[CH2:36][CH2:37][NH:38][C:29]([C:28]1[CH:27]=[C:26]([CH3:32])[NH:25][C:24]=1/[CH:23]=[C:16]1\[C:17](=[O:22])[NH:18][C:19]2[C:15]\1=[CH:14][C:13]([S:10]([CH2:9][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[Cl:8])(=[O:12])=[O:11])=[CH:21][CH:20]=2)=[O:31])[CH3:34]
Reactant: CCN(CC)CCN
Reactant: Cc1cc(C(=O)O)c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)[nH]1
Product: CCN(CC)CCNC(=O)c1cc(C)[nH]c1/C=C1\C(=O)Nc2ccc(S(=O)(=O)Cc3c(Cl)cccc3Cl)cc21

Procedure:
2-[5-(2,6-Dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid was coupled with N,N-diethylethylenediamine to give the titled compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:7]=1[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:5])[CH3:2].[F:28][C:29]([F:40])([F:39])[C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:33]3[CH:34]=[CH:35][C:30]([C:29]([F:40])([F:39])[F:28])=[CH:31][CH:32]=3)[CH:13]=2)[N:8]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:7]=1[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:5])[CH3:2]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(O)ccc2n1-c1ccccc1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3ccc(C(F)(F)F)cc3)ccc2n1-c1ccccc1

Procedure:
The sub-title compound was prepared in accordance with step (c) Example 1 from 2-ethoxycarbonylmethyl-5-hydroxy-1-phenylindole-3-carboxylic acid ethyl ester (170 mg, 0.46 mmol, see step (b) Example 3) and 4-trifluoromethylphenylboronic acid (129 mg, 0.68 mmol). Yield 150 mg (64%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[OH:11].C(=S)=S.[Br:15]Br>O>[Br:15][C:6]1[CH:5]=[C:4]([OH:11])[C:3]([O:2][CH3:1])=[CH:8][C:7]=1[O:9][CH3:10]
Reactant: COc1ccc(O)c(OC)c1
Reactant: BrBr
Solvent: S=C=S
Solvent: O
Product: COc1cc(OC)c(Br)cc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
To a mixed solution comprising 8.6 g of 2,4-dimethoxyphenol and 80 ml of carbon disulfide (CS2) was added dropwise 2.86 ml of bromine at 10° to 15° C. After stirring the mixture at room temperature for one hour, water was added to the reaction mixture and the reaction mixture was extracted with diethyl ether. The extract was washed and dried, and the solvent was removed under reduced pressure. Hexane was added to the obtained residue and the precipitated crystals were collected by filtration to give 12.0 g of 3-bromo-4,6-dimethoxyphenol (yield: 92%, melting point: 78°-80° C.).
Reaction SMILES: [F:1][C:2]1[C:3]([NH2:10])=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1.[CH3:11][N:12]([CH3:15])[CH:13]=O>C(OCC)C>[F:1][C:2]1[C:3]([N:10]=[CH:11][N:12]([CH3:15])[CH3:13])=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: CSc1ncc(F)c(N)n1
Solvent: CCOCC
Product: CSc1ncc(F)c(N=CN(C)C)n1
Reaction time: 4 h
Yield: 84 %

Procedure:
To a solution of 5-fluoro-2-methylsulfanylpyrimidin-4-ylamine (7.5 g, 47.1 mmol) in N,N-dimethylformamide (DMF; 18 mL) was added DMF-dimethylacetal (DMF-DMA; 8.42 g, 70.7 mmol), and the resulting solution was stirred under nitrogen (N2) for 4 h. The homogeneous solution was diluted with diethyl ether (Et2O; 500 mL), washed with H2O (5×100 mL), and the organic phase was dried over Na2SO4, filtered, and concentrated to a white solid. Recrystallization from hexane afforded N′-(5-fluoro-2-methylsulfanylpyrimidin-4-yl)-N,N-dimethylformamidine (8.47 g, 84%) as white needles: mp 75-77° C.; 1H NMR (400 MHz, CDCl3) δ 8.67 (s, 1H), 8.12 (d, J=3.1 Hz, 1H), 3.19 (s, 3H), 3.18 (s, 3H), 2.53 (s, 3H); CIMS m/z 214 ([M]+).