Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13]C)[CH:11]=2)[C:6]([CH3:15])=[CH:5][C:4]1([CH3:17])[CH3:16])[CH3:2].Br.[OH-].[Na+]>C(O)(=O)C>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:13])[CH:11]=2)[C:6]([CH3:15])=[CH:5][C:4]1([CH3:16])[CH3:17])[CH3:2]
Reactant: CCN1c2cc(OC)ccc2C(C)=CC1(C)C
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCN1c2cc(O)ccc2C(C)=CC1(C)C
Yield: 112 %

Procedure:
The compound 1-ethyl-7-methoxy-2,2,4-trimethyl-1,2-dihydroquinoline (5.72 g) from Example 2 was added to a mixture of concentrated hydrobromic acid (13 mL) and glacial acetic acid (13 mL). After the mixture was stirred at reflux for 6 hours, it was cooled with ice and neutralized with 10 N aqueous sodium hydroxide to pH 7. The mixture was then extracted with chloroform (3×50 ml) and dried over anhydrous sodium sulfate, then filtered and evaporated to give a sticky green oil as the crude product (6.02 g), which was used without further purification. The structure of 1-ethyl-2,2,4-trimethyl-1,2-dihydroquinolin-7-ol is given below;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@H:21]([CH3:29])[C:22]([O:24]C(C)(C)C)=O)[C:17]1=[O:30])(=[O:14])=[O:13])[CH:6]=[CH:5]2.FC(F)(F)C(O)=O.Cl.CN(C)CCCN=C=NCC.[CH:50]1[CH:51]=[CH:52]C2N(O)N=[N:56][C:54]=2[CH:55]=1.N1CCCCC1>C(Cl)Cl.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@H:21]([CH3:29])[C:22](=[O:24])[N:56]3[CH2:52][CH2:51][CH2:50][CH2:55][CH2:54]3)[C:17]1=[O:30])(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: On1nnc2ccccc21
Reactant: C[C@H](C(=O)OC(C)(C)C)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](C(=O)N1CCCCC1)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
A solution of tert-butyl (2R)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoate (0.025 g) in DCM (3 ml) was treated with trifluoroacetic acid (3 ml) and stirred at room temperature for 2 h. The mixture was then concentrated under reduced pressure to give an oil which was subsequently treated with 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.013 g), HOBT (0.009 g) and triethylamine (0.023 ml). After stirring at room temperature for 1 h, piperidine (0.007 ml) was added and stirring was continued for 48 h. The reaction mixture was partitioned between DCM and water. The organic extract was concentrated under reduced pressure and the residue purified using SPE (silica, eluting with cyclohexane:ethyl acetate 5:1, 3:1, 1:1, 1:3 and ethyl acetate) to give the title compound (0.021 g) as a colourless gum.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]([OH:10])=O)[C:4](=[O:11])[N:3]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[NH2:18][C:19]1[CH:40]=[CH:39][C:22]([O:23][C:24]2[CH:25]=[CH:26][C:27]3[N:28]([CH:30]=[C:31]([NH:33][C:34]([CH:36]4[CH2:38][CH2:37]4)=[O:35])[N:32]=3)[CH:29]=2)=[C:21]([F:41])[CH:20]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O1CCCC1.CN(C)C=O>[CH:36]1([C:34]([NH:33][C:31]2[N:32]=[C:27]3[CH:26]=[CH:25][C:24]([O:23][C:22]4[CH:39]=[CH:40][C:19]([NH:18][C:8]([C:5]5[C:4](=[O:11])[N:3]([C:12]6[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=6)[N:2]([CH3:1])[C:6]=5[CH3:7])=[O:10])=[CH:20][C:21]=4[F:41])=[CH:29][N:28]3[CH:30]=2)=[O:35])[CH2:37][CH2:38]1
Reactant: Cc1c(C(=O)O)c(=O)n(-c2ccccc2)n1C
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1c(C(=O)Nc2ccc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)c(F)c2)c(=O)n(-c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 68.5 %

Procedure:
A mixture of 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (279 mg, 1.2 mmol), N-[6-(4-amino-2-fluorophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (265 mg, 0.81 mmol), HATU (460 mg, 1.2 mmol), N,N-diisopropylethylamine (320 mg, 2.4 mmol) and N,N-dimethylformamide (9 mL) was stirred at room temperature for 18 hr. Ethyl acetate/tetrahydrofuran and saturated aqueous sodium hydrogen carbonate solution were added to the mixture, and the aqueous layer was extracted with ethyl acetate/tetrahydrofuran (×3). The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH silica gel, ethyl acetate/hexane=40/60→100/0) to give the title compound (300 mg, 69%) as a white solid.
Reaction SMILES: C([N:3](CC)CC)C.[F:8][C:9]1[CH:10]=[C:11]([S:16][C:17]2C=[C:19]3[C:25]([NH:26][C:27](=[O:59])[C:28]4[CH:33]=[CH:32][C:31]([N:34]5[CH2:38][CH2:37][C@H:36]([NH:39]C(=O)C(F)(F)F)[CH2:35]5)=[CH:30][C:29]=4[N:46]([CH:53]4[CH2:58][CH2:57][O:56][CH2:55][CH2:54]4)C(=O)C(F)(F)F)=[N:24][NH:23][C:20]3=[N:21][CH:22]=2)[CH:12]=[C:13]([F:15])[CH:14]=1.C(O)CCC.C(=O)([O-])[O-].[K+].[K+]>CO>[NH2:39][C@H:36]1[CH2:37][CH2:38][N:34]([C:31]2[CH:32]=[CH:33][C:28]([C:27]([NH:26][C:25]3[C:19]4[C:20](=[N:21][CH:22]=[C:17]([S:16][C:11]5[CH:10]=[C:9]([F:8])[CH:14]=[C:13]([F:15])[CH:12]=5)[N:3]=4)[NH:23][N:24]=3)=[O:59])=[C:29]([NH:46][CH:53]3[CH2:58][CH2:57][O:56][CH2:55][CH2:54]3)[CH:30]=2)[CH2:35]1
Reactant: CCN(CC)CC
Reactant: O=C(Nc1n[nH]c2ncc(Sc3cc(F)cc(F)c3)cc12)c1ccc(N2CC[C@H](NC(=O)C(F)(F)F)C2)cc1N(C(=O)C(F)(F)F)C1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Solvent: CO
Product: N[C@H]1CCN(c2ccc(C(=O)Nc3n[nH]c4ncc(Sc5cc(F)cc(F)c5)nc34)c(NC3CCOCC3)c2)C1
Temperature: 65 °C
Reaction time: 4 h
Yield: 49 %

Procedure:
876 μl (20 eq) of triethylamine is added to a solution of 238 mg (0.314 mmol) of (S)—N-(5-(3,5-difluorophenylthio)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-(2,2,2-trifluoro-N-(tetrahydro-2H-pyran-4-yl)acetamido)-4-(3-(2,2,2-trifluoroacetamido)pyrrolidin-1-yl)benzamide in 6 ml of methanol. The reaction medium is stirred at 65° C. for 4 hours. After returning to room temperature, 8 ml of n-butanol and 260 mg (6 eq) of potassium carbonate are added. The reaction medium is stirred at 80° C. for 24 hours. After returning to room temperature, the solvents are evaporated, water is added and the product is extracted with dichloromethane. The organic phase is washed with saturated sodium chloride solution, dried on magnesium sulfate, filtered and evaporated. The residue is purified by silica gel chromatography (8:2 dichloromethane/methanol as eluent) to yield 87 mg (yield=49%) of (S)-4-(3-aminopyrrolidin-1-yl)-N-(5-(3,5-difluorophenylthio)-1H-pyrazolo[3,4-b]pyrazine-3-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide in the form of a brown powder.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:3]=1.[I:25]N1C(=O)CCC1=O>C(#N)C>[NH2:1][C:2]1[N:6]([C:7]2[C:8]([Cl:18])=[CH:9][C:10]([C:14]([F:16])([F:15])[F:17])=[CH:11][C:12]=2[Cl:13])[N:5]=[C:4]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:3]=1[I:25]
Reactant: O=C1CCC(=O)N1I
Reactant: Nc1cc(-c2ccccc2)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Solvent: CC#N
Product: Nc1c(I)c(-c2ccccc2)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl

Procedure:
To a stirred solution of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-phenylpyrazole (0.12 g) and N-iodosuccinirnide (0.08 g) in acetonitrile (5 ml) were left at room temperature overnight. The mixture was evaporated to dryness and the residue partitioned between dichloromethane (15 ml) and water (10 ml). The organic layer was separated and washed with water (20 ml, ×2), brine (15 ml) and dried (MgSO4) and evaporated. The residue was triturated with hexane to give the title compound as a yellow solid, m.p. 162-164° C.
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1.C1(C)C=CC=CC=1.Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][S:24][C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([CH2:32][CH2:33][CH3:34])[CH:26]=1>O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][S:24][C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([CH2:32][CH2:33][CH3:34])[CH:26]=2)=[CH:6][CH:5]=1
Reactant: Sc1ccc(Br)cc1
Reactant: CCCc1cc(SCCCCCBr)ccc1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCc1cc(SCCCCCSc2ccc(Br)cc2)ccc1C
Reaction time: 4 h
Yield: 79 %

Procedure:
10 g of sodium hydroxide was dissolved in 20 ml of water, and then added with 2.0 g of 4-bromothiophenol, 0.5 g of tetrabutylammonium bromide, 3 ml of toluene and 3.3 g of 1-bromo-5(4-methyl-3-n-propylthiophenoxy)-n-pentane obtained by ◯1 , followed by drastic stirring at 80° to 90° C. for 4 hours. After cooling, the reaction solution was poured into 100 ml of water, and extracted two times by 150 ml of toluene. The toluene layer was washed with water and saturated solution of common salt, and distilled to remove the solvent. The obtained residue was purified by silica-gel column chromatography (developing solvents: toluene+n-hexane) to give 3.5 g (yield: 79.6%) of the intended 1-(4-bromophenylthio)-5-(4-methyl-3-n-propylthiophenoxy)-n-pentane as a colorless crystal. Furthermore, it was recrystallized by n-hexane to give m.p. 42° to 43° C.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([Br:11])[C:5]=1[OH:12])[CH:2]=[CH2:3].ClC1C=C(C=CC=1)C(OO)=[O:18].C(=O)([O-])[O-].[K+].[K+]>>[Br:11][C:6]1[C:5]2[O:12][CH:2]([CH2:3][OH:18])[CH2:1][C:4]=2[CH:9]=[C:8]([F:10])[CH:7]=1
Reactant: C=CCc1cc(F)cc(Br)c1O
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: OCC1Cc2cc(F)cc(Br)c2O1
Yield: 77.9 %

Procedure:
Treatment of 2-allyl-6-bromo-4-fluorophenol (25.1 g, 0.109 mol) with 3-chloroperoxybenzoic acid (77%, 56.24 g, 0.326 mol) followed by potassium carbonate (62.19 g, 0.45 mol) generally according to the procedure described for Intermediate 9 provided 20.98 g (78%) of (±)-(7-bromo-5-fluoro-2,3-dihydro-1-benzofuran-2-yl)methanol as a white solid. Rf=0.54 (silica, ethyl acetate:hexanes 1:1); mp 53-57° C.; Anal. calcd. for C9H8BrFO2.0.1 C4H8O2: C, 44.13; H, 3.47. Found: C, 44.17; H, 3.16.
Reaction SMILES: [H-].[Na+].[CH:3]([N:6]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:7](=[O:38])[CH2:8][N:9]1[C:15](=[O:16])[C:14]([CH3:26])([CH2:17][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:19])[C:13](=[O:27])[N:12]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:11]2[CH:34]=[CH:35][CH:36]=[CH:37][C:10]1=2)([CH3:5])[CH3:4].I[CH3:46]>CN(C=O)C.Cl>[CH:3]([N:6]([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C:7](=[O:38])[CH2:8][N:9]1[C:15](=[O:16])[C:14]([CH3:26])([CH:17]([CH3:46])[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:19])[C:13](=[O:27])[N:12]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:11]2[CH:34]=[CH:35][CH:36]=[CH:37][C:10]1=2)([CH3:5])[CH3:4]
Reactant: CC(C)N(C(=O)CN1C(=O)C(C)(CC(=O)c2ccccc2)C(=O)N(c2ccccc2)c2ccccc21)c1ccccc1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N(C(=O)CN1C(=O)C(C)(C(C)C(=O)c2ccccc2)C(=O)N(c2ccccc2)c2ccccc21)c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 21.2 %

Procedure:
8.2 mg (0.21 mmol) of 60% sodium hydride is added to a solution of 0.075 g (0.14 mmol) of N-Isopropyl-2-[3-methyl-2,4-dioxo-3-(2-phenyl-2-oxoethyl)-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl]-N-phenyl acetamide, prepared as in Example 7, in 2 ml of DMF. After 5 min, 0.009 mL (0.15 mmol) of iodomethane is added and the solution stirred at RT for 25 min. The reaction mixture is diluted with 10 mL of 1N HCl and extracted with EtOAc (×3). The organic extracts are washed with H2O and brine, dried over MgSO4 and concentrated in vacuo to a bright yellow oil. Purification by reverse phase C-18 MPLC (70-75% methanol/H2O) gave 17 mg of the title compound as a white powder: 1H NMR (CDCl3 300 MHz) δ8.04 (d, 2H, J=7), 7.6-6.9 (m, 17H), 5.03 (m, 0.5H), 4.92 (m, 0.5H), 4.8-3.9 (m, 3H), 1.26 (dd, 3H, J=7,11), 1.12 (dd, 3H, J=2,7), 0.98 (t, 3H, J=7); low resolution MS (FAB) m/e 560 (MH+).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[OH:11])(=[O:3])[CH3:2].[O:12]1[CH2:16][CH2:15][CH2:14][CH:13]1[CH2:17][CH:18]=O>CO>[Br:10][C:8]1[CH:9]=[C:4]2[C:5](=[CH:6][CH:7]=1)[O:11][CH:18]([CH2:17][CH:13]1[CH2:14][CH2:15][CH2:16][O:12]1)[CH2:2][C:1]2=[O:3]
Reactant: CC(=O)c1cc(Br)ccc1O
Reactant: O=CCC1CCCO1
Solvent: CO
Product: O=C1CC(CC2CCCO2)Oc2ccc(Br)cc21
Temperature: 25 °C
Yield: 18.3 %

Procedure:
The solution of 2-Acetyl-4-bromophenol (1.754 g, 8.16 mmol), 2-(tetrahydrofuran-2-yl)acetaldehyde (2.1 g) and purrolidine (0.4 mL) in MeOH was heated to reflux for 2 h. The reaction mixture was cool down to room temperature and evaporated. The residue was dissolved in EA, washed with 1 M HCl, 1 M NaOH (2×50 mL), brine (100 mL) successively, then, dried over anhydrous Na2SO4, and filtered, and concentrated. The residue was purified by flash chromatography on silica gel eluting with EA in hexane (0-20%) to give 6-bromo-2-((tetrahydrofuran-2-yl) methyl)chroman-4-one (464 mg); MS ESI +ve m/z 311 (M+H)+.
Reaction SMILES: [CH2:1]([S:5]([NH:8][C:9](=[O:23])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[C:12]([N+:20]([O-])=O)[CH:11]=1)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4].CO.C(=O)(O)[O-].[K+]>[Pd].O>[CH2:1]([S:5]([NH:8][C:9](=[O:23])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[C:12]([NH2:20])[CH:11]=1)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCS(=O)(=O)NC(=O)c1ccc(NC(C)=O)c([N+](=O)[O-])c1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCCCS(=O)(=O)NC(=O)c1ccc(NC(C)=O)c(N)c1
Yield: 68.5 %

Procedure:
N-(1-butanesulfonyl)-4-acetylamino-3-nitrobenzamide (10.75 g) is dissolved with methanol (200 ml) and water (30 ml), and potassium bicarbonate (7.59 g) is added. The solution is hydrogenated with a 5% palladium/carbon (2.53 g) catalyst under a hydrogen environment for 24 hours at 40° C. The solids are separated through filtration, the residue, which is obtained by concentrating the filtrate, is purified using silica gel column chromatography (eluate: ethyl acetate/methanol=4/1), and 6.72 g of N-1-butylsulfonyl-4-acetylamino-3-aminobenzamide is obtained. 1H-NMR (DMSO-d6, δ): 0.86 (3H, t, J=7.3 Hz), 1.33-1.43 (2H, m), 1.59-1.67 (2H, m), 2.07 (3H, s), 3.37-3.43 (2H, t), 5.12 (2H, br s), 7.13 (1H, dd, J=8.2 and 2.0 Hz), 7.28 (1H, d, J=1.9 Hz), 7.40 (1H, d, J=8.3 Hz), 9.09 (1H, s).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[C:12]([OH:14])[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=1.Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:10][O:9][C:7](=[O:8])[C:6]1[CH:11]=[C:12]([O:14][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH3:17])[CH:13]=[C:4]([C:3]([O:2][CH3:1])=[O:15])[CH:5]=1
Reactant: CCCCCCCCCCCCCCBr
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCCCCCCCCCCCOc1cc(C(=O)OC)cc(C(=O)OC)c1
Yield: 66.4 %

Procedure:
The product was generated using general protocol D using dimethyl-5-hydroxyisophthalate (1.037 g, 4.93 mmol), 1-bromotetradecane (1.34 mL, 4.48 mmol), K2CO3 (2.48 g, XXmol), CH3CN (50 mL) yielded 1.21 g (60.2%) of a white solid. 1H NMR (CDCl3, 400 MHz) δ: 8.2607 (s, 1H, Ar—H), 7.7396 (s, 2H, Ar—H), 4.0315 (t, 2H, O—CH2, 3J=6.62 Hz), 3.9374 (s, 6H, COOCH3), 1.8046 (p, 2H, O—CH2—CH23J=6.82 Hz), 1.4660 (p, 2H, O—CH2—CH2—CH2, 3J=6.86 Hz), 1.2582 (m, 22H), 0.8809 (t, 3H, CH2—CH3, 3J=6.69 Hz
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](O)[C:5]([S:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]#[N:18])=[CH:12][CH:11]=2)=[C:4]([CH3:19])[N:3]=1.O=P(Cl)(Cl)[Cl:22]>>[NH2:1][C:2]1[N:7]=[C:6]([Cl:22])[C:5]([S:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]#[N:18])=[CH:12][CH:11]=2)=[C:4]([CH3:19])[N:3]=1
Reactant: Cc1nc(N)nc(O)c1Sc1ccc(CC#N)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1nc(N)nc(Cl)c1Sc1ccc(CC#N)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of the product from step (iii) (2.3 g) and POCl3 (25 ml) was heated under reflux for 8 h. The mixture was evaporated under reduced pressure and ice/water added to the residue. The mixture was stirred at rt for 15 min then neutralised with aq. 2M NaOH solution and heated at 40° C. for 2 h then extracted with DCM. The organics were dried, evaporated under reduced pressure and the residue purified by column chromatography (2% MeOHIDCM), to give the subtitle compound as a solid, 530 mg.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:12]=[CH:11][C:10]2[NH:9][C:8]3[CH2:13][CH2:14][NH:15][C:16](=[O:17])[C:7]=3[C:6]=2[CH:5]=1.[CH3:18]I.O>CN(C=O)C>[F:3][C:4]1[CH:12]=[CH:11][C:10]2[N:9]([CH3:18])[C:8]3[CH2:13][CH2:14][NH:15][C:16](=[O:17])[C:7]=3[C:6]=2[CH:5]=1
Reactant: CI
Reactant: O=C1NCCc2[nH]c3ccc(F)cc3c21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c2c(c3cc(F)ccc31)C(=O)NCC2
Reaction time: 0.25 h

Procedure:
Sodium hydride (60% dispersion in oil; 196 mg) was added to a stirred solution of 8-fluoro-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-one (500 mg) in dry DMF (20 ml) at 21° under nitrogen. After 15 min, the solution was cooled (0°) and a 10% (v/v) solution of methyl iodide in DMF (1.6 ml) was added dropwise. After 10 min, water (150 ml) was added and the mixture was extracted with ethyl acetate (3×50 ml). The combined organic extracts were washed with water (3×50 ml), then brine (100 ml) and evaporated to give a solid which was purified by FCC Eluting with dichloromethane:methanol (80:1) to give the title compound (240 mg), m.p. 200°-202°.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[C@@H:20]([CH3:25])[CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH3:26][O:27][CH2:28][CH2:29]Br.[H-].[Na+]>>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[C@@H:20]([CH3:25])[CH2:21][N:22]([CH2:29][CH2:28][O:27][CH3:26])[C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3[C@@H](C)CNC2=O)CC1
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Product: COCCN1C[C@H](C)n2c(cc3cc(OC4CCN(C(C)C)CC4)ccc32)C1=O
Yield: 50 %

Procedure:
The title compound was synthesized in analogy to example 17, from (S)-8-(1-isopropyl-piperidin-4-yloxy)-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 11), 2-bromoethyl methyl ether and sodium hydride, to give the desired product as a colorless oil (50%).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[NH:9][CH:8]=[C:7](C[C@@H](N)C(O)=O)[C:5]=2[CH:6]=1.O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.C[N:29](C1C=CC2N=C3C(=CC(C=C3)=[N+](C)C)SC=2C=1)C.C1C=C(C(C[C@H](N)C(O)=O)=O)C(NC=O)=CC=1>P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[NH:9]1[C:4]2[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=2)[CH:7]=[C:8]1[NH2:29]
Reactant: CN(C)c1ccc2nc3ccc(=[N+](C)C)cc-3sc2c1
Reactant: N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: N[C@@H](CC(=O)c1ccccc1NC=O)C(=O)O
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: O=P([O-])([O-])[O-]
Product: Nc1cc2ccccc2[nH]1

Procedure:
Human indoleamine 2,3-dioxygenasae (IDO) with an N-terminal H is tag was expressed in E. coli and purified to homogeneity. IDO catalyzes the oxidative cleavage of the pyrrole ring of the indole nucleus of tryptophan to yield N′-formylkynurenine. The assays were performed at room temperature as described in the literature using 95 nM IDO and 2 mM D-Trp in the presence of 20 mM ascorbate, 5 μM methylene blue and 0.2 mg/mL catalase in 50 mM potassium phosphate buffer (pH 6.5). The initial reaction rates were recorded by continuously following the absorbance increase at 321 nm due to the formation of N′-formylkynurenine. See: Sono, M., Taniguchi, T., Watanabe, Y., and Hayaishi, O. (1980) J. Biol. Chem. 255, 1339-1345 Compounds of the invention having an IC50 less than about 100 μM were considered active.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]1.[F:7][C:8]1[CH:9]=[C:10]([N+:15]([O-:17])=[O:16])[CH:11]=[CH:12][C:13]=1F.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:7][C:8]1[CH:9]=[C:10]([N+:15]([O-:17])=[O:16])[CH:11]=[CH:12][C:13]=1[N:1]1[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]1
Reactant: OC1CCNC1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(N2CCC(O)C2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 113.2 %

Procedure:
To a solution of 3-pyrrolidinol (1.82 g) and 3,4-difluoronitrobenzene (3.0 g) in dimethylformamide (30 ml) was added potassium carbonate (3.94 g). The mixture was stirred at room temperature overnight and then filtered followed by washing with dichloromethane. The filtrate combined was concentrated under reduced pressure. The residue obtained was chromatographed over a silica gel column eluting with ethyl acetate/hexane with increasing in the content of ethyl acetate (50% to 60%). The appropriate fractions were pooled and concentrated under reduced pressure to give the title compound (4.83 g); 1H NMR (CD3OD, 270 MHz), δ 0.85 (2H, m), 2.25-2.57 (4H, m), 3.26 (1H, m), 5.47 (1H, t, J=8.6 Hz), 6.62 (1H, dd, J=2.4, 14.0 Hz), 6.69 (1H, dd, J=2.4, 8.6 Hz).
Reaction SMILES: N#N.[CH2:3]([C:6]1[C:11]2[O:12][C@@H:13]([CH2:16][O:17][S:18]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH2:14][O:15][C:10]=2[CH:9]=[CH:8][C:7]=1[N+:28]([O-:30])=[O:29])[CH:4]=[CH2:5].[OH-].[Na+].OO.C([O-])([O-])=[O:36].[K+].[K+]>C1COCC1.O.C(O)C>[OH:36][CH2:5][CH2:4][CH2:3][C:6]1[C:11]2[O:12][C@@H:13]([CH2:16][O:17][S:18]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH2:14][O:15][C:10]=2[CH:9]=[CH:8][C:7]=1[N+:28]([O-:30])=[O:29]
Reactant: O=C([O-])[O-]
Reactant: C=CCc1c([N+](=O)[O-])ccc2c1O[C@@H](COS(=O)(=O)c1ccc(C)cc1)CO2
Agent: N#N
Agent: OO
Agent: [K+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc([N+](=O)[O-])c(CCCO)c3O2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
A 1M solution of BH3 ·THF (11.00 ml, 11.00 mmole) was placed in a 100 ml round-bottom flask equipped with N2 line, dropping funnel and thermometer. The solution was cooled to 0° C. in an ice-water bath. To this cooled solution was added dropwise, (R)-toluene-4-sulfonic acid 8-allyl-7-nitro-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl ester (2.25 g, 5.56 mmole) in 10 ml of dry THF over a 10 minute period. The reaction was allowed to reach room temperature and then stirred overnight. It was then cooled to 0 ° C. and to it was added dropwise 2.42 ml of absolute ethanol and 6.16 ml (18.5 mmole) of a 3N NaOH solution. After a few minutes, 4.2 ml of a 30% aqueous H2O2 solution was added over a 20 minute period. The mixture was heated to 48° C. for three hours. The mixture was then cooled to 0° C. and to it was added 6.08 g of K2CO3. The mixture was stirred for 0.5 hr and then left standing overnight. The following morning the solid had disappeared. The reaction was diluted with water and extracted with ethyl acetate. The organic layer washed with brine, dried over MgSO4, filtered and concentrated to yield a clear viscous oil (1.20 g, 51%) of (R)-toluene-4-sulfonic acid 8-(3-hydroxy-propyl)-7-nitro-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl ester.