Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=O)(C)(C)C.ClC[C:16](Cl)=[O:17].[CH3:19][O:20][NH:21][CH3:22]>>[CH3:19][O:20][N:21]([CH3:22])[C:16](=[O:17])[CH2:6][N:8]1[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CNOC
Product: CON(C)C(=O)CN1CCNCC1

Procedure:
The title compound was prepared from 1-tert-butyloxycarbonyl-piperazine, chloroacetylchloride and N-methoxy-N-methylamine in an analogous manner as described in example 21.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][N:3]=1.[Cl:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([S:19](OC3C(F)=C(F)C(F)=C(F)C=3F)(=[O:21])=[O:20])=[CH:16][CH:17]=2)[N:12]=[CH:11][CH:10]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[Cl:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([S:19]([NH:1][C:2]3[CH:7]=[CH:6][N:5]=[CH:4][N:3]=3)(=[O:20])=[O:21])=[CH:16][CH:17]=2)[N:12]=[CH:11][CH:10]=1
Reactant: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc2c(Cl)ccnc2c1
Reactant: Nc1ccncn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=S(=O)(Nc1ccncn1)c1ccc2c(Cl)ccnc2c1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 67.6 %

Procedure:
A flask containing a solution of 4-aminopyrimidine (0.026 g, 0.268 mmol) and perfluorophenyl 4-chloroquinoline-7-sulfonate (from Step 2, Intermediate LLLL; 0.100 g, 0.244 mmol) in THF (1.220 ml) was cooled to −78° C. for 10 minutes, and then lithium bis(trimethylsilyl)amide, 1.0 m solution in tetrahydrofuran (0.488 ml, 0.488 mmol) was added dropwise. After 20 minutes, the reaction had gone to completion. The reaction mixture was quenched with aq ammonium chloride, and concentrated under a vacuum. A 2:1 mixture of DCM:H2O was added, the flask sonicated, and the solids filtered to yield 4-chloro-N-(pyrimidin-4-yl)quinoline-7-sulfonamide (0.053 g, 0.165 mmol, 67.7% yield) as a light brown solid (carried forward crude). m/z (ESI) 321.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7]([F:24])[C:8]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=3[F:23])=[C:9]([C:12]([OH:14])=O)[CH:10]=2)[N:5]=[N:4][CH:3]=1.C1C=CC2N(O)[N:32]=[N:31]C=2C=1.CCN=C=NCCCN(C)C.NN>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([F:24])[C:8]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=3[F:23])=[C:9]([C:12]([NH:31][NH2:32])=[O:14])[CH:10]=2)[N:5]=[N:4][CH:3]=1
Reactant: On1nnc2ccccc21
Reactant: Nc1cnnc2c(F)c(Nc3ccc(Br)cc3F)c(C(=O)O)cc12
Agent: CCN=C=NCCCN(C)C
Agent: NN
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NNC(=O)c1cc2c(N)cnnc2c(F)c1Nc1ccc(Br)cc1F
Reaction time: 1 h

Procedure:
To a solution of 4-amino-7-(4-bromo-2-fluorophenylamino)-8-fluoro-cinnoline-6-carboxylic acid (1.00 equiv.) and HOBt (3.00 equiv.) in DMF is added EDCI (3.00 equiv.) at room temperature. After stirring for 1 hour, hydrazine (3.00 equiv.) and TEA (3.00 equiv.) are added. The reaction mixture is stirred for 1 hour and diluted with EtOAc. The resulting mixture is washed with saturated aqueous NH4Cl, brine, saturated aqueous NaHCO3, and brine. The organic layer is dried over MgSO4, filtered, and concentrated under reduced pressure to give the crude material that is used directly without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][N:13]([CH3:15])[CH3:14])#[N:2].[CH3:16][I:17]>C1COCC1>[I-:17].[CH3:14][N+:13]([CH3:16])([CH3:15])[CH2:12][C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[C:3]([C:1]#[N:2])[CH:4]=2)[NH:8][CH:7]=1
Reactant: CI
Reactant: CN(C)Cc1c[nH]c2ccc(C#N)cc12
Solvent: C1CCOC1
Product: C[N+](C)(C)Cc1c[nH]c2ccc(C#N)cc12
Product: [I-]
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 94.8 %

Procedure:
To a solution of 2.7 g (13.6 mmol, 1.0 equiv.) of 5-cyano-3-(dimethylamino)methyl-1H-indole in 125 mL of THF at 0° C. was added 1.3 mL (20.3 mmol, 1.5 equiv.) of methyl iodide dropwise. After five minutes the solution was allowed to warm to room temperature and stirred for one hour. The resulting precipitate was filtered and dried in vacuo to yield 4.4 g (96%) of N,N,N-trimethyl-1-(5-cyano-1H-indol-3-yl)methanaminium iodide, pure by 1H NMR analysis.
Reaction SMILES: C(O[C:9]1[C:14]([CH:15]=O)=[CH:13][CH:12]=[CH:11][C:10]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)C1C=CC=CC=1.[CH3:23]OC1C(N)=CC=CC=1.[OH2:32]>C1(C)C=CC=CC=1>[CH3:15][C:14]1[CH:13]=[CH:12][CH:11]=[CH:23][C:9]=1[CH:10]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[OH:32]
Reactant: O=Cc1cccc(-c2ccccc2)c1OCc1ccccc1
Reactant: COc1ccccc1N
Reactant: O
Solvent: Cc1ccccc1
Product: Cc1ccccc1C(O)c1ccccc1
Temperature: 25 °C

Procedure:
A solution of 15 (1.44 g, 5 mmol, 1.0 equiv) and o-anisidine (16) (0.62 g, 0.56 mL, 5 mmol, 1.0 equiv) in toluene (15 mL) was refluxed overnight with H2O removal (Dean-Stark trap). The mixture was cooled to room temperature and concentrated under reduced pressure to give crude 5 as a yellow oil that was used without purification.
Reaction SMILES: [O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][NH:16][CH2:15][C:14]3=[O:19])=[CH:10][C:5]=2[CH2:4][O:3]1.[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:27]([CH2:30][CH:31]=O)=[CH:26][C:23]=1[C:24]#[N:25]>>[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][N:16]2[CH2:17][CH2:18][N:13]([CH2:12][CH2:11][C:9]3[CH:8]=[CH:7][C:6]4[C:2](=[O:1])[O:3][CH2:4][C:5]=4[CH:10]=3)[C:14](=[O:19])[CH2:15]2)=[CH:26][C:23]=1[C:24]#[N:25]
Reactant: COc1ccc(CC=O)cc1C#N
Reactant: O=C1OCc2cc(CCN3CCNCC3=O)ccc21
Product: COc1ccc(CCN2CCN(CCc3ccc4c(c3)COC4=O)C(=O)C2)cc1C#N

Procedure:
The title compound was prepared from 1-[2-(1-Oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-2-one and 2-Methoxy-5-(2-oxoethyl)benzonitrile following essentially the same procedure as Example 6. The product was purified by mass-directed reverse phase HPLC (AcCN-Water with 0.1% TFA). LC-MS (IE, m/z): 420 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=2)[C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=3)[C:11]3[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1ncc[nH]1
Reactant: COc1ccc(CNc2nc(Cl)nc3sc([N+](=O)[O-])cc23)cc1OC
Product: COc1ccc(CNc2nc(-n3ccnc3C)nc3sc([N+](=O)[O-])cc23)cc1OC

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-6-nitro-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-6-nitro-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][NH:7][C:8](=[O:19])[C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([F:16])=[CH:11][C:10]=2[O:17]C)=[C:4]([F:22])[CH:3]=1.Br.[Na+].[Cl-].C(OCC)(=O)C>C(O)(=O)C>[Br:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][NH:7][C:8](=[O:19])[C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([F:16])=[CH:11][C:10]=2[OH:17])=[C:4]([F:22])[CH:3]=1
Reactant: COc1cc(F)c(C)cc1C(=O)NCc1ccc(Br)cc1F
Agent: Br
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1cc(C(=O)NCc2ccc(Br)cc2F)c(O)cc1F
Temperature: 120 °C
Yield: 73 %

Procedure:
A stirring suspension of N-(4-bromo-2-fluoro-benzyl)-4-fluoro-2-methoxy-5-methyl-benzamide (2.32 g, 6.51 mmol) in a 25% solution of HBr in acetic acid (60 mL, 0.11 M) was equipped with a refllux condenser and heated to 120° C. for 3.5 h. The mixture was allowed to cool and saturated aq NaCl (50 mL) and ethyl acetate (50 mL) were added. The layers were allowed to separate and the organic layer was collected. The aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organics were dried over Na2SO4, filtered, and concentrated to provide an orange powder. Purification of the solid via silica gel flash chromatography (30% ethyl acetate in heptane) provided N-(4-bromo-2-fluoro-benzyl)-4-fluoro-2-hydroxy-5-methyl-benzamide (1.69, 73%) as a white powder: mp 149–150° C.; Rf 0.51 (30% ethyl acetate in heptane); 1H NMR (CDCl3, 300 MHz) δ 12.20 (d, J=1.5, 1 H), 7.30–7.29 (m, 2 H), 7.26 (s, 1 H), 7.14 (d, J=8.1 Hz, 1 H), 6.64 (d, J=10.8, 1 H), 6.48 (bd s, 1 H), 4.62 (d, J=5.7 Hz, 2 H), 2.19 (8, 3 H); ESI-LC/MS m/z calcd for C15H12BrF2NO2: 355.0. Found 354.0 (M−1)−. Anal. calcd for C15H12BrF2NO2: C, 50.58; H, 3.40; N, 3.93. Found C, 50.65; H, 3.47; N, 3.87.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1.[C:13](=O)([O-])[O-].[K+].[K+].CN(C)C=O.CI>C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[CH3:13])=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Brc1ccc(C2CCCN2)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCOC(C)=O
Product: CN1CCCC1c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 44.2 %

Procedure:
To a mixture of 2-(4-bromophenyl)pyrrolidine (231.9 mg, 1.026 mmol) and potassium carbonate (216.6 mg, 1.567 mmol) was added N,N-dimethylformamide (4.0 mL, 52 mmol) and methyl iodide (77 uL, 1.2 mmol). The reaction mixture was stirred at room temperature for 2 days and then methyl iodide (39.0 uL, 0.626 mmol) was added. After stirring at room temperature for an additional two hours, the reaction mixture was poured into ethyl acetate and washed three times with 2M aqueous Na2CO3. The ethyl acetate layer was then dried over MgSO4, filtered, and evaporated in vacuo to yield 108.9 mg (44%) of 2-(4-bromophenyl)-1-methylpyrrolidine. LCMS (ESI): M+H=240.2.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.[CH2:56]([O:58][C:59](=[O:68])[CH2:60][N:61]1[CH2:66][CH2:65][CH2:64][CH:63]([NH2:67])[CH2:62]1)[CH3:57]>CN(C=O)C>[CH2:56]([O:58][C:59](=[O:68])[CH2:60][N:61]1[CH2:66][CH2:65][CH2:64][CH:63]([NH:67][C:19]([C:18]2[CH:17]=[N:16][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[CH:23][CH:22]=2)=[O:21])[CH2:62]1)[CH3:57]
Reactant: CCOC(=O)CN1CCCC(N)C1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CCCC(NC(=O)c2ccc(OCc3c(-c4ccccc4)noc3C)nc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.2 %

Procedure:
To a solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (500 mg, 1.6 mmol) in DMF (10 mL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (569 mg, 1.8 mmol), N,N-diisopropyl ethyl amine (1.38 mL, 8.1 mmol) and (3-amino-piperidin-1-yl)-acetic acid ethyl ester hydrochloride (459 mg, 1.8 mmol). The resulting reaction mixture was stirred overnight at room temperature. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1 and then dichloromethane:methanol=9:1) afforded the title compound (622 mg, 81%) as a light brown gum. MS: m/e=479.1 [M+H]+.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:18]=[CH:17][C:16]2[C:6](=[C:7]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[C:8]3[C:12](=O)[O:11][C:10](=[O:14])[C:9]=3[CH:15]=2)[CH:5]=1.Cl>C(COC)OC.C1COCC1>[Cl:3][C:4]1[CH:18]=[CH:17][C:16]2[C:6](=[C:7]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[C:8]3[CH2:12][O:11][C:10](=[O:14])[C:9]=3[CH:15]=2)[CH:5]=1
Reactant: O=C1OC(=O)c2c1cc1ccc(Cl)cc1c2-c1ccc(Cl)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: COCCOC
Product: O=C1OCc2c1cc1ccc(Cl)cc1c2-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.3 %

Procedure:
To a suspension of sodium borohydride (0.5 g) in dimethoxyethane (20 ml), a solution of 6-chloro-4-(4-chlorophenyl) naphtho[2,3-c]furan-1,3-dione (1.0 g) in THF (20 ml) was added dropwise, followed by stirring at room temperature for 1 hour. The reaction mixture was poured into 1N hydrochloric acid to stop the reaction; the product was extracted with ethyl acetate. After being washed with water, the extract was dried over magnesium sulfate and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (eluent: hexane−ethyl acetate=3:1) and recrystallized from THF to yield the title compound (300 mg).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][N:20]2[C:25](=[O:26])[C:24]([CH3:27])=[CH:23][NH:22][C:21]2=[O:28])[CH2:13][CH2:12]1.[CH3:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][Cl:37])=[CH:34][CH:33]=1>>[ClH:37].[F:30][C:2]([F:29])([F:1])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][CH2:19][N:20]2[C:25](=[O:26])[C:24]([CH3:27])=[CH:23][N:22]([CH2:31][C:32]3[CH:39]=[CH:38][C:35]([CH3:36])=[CH:34][CH:33]=3)[C:21]2=[O:28])[CH2:15][CH2:16]1
Reactant: Cc1ccc(CCl)cc1
Reactant: Cc1c[nH]c(=O)n(CCCN2CCN(c3ccccc3OCC(F)(F)F)CC2)c1=O
Product: Cc1ccc(Cn2cc(C)c(=O)n(CCCN3CCN(c4ccccc4OCC(F)(F)F)CC3)c2=O)cc1
Product: Cl

Procedure:
substituting 3-(3-{4-[2-(2,2,2-trifluoroethoxy)phenyl]piperazin-1-yl}propyl)-5-methyl-2,4(1H,3H)-pyrimidinedione and 4-methylbenzyl chloride gave 3-(3-{4-[2-(2,2,2-trifluoroethoxy)phenyl]piperazin-1-yl}propyl)-1-(4-methylbenzyl)-5-methyl-2,4(1H,3H)-pyrimidinedione hydrochloride, m.p. 141°-143° C.; Anal.: Calcd. for C28H33F3N4O3.(HCl)2 : C, 55.89; H, 5.99; N, 9.12%; Found: C, 56.18; H, 5.99; N, 9.31%.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:23])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([NH:13][C:14](=[O:22])[C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)[CH:7]=2)[CH2:3][CH2:2]1.[O:24]1[CH2:28][CH2:27][O:26][CH:25]1[CH2:29][O:30][C:31]1[CH:32]=[CH:33][C:34]([CH2:37]O)=[N:35][CH:36]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[CH:1]1([NH:4][C:5](=[O:23])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([NH:13][C:14](=[O:22])[C:15]3[CH:16]=[CH:17][C:18]([O:21][CH2:37][C:34]4[CH:33]=[CH:32][C:31]([O:30][CH2:29][CH:25]5[O:26][CH2:27][CH2:28][O:24]5)=[CH:36][N:35]=4)=[CH:19][CH:20]=3)[CH:7]=2)[CH2:2][CH2:3]1
Reactant: OCc1ccc(OCC2OCCO2)cn1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(O)cc1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(OCc2ccc(OCC3OCCO3)cn2)cc1
Reaction time: 16 h
Yield: 75.5 %

Procedure:
To a stirred solution of N-cyclopropyl-3-[(4-hydroxybenzoyl)amino]-4-methylbenzamide (3.1 g, 10 mmol) in dry THF (200 mL) at 25° C. was added [5-(1,3-dioxolan-2-ylmethoxy)-pyridin-2-yl]methanol (2.4 g, 11 mmol), triphenylphosphine (2.9 g, 11 mmol) and di-tert-butyl azodicarboxylate (2.6 g, 11 mmol). The solution was stirred for 16 hours, then the solvent was evaporated and the residue dissolved in ethyl acetate/methanol (19:1, 50 mL) and purified by chromatography on silica, eluting with a gradient of 5-20% methanol in ethyl acetate, to give the title compound as a white solid (3.8 g, 76%). NMR Spectrum: (DMSOd6) 0.56 (m, 2H), 0.68 (m, 2H), 2.24 (s, 3H), 2.84 (m, 1H), 3.85 (m, 2H), 3.92 (m, 2H), 4.10 (m, 2H), 5.20 (m, 3H), 7.12 (d, 2H), 7.30 (d, 1H), 7.45 (s, 2H), 7.62 (dd, 1H), 7.78 (s, 1H), 7.95 (d, 2H), 8.30 (s, 1H), 8.35 (d, 1H), 9.80 (s, 1H); Mass Spectrum: M+H+ 504.
Reaction SMILES: [N:1]1[CH:2]=[C:3]([C:10]([OH:12])=O)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.C(Cl)(=O)C(Cl)=O.[NH2:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[F:28])[C:23]#[N:24]>ClCCl.CN(C=O)C.N1C=CC=CC=1>[C:23]([C:22]1[CH:25]=[CH:26][C:27]([F:28])=[C:20]([NH:19][C:10]([C:3]2[N:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]3=[N:1][CH:2]=2)=[O:12])[CH:21]=1)#[N:24]
Reactant: O=C(O)c1cnc2ccccn12
Reactant: N#Cc1ccc(F)c(N)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#Cc1ccc(F)c(NC(=O)c2cnc3ccccn23)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirring suspension of imidazo[1,2-a]pyridine-3-carboxylic acid (1) (3.0 g, 18.5 mmol) in anhydrous dichloromethane (50 mL) at 0° C. was added dropwise oxalyl chloride (4.84 mL, 55.5 mmol). Then, three drops of anhydrous DMF was added and the reaction mixture was stirred at room temperature for 15 minutes. The solvent was concentrated and the crude solid was added to a stirring solution of 3-amino-4-fluorobenzonitrile (48) (2.5 g, 18.5 mmol) in anhydrous pyridine (50 mL) at room temperature. The reaction was stirred for 20 minutes and quenched with water (200 mL) with stirring for another 10 minutes. Then the precipitate was filtered and dried in air to yield N-(5-cyano-2-fluorophenyl)imidazo[1,2-a]pyridine-3-carboxamide (49). 1H NMR (400 MHz, d6-DMSO) δ 10.40 (s, 1H), 9.43 (td, J=1.2, 6.8 Hz, 1H), 8.63 (s, 1H), 8.21 (dd, J=2.0, 7.2 Hz, 1H), 7.78-7.84 (m, 2H), 7.54-7.63 (m, 2H), 7.22 (dt, J=1.2, 6.8, 1H). MS m/z 281.1 (M+1)+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[F:15])[CH2:5][C:4](=[O:16])[CH2:3]1.CO[CH:19](OC)[CH2:20][C:21](=O)[CH3:22].C1(C)C=CC=CC=1.[OH-].[K+]>C(O)C>[ClH:14].[Cl:14][C:12]1[CH:11]=[CH:10][C:9]([F:15])=[C:8]([CH:6]2[CH2:7][C:2]3[N:1]=[CH:19][CH:20]=[C:21]([CH3:22])[C:3]=3[C:4](=[O:16])[CH2:5]2)[CH:13]=1
Reactant: NC1CC(=O)CC(c2cc(Cl)ccc2F)C1
Reactant: COC(CC(C)=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1ccnc2c1C(=O)CC(c1cc(Cl)ccc1F)C2
Product: Cl

Procedure:
To a mixture of 1-amino-5-(5-chloro-2-fluorophenyl)cyclohexan-3-one (1.33 g), 1,1-dimethoxy-3-butanone (2 ml), toluene (20 ml) and ethanol (9 ml) was added granulated potassium hydroxide (0.4 g) at 110-115° C. while stirring. Just after potassium hydroxide was dissolved, granulated potassium hydroxide (0.3 g) was added to the mixture. With 30 minutes intervals, granulated potassium hydroxide (0.1 g) was added three times to the mixture. To the mixture was added 1,1-dimethoxy-3-butanone (1ml) 2 hours after the reaction had started, and then granulated potassium hydroxide (0.1 g) was added to the mixture. The mixture was stirred for 1 hour under the same conditions. The reaction solution was concentrated under reduced pressure, and to the residue was added water (30 ml) and ethyl acetate (100 ml). The mixture was shaken and the separated upper layer was washed with water. To the mixture was added concentrated hydrochloric acid (0.5 ml). The mixture was concentrated under reduced pressure, and the residue washed with a little amount of ethanol and dried to give 7-(5-chloro-2-fluorophenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one hydrochloride (1.05 g).
Reaction SMILES: [CH3:1][O:2][C:3]1C=C[C:6](C2C=CC=C3C=2C=CN3)=[CH:5][CH:4]=1.[Br-].[Br-].[Br-].[NH+:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[NH+]1C=C[CH:30]=[CH:29][CH:28]=1.[NH+]1C=CC=CC=1.[C:39]([OH:42])(=O)[CH3:40]>CC(O)(C)C.C(O)C.C(O)(=O)C.[Zn]>[CH3:1][O:2][C:3]1[CH:22]=[C:23]([C:24]2[CH:30]=[CH:29][CH:28]=[C:26]3[C:25]=2[CH2:40][C:39](=[O:42])[NH:21]3)[CH:6]=[CH:5][CH:4]=1
Reactant: c1cc[nH+]cc1
Reactant: COc1ccc(-c2cccc3[nH]ccc23)cc1
Reactant: CC(=O)O
Agent: [Br-]
Agent: [Zn]
Solvent: CCO
Solvent: CC(C)(C)O
Product: COc1cccc(-c2cccc3c2CC(=O)N3)c1
Temperature: 27 °C
Reaction time: 3 h
Yield: 52 %

Procedure:
To the suspension of 4-(4-methoxy-phenyl)-1H-indole (1.73 g, 7.75 mmol) in t-BuOH-ethanol-acetic acid (3:2:1) (93 mL) was added pyridinium tribromide (90% purity from Aldrich, 8.26 g, 23.24 mmol)) portionwise. The mixture was stirred at 27° C. for 3 hours, and then to the mixture was added acetic acid (38 mL). Zinc dust was added to the reaction mixture portionwise until the color changed from deep red to light yellow, and the reaction mixture was stirred at room temperature for one hour. The unreacted zinc dust was filtered off and washed with ethanol. The filtrate was concentrated, and the syrupy residue was dissolved in ethyl acetate, which was washed with water, 0.5 N HCl, sat. NaHCO3 and brine, and dried over Na2SO4. After filtration and evaporation, the crude product was triturated with diethyl ether to provide product 4-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one (0.97 g, 52%) as a tan solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([OH:9])=[O:8])=[CH:3][C:2]=1[C:10]([OH:12])=[O:11].O.[C:14]1(C)C=CC(S(O)(=O)=O)=C[CH:15]=1.[CH2:25](O)[CH3:26]>C1(C)C=CC=CC=1>[CH2:14]([O:11][C:10]([C:2]1[CH:3]=[C:4]([C:7]([O:9][CH2:25][CH3:26])=[O:8])[CH:5]=[CH:6][N:1]=1)=[O:12])[CH3:15]
Reactant: CCO
Reactant: O=C(O)c1ccnc(C(=O)O)c1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1ccnc(C(=O)OCC)c1
Temperature: 110 °C

Procedure:
4.7 g (28.12 mmol) of 2,4-pyridinedicarboxylic acid and 8.02 g (42.19 mmol) of 4-toluenesulfonic acid monohydrate were suspended in 47 ml of toluene, the mixture was heated to 110° C. and 170 ml (2.87 mol) of ethanol were slowly added dropwise. The reaction mixture was stirred under reflux overnight. The reaction mixture was evaporated and the residue was purified by column chromatography on silica gel 60 (mobile phase: dichloromethane/ethanol 40/1→10/1).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([OH:26])([CH3:25])[CH2:9][N:10]2[C:18]3[CH:17]=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=3[C:12]3[CH2:20][N:21]([CH3:24])[CH2:22][CH2:23][C:11]2=3)=[CH:6][CH:5]=[CH:4][N:3]=1.[OH-:27].[K+]>C(O)(C)(C)C.[Cl-].[Na+].O>[CH3:24][N:21]1[CH2:22][CH2:23][C:11]2[N:10]([CH2:9][C:8]([C:7]3[C:2](=[O:27])[NH:3][CH:4]=[CH:5][CH:6]=3)([OH:26])[CH3:25])[C:18]3[CH:17]=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=3[C:12]=2[CH2:20]1
Reactant: Cc1ccc2c(c1)c1c(n2CC(C)(O)c2cccnc2Cl)CCN(C)C1
Reactant: [OH-]
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: Cc1ccc2c(c1)c1c(n2CC(C)(O)c2ccc[nH]c2=O)CCN(C)C1
Temperature: 90 °C
Yield: 36 %

Procedure:
2-(2-Chloropyridin-3-yl)-1-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)propan-2-ol (100 mg, 0.277 mmol) and crushed potassium hydroxide (106 mg, 1.89 mmol) in 3 mL tert. butanol were heated at 90° C. for 4 h. The reaction mixture was monitored by TLC and LCMS. The reaction mixture was cooled at RT, diluted with 100 mL brine solution and extracted with EtOAc (3×100 mL). The combined organic layer was washed with brine (3×100 mL), dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by reverse phase chromatography to get the 35 mg of 3-(1-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-2-hydroxypropan-2-yl)pyridin-2(1H)-one as the TFA salt. 1H NMR (CD3OD, TFA salt) δ (ppm): 7.79 (d, 1H), 7.35 (m, 2H), 7.17 (s, 1H), 6.93 (d, 1H), 6.34 (t, 1H), 4.61 (d, 2H), 4.3 (d, 2H), 3.9 (m, 1H), 3.8 (m, 1H), 3.36 (m, 2H), 3.1 (s, 3H), 2.37 (s, 3H), 1.51 (s, 3H). Separation by chiral HPLC provides enantiomers II-143a-b.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)C=O.[OH:11][C:12]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][C:15]([C:16]([NH2:18])=O)=[CH:14][N:13]=1>O>[C:16]([C:15]1[CH:19]=[C:20]([N+:21]([O-:23])=[O:22])[C:12]([OH:11])=[N:13][CH:14]=1)#[N:18]
Reactant: NC(=O)c1cnc(O)c([N+](=O)[O-])c1
Solvent: O
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1cnc(O)c([N+](=O)[O-])c1
Reaction time: 0.25 h
Yield: 71.8 %

Procedure:
Phosphorus oxychloride (2.99 mL) was added dropwise to N,N-dimethylformamide (49 mL) at 0° C., and the mixture was stirred at the same temperature for 15 minutes. Then 6-hydroxy-5-nitronicotinamide (4.9 g) was added portionwise to the mixture, and the reaction mixture was stirred at 50° C. for an hour. Water was added to the reaction mixture at 0° C., and the resulting precipitate was collected by filtration in vacuo. The obtained solid was washed with water to give 5-cyano-2-hydroxy-3-nitropyridine (3.17 g) as a pale brown solid.