Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:35])[CH2:3][CH2:4][NH:5][C:6]1[C:7]([F:34])=[CH:8][C:9]2[N:13]=[C:12]([C:14]3[C:18]([NH:19][C:20](=[O:26])[N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[CH:17][N:16](C4CCCCO4)[N:15]=3)[NH:11][C:10]=2[CH:33]=1>ClCCl.FC(F)(F)C(O)=O>[CH3:35][N:2]([CH3:1])[CH2:3][CH2:4][NH:5][C:6]1[C:7]([F:34])=[CH:8][C:9]2[N:13]=[C:12]([C:14]3[C:18]([NH:19][C:20](=[O:26])[N:21]([CH2:22][CH3:23])[CH2:24][CH3:25])=[CH:17][NH:16][N:15]=3)[NH:11][C:10]=2[CH:33]=1
Reactant: CCN(CC)C(=O)Nc1cn(C2CCCCO2)nc1-c1nc2cc(F)c(NCCN(C)C)cc2[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN(CC)C(=O)Nc1c[nH]nc1-c1nc2cc(F)c(NCCN(C)C)cc2[nH]1
Yield: 67.2 %

Procedure:
A solution of 18 mg of 3-[3-[6-(2-dimethylaminoethylamino)-5-fluoro-1H-benzimidazol-2-yl]-1-(tetrahydro-pyran-2-yl)-1H-pyrazol-4-yl]-1,1-diethylurea in 1 mL of dichloromethane and 500 μL of trifluoroacetic acid are stirred for 72 hours at ambient temperature. After evaporation of the solvent under vacuum in a rotary evaporator, the reaction crude is purified by flash chromatography on an Analogix RS-4 cartridge with an eluent of 100% dichloromethane to 90/10 dichloromethane/ammoniacal methanol. 10 mg of 3-{3-[6-(2-dimethylaminoethylamino)-5-fluoro-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl}-1,1-diethylurea in the form of trifluoroacetate are isolated. 1H NMR (300 MHz, DMSO-d6, δ in ppm), after addition of a drop of TFA-d1 (CF3COOD-d1) and of a drop of acetic acid-d4-(CD3OD-d4): 1.16 (t, J=7.0 Hz, 6H); 2.87 (s, 6H); 3.38 (m, 6H); 3.51 (t, J=6.0 Hz, 2H); 6.89 (d, J=7.5 Hz, 1H); 7.44 (d, J=11.0 Hz, 1H); 7.98 (s, 1H).
Reaction SMILES: O[CH2:2][C:3]1[O:4][C:5]([C:8]23[CH2:15][N:12]([CH2:13][CH2:14]2)[CH2:11][CH2:10][CH2:9]3)=[CH:6][N:7]=1.S(Cl)([Cl:18])=O>C(Cl)(Cl)Cl>[ClH:18].[Cl:18][CH2:2][C:3]1[O:4][C:5]([C:8]23[CH2:15][N:12]([CH2:13][CH2:14]2)[CH2:11][CH2:10][CH2:9]3)=[CH:6][N:7]=1
Reactant: OCc1ncc(C23CCCN(CC2)C3)o1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cl
Product: ClCc1ncc(C23CCCN(CC2)C3)o1
Temperature: 25 °C

Procedure:
A solution of (±)5-(2-hydroxymethyl-1,3-oxazol-5-yl)-1-azabicyclo[3.2.1]octane (E10) (0.3g, 1.4 mmol) in absolute chloroform (10 ml) under nitrogen, cooled in ice was treated with thionyl chloride (0.31 ml, 4.3 mmole) over 5 minutes. The reaction was allowed to warm up to room temperature over 45 minutes. Evaporation of solvent in vacuo afforded the title compound (D25) as a brown solid (380 mg, 100%) which was used without purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[NH:8][C:9](=[O:11])[NH:10][C:6]=2[CH:5]=[C:4]([C:12]([O:14]C)=[O:13])[CH:3]=1.[OH-].[Li+].O1CCCC1>CO>[Cl:1][C:2]1[C:7]2[NH:8][C:9](=[O:11])[NH:10][C:6]=2[CH:5]=[C:4]([C:12]([OH:14])=[O:13])[CH:3]=1
Reactant: COC(=O)c1cc(Cl)c2[nH]c(=O)[nH]c2c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc(Cl)c2[nH]c(=O)[nH]c2c1
Temperature: 50 °C
Yield: 89.8 %

Procedure:
Methyl 7-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate (351 mg, 1.55 mmol), 1 M aqueous lithium hydroxide (0.774 mL, 1.55 mmol) and tetrahydrofuran (5 mL) were combined and heated to 50° C. for 2 hours. To the reaction was added 1 M aqueous lithium hydroxide (0.774 mL, 1.55 mmol) and methanol (10 mL) and the reaction was heated to reflux for 6 hours and then allowed to cool to ambient temperature overnight. The reaction solution was concentrated in vacuo to remove the tetrahydrofuran and methanol. The residual aqueous layer was extracted with ethyl acetate (2 mL). To the aqueous layer was added water (2 mL) ethyl acetate (2 mL) and 3 M aqueous hydrochloric acid. A precipitate formed. The mixture was filtered and the solids were washed with water and ethyl acetate. The solids were dried under a stream of nitrogen to give the title compound (296 mg, 90%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.54 (s, 1H) 11.12 (s, 1H) 7.54 (d, J=1.37 Hz, 1H) 7.38 (d, J=1.37 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5](B(O)O)=[CH:4][C:3]=1[O:13][CH3:14].Cl[C:16]1[CH:17]=[C:18]([CH:24]=[CH:25][N:26]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:16]2[CH:17]=[C:18]([CH:24]=[CH:25][N:26]=2)[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:4][C:3]=1[O:13][CH3:14]
Reactant: CCOC(=O)c1ccnc(Cl)c1
Reactant: COc1cc(B(O)O)cc(OC)c1Cl
Product: CCOC(=O)c1ccnc(-c2cc(OC)c(Cl)c(OC)c2)c1

Procedure:
4-Chloro-3,5-dimethoxyphenylboronic acid (7.45 g) and ethyl 2-chloroisonicotinate (6.39 g) were condensedn in the same manner as described in Preparation Example 1 to give the title compound.
Reaction SMILES: FC(F)C1C([C:8](Cl)=[O:9])=CN(C)N=1.Cl.[Cl:14][C:15]1[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([Cl:29])[C:16]=1[O:17][CH2:18][C@@H:19]1[CH2:23][CH2:22][CH2:21][NH:20]1.C(N(CC)CC)C>ClCCl>[Cl:14][C:15]1[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([Cl:29])[C:16]=1[O:17][CH2:18][C@@H:19]1[CH2:23][CH2:22][CH2:21][N:20]1[CH:8]=[O:9]
Reactant: Clc1cc(Cl)c(OC[C@@H]2CCCN2)c(Cl)c1
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=CN1CCC[C@H]1COc1c(Cl)cc(Cl)cc1Cl
Reaction time: 3 h

Procedure:
At a temperature of 0° C., a solution of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride (0.243 g; 1.24 mmol) in dichloromethane (5 ml) was added dropwise to a stirred solution of (S)-2-(2,4,6-trichloro-phenoxymethyl)-pyrrolidine hydrochloride (0.35 g; 1.24 mmol), which was prepared as described in example P12, and triethylamine (0.35 ml; 2.48 mmol) in dichloromethane (10 ml). The ice bath was removed and reaction mixture was allowed stirring for 3 hours. The reaction mixture was washed with 1M NaOH (10 ml), 2M HCl (10 ml) and saturated NaCl (50 ml) and then dried over Na2SO4. After removal of the solvent, the residue (0.45 g in the form of an oil) was purified by flash chromatography over silica gel (eluent:cyclohexane/ethyl acetate 2:8). 0.27 g (50% of theory) of 3-difluoromethyl-1-methyl-1H-pyrazol-4-yl)-[(S)-2-(2,4,6-trichloro-phenoxymethyl)-pyrrolidin-1-yl]-methanone was obtained in form of an oil which solified after standing.
Reaction SMILES: CO[CH2:3][N:4]([CH2:12][Si](C)(C)C)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH:17]1([O:22][C:23]2[CH:24]=[C:25]([C:31](=[CH2:36])[C:32]([O:34][CH3:35])=[O:33])[CH:26]=[CH:27][C:28]=2[O:29][CH3:30])[CH2:21][CH2:20][CH2:19][CH2:18]1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:17]1([O:22][C:23]2[CH:24]=[C:25]([C:31]3([C:32]([O:34][CH3:35])=[O:33])[CH2:36][CH2:3][N:4]([CH2:5][C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=4)[CH2:12]3)[CH:26]=[CH:27][C:28]=2[O:29][CH3:30])[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: C=C(C(=O)OC)c1ccc(OC)c(OC2CCCC2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C1(c2ccc(OC)c(OC3CCCC3)c2)CCN(Cc2ccccc2)C1
Reaction time: 12 h
Yield: 97.7 %

Procedure:
To a solution of N-methoxymethyl-N-(phenylmethyl)trimethylsilylmethylamine (1.42 g, 6.0 mmol) and methyl 2-(3-cyclopentoxy-4-methoxyphenyl)prop-2-enoate (1.38 g, 5.0 mmol) in 10 mL of CH2Cl2 cooled to 0° C. was added a 0.7 mL of a 1M solution of trifluoroacetic acid. Stirring was continued for 12 hr, and the solution was partitioned between ether and sat. NaHCO3. The layers were separated and the aqueous layer was extracted ethyl acetate (2×). The combined organic layers were dried (K2CO3), filtered, and concentrated under reduced pressure to a pale yellow oil. Chromatography on silica gel (3:1, hexanes:ethyl acetate) provided 3-(3-cyclopentoxy-4-methoxyphenyl)-3-methoxycarbonyl-1-(phenylmethyl)pyrrolidine (2.0 g, 99%) as a colorless oil. 1H-NMR (300 MHz): δ 2.75 (d, 1, J=9), 3.54 (d, 1, J=9), 3.67 (s, 3), 3.69 (s, 2), 3.81 (s, 3). Anal. Calcd for C25H31NO4 : C, 73.32; H, 7.63; N, 3.42. Found: C, 73.25; H, 7.65; N, 3.40.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[N:11]=[C:10]2[N:12]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[C:13](O)=[N:14][C:9]2=[CH:8][CH:7]=1)(=[O:4])=[O:3].O=P(Cl)(Cl)[Cl:24]>>[CH3:1][S:2]([O:5][C:6]1[N:11]=[C:10]2[N:12]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[C:13]([Cl:24])=[N:14][C:9]2=[CH:8][CH:7]=1)(=[O:4])=[O:3]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CS(=O)(=O)Oc1ccc2nc(O)n(C3CCCCC3)c2n1
Product: CS(=O)(=O)Oc1ccc2nc(Cl)n(C3CCCCC3)c2n1
Temperature: 80 °C

Procedure:
3-Cyclohexyl-2-hydroxy-3H-imidazo[4,5-b]pyridin-5-yl methanesulfonate (0.4 g, 1.285 mmol) and POCl3 (2.395 ml, 25.7 mmol) were placed in a sealed tube and heated to 80° C. for 48 h. The volatiles were removed under reduced pressure. The residue was dissolved in aqueous NaHCO3 giving a basic solution. The solution was further diluted with water and extracted with EtOAc. The combined organics was dried over MgSO4 and concentrated to give the title compound without further purification. LCMS m/z=330.30 [M+H]+.
Reaction SMILES: C(N(CC)CC)C.C(OS(OCCC)(=O)=O)CC.C(OC([N:26]1[CH2:31][CH2:30][CH:29]([NH:32][S:33]([C:36]2[CH:45]=[CH:44][C:43]3[NH:42][C:41](=[O:46])[C:40]4[NH:47][CH:48]=[C:49]([C:50]([OH:52])=[O:51])[C:39]=4[C:38]=3[CH:37]=2)(=[O:35])=[O:34])[CH2:28][CH2:27]1)=O)(C)(C)C.N>CN(C)C=O.O>[O:46]=[C:41]1[C:40]2[NH:47][CH:48]=[CH:49][C:39]=2[C:38]2[CH:37]=[C:36]([S:33](=[O:35])(=[O:34])[NH:32][CH:29]3[CH2:28][CH2:27][NH:26][CH2:31][CH2:30]3)[CH:45]=[CH:44][C:43]=2[NH:42]1.[CH2:49]([C:50]([O-:52])=[O:51])[CH2:39][CH3:38]
Reactant: CC(C)(C)OC(=O)N1CCC(NS(=O)(=O)c2ccc3[nH]c(=O)c4[nH]cc(C(=O)O)c4c3c2)CC1
Agent: CCCOS(=O)(=O)OCCC
Agent: N
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCCC(=O)[O-]
Product: O=c1[nH]c2ccc(S(=O)(=O)NC3CCNCC3)cc2c2cc[nH]c12
Temperature: 25 °C
Reaction time: 20 h
Yield: 67.7 %

Procedure:
107 μL (0.76 mmol) of triethylamine and 100 μL (0.61 mmol) of di-n-propylsulfate are added to a solution of 150 mg (0.3 mmol) of 8-(1-tert-butoxycarbonyl-piperidin-4-ylsulfamoyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid dissolved in 2 mL of anhydrous dimethylformamide. The solution is stirred at room temperature for 20 hours then 43 μL (0.3 mmol) of triethylamine and 51 μL (0.3 mmol) of di-n-propylsulfate are added again. Stirring is continued for a further 24 hours and 3 mL of ammonia is added. After stirring for a further 15 minutes, water is added and the product is extracted with dichloromethane. The organic phases are dried over magnesium sulfate, filtered then evaporated. The residue is dissolved in 2 mL of dichloroethane and 1 mL of trifluoroacetic acid. The solution is stirred at room temperature for 1 hour then the solvents are evaporated. The solid is taken up in dichloromethane then triethylamine is added to release the amine. The solvents are evaporated again and the residue is purified by chromatography on silica (eluent chloroform/methanol/ammonia 160/25/4) to give 44 mg (33% in two stages) of 4-oxo-8-(piperidin-4-ylsulfamoyl)-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-propyl carboxylate in the form of a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:9]1[NH:10][C:11]2[C:12]([N:28]=1)=[CH:13][C:14]1[CH2:15][N:16]([CH2:21][CH2:22][N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[C:17](=[O:20])[C:18]=1[CH:19]=2.[Br:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=1[CH2:37][C@@H:38]([NH2:40])[CH3:39].CCN(C(C)C)C(C)C>CCO>[Br:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=1[CH2:37][C@@H:38]([NH:40][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:9]1[NH:10][C:11]2[C:12]([N:28]=1)=[CH:13][C:14]1[CH2:15][N:16]([CH2:21][CH2:22][N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[C:17](=[O:20])[C:18]=1[CH:19]=2)[CH3:39]
Reactant: O=C1c2cc3[nH]c(-c4c(Cl)cc[nH]c4=O)nc3cc2CN1CCN1CCCC1
Reactant: C[C@H](N)Cc1cc(F)ccc1Br
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Cc1cc(F)ccc1Br)Nc1cc[nH]c(=O)c1-c1nc2cc3c(cc2[nH]1)C(=O)N(CCN1CCCC1)C3
Yield: 22.7 %

Procedure:
A solution of 2-(4-chloro-2-oxo-1,2-dihydropyridin-3-yl)-6-(2-pyrrolidin-1-ylethyl)-6,7-dihydroimidazo[4,5-f]isoindol-5(3H)-one (50 mg, 0.126 mmol), (1S)-2-(2-bromo-5-fluorophenyl)-1-methylethylamine (48 mg, 0.164 mmol) and DIEA (66 uL, 0.38 mmol) in 2 mL of EtOH was heated at 80° C. for 24 h. Then the solvent was evaporated and the residue was purified by column (silicagel, DCM:MeOH 9:1) to give 2-(4-((1S)-2-(2-bromo-5-fluorophenyl)-1-methylethylamino)-2-oxo-1,2-dihydropyridin-3-yl)-6-(2-pyrrolidin-1-ylethyl)-6,7-dihydroimidazo[4,5-f]isoindol-5(3H)-one (17 mg, 23%) as yellow solid. ESI-MS: m/z (MH+) 593.0. 1H NMR (300 MHz, CDCl3): δ 8.04 (d, J=58.6 Hz, 1H), 7.53 (d, J=80.9 Hz, 1H), 7.47 (m, 1H), 7.15 (m, 2H), 6.80 (m, 1H), 6.00 (m, 1H), 4.56 (m, 2H), 4.13 (m, 1H), 3.82 (m, 2H), 3.10 (m, 2H), 2.83 (m, 2H), 2.65 (m, 4H), 1.80 (m, 4H), 1.43 (d, J=6.60 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]2[C:9]([CH:10]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([Br:24])[CH:15]=3)[C:11]=1[C:12]#[N:13])=[CH:8][C:7]([OH:25])=[C:6]1[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=21.[C:30](=O)([O-])[O-].[K+].[K+].IC>C(#N)C.O>[NH2:1][C:2]1[O:3][C:4]2[C:9]([CH:10]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([Br:24])[CH:15]=3)[C:11]=1[C:12]#[N:13])=[CH:8][C:7]([O:25][CH3:30])=[C:6]1[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=21
Reactant: COc1cc(C2C(C#N)=C(N)Oc3c2cc(O)c2ccccc32)cc(Br)c1OC
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CC#N
Product: COc1cc(C2C(C#N)=C(N)Oc3c2cc(OC)c2ccccc32)cc(Br)c1OC
Reaction time: 1 h
Yield: 85.6 %

Procedure:
2-Amino-6-hydroxy-4-(3-bromo-4,5-dimethoxy-phenyl)-4H-benzo[h]chromene-3-carbonitrile (9) (45 mg, 0.1 mmol) and potassium carbonate (14 mg, 0.1 mmol) were taken in dry acetonitril (5 ml) at room temperature, stirred for 1 h, charged with iodomethane (15.6 mg, 0.11 mmol) and stirred further at room temperature under LC-MS control. The reaction mixture was diluted with water (10 ml) under stirring, stirred further at room temperature for 2 h, the precipitates were collected by filtration, washed with water and dried to get the title compound (40 mg, 85.6%).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([S:12](=[O:15])(=[O:14])[NH2:13])[CH:6]=1)=[O:4].[CH2:16]([NH:19][C:20]([NH:22][CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)=[S:21])[CH:17]=[CH2:18]>>[BrH:1].[CH2:16]([N:19]1[C:3]([C:5]2[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([S:12](=[O:15])(=[O:14])[NH2:13])[CH:6]=2)([OH:4])[CH2:2][S:21][C:20]1=[N:22][CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[CH:17]=[CH2:18]
Reactant: C=CCNC(=S)NCc1cccnc1
Reactant: NS(=O)(=O)c1cc(C(=O)CBr)ccc1Cl
Product: Br
Product: C=CCN1C(=NCc2cccnc2)SCC1(O)c1ccc(Cl)c(S(N)(=O)=O)c1

Procedure:
4.7 g of 2-bromo-4'-chloro-3'-sulfamoylacetophenone and 3 g of 1-allyl-3-(3-pyridylmethyl)-thiourea were reacted as prescribed in Example 23 and the end product was filtered off. Colorless solid body, decomposition beginning at 82° C γC=N 1605 cm-1.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][C:37]=1[F:38]>>[Cl:31][C:32]1[CH:33]=[CH:34][C:35]([C:12]2[N:13]([CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22]3)[N:14]=[C:15]3[C:11]=2[CH2:10][CH2:9][NH:8][CH2:17][CH2:16]3)=[CH:36][C:37]=1[F:38]
Reactant: CC(C)(C)OC(=O)N1CCc2nn(C3CCCC3)c(OS(=O)(=O)C(F)(F)F)c2CC1
Reactant: OB(O)c1ccc(F)c(Cl)c1
Product: Fc1cc(-c2c3c(nn2C2CCCC2)CCNCC3)ccc1Cl
Yield: 28.8 %

Procedure:
The title compound (31 mg) was prepared according to Example 180 using 146 mg of 2-cyclopentyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 180, Step A) and 168 mg of 3-chloro-4-fluorophenylboronic acid. MS (ESI): exact mass calculated for C18H21ClFN3, 333.14. found, m/z 334.4 [M+H]+, 336.4 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.39-7.31 (m, 2H), 7.22-7.18 (m, 1H), 4.37 (m, 1H), 3.31-3.28 (m, 2H), 3.07-3.03 (m, 2H), 2.67-2.64 (m, 2H), 2.11-1.78 (m, 6H), 1.56-1.47 (m, 2H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[N:9][C:10]3[C:15]([N:16]=2)=[CH:14][C:13]([C:17]2[CH:18]=[C:19]([NH2:23])[CH:20]=[N:21][CH:22]=2)=[CH:12][CH:11]=3)[CH:4]=[N:3]1.[C:24]([C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1)#[N:25]>N1C=CC=CC=1>[C:24]([C:26]1[CH:27]=[CH:28][C:29]([S:32]([NH:23][C:19]2[CH:20]=[N:21][CH:22]=[C:17]([C:13]3[CH:14]=[C:15]4[C:10](=[CH:11][CH:12]=3)[N:9]=[CH:8][C:7]([C:5]3[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=3)=[N:16]4)[CH:18]=2)(=[O:34])=[O:33])=[CH:30][CH:31]=1)#[N:25]
Reactant: Cn1cc(-c2cnc3ccc(-c4cncc(N)c4)cc3n2)cn1
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cn1cc(-c2cnc3ccc(-c4cncc(NS(=O)(=O)c5ccc(C#N)cc5)c4)cc3n2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.2 %

Procedure:
To a solution of 5-[3-(1-methyl-1H-pyrazol-4-yl)-6-quinoxalinyl]-3-pyridinamine (52 g, 0.172 mmol) in pyridine (1.7 mL) was added 4-cyanobenzenesulfonyl chloride (56 mg, 0.278 mmol). The reaction mixture was stirred at room temperature overnight. Monitoring by LCMS still showed 30% of starting material. An additional portion of 4-cyanobenzenesulfonyl chloride (17 mg, 0.084 mmol) was added to the reaction mixture and after stirring for a further 30 minutes, all starting material was consumed. Cold water was poured into the reaction resulting in precipitate formation. This solid was collected by filtration, washed with water and dried under vacuum to give the title compound (54 mg, 67%) as a brown colored solid. MS(ES)+ m/e 468 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][C:3]=1[C:4]([N:6]([CH3:8])[CH3:7])=[O:5].C(N(CC)CC)C.[F:28][C:29]([F:46])([F:45])[C:30]1[CH:35]=[CH:34][C:33]([C:36]2[C:37]([C:42](Cl)=[O:43])=[CH:38][CH:39]=[CH:40][CH:41]=2)=[CH:32][CH:31]=1>C(OCC)(=O)C>[CH2:14]([O:13][C:10]1[CH:11]=[CH:12][C:2]([NH:1][C:42]([C:37]2[C:36]([C:33]3[CH:34]=[CH:35][C:30]([C:29]([F:28])([F:45])[F:46])=[CH:31][CH:32]=3)=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:43])=[C:3]([C:4](=[O:5])[N:6]([CH3:7])[CH3:8])[CH:9]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reactant: CN(C)C(=O)c1cc(OCc2ccccc2)ccc1N
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CN(C)C(=O)c1cc(OCc2ccccc2)ccc1NC(=O)c1ccccc1-c1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 72.3 %

Procedure:
2-Amino-5-benzyloxy-N,N-dimethylbenzamide (950 mg) was dissolved in ethyl acetate (10 mL), and thereto was added triethylamine (533 mg). The solution was cooled to 0° C. and 4′-trifluoromethylbiphenyl-2-carbonyl chloride (synthesized from 0.934 g of corresponding carboxylic acid) was added. The mixture was stirred overnight at room temperature. After removal of the insoluble materials by filtration, the filtrate was concentrated and purified by column chromatography on silica gel to give 4′-trifluoromethylbiphenyl-2-carboxylic acid (4-benzyloxy-2-dimethylcarbamoylphenyl)amide (1.23 g).
Reaction SMILES: Cl.[NH2:2][C:3]([CH2:25][CH3:26])([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:10][CH:9]=1)[CH2:4][OH:5].[C:27](=[O:30])([O-])O.[K+].[N+:32]([C:35]1[CH:36]=[C:37]([CH:41]=[C:42]([N+:44]([O-:46])=[O:45])[CH:43]=1)[C:38](Cl)=[O:39])([O-:34])=[O:33]>C(OCC)(=O)C.O>[N+:32]([C:35]1[CH:36]=[C:37]([CH:41]=[C:42]([N+:44]([O-:46])=[O:45])[CH:43]=1)[C:38]([O:5][CH2:4][C:3]([CH2:25][CH3:26])([NH:2][C:27](=[O:30])[C:37]1[CH:36]=[C:35]([N+:32]([O-:34])=[O:33])[CH:43]=[C:42]([N+:44]([O-:46])=[O:45])[CH:41]=1)[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:10][CH:9]=1)=[O:39])([O-:34])=[O:33]
Reactant: CCC(N)(CO)CCc1ccc(OCCCCc2ccccc2)cc1
Reactant: O=C([O-])O
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCC(CCc1ccc(OCCCCc2ccccc2)cc1)(COC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1)NC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 50.9 %

Procedure:
To a solution of 2-amino-2-ethyl-4-(4-(4-phenylbutyloxy)phenyl)butanol hydrochloride (3.0 g) in ethyl acetate (100 ml) were added a solution of potassium hydrogencarbonate (1.6 g) in water (50 ml) and 3,5-dinitrobenzoyl chloride (3.6 g). The mixture was stirred vigorously at room temperature for 2.5 hours and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous sodium hydrogencarbonate solution and a saturated brine, dried over anhydrous sodium sulfateand the solvent was distilled away under reduced pressure. The yellow residue obtained was subjected to the same procedure as mentioned above, and the resulting residue was purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=2:1) to give the subject compound (1.5 g) and 2-ethyl-2-(3,5-dinitrobenzamido)-4-(4-(4-phenylbutyloxy)phenyl)butyl 3,5-dinitrobenzoate (2.9 g) as a by-product. To a solution of the by-product (2.7 g) in a mixed solvent of methanol (50 ml) and tetrahydrofuran (30 ml) was added a solution of lithium hydroxide monohydrate (0.15 g) in water (10 ml) and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water and extracted with ethyl acetate, the ethyl acetate layer was washed with water and a saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure and the residue obtained was purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=1:1) to give the subject compound (2.4 g). The combined subject compound was recrystallized from ethyl acetate and hexane to give the subject compound (2.6 g) as pure white crystals, melting at 121-122° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:22])[C:7]([CH3:21])=[C:8]([C:18](O)=[O:19])[N:9]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)[N:32]1[CH2:36]CC[CH2:33]1.C(N(CC)C(C)C)(C)C.CNC>CN(C=O)C>[CH3:33][N:32]([CH3:36])[C:18]([C:8]1[N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]2[C:5]([C:6](=[O:22])[C:7]=1[CH3:21])=[CH:4][CH:3]=[C:2]([Cl:1])[CH:11]=2)=[O:19]
Reactant: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: Cc1c(C(=O)O)n(-c2ccccc2)c2cc(Cl)ccc2c1=O
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(C(=O)N(C)C)n(-c2ccccc2)c2cc(Cl)ccc2c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 110 %

Procedure:
In a 50 mL round bottom flask, 7-chloro-3-methyl-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid (0.5 g, 1.60 mmol), bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBrOP, 1.11 g, 2.39 mmol) and N,N-diisopropylethylamine (1.11 mL, 6.37 mmol) were added to anhydrous DMF (5.0 mL). The mixture was stirred at room temperature for 30 min. Dimethylamine (2M in THF, 1.6 mL, 3.2 mmol) was added and the reaction mixture was stirred at room temperature for 48 hr. The mixture was concentrated to dryness and the crude was purified by flash chromatography using 3:2 hexane-ethyl acetate to afford 7-chloro-3-methyl-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid dimethylamide (600 mg, >100% yield). MS calcd for C19H17ClN2O2 [(M+H)+] 341, obsd 341.
Reaction SMILES: [Na].Cl.[C:3]([NH2:6])(=[NH:5])[CH3:4].C[CH2:8][CH:9]([C:14](OCC)=[O:15])[C:10](OC)=[O:11]>CO>[CH3:4][C:3]1[N:6]=[C:10]([OH:11])[C:9]([CH3:8])=[C:14]([OH:15])[N:5]=1
Reactant: CCOC(=O)C(CC)C(=O)OC
Reactant: CC(=N)N
Agent: Cl
Agent: [Na]
Solvent: CO
Product: Cc1nc(O)c(C)c(O)n1
Temperature: 23 °C
Yield: 88.8 %

Procedure:
According to the procedure of D. J. Brown et al., J. Chem. Soc. 1964, 3204, a solution of 9.2 g (400 mmol) of sodium metal dissolved in 200 mL of methanol was treated first with 19.8 g. (210 mmol) of acetamidine hydrochloride and then with 34.4 mL (34.8 g, 200 mmol) of diethyl methyl malonate. The reaction mixture was heated to reflux for 4 hours, cooled to 23° C., and filtered. The filtrate was concentrated in vacuo. The residue from the filtrate and the isolated solids were combined and dissolved in water (300 mL). The aqueous solution was acidified with aqueous 3N HCl (133 mL). The fine white solid which precipitated from this solution was isolated by filtration and dried in vacuo to give 24.9 g (89%) of pure product, m.p. 300° C.