Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][N:6]=[C:5]2[Cl:13].[CH2:14]([NH:21][CH3:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>CC(N(C)C)=O.CCOC(C)=O.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]>[CH2:14]([N:21]([CH3:22])[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][N:6]=[C:5]2[Cl:13])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CNCc1ccccc1
Reactant: O=c1[nH]nc(Cl)c2cc(Br)ccc12
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CN(Cc1ccccc1)c1ccc2c(=O)[nH]nc(Cl)c2c1

Procedure:
A mixture 6-bromo-4-chloro-2H-phthalazin-1-one (70 mg, 0.27 mmol), benzyl-methyl-amine (43 mg, 0.35 mmol), Pd2(dba)3 (25 mg, 0.027 mmol), rac-BINAP (51 mg, 0.081 mmol) and NaOt-Bu (76 mg, 0.81 mmol) in DMA (6 mL) was heated at 80° C. for 1 h. The mixture was allowed to cool, diluted with EtOAc (25 mL) and washed with water (25 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. Chromatography on silica (EtOAc/hexanes) yielded the title compound. 6-(Benzyl-methyl-amino)-4-chloro-2H-phthalazin-1-one: 10 mg (12.4%): m/z (M+H)=300.
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([O:19][C@H:20]([C:22]2[N:26]([CH3:27])[C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]([F:37])([F:36])[F:35])=[N:24][N:23]=2)[CH3:21])=[C:7]([C:9]2[O:13][C:12]([C:14]([O:16]CC)=O)=[N:11][N:10]=2)[CH:8]=1.O>C(O)C>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([O:19][C@H:20]([C:22]2[N:26]([CH3:27])[C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]([F:36])([F:35])[F:37])=[N:24][N:23]=2)[CH3:21])=[C:7]([C:9]2[O:13][C:12]([C:14]([NH2:1])=[O:16])=[N:11][N:10]=2)[CH:8]=1
Reactant: N
Reactant: CCOC(=O)c1nnc(-c2cc(Cl)ccc2O[C@@H](C)c2nnc(-c3ccccc3C(F)(F)F)n2C)o1
Solvent: O
Solvent: CCO
Product: C[C@H](Oc1ccc(Cl)cc1-c1nnc(C(N)=O)o1)c1nnc(-c2ccccc2C(F)(F)F)n1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 29% aqueous ammonia solution (0.3 ml) was added to a solution of ethyl 5-{5-chloro-2-[(1S)-1-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}ethoxy]phenyl}-1,3,4-oxadiazole-2-carboxylate (120 mg) in ethanol (1 ml), followed by stirring at room temperature for one hour. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution and then saturated brine in this order, and dried over anhydrous magnesium sulfate, and the solvent was then evaporated under reduced pressure. The residue was powdered with diisopropylether to obtain, as a light yellow solid, 5-{5-chloro-2-[(1S)-1-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}ethoxy]phenyl}-1,3,4-oxadiazole-2-carboxamide (86 mg).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:9][CH:8]2[N:10]([C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14]([C:21]#[N:22])=[CH:13][CH:12]=3)[CH:5]([CH2:6][CH2:7]2)[CH2:4]1.ClC(Cl)(Cl)[C:25]([N:27]=C=O)=[O:26]>O1CCCC1>[C:21]([C:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:11]([N:10]2[CH:8]3[CH2:7][CH2:6][CH:5]2[CH2:4][CH:3]([NH:2][C:25]([NH2:27])=[O:26])[CH2:9]3)=[CH:12][CH:13]=1)#[N:22]
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: N#Cc1ccc(N2C3CCC2CC(N)C3)c2ccccc12
Agent: Cl
Solvent: C1CCOC1
Product: N#Cc1ccc(N2C3CCC2CC(NC(N)=O)C3)c2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
The amine 165RL21 (40 mg, 0.144 mmol) was dissolved in tetrahydrofuran (1 mL) and cooled to 0° C. Trichloroacetyl isocyanate (0.019 mL) was added and the solution was left to warm to rt and stirring was continued for 30 minutes. The mixture was concentrated and the residue was dissolved in methanol (1 mL). 2 M NaOH (1 mL) was added, and the mixture was heated to 70° C. for 1 hour. Then, water (20 mL) was added and methanol was removed by evaporation in vacuo. The aqueous phase was extracted with dichloromethane (2×20 mL), and the combined organic phases were dried over sodium sulfate, filtered and evaporated. The residue was purified by preparative TLC (0-5% methanol in dichloromethane) to give the title compound (24 mg, 52% yield) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:29])=[C:4]([C:8]2[C:20]3[C:19]4[C:14](=[CH:15][C:16]([O:21][CH2:22][CH2:23][O:24][CH3:25])=[CH:17][CH:18]=4)[NH:13][C:12]=3[C:11]([C:26]([NH2:28])=[O:27])=[N:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH:30]([C:32]1[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][C:33]=1[C:34]([OH:36])=[O:35])=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C1COCC1.O.CCOC(C)=O>[C:26]([C:11]1[C:12]2[NH:13][C:14]3[C:19]([C:20]=2[C:8]([C:4]2[C:3]([F:29])=[C:2]([NH:1][CH2:30][C:32]4[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][C:33]=4[C:34]([OH:36])=[O:35])[CH:7]=[CH:6][CH:5]=2)=[CH:9][N:10]=1)=[CH:18][CH:17]=[C:16]([O:21][CH2:22][CH2:23][O:24][CH3:25])[CH:15]=3)(=[O:27])[NH2:28]
Reactant: COCCOc1ccc2c(c1)[nH]c1c(C(N)=O)ncc(-c3cccc(N)c3F)c12
Reactant: Cc1ccc(C=O)c(C(=O)O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: COCCOc1ccc2c(c1)[nH]c1c(C(N)=O)ncc(-c3cccc(NCc4ccc(C)cc4C(=O)O)c3F)c12
Reaction time: 8 h

Procedure:
To a light orange, homogeneous solution of 4-(3-amino-2-fluorophenyl)-7-(2-methoxyethoxy)-9H-pyrido[3,4-b]indole-1-carboxamide (0.0767 g, 0.194 mmol), 2-formyl-5-methylbenzoic acid (0.096 g, 0.583 mmol) and acetic acid (0.033 mL, 0.583 mmol) in dichloromethane (3.89 mL) and THF (2.59 mL) under nitrogen was added sodium triacetoxyborohydride (0.206 g, 0.972 mmol). The reaction was stirred overnight. More sodium triacetoxyborohydride (0.206 g, 0.972 mmol) and acetic acid (0.033 mL, 0.583 mmol) were added. After 4.5 hr, water (3 mL) was added, and the reaction was stirred for 10 min. EtOAc (50 mL) and water (20 mL) were added, and the layers were separated. The organic layer was washed with water (6×20 mL) and brine (20 mL), dried over MgSO4, and concentrated in vacuo to give a crude product used in subsequent step.
Reaction SMILES: CC1(C)[O:20][C:5]2=[CH:6][C:7]3[N:8]=[C:9]([C:17]([OH:19])=[O:18])[C:10]([C:14]([OH:16])=[O:15])=[N:11][C:12]=3[CH:13]=[C:4]2[O:3]1>Cl>[OH:3][C:4]1[CH:13]=[C:12]2[C:7](=[CH:6][C:5]=1[OH:20])[N:8]=[C:9]([C:17]([OH:19])=[O:18])[C:10]([C:14]([OH:16])=[O:15])=[N:11]2
Reactant: CC1(C)Oc2cc3nc(C(=O)O)c(C(=O)O)nc3cc2O1
Agent: Cl
Product: O=C(O)c1nc2cc(O)c(O)cc2nc1C(=O)O
Temperature: 75 °C

Procedure:
Compound from Example 3E (145 mg, 0.5 mmole) was slurried in 10 ml of concentrated HCl and heated at 75° C. for 1 hour with stirring. On initial heating, the compound dissolved, then a precipitate eventually formed. The slurry was evaporated to dryness in vacuo. The residue was initially soluble in water but formed a yellow-brown precipitate within a few minutes. The water was evaporated again and the residue was dried in vacuo for 3 hours to give the title compound as a brown solid, 125 mg, m.p. >300° C.
Reaction SMILES: FC1C=CC(OC)=C(C2C(C(O)=O)=CC([N+]([O-])=O)=CC=2)C=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=1[C:31]1[C:32]([C:41]([O:43]C)=[O:42])=[CH:33][C:34]([N+:38]([O-:40])=[O:39])=[CH:35][C:36]=1C>>[F:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=1[C:31]1[C:32]([C:41]([OH:43])=[O:42])=[CH:33][C:34]([N+:38]([O-:40])=[O:39])=[CH:35][CH:36]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])cc(C)c1-c1cc(OC)ccc1F
Agent: COc1ccc(F)cc1-c1ccc([N+](=O)[O-])cc1C(=O)O
Product: COc1ccc(F)c(-c2ccc([N+](=O)[O-])cc2C(=O)O)c1
Yield: 103.9 %

Procedure:
This compound was prepared in a manner similar to that of 5'-fluoro-2'-methoxy-4-nitro-2-biphenylcarboxylic acid (EXAMPLE 107) from methyl 2'-fluoro-5'-methoxy-6-methyl-4-nitro-2-biphenylcarboxylate (0.77 g) to afford 0.73 g (99%) of 2'-fluoro-5'-methoxy-4-nitro-2-biphenylcarboxylic acid as a white solid, which as used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:17][CH2:18][CH:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[OH:20])[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:27][O:28][C:29]1[C:30](=O)[C:31](=[O:35])[C:32]=1[O:33]C>CO>[OH:20][CH:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:18][NH:17][CH:8]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)[C:4]1[CH:3]=[C:2]([NH:1][C:30]2[C:31](=[O:35])[C:32](=[O:33])[C:29]=2[O:28][CH3:27])[CH:7]=[CH:6][CH:5]=1
Reactant: COc1c(OC)c(=O)c1=O
Reactant: COc1ccc(C(NCC(O)c2ccccc2)c2cccc(N)c2)cc1
Solvent: CO
Product: COc1ccc(C(NCC(O)c2ccccc2)c2cccc(Nc3c(OC)c(=O)c3=O)c2)cc1
Yield: 45.6 %

Procedure:
In a similar manner to that described in Example (1c), a solution of 2-{[(3-aminophenyl)-(4-methoxyphenyl)methyl]amino}-1-phenylethanol (2.2 g) [prepared as described in step (c) above] in methanol (40 ml) and 3,4-dimethoxy-3-cyclobutene-1,2-dione (940 mg) were reacted, to afford the title compound (1.32 g) as a white foamy solid.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](C)(O)[C:17]([O:19][CH3:20])=O)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:23][C:24]1[CH:31]=[CH:30][C:27](CBr)=[CH:26][CH:25]=1>[Ag]=O.C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][CH:17]([O:19][CH2:20][C:27]2[CH:30]=[CH:31][C:24]([F:23])=[CH:25][CH:26]=2)[C:6]([O:5][CH3:1])=[O:7])=[CH:14][CH:15]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)C(C)(O)c1ccc(OCC(=O)OC(C)(C)C)cc1
Reactant: Fc1ccc(CBr)cc1
Agent: O=[Ag]
Solvent: Cc1ccccc1
Product: COC(=O)C(Cc1ccc(OCC(=O)OC(C)(C)C)cc1)OCc1ccc(F)cc1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of methyl 4-(t-butoxycarbonylmethoxy)phenyllactate (3.0 g), 4-fluorobenzylbromide (2.4 ml), silver oxide (9.0 g) and toluene (60 ml) was stirred at 80° C. under a nitrogen atmosphere for 3 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was chromatographed on a silica gel column using hexane:ethyl acetate=5:1 as the eluant to afford the title compound (2.9 g, Rf=0.39: thin layer chromatography on a silica gel plate using hexane:ethyl acetate=3:1 as the eluant).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH3:16][O:17][N:18]=[C:19]([C:23]1[N:24]=[C:25]([NH:28][C:29]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[S:26][CH:27]=1)[C:20]([OH:22])=O.[CH3:48][O:49][CH:50]([O:61][CH3:62])[CH2:51][N:52]1[C:57](=[O:58])[C:56](=[O:59])[NH:55][NH:54][C:53]1=[S:60]>CN(C)C=O>[CH3:62][O:61][CH:50]([O:49][CH3:48])[CH2:51][N:52]1[C:57](=[O:58])[C:56](=[O:59])[NH:55][N:54]=[C:53]1[S:60][C:20](=[O:22])[C:19](=[N:18][O:17][CH3:16])[C:23]1[N:24]=[C:25]([NH:28][C:29]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[S:26][CH:27]=1
Reactant: COC(Cn1c(=S)[nH][nH]c(=O)c1=O)OC
Reactant: CON=C(C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: CON=C(C(=O)Sc1n[nH]c(=O)c(=O)n1CC(OC)OC)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 4 °C
Reaction time: 1 h
Yield: 68.8 %

Procedure:
N,N'-Dicyclohexylcarbodiimide (0.50 g) is added all at once to a solution, cooled to 4° C., of the syn isomer of 2-methoxyimino-2-(2-tritylaminothiazol-4-yl)acetic acid (0.89 g) and 4-(2,2-dimethoxyethyl)-5,6-dioxo-3-thioxo-perhydro-1,2,4-triazine (0.47 g) in dimethylformamide (20 cc); the mixture is stirred for 1 hour at 4° C. and then for 3 hours at 20° C. The reaction suspension is filtered, the filtrate is diluted with ethyl acetate (100 cc), the mixture is washed with water (2×50 cc), a 1% strength solution of sodium bicarbonate (2×50 cc) and a semi-saturated solution of sodium chloride (2×50 cc), dried over sodium sulphate and filtered and the filtrate is concentrated to dryness at 20° C. under 20 mm Hg (2.7 kPa). The residue is triturated in isopropyl ether (10 cc) and, after filtration and drying, the syn isomer of 4-(2,2-dimethoxyethyl)-5,6-dioxo-3-[2-methoxyimino-2-(2-tritylaminothiazol-4-yl)-acetylthio]-1,4,5,6-tetrahydro-1,2,4-triazine (0.91 g) is obtained in the form of a yellow powder.
Reaction SMILES: C(OC([N:8]1[C:12]([NH:13][C:14](=[O:30])[CH:15]([CH3:29])[CH2:16][CH2:17][CH2:18][N:19]2[CH2:25][CH2:24][CH2:23][N:22]([C:26](=[O:28])[CH3:27])[CH2:21][CH2:20]2)=[CH:11][C:10]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)=[N:9]1)=O)(C)(C)C.Cl.O1CCOCC1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([C:10]2[CH:11]=[C:12]([NH:13][C:14](=[O:30])[CH:15]([CH3:29])[CH2:16][CH2:17][CH2:18][N:19]3[CH2:25][CH2:24][CH2:23][N:22]([C:26](=[O:28])[CH3:27])[CH2:21][CH2:20]3)[NH:8][N:9]=2)=[CH:36][CH:35]=1
Reactant: COc1ccc(-c2cc(NC(=O)C(C)CCCN3CCCN(C(C)=O)CC3)n(C(=O)OC(C)(C)C)n2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccc(-c2cc(NC(=O)C(C)CCCN3CCCN(C(C)=O)CC3)[nH]n2)cc1
Yield: 82.6 %

Procedure:
5-[5-(4-Acetyl-[1,4]diazepan-1-yl)-2-methyl-pentanoylamino]-3-(4-methoxy-phenyl)-pyrazole-1-carboxylic acid tert-butyl ester (181.0 mg, 0.34 mmol, 1.0 eq) was dissolved in DCM (3 mL) and HCl 4.0 M in dioxane (0.16 mL, 0.64 mmol, 1.9 eq) was added at room temperature. After 3 hours another 1.9 eq of HCl was added and the mixture stirred for 3 additional hours. NaHCO3 saturated solution was added and the organic layer collected and dried. Evaporation of solvent gave the title product (120 mg; Yield 82%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[N:30](C(OC(C)(C)C)=O)[C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23]([OH:25])=O.[CH:43]1([NH2:48])[CH2:47][CH2:46][CH2:45][CH2:44]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.FC(F)(F)C(O)=O>C(#N)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:15][CH2:16][CH2:17][CH2:18]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[NH:30][C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23]([NH:48][CH:43]1[CH2:47][CH2:46][CH2:45][CH2:44]1)=[O:25]
Reactant: CC(C)(C)OC(=O)n1c(C(CCC(=O)O)Nc2ncnc3cc(C(=O)N4CCCC4)c(Cl)cc23)nc2cc(Cl)ccc21
Reactant: NC1CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: C1CCOC1
Product: O=C(CCC(Nc1ncnc2cc(C(=O)N3CCCC3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1)NC1CCCC1

Procedure:
Prepared analogously to Example 61 from 6-chloro-4-[1-(1-tert.-butyloxycarbonyl-5-chloro-1H-benzimidazol-2-yl)-3-hydroxycarbonyl-propyl-amino]-7-(pyrrolidin-1-yl-carbonyl)-quinazoline and cyclopentylamine with TBTU in acetonitrile/tetrahydrofuran and subsequent reaction with trifluoroacetic acid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH:16][C:17]2[CH:32]=[CH:31][C:30](I)=[CH:29][C:18]=2[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][N:23]=2)=[O:20])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:41]([O:45][CH3:46])(=[O:44])[CH:42]=[CH2:43]>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH:16][C:17]2[CH:32]=[CH:31][C:30](/[CH:43]=[CH:42]/[C:41]([O:45][CH3:46])=[O:44])=[CH:29][C:18]=2[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][N:23]=2)=[O:20])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccc(I)cc2C(=O)Nc2ccc(Cl)cn2)CC1
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)/C=C/c1ccc(NC(=O)C2CCN(C(=O)OC(C)(C)C)CC2)c(C(=O)Nc2ccc(Cl)cn2)c1
Temperature: 100 °C
Reaction time: 15 h
Yield: 88.4 %

Procedure:
To a stirring solution of 2-[(1-tert-butoxycarbonylpiperidin-4-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)-5-iodobenzamide (1.17 g, 2 mmol) in acetonitrile (4 mL) was added triethylamine (2 mL, 14.3 mmol) followed by palladium(II) acetate (22 mg, 0.1 mmol) and then methyl acrylate (0.36 mL, 4 mmol). The mixture was heated to 100° C. in a sealed tube. After 15 h, the reaction mixture was cooled to room temperature and concentrated in vacuo. The crude product was purified by chromatography on silica gel, eluting with 20% ethyl acetate in dichloromethane, to give 0.96 g (88%) of a white solid.
Reaction SMILES: Cl[C:2]1[C:14]2[C:13]3[CH:12]=[C:11]([F:15])[CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[C:5]([C:16]#[N:17])=[CH:4][N:3]=1.[F:18][C:19]1[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[C:20]=1[NH2:21].CC(C)([O-])C.[Na+].COCCOC>C(OCC)(=O)C.O>[F:15][C:11]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[C:5]([C:16]#[N:17])=[CH:4][N:3]=[C:2]([NH:21][C:20]4[C:19]([F:18])=[CH:25][C:24]([F:26])=[CH:23][C:22]=4[F:27])[C:14]=3[C:13]=2[CH:12]=1
Reactant: Nc1c(F)cc(F)cc1F
Reactant: N#Cc1cnc(Cl)c2c1[nH]c1ccc(F)cc12
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: N#Cc1cnc(Nc2c(F)cc(F)cc2F)c2c1[nH]c1ccc(F)cc12
Temperature: 85 °C
Reaction time: 20 h

Procedure:
1-Chloro-8-fluoro-5H-pyrido[4,3-b]indole-4-carbonitrile (150 mg, 0.611 mmol), 2,4,6-trifluoroaniline (269 mg, 1.83 mmol), and sodium tert-butoxide (188 mg, 1.95 mmol) were placed in a reaction vessel which was placed under an argon atmosphere. DME (3.0 ml) was added. The vessel was sealed and the reaction was heated to 85° C. and stirred for 20 hrs. The resulting solution was cooled to ambient temperature, diluted with ethyl acetate and water. The aqueous layer was extracted with ethyl acetate three times. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by reverse phase HPLC. Desired fractions were combined, diluted with ethyl acetate, and washed with saturated aqueous sodium bicarbonate solution. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the title compound. LRMS (APCI) calc'd for (C18H8F4N4) [M+H]+, 357.1. found 357.0.
Reaction SMILES: [I:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[I:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: Cc1cccc(C(=O)Cl)c1I
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cccc(CO)c1I
Temperature: -78 °C

Procedure:
2-Iodo-3-methyl-benzoyl chloride (1360 mg, 4.86 mmol, Example 131: a) was dissolved into THF (2 mL) and cooled to −78° C. To this was slowly added a slurry of lithium aluminum hydride (184.3 mg, 4.86 mmol) that was carefully weighed into a dry flask and cooled to 78° C., before THF (2 mL) was added. The reaction was warmed to RT slowly and stirred for an hour. The reaction was quenched by cooling back to −78° C. and adding 200 μL water, 200 μL 15% NaOH, 600 μL water and then poured over celite and filtered with THF. The title compound was obtained as a yellow solid. 1H-NMR (CDCl3): δ 7.21–7.19 (m, 2H), 7.14–7.11 (m, 1H,), 4.61 (s, 2H), 2.43 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=3)[CH2:14][CH2:13]2)[N:3]=1.[Cl:29]C1C=C2C(C=CC(C)=N2)=C(N2CCNCC2)C=1.[N+](C1C=CC(S(OCCC2C=CC=C([N+]([O-])=O)C=2)(=O)=O)=CC=1)([O-])=O>>[Cl:29][C:6]1[CH:5]=[C:4]2[C:9]([CH:10]=[CH:11][C:2]([CH3:1])=[N:3]2)=[C:8]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=3)[CH2:14][CH2:13]2)[CH:7]=1
Reactant: Cc1ccc2c(N3CCN(CCc4cccc([N+](=O)[O-])c4)CC3)cccc2n1
Reactant: Cc1ccc2c(N3CCNCC3)cc(Cl)cc2n1
Agent: O=[N+]([O-])c1ccc(S(=O)(=O)OCCc2cccc([N+](=O)[O-])c2)cc1
Product: Cc1ccc2c(N3CCN(CCc4cccc([N+](=O)[O-])c4)CC3)cc(Cl)cc2n1
Yield: 92 %

Procedure:
The title compound was prepared in 92% yield using a similar procedure to description D5 starting from 7-chloro-2-methyl-5-(1-piperazinyl)quinoline (D16) and 2-(3-Nitrophenyl)ethyl 4-nitrobenzenesulfonate (D15).
Reaction SMILES: [OH:1][C:2]1([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[NH2-:21].[Na+].ClCl>C1C=CC=CC=1>[N:17]1[CH:18]=[CH:19][CH:20]=[C:15]([C:2]2([O:1][CH2:12][CH2:11][CH2:13][N:21]3[CH2:4][CH2:3][CH2:2][CH2:7]3)[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]2)[CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2cccnc2)CC1
Reactant: [NH2-]
Agent: ClCl
Agent: [Na+]
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(OCCCN2CCCC2)(c2cccnc2)CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
tert-Butyl 4-hydroxy-4-(pyridin-3-yl)piperidine-1-carboxylate (2 g) was dissolved in benzene (20 ml), sodium amide (10 eq.) was added at 25° C. and the mixture was stirred at this temperature for 15 min. The corresponding chlorine compound (1.2 eq.) was then added and the mixture was heated under reflux for 16 h. When the reaction had ended (TLC control), the mixture was cooled to 0° C. and hydrolysis was carried out with ice. The aqueous phase was extracted with ethyl acetate. The organic phase was then washed successively with water and saturated NaCl solution and dried over Na2SO4. The solvent was removed on a rotary evaporator and the crude product obtained was purified by column chromatography (silica gel, MC/methanol, 95:5).
Reaction SMILES: [CH3:1][N:2]([CH3:41])[CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([C:15]3[CH:16]=[N:17][C:18]([NH:30][C:31]([NH:33][CH2:34][CH2:35][CH3:36])=[O:32])=[CH:19][C:20]=3[C:21]3[S:22][CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[N:25]=3)=[CH:12][CH:13]=2)[C:8](=[O:37])[C:7]([C:38]([OH:40])=O)=[CH:6]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH3:75][N:76]([CH3:86])[S:77]([N:80]1[CH2:85][CH2:84][NH:83][CH2:82][CH2:81]1)(=[O:79])=[O:78]>CN(C)C=O>[CH3:1][N:2]([CH3:41])[CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([C:15]3[CH:16]=[N:17][C:18]([NH:30][C:31]([NH:33][CH2:34][CH2:35][CH3:36])=[O:32])=[CH:19][C:20]=3[C:21]3[S:22][CH:23]=[C:24]([C:26]([F:28])([F:27])[F:29])[N:25]=3)=[CH:12][CH:13]=2)[C:8](=[O:37])[C:7]([C:38]([N:83]2[CH2:82][CH2:81][N:80]([S:77]([N:76]([CH3:86])[CH3:75])(=[O:79])=[O:78])[CH2:85][CH2:84]2)=[O:40])=[CH:6]1
Reactant: CN(C)S(=O)(=O)N1CCNCC1
Reactant: CCCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)O)cn3CCN(C)C)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)N2CCN(S(=O)(=O)N(C)C)CC2)cn3CCN(C)C)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(2-(dimethylamino)ethyl)-4-oxo-6-(6-(3-propylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-1,4-dihydroquinoline-3-carboxylic acid (Example 153, 80 mg, 0.14 mmol) in dimethylformamide (0.5 mL) was added HATU (78.4 mg, 0.20 mmol) then diisopropylethylamine (95.2 uL, 0.55 mmol). This was followed by N,N-dimethylpiperazine-1-sulfonamide (52.7 mg, 0.27 mmol) and the reaction was stirred at room temperature for 1 h. The solvent was removed under reduced pressure and the residue purified by prep HPLC (Water-methanol-0.1% Formic acid).