Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[C:15]([OH:16])[C:10]=2[N:9]=[C:8]1[CH2:17][CH3:18])=[O:5])[CH3:2].[Cl:19][C:20]1[C:27]([N:28]([CH3:47])[C:29](=[O:46])[CH2:30][NH:31][C:32](=[O:45])[CH:33]=[CH:34][C:35]2[CH:40]=[CH:39][C:38]([C:41](=[O:44])[NH:42][CH3:43])=[CH:37][CH:36]=2)=[CH:26][CH:25]=[C:24]([Cl:48])[C:21]=1[CH2:22]Br.C(=O)([O-])[O-].[K+].[K+].C(=O)(O)[O-].[Na+]>CN(C)C=O>[Cl:19][C:20]1[C:27]([N:28]([CH3:47])[C:29](=[O:46])[CH2:30][NH:31][C:32](=[O:45])[CH:33]=[CH:34][C:35]2[CH:36]=[CH:37][C:38]([C:41](=[O:44])[NH:42][CH3:43])=[CH:39][CH:40]=2)=[CH:26][CH:25]=[C:24]([Cl:48])[C:21]=1[CH2:22][O:16][C:15]1[C:10]2[N:9]=[C:8]([CH2:17][CH3:18])[N:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:11]=2[CH:12]=[CH:13][CH:14]=1
Reactant: CNC(=O)c1ccc(C=CC(=O)NCC(=O)N(C)c2ccc(Cl)c(CBr)c2Cl)cc1
Reactant: CCOC(=O)Cn1c(CC)nc2c(O)cccc21
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(CC)nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)C=Cc4ccc(C(=O)NC)cc4)c3Cl)cccc21
Reaction time: 0.5 h
Yield: 82.7 %

Procedure:
To a solution of 1-ethoxycarbonylmethyl-2-ethyl-4-hydroxy-1H-benzimidazole (140 mg) and 2,6-dichloro-3-[N-methyl-N-[4-(methylcarbamoyl)cinnamoylglycyl]amino]benzyl bromide (289 mg) in dimethylformamide (3 ml) was added potassium carbonate (117 mg) under ice-cooling, and the mixture was stirred for 30 minutes at the same temperature and then for 2 hours at ambient temperature. To the reaction mixture was added saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel flash chromatography (5% methanol-ethyl acetate) and pulverized with diisopropyl ether to give 4-[2,6-dichloro-3-[N-methyl-N-[4-(methylcarbamoyl)cinnamoylglycyl]amino]benzyloxy]-1-ethoxycarbonylmethyl-2-ethyl-1H-benzimidazole (317 mg) as pale yellow solid.
Reaction SMILES: [CH:1]([NH2:3])=[S:2].[CH2:4]([O:6][C:7](=[O:15])[CH:8](Cl)[C:9](=O)[CH:10]([CH3:12])[CH3:11])[CH3:5]>C(O)C>[CH2:4]([O:6][C:7]([C:8]1[S:2][CH:1]=[N:3][C:9]=1[CH:10]([CH3:12])[CH3:11])=[O:15])[CH3:5]
Reactant: CCOC(=O)C(Cl)C(=O)C(C)C
Reactant: NC=S
Solvent: CCO
Product: CCOC(=O)c1scnc1C(C)C
Yield: 36 %

Procedure:
A solution of thioformamide (prepared according to A1-Razzar et al. U.S. Pat, No. 5,559158; 1.2 g, 20 mmol) and 2-chloro-4-methyl-3-oxopentanoic acid ethyl ester (2.0 g, 10 mmol) in ethanol (20 mL) was heated at reflux for 17 h. The reaction mixture was evaporated to dryness and the residue was chromatographed over silica gel (5-20% ethyl acetate/hexanes) to give 4-(1-methylethyl)thiazole-5-carboxylic acid ethyl ester (720 mg, 36% yield).
Reaction SMILES: [CH3:1][C:2]1[C:7]2[C:8]3([CH2:13][CH2:14][S:15](=[O:17])(=[O:16])[C:6]=2[C:5]([CH3:18])=[CH:4][C:3]=1[C:19]([OH:21])=[O:20])[S:12][CH2:11][CH2:10][S:9]3.BrBr.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH3:18][C:5]1[C:6]2[S:15](=[O:16])(=[O:17])[CH2:14][C:13]3[S:12][CH2:11][CH2:10][S:9][C:8]=3[C:7]=2[C:2]([CH3:1])=[C:3]([C:19]([OH:21])=[O:20])[CH:4]=1
Reactant: Cc1cc(C(=O)O)c(C)c2c1S(=O)(=O)CCC21SCCS1
Agent: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1cc(C(=O)O)c(C)c2c1S(=O)(=O)CC1=C2SCCS1
Temperature: 0 °C
Reaction time: 2 h
Yield: 82.5 %

Procedure:
A mixture of 0.50 g of the title compound of Step A in 200 mL of chloroform was cooled to 0° C. To this mixture was added a solution of 0.45 g of bromine in 35 mL of chloroform dropwise. The mixture was stirred at room temperature for 2 h and then 10% aqueous sodium thiosulfate solution was added. The organic layer was separated and dried over MgSO4, filtered, and concentrated under reduced pressure to dryness. The resulting residue was crystallized from 1-chlorobutane to yield 0.41 g of the title compound of Step B as a solid melting at 145° C. (dec.). 1H NMR (CDCl3): δ 2.49 (s, 3H), 2.56 (s, 3H), 3.11 (br s, 2H), 3.48 (m, 2H), 4.24 (br s, 2H), 7.57 (s, 1H).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[F:12].[F:13][C:14]1[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[C:16]([F:22])[C:15]=1B(O)O.[F-].[K+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1COCC1.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]>[F:13][C:14]1[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[C:16]([F:22])[C:15]=1[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[F:12]
Reactant: COC(=O)c1ccc(F)c(Br)n1
Reactant: COc1ccc(F)c(B(O)O)c1F
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(F)c(-c2c(F)ccc(OC)c2F)n1
Temperature: 100 °C
Yield: 35.1 %

Procedure:
In a sealed tube to a mixture of methyl 6-bromo-5-fluoropyridine-2-carboxylate (374 mg, 1.60 mmol) and (2,6-difluoro-3-methoxyphenyl)boronic acid (150 mg, 0.798 mmol) in THF (6.0 mL) and water (0.6 mL) was added potassium fluoride (153 mg, 2.64 mmol). The reaction mixture was purged with N2 for 5 min., then tris(dibenzylideneacetone)dipalladium (0) (180 mg, 0.20 mmol) and tri-tert-butylphosphine (81 mg, 0.40 mmol) were added subsequently. The reaction mixture was then heated at 100° C. for 30 min. After filtration and concentration of the solution under reduced pressure, the residue was purified by silica gel column chromatography using CombiFlash® (0 to 40% EtOAc in hexanes) to give the sub-title compound as a white powder (83.3 mg, 35%). LCMS calc. for C14H11F3NO3 (M+H)+: m/z=298.1. Found: 298.2.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:19])=[C:7]([O:9][C:10]2[CH:11]=[C:12]([CH:15]=[C:16]([Cl:18])[CH:17]=2)[C:13]#[N:14])[CH:8]=1.[CH3:20][O:21][C:22]1[CH:30]=[C:29]2[C:25]([C:26]([C:31](O)=[O:32])=[CH:27][NH:28]2)=[CH:24][CH:23]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.C(#N)C>[Cl:19][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:31]([C:26]2[C:25]3[C:29](=[CH:30][C:22]([O:21][CH3:20])=[CH:23][CH:24]=3)[NH:28][CH:27]=2)=[O:32])=[CH:8][C:7]=1[O:9][C:10]1[CH:11]=[C:12]([C:13]#[N:14])[CH:15]=[C:16]([Cl:18])[CH:17]=1
Reactant: COc1ccc2c(C(=O)O)c[nH]c2c1
Reactant: N#Cc1cc(Cl)cc(Oc2cc(CN)ccc2Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CC#N
Product: COc1ccc2c(C(=O)NCc3ccc(Cl)c(Oc4cc(Cl)cc(C#N)c4)c3)c[nH]c2c1
Yield: 75.7 %

Procedure:
N-({4-Chloro-3-[(3-chloro-5-cyanophenyl)oxy]phenyl}methyl)-6-(methyloxy)-1H-indole-3-carboxamide was prepared in a similar manner as described herein from 3-{[5-(aminomethyl)-2-chlorophenyl]oxy}-5-chlorobenzonitrile (0.05 g, 0.17 mmol), 6-(methyloxy)-1H-indole-3-carboxylic acid, (0.035 g, 0.18 mmol), HATU (0.1 g, 0.25 mmol), DIPEA (0.05 mL, 0.25 mmol), acetonitrile (3 mL) and DMF (1 mL). The crude material was purified by Reverse-Phase HPLC (water/acetonitrile with 0.1% TFA). The desired fractions were neutralized and extracted with EtOAc. The organic extracts were combined, dried over Na2SO4, filtered and evaporated to afford the title compound (0.06 g, 75%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 11.33 (br. s., 1H), 8.39 (s, 1H), 7.93 (d, 1H), 7.86 (d, 1H), 7.77 (d, 1H), 7.58 (d, 1H), 7.43 (dd, 1H), 7.34 (t, 1H), 7.27 (dd, 1H), 7.22 (d, 1H), 6.88 (d, 1H), 6.71 (dd, 1H), 4.43 (d, 2H), 3.74 (s, 3H). MS: m/z 466.0 (M+1).
Reaction SMILES: FC1C=CC(S(CCC)(=O)=O)=CC=1C#C[Si](C)(C)C.[C:20]([O:24][C:25](=[O:37])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[C:35]#[CH:36])([CH3:23])([CH3:22])[CH3:21].Br[C:39]1[CH:53]=[CH:52][C:42]2[C:43]([CH3:51])([OH:50])[C:44]([CH3:49])([CH3:48])[S:45](=[O:47])(=[O:46])[C:41]=2[CH:40]=1>>[C:20]([O:24][C:25](=[O:37])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[C:35]#[C:36][C:39]1[CH:53]=[CH:52][C:42]2[C:43]([OH:50])([CH3:51])[C:44]([CH3:49])([CH3:48])[S:45](=[O:46])(=[O:47])[C:41]=2[CH:40]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Reactant: CC1(O)c2ccc(Br)cc2S(=O)(=O)C1(C)C
Agent: CCCS(=O)(=O)c1ccc(F)c(C#C[Si](C)(C)C)c1
Product: CC(C)(C)OC(=O)COc1ccc(Cl)cc1C#Cc1ccc2c(c1)S(=O)(=O)C(C)(C)C2(C)O

Procedure:
Following the general method as outlined in Intermediate 107, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 6-bromo-2,2,3-trimethyl-2,3-dihydro-1-benzothiophene-3-ol 1,1-dioxide (Intermediate 246), the title compound was obtained as a white foam after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: Br[C:2]1[C:3]([F:9])=[C:4]([F:8])[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[C:15]([N:22]1[CH2:25][C:24](=[O:26])[CH2:23]1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].[Cl-].[NH4+]>C(OCC)C>[F:9][C:3]1[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=1[C:24]1([OH:26])[CH2:23][N:22]([C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[CH2:25]1
Reactant: Fc1cccc(Br)c1F
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CC(O)(c2cccc(F)c2F)C1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 56.9 %

Procedure:
To a solution of 3-bromo-1,2-difluorobenzene (2.3 g, 11.8 mmol) in dry diethylether (20 ml) at −78° C., under nitrogen was added n-butyllithium (2.5 M in hexane, 4.7 ml, 11.8 mmol) dropwise. The mixture was stirred for 1 h after which a solution of 1-Boc-3-azetidinone (2.0 g, 11.7 mmol) in dry diethyl ether (20 mL) was added dropwise. The resulting mixture was stirred at −78° C. for 15 min and then brought to ambient temperature and stirred for 2 h. Aqueous ammonium chloride (50 mL, 50%) and diethylether was added, the organic phase was collected and the aqueous phase was extracted with ethyl acetate (2×50 ml). The combined organic phase was dried (Na2SO4), filtered and evaporated to dryness. The crude product was purified by flash column chromatography on silica gel (ethylacetate/isooctane 1:4 to 1:1) to give the title compound (1.9 g). MS m/z (rel. intensity, 70 eV) 285 (M+, 1), 156 (55), 141 (69), 127 (bp), 57 (88).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[CH:5][C:4]([C:8]([OH:10])=O)=[N:3]1.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:22][C:23]1[CH:24]=[C:25]([CH:42]=[CH:43][C:44]=1[CH3:45])[O:26][C:27]1[CH:28]=[CH:29][C:30]2[N:31]([CH:33]=[C:34]([NH:36][C:37]([CH:39]3[CH2:41][CH2:40]3)=[O:38])[N:35]=2)[N:32]=1>CN(C)C=O.CN(C)C(=O)C>[CH:39]1([C:37]([NH:36][C:34]2[N:35]=[C:30]3[CH:29]=[CH:28][C:27]([O:26][C:25]4[CH:42]=[CH:43][C:44]([CH3:45])=[C:23]([NH:22][C:8]([C:4]5[CH:5]=[C:6]([CH3:7])[N:2]([CH3:1])[N:3]=5)=[O:10])[CH:24]=4)=[N:32][N:31]3[CH:33]=2)=[O:38])[CH2:40][CH2:41]1
Reactant: Cc1cc(C(=O)O)nn1C
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1NC(=O)c1cc(C)n(C)n1
Yield: 16.6 %

Procedure:
In the same manner as in Example 259 and using 1,5-dimethyl-1H-pyrazole-3-carboxylic acid (145 mg, 1.0 mmol), tetrahydrofuran (5 mL), N,N-dimethylformamide (1 drop), oxalyl chloride (320 μL, 4.44 mmol), N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (250 mg, 0.77 mmol) and N,N-dimethylacetamide (7 mL) as starting materials, the title compound (57 mg, 17%) was obtained as a white solid.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.[O:18]=[C:19]1[NH:27][C:22]2=[N:23][CH:24]=[CH:25][CH:26]=[C:21]2[C@@:20]21[CH2:39][C:30]1=[N:31][CH:32]=[C:33]([C:35](OC)=[O:36])[CH:34]=[C:29]1[CH2:28]2>C1COCC1>[OH:36][CH2:35][C:33]1[CH:34]=[C:29]2[CH2:28][C@@:20]3([C:21]4[C:22](=[N:23][CH:24]=[CH:25][CH:26]=4)[NH:27][C:19]3=[O:18])[CH2:39][C:30]2=[N:31][CH:32]=1
Reactant: COC(=O)c1cnc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C1Nc2ncccc2[C@@]12Cc1cc(CO)cnc1C2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of diisobutylaluminum hydride (DIBAL) in toluene (1 M, 2.2 mL, 2.2 mmol) was added dropwise to a solution of methyl (6S)-2′-oxo-1′,2′,5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridine]-3-carboxylate (described in Intermediate 5) (0.184 g, 0.62 mmols) in anhydrous THF at 0° C. The resulting mixture was stirred for 1 h at 0° C., then gradually warmed to ambient temperature and stirred for an additional 1 h. Excess DIBAL was quenched with ice and the mixture was partitioned between water and EtOAc (4×20 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with 5% MeOH in chloroform, to afford the title compound. MS: m/z=268.0 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][OH:9])=[N:6][CH:7]=1.[H-].[Na+].Br[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]>CN(C=O)C.C(OCC)(=O)C>[C:17]([O:16][C:14]([CH2:13][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][OH:9])=[N:6][CH:7]=1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: OCc1ccc(O)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)COc1ccc(CO)nc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 85 %

Procedure:
The solution of 5-hydroxy-2-hydroxymethylpyridine (5.0 g) in DMF (10 ml) was titrated under ice-cooling in the suspension of sodium hydride (60% purity, 1.6 g) in DMF (10 ml). After 10 minutes, the mixture was heated to room temperature and stirred for 15 minutes. After t-butyl bromoacetate (6 ml) was added to the mixture under ice-cooling, the resulting mixture was stirred under ice-cooling for 10 minutes and at room temperature for 45 minutes. The reaction mixture was diluted with ethyl acetate, washed with water and brine and dried over anhydrous magnesium sulfate. After the solvents were removed by distillation, the residue was purified by column chromatography on silica gel with an eluent system of chloroform→chloroform: methanol=50:1 to give 8.16 g of 5-(t-butoxycarbonylmethyl)oxy-2-hydroxymethylpyridine (yield, 85%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Br[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]#[N:16])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+]>[N+](C1C=CC=CC=1)([O-])=O>[N:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]#[N:16])=[CH:9][CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: N#CCCc1ccc(Br)cc1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=[N+]([O-])c1ccccc1
Product: N#CCCc1ccc(-n2ccnc2)cc1
Temperature: 160 °C

Procedure:
A mixture of 2.8 g of imidazole, 7.6 g of 3-(p-bromophenyl)propionitrile, 4.7 g of anhydrous potassium carbonate, and 0.4 g of cuprous bromide in 15 ml of nitrobenzene was heated at 160° C. for 25 hours under stirring.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1.[NH2:19][CH2:20][CH2:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1>ClCCl>[NH2:26][C:25]1[CH:27]=[CH:28][C:22]([CH2:21][CH2:20][NH:19][S:15]([C:12]2[CH:13]=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=2)(=[O:17])=[O:16])=[CH:23][CH:24]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: NCCc1ccc(N)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Nc1ccc(CCNS(=O)(=O)c2ccc(Cl)cc2)cc1

Procedure:
47.5 ml of triethylamine and then, in portions, 72 g of 4-chlorobenzenesulphonyl chloride, are added at ambient temperature to a solution of 46.5 g (340 mmol) of 4-(2-aminoethyl)aniline in a liter of dichloromethane. The mixture is then stirred for one night and subsequently filtered. The solid obtained is washed with water and dried using a dessicator to yield the expected product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:33](=[O:34])[C:12]2=[N:13][N:14]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH:32]=[CH:31][CH:30]=[N:29]4)=[CH:24][CH:23]=3)[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=3[C:11]2=[N:10]1.O.[CH3:36][N:37](C)C=O>[C-]#N.[Zn+2].[C-]#N.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[F:8][C:4]1[C:3]([N:9]2[C:33](=[O:34])[C:12]3=[N:13][N:14]([CH2:21][C:22]4[CH:23]=[CH:24][C:25]([N:28]5[CH:32]=[CH:31][CH:30]=[N:29]5)=[CH:26][CH:27]=4)[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=4[C:11]3=[N:10]2)=[C:2]([CH:7]=[CH:6][CH:5]=1)[C:36]#[N:37]
Reactant: CN(C)C=O
Reactant: O=c1c2nn(Cc3ccc(-n4cccn4)cc3)c3ccccc3c-2nn1-c1c(F)cccc1Br
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: N#Cc1cccc(F)c1-n1nc2c3ccccc3n(Cc3ccc(-n4cccn4)cc3)nc-2c1=O
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
2-(2-Bromo-6-fluorophenyl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]cinnolin-3-one [(Example 12) 46 mg, 0.089 mmol] was dissolved in degassed N,N-dimethylformamide (1.5 mL) and treated with zinc cyanide (18 mg, 0.15 mmol, 1.7 equiv) and bis(tri-tert-butylphosphine)palladium(0) (9.0 mg, 0.018 mmole, 0.2 equiv). The mixture was stirred under nitrogen at 100° C. for 30 minutes, cooled to ambient temperature, poured into water and extracted twice with ethyl acetate. The combined organic extracts were washed once with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (100:0 to 90:10; chloroform:methanol), providing the titled compound: 1H-NMR (400 MHz, CDCl3) δ 8.32 (1H, d, J=7.8 Hz), 7.90 (1H, s), 7.72 (2H, d, J=9.4 Hz), 7.67-7.51 (7H, m), 7.44 (2H, d, J=9.4 Hz), 6.47 (1H, s), 5.89 (2H, s) ppm; low resolution mass spectrometry (ES+) m/z 461.9 [(M+H)+; calculated for C26H16FN7O: 461.4].
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:33])=[C:24]([NH:27][C:28]([CH:30]3[CH2:32][CH2:31]3)=[O:29])[CH:25]=2)[NH:20][C:19](=[O:34])[C:18]=1[C:35]1[CH:40]=[C:39]([CH3:41])[CH:38]=[C:37]([CH3:42])[CH:36]=1)=O)(C)(C)C>FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>[Cl:33][C:23]1[CH:22]=[C:21]2[C:26]([C:17]([O:16][CH2:15][CH2:14][CH:9]3[CH2:10][CH2:11][CH2:12][CH2:13][NH:8]3)=[C:18]([C:35]3[CH:36]=[C:37]([CH3:42])[CH:38]=[C:39]([CH3:41])[CH:40]=3)[C:19](=[O:34])[NH:20]2)=[CH:25][C:24]=1[NH:27][C:28]([CH:30]1[CH2:31][CH2:32]1)=[O:29]
Reactant: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OC(C)(C)C)c3cc(NC(=O)C4CC4)c(Cl)cc3[nH]c2=O)c1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: Cc1cc(C)cc(-c2c(OCCC3CCCCN3)c3cc(NC(=O)C4CC4)c(Cl)cc3[nH]c2=O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-{2-[7-chloro-6-(cyclopropanecarbonylamino)-3-(3,5-dimethylphenyl)-2-oxo-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester (80 mg in a mixture of 8 mL trifluoroacetic acid and 0.03 mL anisole) was stirred at room temperature for 1 hour. The mixture was then concentrated in vacuo, resolvated in methylene chloride and washed with saturated sodium bicarbonate. The concentrated organics were purified by flash chromatography on silica gel (methylene chloride:methanol:ammonium hydroxide, 94:3:1) to give the title compound (52 mg). MASS: 494 (M+H)
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:5]=[CH:6][C:7]([N+:29]([O-:31])=[O:30])=[C:8]([NH:10][C:11]2[S:12][C:13]([C:26]([NH2:28])=[O:27])=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)[N:15]=2)[CH:9]=1.C(#N)C.Cl>O>[CH:3]([C:4]1[CH:5]=[CH:6][C:7]([N+:29]([O-:31])=[O:30])=[C:8]([NH:10][C:11]2[S:12][C:13]([C:26]([NH2:28])=[O:27])=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:23])([F:24])[F:25])[CH:17]=3)[N:15]=2)[CH:9]=1)=[O:2]
Reactant: COC(OC)c1ccc([N+](=O)[O-])c(Nc2nc(-c3cccc(C(F)(F)F)c3)c(C(N)=O)s2)c1
Agent: Cl
Solvent: CC#N
Solvent: O
Product: NC(=O)c1sc(Nc2cc(C=O)ccc2[N+](=O)[O-])nc1-c1cccc(C(F)(F)F)c1
Yield: 85.1 %

Procedure:
A mixture of 0.4154 g (0.861 mmole) of 2-(5-dimethoxymethyl-2-nitro-phenylamino)-4-(3-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid amide, 16 mL of acetonitrile and 8 mL of 1M hydrochloric acid was heated at 60 degrees for 1.5 hours. The cooled mixture diluted with 50 mL of water. The precipitate was collected by filtration, washed with water and dried to give 0.3198 g of 2-(5-formyl-2-nitro-phenylamino)-4-(3-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid amide (VI.48b) as an orange solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([CH2:11][CH:12]=[O:13])=[CH:7][N:6]=1)=[O:4].[CH2:14](O)[CH2:15][OH:16].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([CH2:11][CH:12]2[O:16][CH2:15][CH2:14][O:13]2)=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1cnc(CC=O)cn1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: COC(=O)c1cnc(CC2OCCO2)cn1
Yield: 85.7 %

Procedure:
A solution of 5-(2-oxo-ethyl)-pyrazine-2-carboxylic acid methyl ester (295 mg, 1.42 mmol) and ethylene glycol (100 μL, 1.79 mmol) in benzene (10 mL) was treated with p-toluenesulfonic acid monohydrate (27 mg, 0.142 mmol), and the mixture was heated under reflux with a Dean-Stark condenser for 20 h. The mixture was cooled, diluted with benzene (15 mL), and then washed with a saturated aqueous sodium bicarbonate solution (10 mL) followed by a saturated aqueous sodium chloride solution (10 mL). Each aqueous phase was extracted with a small portion of benzene. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to dryness to afford 5-[1,3]dioxolan-2-ylmethyl-pyrazine-2-carboxylic acid methyl ester as an orange oil (273 mg, 86%).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C@H:4](/[CH:5]=[C:6](\[CH3:9])/[CH:7]=O)[C@H:3]1[C:10]([O:12][CH3:13])=[O:11].Cl.[CH:16]([O:19][NH2:20])([CH3:18])[CH3:17].N1C=CC=CC=1>C(OCC)(=O)C>[CH:16]([O:19][N:20]=[CH:7]/[C:6](/[CH3:9])=[CH:5]/[C@@H:4]1[C@@H:3]([C:10]([O:12][CH3:13])=[O:11])[C:2]1([CH3:14])[CH3:1])([CH3:18])[CH3:17]
Reactant: CC(C)ON
Reactant: COC(=O)[C@@H]1[C@@H](/C=C(\C)C=O)C1(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COC(=O)[C@@H]1[C@@H](/C=C(\C)C=NOC(C)C)C1(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 69.9 %

Procedure:
Under nitrogen atmosphere, a mixture of 0.30 g of methyl (1R)-trans-2,2-dimethyl-3-[(E)-2-methyl-3-oxo-1-propenyl]cyclopropanecarboxylate, 0.17 g of O-isopropylhydroxylamine hydrochloride and 2 ml of pyridine was stirred at room temperature for 6 hours. Then, ethyl acetate was added to the reaction mixture, and the mixture was washed with 1 mol/L hydrochloric acid and saturated brine respectively. The organic layer was dried over anhydrous magnesium sulfate, then, filtrated, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.27 g of methyl (1R)-trans-3-[(E)-3-isopropoxyimino-2-methyl-1-propenyl]-2,2-dimethylcyclopropanecarboxylate:
Reaction SMILES: O[CH2:2][CH2:3][N:4]([CH3:35])[C:5]([C:7]1[C:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:11]([OH:21])[N:10]=[C:9]([CH2:22][C:23]2([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)[CH2:27][CH2:26][CH2:25][CH2:24]2)[N:8]=1)=[O:6].C(OC1C(=O)N=C(CC2C=CC=CC=2C2C=CC=CC=2)N2CCN(C)C(=O)C=12)C1C=CC=CC=1>>[CH2:14]([O:13][C:12]1[C:11](=[O:21])[N:10]=[C:9]([CH2:22][C:23]2([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)[CH2:24][CH2:25][CH2:26][CH2:27]2)[N:8]2[CH2:2][CH2:3][N:4]([CH3:35])[C:5](=[O:6])[C:7]=12)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CN(CCO)C(=O)c1nc(CC2(c3ccc(Cl)cc3)CCCC2)nc(O)c1OCc1ccccc1
Agent: CN1CCn2c(Cc3ccccc3-c3ccccc3)nc(=O)c(OCc3ccccc3)c2C1=O
Product: CN1CCn2c(CC3(c4ccc(Cl)cc4)CCCC3)nc(=O)c(OCc3ccccc3)c2C1=O
Yield: 51.9 %

Procedure:
9-Benzyloxy-6-[1-(4-chlorophenyl)-cyclopentylmethyl]-2-methyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (31-02) (500 mg, 51.88%) was synthesized from 5-benzyloxy-2-[1-(4-chlorophenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid (2-hydroxyethyl)-methyl-amide (30-02) (1 g, 2.016 mmol) as an off-white solid following the procedure as described for 9-benzyloxy-6-biphenyl-2-ylmethyl-2-methyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (11-01).