Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.CCCCCC.Br[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19].[F:20][CH2:21][C@@H:22]([O:25][CH2:26][C:27](N(OC)C)=[O:28])[CH:23]=[CH2:24].[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[F:20][CH2:21][C@@H:22]([O:25][CH2:26][C:27]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19])=[O:28])[CH:23]=[CH2:24]
Reactant: Fc1ccccc1Br
Reactant: C=C[C@@H](CF)OCC(=O)N(C)OC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: C=C[C@@H](CF)OCC(=O)c1ccccc1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 79.9 %

Procedure:
A solution of n-butyllithium in hexane (2.50 M; 176.52 mL, 441.29 mmol) was added dropwise over 20 mins to a solution of 2-bromofluorobenzene (49.00 mL, 451.88 mmol) in THF (670 mL) under a N2 atmosphere at −78° C. The temperature of the reaction was kept below −60° C. during the addition. The yellow solution was stirred at −78° C. for 30 mins. (S)-2-((1-fluorobut-3-en-2-yl)oxy)-N-methoxy-N-methylacetamide (67.50 g, 353.03 mmol) was added dropwise as a solution in THF (100 mL) keeping the internal temperature below −60° C. The reaction was stirred at −78° C. for 45 mins. Aqueous NH4Cl (200 mL) was added to the reaction solution and was allowed to warm up to RT and EtOAc (700 mL) was added. The two layers were separated. The aqueous layer was extracted with EtOAc (300 mL). The combined organic portions were washed with water 9300 mL), dried over MgSO4, (40 g) and concentrated. The crude product was purified by silica gel column chromatography (1% to 10% EtOAc in hexanes) to obtain the title compound as a yellow liquid (63.78 g, 80%). 1H-NMR (400 MHz, CDCl3) δ ppm 4.16-4.31 (m, 1H) 4.42-4.51 (m, 1H) 4.54-4.61 (m, 1H) 4.67-4.88 (m, 2H) 5.35-5.52 (m, 2H) 5.80 (ddd, J=17.43, 10.29, 7.26 Hz, 1H) 7.11-7.19 (m, 1H) 7.24-7.31 (m, 1H) 7.49-7.60 (m, 1H) 7.92-8.00 (m, 1H).
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[NH:11][C:10](=[O:14])[C:9]([C:15]#[N:16])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C=O)C.[H-].[Na+].[CH2:24](Br)[CH2:25][CH2:26][CH3:27]>O>[C:1]1([N:7]2[C:12](=[O:13])[N:11]([CH2:24][CH2:25][CH2:26][CH3:27])[C:10](=[O:14])[C:9]([C:15]#[N:16])=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#Cc1nn(-c2ccccc2)c(=O)[nH]c1=O
Reactant: CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCn1c(=O)c(C#N)nn(-c2ccccc2)c1=O
Reaction time: 0.5 h
Yield: 72.2 %

Procedure:
Intermediate c (9 g, 0.042 mol) was added to DMF (100 mL). To the mixture was added NaH (1.3 g, 0.054 mol) in batch under an ice bath. After stirring for 30 min, n-butyl bromide (3.4 mL, 0.042 mol) was added dropwise. After the dropwise addition, the reaction was conducted at 70° C. for 6 h. After completion of the reaction, the reaction solution was poured into water (600 mL). A great deal of solid separated out and was filtered by suction. The filtered cake was washed with water and dried to produce Intermediate f (8.2 g) in a yield of 81.4%.
Reaction SMILES: Cl.[NH:2]([C:6]1[CH:15]=[C:14]2[C:9]([C:10]([CH2:17][C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[N:11][N:12]=[C:13]2O)=[CH:8][CH:7]=1)[C:3]([CH3:5])=[O:4].O=P(Cl)(Cl)[Cl:26].C([O-])(O)=O.[Na+]>C(#N)C.O>[NH:2]([C:6]1[CH:15]=[C:14]2[C:9]([C:10]([CH2:17][C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[N:11][N:12]=[C:13]2[Cl:26])=[CH:8][CH:7]=1)[C:3]([CH3:5])=[O:4]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(=O)Nc1ccc2c(Cc3ccncc3)nnc(O)c2c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(=O)Nc1ccc2c(Cc3ccncc3)nnc(Cl)c2c1
Temperature: 10 °C
Reaction time: 0.25 h

Procedure:
Under a nitrogen atmosphere, a suspension of 2.24 g (7.6 mmol) 7-acetamino-1-hydroxy-4-(4-pyridylmethyl)phthalazine hydrochloride (=1-oxo-4-[pyridyl-(4′)-methyl]-7-acetamino-1,2-dihydrophthalazine hydrochloride: for preparation see German Auslegeschrift no. 1 061 788 [published Jul. 23, 1959]) in 22 ml acetonitrile is spiked with 1.74 ml (19 mmol) phosphoroxychloride and heated for 4 h to 95° C. The mixture is cooled to 10° C., and 7.5 g NaHCO3 in 30 ml water is added. The deep-red suspension is stirred for 15 min, filtered, and washed out with water. Drying under HV yields the title compound: HPLC: tRet(Grad5-40)=10.2; FAB MS (M+H)+=313.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C([Li])(C)(C)C.[Br:30][CH2:31][Si:32]([CH3:35])([CH3:34])Cl.O>C(OCC)C>[C:21]([O:20][C:18]([N:15]1[CH2:14][CH2:13][N:12]([C:4]2[CH:5]=[C:6]([C:8]([F:10])([F:9])[F:11])[CH:7]=[C:2]([Si:32]([CH2:31][Br:30])([CH3:35])[CH3:34])[CH:3]=2)[CH2:17][CH2:16]1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: C[Si](C)(Cl)CBr
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(Br)cc(C(F)(F)F)c2)CC1
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2cc(C(F)(F)F)cc([Si](C)(C)CBr)c2)CC1
Temperature: -65 °C
Reaction time: 2 h

Procedure:
A solution of tert-butyl 4-[3-bromo-5-(trifluoromethyl)-phenyl]-1-piperazine carboxylate (75 g, 183 mmoles) in diethyl ether, previously dried on molecular sieves, (1000 ml) was cooled to −65° C. and a 1.7M solution of tert-butyl lithium (215,6 ml, 366 mmoles) was added. After 30 minutes stirring bromomethyl-dimethyl-chlorosilane (49.9 ml, 366 mmoles) was added dropwise. After 2 hours stirring at −65° C., the reaction mixture was left at room temperature overnight. Water (600 ml) was added and the organic layer was washed with water, dried on MgSO4, filtered and evaporated.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][CH2:21][NH2:22].C(N(CC)CC)C.Cl.C([O:33][C:34](=[O:54])[CH2:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:38]=1[CH:44]1[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH2:47][CH2:46][NH:45]1)C>CC#N.CCOC(C)=O>[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][CH2:21][NH:22][C:2]([N:45]1[CH2:46][CH2:47][C:48]2[C:53](=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH:44]1[C:38]1[CH:39]=[C:40]([F:43])[CH:41]=[CH:42][C:37]=1[O:36][CH2:35][C:34]([OH:33])=[O:54])=[O:4]
Reactant: CCOC(=O)COc1ccc(F)cc1C1NCCc2ccccc21
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: NCCc1ccccc1Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(O)COc1ccc(F)cc1C1c2ccccc2CCN1C(=O)NCCc1ccccc1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of triphosgene (20 mg, 0.07 mmol, 0.33 eq.) in MeCN (0.3 mL) at −10° C. (acetone/ice bath), a solution of 2-(2-chlorophenyl)ethylamine (33 μL, 0.22 mmol, 1.10 eq.) and triethylamine (39 μL, 0.28 mmol, 1.30 eq.) in MeCN (2 mL) was added over a period of 15 min. The mixture was stirred for an additional 30 min at 0° C. and then a solution of (±)-[4-fluoro-2-(1,2,3,4-tetrahydro-isoquinolin-1-yl)-phenoxy]-acetic acid ethyl ester hydrochloride (73 mg, 0.20 mmol, 1.00 eq.) and triethylamine (78 μL, 0.56 mmol, 2.80 eq.) in MeCN (1 mL) was slowly added. The reaction mixture was slowly warmed to r.t. (ice bath during 30 min, then r.t.) and stirred at r.t. for 60 hours. The mixture was diluted with AcOEt, washed with water and sat. aq. NaCl soln., dried over MgSO4, filtered, and evaporated. To a solution of the crude product in DMF (0.9 mL), 1M aq. NaOH soln. (0.25 mL) was added. The solution was stirred at r.t. for 18 hours. The solution was acidified with 1M aq. HCl soln. (0.25 mL) then purified by prep. HPLC (column: Waters X-Bridge, 30×75 mm, 10 um, UV/MS, acidic conditions) to afford the title compound.
Reaction SMILES: [N+:1]([C:4]1[C:17]2[C:8](=[N:9][C:10]3[C:15]([C:16]=2OC2C=CC=CC=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].[ClH:25].Cl.[CH2:27]([NH:31][CH2:32][CH2:33][NH2:34])[CH:28]([CH3:30])[CH3:29]>C1(O)C=CC=CC=1>[ClH:25].[ClH:25].[N+:1]([C:4]1[C:17]2[C:8](=[N:9][C:10]3[C:15]([C:16]=2[NH:34][CH2:33][CH2:32][NH:31][CH2:27][CH:28]([CH3:30])[CH3:29])=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc2nc3ccccc3c(Oc3ccccc3)c12
Reactant: CC(C)CNCCN
Agent: Cl
Solvent: Oc1ccccc1
Product: CC(C)CNCCNc1c2ccccc2nc2cccc([N+](=O)[O-])c12
Temperature: 90 °C

Procedure:
1-Nitro-9-phenoxyacridine (1.58 g) is dissolved in about 5 g of phenol, and then 0.95 g of 2-isobutylaminoethylamine dihydrochloride is added and is heated at a temperature of 90° C. for 1.2 hour. It is isolated in a similar manner, as in Example VII. There is obtained 1-nitro-9-isobutylaminoethylaminoacridine dihydrochloride with a melting point of 230° C. (with decomposition).
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15](=[O:43])[C@H:16]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[N:17]=[CH:18][C:19]1[N:23]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])[C:22]([CH2:32][CH2:33][CH2:34][CH3:35])=[N:21][CH:20]=1.CI>O1CCCC1>[CH3:13][O:14][C:15](=[O:43])[C@:16]([CH3:1])([CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[N:17]=[CH:18][C:19]1[N:23]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])[C:22]([CH2:32][CH2:33][CH2:34][CH3:35])=[N:21][CH:20]=1
Reactant: CCCCc1ncc(C=N[C@@H](Cc2ccccc2)C(=O)OC)n1Cc1ccccc1Cl
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: CCCCc1ncc(C=N[C@@](C)(Cc2ccccc2)C(=O)OC)n1Cc1ccccc1Cl
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of diisopropylamine (1.27 g, 12.6 mmol) in tetrahydrofuran (50 ml) was added n-butyl lithium (5 ml of 2.5M in hexane, 12.6 mmol) at 0° C. After being stirred at 0° C. for 15 minutes, the solution was cooled to -78° C. and a solution of the imine, N [{1-[(2-chlorophenyl)methyl]-2-n-butyl-1H-imidazol-5-yl}methylene]phenylalanine methyl ester (Example 3(i) Method B) (5.51 g, 12.6 mmol) in tetrahydrofuran (35 ml) was added dropwise. The mixture was stirred for 30 minutes at -78° C. under argon and methyl iodide (2.06 q, 14.5 mmol) in tetrahydrofuran (15 ml) was added at 78° C. The mixture was allowed to slowly warm to ambient temperature and then stirred for 18 hours. The solvent was evaporated, the residue dissolved in ethyl acetate, the insoluble materials were filtered and the concentrated product was used without purification to give 8N18 g of N-[{1-[(2-chlorophenyl)-methyl]-2-n-butyl-1H-imidazol-5-yl}methylene]-α-methylphenyl-alanine methyl ester.
Reaction SMILES: [F:1][C:2]1[C:10]([CH2:11][C:12]2[N:16]3[N:17]=[C:18]([C:21](=O)[CH3:22])[CH:19]=[CH:20][C:15]3=[N:14][CH:13]=2)=[C:9]([F:24])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH3:25].[NH2:26][O:27][CH2:28][CH2:29][OH:30]>CO.C(Cl)Cl>[OH:30][CH2:29][CH2:28][O:27]/[N:26]=[C:21](/[C:18]1[CH:19]=[CH:20][C:15]2[N:16]([C:12]([CH2:11][C:10]3[C:2]([F:1])=[C:3]4[C:7](=[CH:8][C:9]=3[F:24])[N:6]([CH3:25])[N:5]=[CH:4]4)=[CH:13][N:14]=2)[N:17]=1)\[CH3:22]
Reactant: CC(=O)c1ccc2ncc(Cc3c(F)cc4c(cnn4C)c3F)n2n1
Reactant: NOCCO
Solvent: ClCCl
Solvent: CO
Product: C/C(=N\OCCO)c1ccc2ncc(Cc3c(F)cc4c(cnn4C)c3F)n2n1
Yield: 58.8 %

Procedure:
A solution of 1-(3-((4,6-difluoro-1-methyl-1H-indazol-5-yl)methyl)imidazo[1,2-b]pyridazin-6-yl)ethanone (62 mg, 0.136 mmol) and 2-(aminooxy)ethanol (intermediate S) (77 mg, 0.681 mmol) in 3 mL of MeOH and 2 mL of DCM was stirred at rt for 2 days. Solvent was evaporated to give a residue, which was purified by chromatography (DCM:MeOH 10:1) and recrystallized from MeOH to give the title compound as a white solid (32 mg, 59%). 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.16 (s, 1H), 8.04 (d, 1H), 7.62 (t, 2H), 7.48 (d, 1H), 4.44 (s, 2H), 4.24 (t, 2H), 4.00 (s, 3H), 3.68 (m, 2H), 2.29 (s, 3H). LCMS (method E): [MH]+=401.1, tR=5.591 min.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:20]=[CH:19][C:8]2[C:9]([C:12]3[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=3)=[N:10][S:11][C:7]=2[CH:6]=1.[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>>[Br:18][C:15]1[CH:16]=[CH:17][C:12]([C:9]2[C:8]3[CH:19]=[CH:20][C:5]([O:4][CH2:3][CH2:2][N:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:6][C:7]=3[S:11][N:10]=2)=[CH:13][CH:14]=1
Reactant: BrCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Reactant: C1CCNC1
Product: Brc1ccc(-c2nsc3cc(OCCN4CCCC4)ccc23)cc1

Procedure:
According to the method in example 4, 6-(2-Bromo-ethoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole and pyrrolidine were converted to yield 3-(4-Bromo-phenyl)-6-(2-pyrrolidin-1-yl-ethoxy)-benzo[d]isothiazole, MS: 404 (MH+, 1Br).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][N:12]([C:14](OC(C)(C)C)=[O:15])[C@H:11]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:10]=1.C(N(CC)CC)C.C(OC([NH:41][C@H:42](C(O)=O)[C:43]([CH3:46])([CH3:45])[CH3:44])=O)(C)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>ClCCl.FC(F)(F)C(O)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][N:12]([C:14]([C@@H:42]([NH2:41])[C:43]([CH3:46])([CH3:45])[CH3:44])=[O:15])[C@H:11]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C(C)(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)[C@H](N)C(=O)N1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl (2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxylate (5-5, 400 mg, 1.12 mmol, 1 equiv) in a 4:1 mixture of dichliromethane and trifluoroacetic acid (20 mL) was stirred for 30 min, then concentrated. The residue was dried via toluene azeotrope (2×10 mL), then dissolved in DMF (5 mL). Triethylamine (0.780 mL, 5.60 mmol, 5.00 equiv), N-(tert-butoxycarbonyl)-3-methyl-L-valine (388 mg, 1.68 mmol, 1.50 equiv), and PYBOP (874 mg, 1.68 mmol, 1.50 equiv) were added, and the resulting mixture was stirred at 23° C. for 24 h. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate solution and ethyl acetate (2×50 mL). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (hexanes initially, grading to 40% ethyl acetate in hexanes) to yield the desired coupled, N-Boc-protected intermediate, which was dissolved in a 2:1 mixture of dichloromethane and trifluoroacetic acid. The resulting solution was allowed to stand for 30 minutes, then concentrated. The residue was purified by reverse-phase LC (H2O/CH3CN gradient w/0.1% TFA present). The desired fractions were partitioned between saturated aqueous sodium bicarbonate solution and ethyl acetate (2×50 mL), then the combined organic layers were dried over sodium sulfate and concentrated to provide (1S)-1-{[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]carbonyl}-2,2-dimethylpropylamine (6-1) as a white solid. 1H NMR (500 MHz, CDCl3) major rotamer: δ 7.40 (t, 2H, J=7.6 Hz), 7.31 (m, 1H), 7.26 (d, 2H, J=7.8 Hz), 7.11-6.93 (m, 3H), 6.38 (s, 1H), 5.81 (m, 1H), 4.88 (m, 2H), 3.03 (s, 1H), 1.00 (s, 9H). LRMS m/z (M+H) 371.0 found, 371.2 required.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[F:5][C:6]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:7]=1[NH2:8]>C1(C)C=CC=CC=1>[F:5][C:6]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:7]=1[NH:8][C:3]([NH:2][CH3:1])=[O:4]
Reactant: Nc1ccc(F)cc1F
Reactant: CN=C=O
Solvent: Cc1ccccc1
Product: CNC(=O)Nc1ccc(F)cc1F
Reaction time: 1 h

Procedure:
Methyl isocyanate (9.6 g, 10 mL, 0.174 mol) is added to a solution of 2,4-difluoroaniline (15 g, 0.116 mol) in toluene. The reaction mixture is stirred for 1 hour and filtered to obtain a solid. The solid is washed with hexanes and air-dried to give the title product as an off-white solid, mp 182°-183° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[Cl:11].[CH2:12]1[C@H:21]2[C@H:16]([CH2:17][CH2:18][C:19]3[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=32)[NH:15][CH2:14][CH2:13]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:15]2[C@@H:16]3[C@@H:21]([C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[CH2:18][CH2:17]3)[CH2:12][CH2:13][CH2:14]2)=[O:8])=[CH:4][C:3]=1[Cl:11]
Reactant: c1ccc2c(c1)CC[C@@H]1NCCC[C@H]21
Reactant: Nc1ccc(C(=O)O)cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Nc1ccc(C(=O)N2CCC[C@@H]3c4ccccc4CC[C@@H]32)cc1Cl
Yield: 52 %

Procedure:
The title compound is prepared from 4-amino-3-chloro-benzoic acid and cis-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa-fluorophosphate is used]. Yield: 52% of theory; LC (method 4): tR=1.99 min; Mass spectrum (ESI+): m/z=341/343 (Cl) [M+H]+.
Reaction SMILES: [C:1]([CH2:4][C:5](=O)[CH3:6])(=O)[CH3:2].[NH2:8][C:9]([NH2:11])=[O:10].[ClH:12]>C(O)C>[ClH:12].[CH3:2][C:1]1[CH:4]=[C:5]([CH3:6])[NH:11][C:9](=[O:10])[N:8]=1
Reactant: CC(=O)CC(C)=O
Reactant: NC(N)=O
Agent: Cl
Solvent: CCO
Product: Cc1cc(C)[nH]c(=O)n1
Temperature: 0 °C
Yield: 55 %

Procedure:
To a mixture of acetyl acetone (4.0 g, 40.0 mmol) and urea (2.0 g, 33.3 mmol) in ethanol (40 mL) was added concentrated HCl (10 mL) and stirred at reflux for 3 h. The reaction mixture was cooled to 0° C. and filtered; the colourless solid was washed thoroughly with ice cold ethanol then ether and dried under vacuum to afford 4,6-dimethyl-1H-pyrimidin-2-one hydrochloride (3.5 g, 55%) as a solid.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].[N+:6]([O-:9])([OH:8])=[O:7].CC(OC(C)=O)=O>CCOC(C)=O.CCCCCC>[N+:6]([O-:9])([O-:8])=[O:7].[CH3:1][NH2+:2][CH2:3][CH2:4][O:5][N+:6]([O-:8])=[O:7]
Reactant: CNCCO
Reactant: O=[N+]([O-])O
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Solvent: CCCCCC
Product: C[NH2+]CCO[N+](=O)[O-]
Product: O=[N+]([O-])[O-]
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 76.2 %

Procedure:
Methyl(2-(hydroxy)ethyl)amine (1.5 g, 20 mmol) in EtOAc (65 mL) was added drop-wise to a mixture of fuming HNO3 (6.3 g, 4.2 mL, 100 mmol) and Ac2O (16.3 g, 15.1 mL, 160 mmol) at −10° C. The reaction mixture was stirred at −10° C. for 30 minutes and diluted with EtOAc and hexane. The precipitate was collected by filtration and washed with hexane to give the title compound (2.79 g, 82% yield) as an off-white solid. Mp 58-62° C. 1H NMR (300 MHz, d6-DMSO) δ 4.59-4.67 (m, 2H), 4.64-4.73 (m, 2H), 2.61 (bs, 3H). 13C NMR (75 MHz, d6-DMSO) δ 59.8, 38.7, 24.4. Mass spectrum (API-TIS) m/z 121 (MH+).
Reaction SMILES: [Br:1][CH:2]([CH2:6][CH2:7]Br)[C:3](Cl)=[O:4].[CH:9]1([NH2:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[OH-].[Na+].[H-].[Na+]>C(Cl)(Cl)Cl.O>[Br:1][CH:2]1[CH2:6][CH2:7][N:15]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[C:3]1=[O:4]
Reactant: O=C(Cl)C(Br)CCBr
Reactant: NC1CCCCC1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C1C(Br)CCN1C1CCCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 40.2 %

Procedure:
Dissolve 2,4-dibromo-butyryl chloride (17.0 g, 64.3 mmol) in chloroform (3 ml) and add to a mixture of cyclohexylamine (7.65 g, 77.2 mmol) in chloroform (20 mL) and H2O (3 mL) at 0° C. Add sodium hydroxide (5.92 g, 147.9 mmol) slowly while keeping the reaction temperature below 10° C. Stir for 1 hour. Wash the organic layer with 0.5M hydrochloride and brine. Dry over sodium sulfate, filter, and concentrate. Place the residue in THF (200 mL) and cool to 0° C. Add sodium hydride (1.02 g, 42.6 mmol) and stir for two days. Add additional sodium hydride (1.02 g, 42.6 mmol) and stir for 3 days. Pour onto water and ice and extract with methylene chloride. Dry over sodium sulfate, filter, and concentrate to yield 6.36 g (34%) of the title compound: NMR (CDCl3) δ 4.41 (dd, 1H), 3.94 (m, 1H), 3.48 (m, 1H), 3.33 (m, 1H), 2.51 (m, 1H), 2.30 (m, 1H), 1.82 (m, 3H), 1.70 (m, 2H), 1.38 (m, 4H), 1.11 (m, 1H).
Reaction SMILES: Br[C:2]1[C:3]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:4][C:5]([NH2:11])=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[F:18][C:19]1[CH:20]=[N:21][CH:22]=[C:23]([F:38])[C:24]=1[Sn](CCCC)(CCCC)CCCC>O1CCOCC1.C1(P([Pd-](Cl)P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[F:18][C:19]1[CH:20]=[N:21][CH:22]=[C:23]([F:38])[C:24]=1[C:2]1[C:3]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:4][C:5]([NH2:11])=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1c(F)cncc1F
Reactant: Nc1nc(-c2cccnc2)c(Br)cc1[N+](=O)[O-]
Agent: Cl[Pd-]([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1COCCO1
Product: Nc1nc(-c2cccnc2)c(-c2c(F)cncc2F)cc1[N+](=O)[O-]
Temperature: 150 °C

Procedure:
A mixture of 3-bromo-5-nitro-2,3′-bipyridin-6-amine (Intermediate 1, step b, 1 g, 3.39 mmol), 3,5-difluoro-4-tributylstannanylpyridine (1.5 g, 3.71 mmol), bis(triphenylphosphino) palladium (II) chloride (0.24 g, 0.34 mmol) and copper (I) iodide (0.13 g, 0.68 mmol) in dioxane (15 mL) was heated at 150° C. for 6 hours in Biotage Initiator Microwave Synthesizer.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13](=[O:18])[CH2:14]C([O-])=O)[CH2:10][C:9]1=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Na+].O>CS(C)=O>[C:13]([CH:11]1[CH2:12][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9](=[O:19])[CH2:10]1)(=[O:18])[CH3:14]
Reactant: O=C([O-])CC(=O)C1CC(=O)N(Cc2ccccc2)C1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)C1CC(=O)N(Cc2ccccc2)C1
Reaction time: 16 h
Yield: 83.2 %

Procedure:
A mixture of 3-(1-benzyl-2-oxopyrrolidin-4-yl)-3-oxopropanoate (24.0 g, 0.083 mole) and sodium chloride (10.6 g, 0.181 mole) in dimethylsulfoxide (105 mL)/water (4.4 mL) was heated at 135° with stirring for 16 hours. On cooling the reaction mixture was poured onto ice water (900 mL) and extracted with dichloromethane (800 mL). The organic phase was washed with water (4×500 mL) and dried (MgSO4). The solvent was removed under reduced pressure to give 4-acetyl-1-benzyl-2-pyrrolidinone (15.0 g, 83%) as a brown oil.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[C:12]([OH:21])(=[O:20])[C:13]1[C:14](=[CH:16][CH:17]=[CH:18][CH:19]=1)[NH2:15]>>[CH3:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]3[C:12](=[O:20])[C:13]4[C:14](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:15]=[C:2]3[NH:3][C:4]=2[CH:10]=1.[CH3:11][C:9]1[CH:8]=[CH:7][C:5]2[NH:6][C:2]3=[N:15][C:14]4[C:13]([C:12](=[O:21])[N:3]3[C:4]=2[CH:10]=1)=[CH:19][CH:18]=[CH:17][CH:16]=4
Reactant: Nc1ccccc1C(=O)O
Reactant: Cc1ccc2nc(Cl)[nH]c2c1
Product: Cc1ccc2[nH]c3nc4ccccc4c(=O)n3c2c1
Product: Cc1ccc2c(c1)[nH]c1nc3ccccc3c(=O)n12

Procedure:
The reaction of 2-chloro-5-methylbenzimidazole with anthranilic acid according to the procedure described in Example 1 yielded a solid mixture comprising 8-methylbenzimidazo[2,1-b]-quinazolin-12(6H)one and 9-methylbenzimidazo[2,1-b]quinazolin-12(6H)one.
Reaction SMILES: CS([O-])(=O)=O.[CH2:6]([C@@:9]1([CH3:35])[CH2:14][C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)[C@@H:12]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[N+:11]2[C@@H:29]([CH:32]3[CH2:34][CH2:33]3)[CH2:30][O:31][C:10]1=2)[CH:7]=[CH2:8].[CH2:36]([S-:38])[CH3:37].[Na+]>>[CH2:6]([C@@:9]1([CH3:35])[CH2:14][C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)[C@@H:12]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[N:11]([C@@H:29]([CH:32]2[CH2:33][CH2:34]2)[CH2:30][S:38][CH2:36][CH3:37])[C:10]1=[O:31])[CH:7]=[CH2:8]
Reactant: CC[S-]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)[N+]2=C1OC[C@@H]2C1CC1
Agent: CS(=O)(=O)[O-]
Agent: [Na+]
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CSCC)C2CC2)C1=O

Procedure:
The title compound was prepared from (3S,5S,6R,8S)-8-allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3-cyclopropyl-8-methyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-ium methanesulfonate (Example 349, Step A) and sodium ethanethiolate as described in Example 339.