Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12]2[CH:13]=[C:14]([C:21]([OH:23])=O)[C:15]([C:17]([F:20])([F:19])[F:18])=[CH:16][C:11]=2[O:10][C:9]([CH3:25])([CH3:24])[C:8]1=[O:26].[CH:27]([NH:30][CH:31]1[CH2:37][CH2:36][CH2:35][CH2:34][N:33]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:32]1)([CH3:29])[CH3:28]>>[CH:27]([N:30]([C:21]([C:14]1[C:15]([C:17]([F:19])([F:20])[F:18])=[CH:16][C:11]2[O:10][C:9]([CH3:25])([CH3:24])[C:8](=[O:26])[N:7]([CH2:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])[C:12]=2[CH:13]=1)=[O:23])[CH:31]1[CH2:37][CH2:36][CH2:35][CH2:34][N:33]([C:38]([O:40][C:41]([CH3:43])([CH3:42])[CH3:44])=[O:39])[CH2:32]1)([CH3:29])[CH3:28]
Reactant: CC(C)NC1CCCCN(C(=O)OC(C)(C)C)C1
Reactant: COCCCCN1C(=O)C(C)(C)Oc2cc(C(F)(F)F)c(C(=O)O)cc21
Product: COCCCCN1C(=O)C(C)(C)Oc2cc(C(F)(F)F)c(C(=O)N(C(C)C)C3CCCCN(C(=O)OC(C)(C)C)C3)cc21

Procedure:
Using 4-(4-methoxybutyl)-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylic acid and tert-butyl 3-(isopropylamino)azepane-1-carboxylate, the title compound was obtained in a similar manner to Reference Example 5.
Reaction SMILES: [Br:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[C:8]([CH2:25][CH2:26][CH2:27][CH3:28])=[N:9][N:10]([C:15]3[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=3[Cl:24])[C:11]=2[C:12]([NH2:14])=O)=[C:4]([F:31])[CH:3]=1.C(N(CC)CC)C.ClC(Cl)(Cl)C(Cl)=O>C(Cl)Cl>[Br:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[C:8]([CH2:25][CH2:26][CH2:27][CH3:28])=[N:9][N:10]([C:15]3[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=3[Cl:24])[C:11]=2[C:12]#[N:14])=[C:4]([F:31])[CH:3]=1
Reactant: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2Cl)c(C(N)=O)c1Cc1ccc(Br)cc1F
Agent: O=C(Cl)C(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2Cl)c(C#N)c1Cc1ccc(Br)cc1F
Temperature: 0 °C
Reaction time: 3 h
Yield: 68.8 %

Procedure:
A mixture of 600 mg (1.18 mmol) of 4-(4-bromo-2-fluorobenzyl)-3-n-butyl-1-(2-chloro-5-nitrophenyl)-1H-pyrazole-5-carboxamide (from Step E), 330 μL (238 mg, 2.35 mmol) of triethylamine, and 7 mL of methylene chloride was cooled to 0° C. and treated with 145 μL of trichloroacetyl chloride. The mixture was stirred under N2 and allowed to warm to room temperature. After 3 hours, the mixture was concentrated to dryness. The orange residue was triturated with ether. The insoluble material was removed by filtration. The filtrate was washed with 0.2N HCl followed by 0.25N NaOH. The organic layer, after being dried over Na2SO4, was filtered and concentrated. The orange residual oil was flash chromatographed on silica gel (elution with 4:1 and then 3:1 hexane-EtOAc) to give 399 mg (69%) of the title compound as a yellow oil; nearly homogeneous by TLC in 3:1 hexane-EtOAc; mass spectrum (FAB) m/e 491, 493 (M+1)+. 200 MHz 1H NMR (CDCl3) δ0.91 (t, J=7.1 Hz, 3H), 1.36 (m, 2H), 1.61 (m, 2H, partially obscured by H2O peak), 2.61 (t, J=7.7 Hz, 2H), 3.97 (s, 2H), 7.07 (dd, J=8, 8 Hz, 1H), 7.26-7.31 (m, 2H), 7.78 (d, J=8.8 Hz, 1H), 8.31-8.39 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH:22]1[CH2:28][CH2:27][CH2:26][C@@H:23]1[CH2:24][OH:25]>CO>[CH2:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:20][CH2:21][N:12]1[C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([N:22]2[CH2:28][CH2:27][CH2:26][C@@H:23]2[CH2:24][OH:25])[CH:11]=1
Reactant: OC[C@H]1CCCN1
Reactant: Clc1cc(N2CCc3ccccc3C2)c2ccccc2n1
Solvent: CO
Product: OC[C@H]1CCCN1c1cc(N2CCc3ccccc3C2)c2ccccc2n1

Procedure:
The title compound, m.p. 74-80° C., [α]D20 =30 63.2° (c=0.53, methanol) and MS: m/e=360.3 (M+H+), was prepared from 2-chloro-4-(3,4-dihydro-1H-isoquinolin-2-yl)-quinoline and D-prolinol.
Reaction SMILES: [CH:1]1([C:7]2[S:8][CH:9]=[C:10]([C:12]3[CH:21]=[C:20]([OH:22])[C:19]4[C:14](=[C:15]([CH3:25])[C:16]([O:23][CH3:24])=[CH:17][CH:18]=4)[N:13]=3)[N:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(OC(C1CC(O)CC1C(=O)NC1(C(OCC)=O)CC1C=C)=O)(C)(C)C.[CH2:52]([O:54][C:55]([C:57]12[CH2:74][CH:73]1[CH:72]=[CH:71][CH2:70][CH2:69][CH2:68][CH2:67][N:66]([CH3:75])[C:65](=[O:76])[CH:64]1[CH:60]([CH2:61][CH:62](OC3C4C(=C(C)C(OC)=CC=4)N=C(C4C=CC=C(C)N=4)C=3)[CH2:63]1)[C:59](=[O:98])[NH:58]2)=[O:56])[CH3:53]>>[CH2:52]([O:54][C:55]([C:57]12[CH2:74][CH:73]1[CH:72]=[CH:71][CH2:70][CH2:69][CH2:68][CH2:67][N:66]([CH3:75])[C:65](=[O:76])[CH:64]1[CH:60]([CH2:61][CH:62]([O:22][C:20]3[C:19]4[C:14](=[C:15]([CH3:25])[C:16]([O:23][CH3:24])=[CH:17][CH:18]=4)[N:13]=[C:12]([C:10]4[N:11]=[C:7]([CH:1]5[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]5)[S:8][CH:9]=4)[CH:21]=3)[CH2:63]1)[C:59](=[O:98])[NH:58]2)=[O:56])[CH3:53]
Reactant: COc1ccc2c(O)cc(-c3csc(C4CCCCC4)n3)nc2c1C
Reactant: CCOC(=O)C12CC1C=CCCCCN(C)C(=O)C1CC(Oc3cc(-c4cccc(C)n4)nc4c(C)c(OC)ccc34)CC1C(=O)N2
Agent: C=CC1CC1(NC(=O)C1CC(O)CC1C(=O)OC(C)(C)C)C(=O)OCC
Product: CCOC(=O)C12CC1C=CCCCCN(C)C(=O)C1CC(Oc3cc(-c4csc(C5CCCCC5)n4)nc4c(C)c(OC)ccc34)CC1C(=O)N2
Yield: 50 %

Procedure:
The title compound 121 was prepared in 50% yield from 2-(2-cyclohexylthiazol-4-yl)-4-hydroxy-7-methoxy-8-methylquinoline (119) and 2-(1-ethoxycarbonyl-2-vinylcyclo-propylcarbamoyl)-4-hydroxycyclopentanecarboxylic acid tert-butyl ester following the procedure reported for the preparation of 17-[2-(6-methylpyridin-2-yl)-7-methoxy-8-methyl-quinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diaza-tricyclo[13.3.0.04,6]-octadec-7-ene-4-carboxylic acid ethyl ester (101): m/z=715 (M+H)+.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]([CH2:37][CH:38]([CH3:40])[CH3:39])[S:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]3[C:31]([CH3:36])=[N:32][O:33][C:34]=3[CH3:35])=[CH:24][CH:23]=2)(=[O:21])=[O:20])=[CH:14][CH:13]=1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O1CCCC1>[CH3:36][C:31]1[C:30]([CH2:29][O:28][C:25]2[CH:24]=[CH:23][C:22]([S:19]([N:18]([C:15]3[CH:16]=[CH:17][C:12]([CH2:11][CH2:10][CH2:9][OH:8])=[CH:13][CH:14]=3)[CH2:37][CH:38]([CH3:40])[CH3:39])(=[O:21])=[O:20])=[CH:27][CH:26]=2)=[C:34]([CH3:35])[O:33][N:32]=1
Reactant: Cc1noc(C)c1COc1ccc(S(=O)(=O)N(CC(C)C)c2ccc(CCCO[Si](C)(C)C(C)(C)C)cc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1noc(C)c1COc1ccc(S(=O)(=O)N(CC(C)C)c2ccc(CCCO)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-(4-(3-((tert-butyldimethylsilyl)oxy)propyl)phenyl)-4-((3,5-dimethylisoxazol-4-yl)methoxy)-N-isobutylbenzenesulfonamide (276.8 mg, 0.472 mmol) was dissolved in Tetrahydrofuran (THF) (10 mL). To this solution was added TBAF in THF (1M) (0.707 mL, 0.707 mmol), and the solution was left to stir for 1 hr at room temperature. The reaction mixture was concentrated on the Biotage V10 evaporator, extracted to the organic phase of an aqueous workup between ethyl acetate (10 mL) and water (10 mL) followed by a brine (10 mL) wash. The organic phase was passed through a hydrophobic frit, and concentrated in vacuo, before being dissolved in DCM and loaded onto a silica column and purified by column chromatography on Biotage II Flashmaster (20 g silica (Si), 40 mins, 0-50% EtOAc in cyclohexane). The relevant fractions were combined and condensed and the sample was freeze dried using a minimum of dioxane in water, to give the final product, 67%. LCMS (M+1) 473.1, RT 1.16 mins.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[O:10][C:11]2[CH:17]=[C:16]([C:18]([OH:20])=O)[CH:15]=[CH:14][C:12]=2[N:13]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[C:57]1([CH3:66])[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=1[CH2:63][CH2:64][NH2:65]>CN(C=O)C>[C:57]1([CH3:66])[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=1[CH2:63][CH2:64][NH:65][C:18]([C:16]1[CH:15]=[CH:14][C:12]2[N:13]=[C:9]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])[O:10][C:11]=2[CH:17]=1)=[O:20]
Reactant: Cc1ccccc1CCN
Reactant: O=C(O)c1ccc2nc(-c3c(Cl)cccc3Cl)oc2c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)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: Cc1ccccc1CCNC(=O)c1ccc2nc(-c3c(Cl)cccc3Cl)oc2c1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(2,6-dichloro-phenyl)-benzooxazole-6-carboxylic acid (8.9 mg) in anhydrous DMF (0.5 mL) was added BOP (17.4 mg), diisopropylethylamine (0.014 mL), and 2-o-tolyl-ethylamine (5.5 mg). The reaction mixture was stirred at 85° C. overnight, quenched with 1N NaOH aqueous solution at 0° C., extracted with EtOAc. The extracts were dried over Na2SO4 and concentrated in vacuo. The crude reaction mixture was purified by silica SPE eluting with EtOAc/Hexane to give 2-(2,6-dichlorophenyl)-benzooxazole-6-carboxylic acid (2-o-tolyl-ethyl)-amide: MS (m/z) 425.1 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[N:5]=[C:4]([NH:12][CH2:13][CH2:14][CH3:15])[N:3]=1.Cl.[CH3:17][O:18][NH2:19].[OH-].[Na+]>O1CCOCC1.O>[CH2:13]([NH:12][C:4]1[N:5]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[N:7]=[C:2]([NH:19][O:18][CH3:17])[N:3]=1)[CH2:14][CH3:15]
Reactant: CON
Reactant: CCCNc1nc(Cl)nc(NCCC)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCCNc1nc(NCCC)nc(NOC)n1
Temperature: 60 °C
Yield: 90.2 %

Procedure:
A mixture of 6-chloro-N,N′-dipropyl-[1,3,5]triazine-2,4-diamine (XXXIV) (2.30 g, 10.01 mmol), O-methyl-hydroxylamine hydrochloride (1.67 g, 20.02 mmol) and NaOH (0.72 g, 18.00 mmol) in 1,4-dioxane (30 mL) and water (6 mL) was heated at 60° C. for 3 h. After this time, NaOH (0.72 g, 18.00 mmol) was added and the reaction mixture was heated for another 3 h. The volatiles were removed under reduced pressure. Saturated NaHCO3 solution (100 mL) was added to the residue, the mixture was extracted with EtOAc (3×25 mL). The combined organic extracts were washed with water (50 mL), brine (50 mL) and dried over Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by flash column chromatography using gradient elution from CH2Cl2/EtOH (99:1) to CH2Cl2/EtOH (95:5) to yield 2.17 g (90%) of N-(4,6-bis-n-propylamino-[1,3,5]triazin-2-yl)-O-methyl-hydroxylamine (XLI). ESI-MS (m/z): 241 [M+H]+
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:18][CH2:19][C:20]([CH3:27])([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH2:18][CH2:19][C:20]([CH3:27])([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)C(C)(C)CCBr
Reactant: Brc1cccc2[nH]ncc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(C)CCn1ncc2c(Br)cccc21
Temperature: 80 °C
Reaction time: 24 h
Yield: 40 %

Procedure:
To a solution of 4-bromo-1H-indazole (commercially available from Insight Chemical Solutions Ltd., 826 mg, 4.19 mmol) in DMF (10 ml) at room temperature were added Cs2CO3 (1.37 g, 4.19 mmol) and ethyl 4-bromo-2,2-dimethylbutanoate (D99) (1.40 g, 6.29 mmol) and the resulting mixture was stirred at 80° C. for 24 h then cooled to room temperature and diluted with AcOEt. The organic phase was washed with water, dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel [15-25% EtOAc/cyclohexane] gave the title compound (600 mg, 40%) as orange oil. MS (ES) C15H1981BrN2O2 requires 340, found 341 [M+H]+
Reaction SMILES: C(O[C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:6]=1[CH3:12])C.BrN1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[F:40][CH:41]([F:44])[CH2:42][NH2:43].C(N(CC)CC)C>CCCCCC.C(OCC)(=O)C.CCCCCC.C(Cl)(Cl)(Cl)Cl>[Br:11][C:8]1[CH:7]=[C:6]2[C:5](=[CH:10][CH:9]=1)[C:4](=[O:13])[N:43]([CH2:42][CH:41]([F:44])[F:40])[CH2:12]2
Reactant: NCC(F)F
Reactant: CCOC(=O)c1ccc(Br)cc1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Solvent: CCCCCC
Solvent: CCN(CC)CC
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1c2ccc(Br)cc2CN1CC(F)F
Temperature: 25 °C
Reaction time: 14 h
Yield: 48.6 %

Procedure:
To carbon tetrachloride (160 ml) were added the compound (10.5 g, 43.2 mmol) of step A, N-bromosuccinimide (8.08 g, 45.4 mmol) and benzoyl peroxide (724 mg), and the mixture was heated under reflux for 50 min. The reaction mixture was cooled and diluted with hexane, the insoluble material was filtered off, and the obtained solution was concentrated under reduced pressure. The obtained oil (18.0 g) was dissolved in N,N-dimethylformamide (180 ml), 2,2-difluoroethylamine (5.99 g, 73.9 mmol) and triethylamine (12.0 ml, 86.1 mmol) were added, and the mixture was stirred at room temperature for 14 hr. The reaction mixture was diluted with an ethyl acetate-hexane=1:1 mixed solvent, washed with water, 10% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure. The obtained oil was purified by silica gel column chromatography (ethyl acetate-hexane) to give the title compound (5.80 g, yield 49%) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:4]=1[C:5]([C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=O)=[O:6]>S(=O)(=O)(O)O>[CH3:21][O:20][C:17]1[C:16]2[C:9](=[O:11])[C:8]3[C:7](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:5](=[O:6])[C:4]=2[C:3]([O:2][CH3:1])=[CH:19][CH:18]=1
Reactant: COc1ccc(OC)c(C(=O)c2ccccc2C(=O)O)c1
Agent: O=S(=O)(O)O
Product: COc1ccc(OC)c2c1C(=O)c1ccccc1C2=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
2-(2' ,5'-Dimethoxybenzoyl)-benzoic acid (I) (3 g, 0.01 mole) is added in portions to stirred concentrated sulfuric acid (20 ml). After addition the mixture is heated on steam bath with constant stirring for 20 minutes, cooled to room temperature and poured onto crushed ice (400 g) and extracted with chloroform (3 × 100 ml). The organic extract is washed with 2% aqueous sodium hydroxide solution (10 × 100 ml) and water (100 ml), then dried over anhydrous sodium sulfate and the solvent stripped off under reduced pressure to yield 1,4-dimethoxyanthraquinone (II), as a brownish yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([OH:9])=[CH:7][CH:6]=[CH:5][C:4]=1[C:10]1[NH:11][C:12]2[C:13]([N:18]=1)=[N:14][CH:15]=[CH:16][CH:17]=2.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>>[CH3:1][O:2][C:3]1[C:8]([O:9][S:20]([CH3:19])(=[O:22])=[O:21])=[CH:7][CH:6]=[CH:5][C:4]=1[C:10]1[NH:11][C:12]2[C:13]([N:18]=1)=[N:14][CH:15]=[CH:16][CH:17]=2
Reactant: COc1c(O)cccc1-c1nc2ncccc2[nH]1
Reactant: CS(=O)(=O)Cl
Product: COc1c(OS(C)(=O)=O)cccc1-c1nc2ncccc2[nH]1

Procedure:
Prepared analogously to Example 1 from 2-(2'-methoxy-3'-hydroxy-phenyl)-imidazo[4,5-b]pyridine and methanesulfonic acid chloride.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:15]2=[N:16][C:17]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)[N:19]=[C:14]2[CH:13]=[CH:12]1)[CH3:2].[Br:35]N1C(=O)CCC1=O>C(Cl)Cl>[Br:35][C:13]1[C:14]2[C:15](=[N:16][C:17]([C:27]3[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=3)=[C:18]([C:20]3[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=3)[N:19]=2)[N:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:34])[CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)CCCCCCn1ccc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Solvent: ClCCl
Product: CCOC(=O)CCCCCCn1cc(Br)c2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
7-(2,3-Di-p-tolyl-pyrrolo[2,3-b]pyrazin-5-yl)-heptanoic acid ethyl ester (Intermediate B) (135 mg, 0.296 mmol) in DCM (5 ml) was treated with N-bromosuccinimide (52.7 mg, 0.296 mmol) and the reaction mixture was stirred at room temperature for 16 hours. The mixture was diluted with DCM (50 ml) and washed with water (×2), brine (×1) and the organic solvent was removed under reduced pressure. Purification of the crude product by chromatography on silica using a gradient from 0-10% EtOAc in iso-hexane afforded the titled compound as an orange oil;
Reaction SMILES: Cl[C:2]1[C:14]([Cl:15])=[CH:13][C:5]2[NH:6][C:7]([C:9]([F:12])([F:11])[F:10])=[N:8][C:4]=2[CH:3]=1.O1CCOCC1.[Cl:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][C:28]=1[Cl:29].C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Cl:15][C:14]1[C:2]([C:26]2[CH:25]=[CH:24][C:23]([Cl:22])=[C:28]([Cl:29])[CH:27]=2)=[CH:3][C:4]2[NH:8][C:7]([C:9]([F:12])([F:11])[F:10])=[N:6][C:5]=2[CH:13]=1
Reactant: FC(F)(F)c1nc2cc(Cl)c(Cl)cc2[nH]1
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: FC(F)(F)c1nc2cc(Cl)c(-c3ccc(Cl)c(Cl)c3)cc2[nH]1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Compound number 258 (i.e., 6-chloro-5-(3,4-dichlorophenyl)-2-trifluoromethylbenzimidazole) was prepared as follows. A 100-mL round-bottom flask was purged and maintained with an inert atmosphere of nitrogen. 5,6-dichloro-2-(trifluoromethyl)-1H-1,3-benzodiazole (200 mg, 0.78 mmol, 1.00 equiv), 1,4-dioxane (30 mL), (3,4-dichlorophenyl)boronic acid (229 mg, 1.20 mmol, 2.00 equiv), sodium carbonate (191 mg), water (8 mL) and Pd(PPh3)4 (34.7 mg) was placed into the flask. The resulting solution was stirred overnight at 100° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:4). This resulted in 82.4 mg (29%) of 6-chloro-5-(3,4-dichlorophenyl)-2-trifluoromethylbenzimidazole as a white solid.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[CH2:20]([O:27][C:28]([N:30]1[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH:31]1[CH:43]([NH2:45])[CH3:44])=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([O:27][C:28]([N:30]1[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:40])([CH3:41])[CH3:42])=[O:37])[CH2:32][CH:31]1[CH:43]([NH:45][C:5]1[N:10]=[C:9]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)[CH3:44])=[O:29])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(N)C1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1ccccc1
Reactant: CS(=O)(=O)c1nccc(-n2ccc3ccccc32)n1
Product: CC(Nc1nccc(-n2ccc3ccccc32)n1)C1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1ccccc1

Procedure:
The title compound was prepared from 2-methanesulfonyl-4-[indol-1-yl]pyrimidine (125 mg) and 1-benzyloxycarbonyl-2-(1-aminoethyl)-4-tert-butyloxycarbonylpiperazine (EXAMPLE 28; 166 mg) according to the procedure described in EXAMPLE 14, Step E. Mass spectrum (ESI) 557.3 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.[CH3:14][NH:15][C@H:16]1[CH2:35][N:20]2[C:21]3[C:26]([C:27]([CH2:28][C:29]([O:31]CCC)=[O:30])=[C:19]2[CH2:18][CH2:17]1)=[CH:25][CH:24]=[CH:23][CH:22]=3>>[CH3:13][N:2]([CH3:1])[C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([N:15]([CH3:14])[C@H:16]2[CH2:35][N:20]3[C:21]4[C:26]([C:27]([CH2:28][C:29]([OH:31])=[O:30])=[C:19]3[CH2:18][CH2:17]2)=[CH:25][CH:24]=[CH:23][CH:22]=4)=[O:12])=[CH:7][CH:8]=1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NC)CC2
Reactant: CN(C)c1ccc(CC(=O)O)cc1
Product: CN(C)c1ccc(CC(=O)N(C)[C@@H]2CCc3c(CC(=O)O)c4ccccc4n3C2)cc1

Procedure:
The title compound was prepared using analogous procedures described in Example 1 (Method A) from [4-(dimethylamino)phenyl]acetic acid and propyl [(7R)-7-(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate. MS (+ESI) m/z: 420.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:12]2[CH2:15][CH2:16][N:17](C)[CH2:18][CH2:19][N:10]3[C:11]=2[C:3]=1[C:4]1[CH2:5][CH2:6][CH2:7][CH2:8][C:9]=13.ClC(OC(Cl)C)=O>ClC(Cl)C>[Cl:1][C:2]1[CH:14]=[CH:13][C:12]2[CH2:15][CH2:16][NH:17][CH2:18][CH2:19][N:10]3[C:11]=2[C:3]=1[C:4]1[CH2:5][CH2:6][CH2:7][CH2:8][C:9]=13
Reactant: CN1CCc2ccc(Cl)c3c4c(n(c23)CC1)CCCC4
Agent: CC(Cl)OC(=O)Cl
Solvent: CC(Cl)Cl
Product: Clc1ccc2c3c1c1c(n3CCNCC2)CCCC1
Temperature: 25 °C
Yield: 101.5 %

Procedure:
To a solution of 8-chloro-3-methyl-2,3,4,5,9,10,11,12-octahydro-1H-[1,4]diazocino[7,8,1-jk]carbazole (0.60 g, 2.08 mmole) in dichloroethane (100 mL) was added 1-chloroethyl chloroformate (1.5 mL, 13.76 mmole) and refluxed for 24 hours. The reaction mixture was cooled to room temperature and the solvent removed in vacuo and replaced with methanol (100 mL) and refluxed for another 3 hours. The reaction mixture was cooled to room temperature and the solvent removed in vacuo. The dark residue was dissolved in methylene chloride (200 mL) and washed with aqueous sodium hydroxide (1N, 150 mL), saturated sodium chloride (150 mL), dried (sodium sulfate) and concentrated. Purification by flash column chromatography (silica gel, 1.5% to 3% methanol in dichloromethane) provided 0.58 g of the title compound. This solid was further treated with one equivalent of fumaric acid in ethanol to form a fumarate salt, mp 199-201° C. MS (ES) m/z 275.10 ([M+H]+), MS (ES) m/z 316.13 ([M+ACN+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](C=O)[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1)[CH2:7]2.C(O)=O.[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][CH:39]([CH2:42][NH2:43])[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30].C([BH3-])#N.[Na+]>CO.O>[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][CH:39]([CH2:42][NH:43][C:4]2[CH:5]=[C:6]3[C:10](=[C:2]([Cl:1])[CH:3]=2)[C:9](=[O:11])[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]([F:21])([F:23])[F:22])=[CH:15][CH:14]=2)[CH2:7]3)[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30]
Reactant: O=Cc1cc(Cl)c2c(c1)CN(Cc1ccc(OC(F)(F)F)cc1)C2=O
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=CO
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(CNc2cc(Cl)c3c(c2)CN(Cc2ccc(OC(F)(F)F)cc2)C3=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.4 %

Procedure:
To a solution of 7-chloro-1-oxo-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-1H-isoindole-5-carbaldehyde (60 mg, 0.162 mmol) in methanol (1.6 mL) was added formic acid (0.02 ml), 4-Aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (35 mg, 0.162 mmol), and Sodium cyanoborohydride (0.2 mL, 1M in THF) respectively. The mixture stirred at room temperature for 1 hour and was then diluted with water and extracted with ethyl acetate. The organic were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography (56-60% ethyl acetate in hexanes) provided the title compound (47 mg, 52%). 1H NMR (300 MHz, CDCl3): δ (7.35 (d, 4H), 7.18 (d, 2H), 4.77 (s, 2H), 4.25 (s, 2H), 4.13 (br s, 1H), 3.86 (s, 2H), 2.65 (t, 4H), 2.54 (d, 2H), 1.70 (t, 4H), 1.45 (s, 9H)
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH2:11])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[C:12](Cl)(Cl)=[O:13]>C1(C)C=CC=CC=1>[CH2:3]1[CH2:2][O:1][C:6]2[CH:7]=[CH:8][C:9]([N:11]=[C:12]=[O:13])=[CH:10][C:5]=2[O:4]1
Reactant: Nc1ccc2c(c1)OCCO2
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C=Nc1ccc2c(c1)OCCO2

Procedure:
A mixture of 1,4-benzodioxan-6-amine (300 mg; 2.0 mmol) in toluene (20 ml) and phosgene (10 ml 20% in toluene; 19 mmol) was refluxed for 6 h. The solvent was removed under reduced pressure to give crude 3,4-ethylenedioxyphenylisocyanate. The crude product was added 3-[4-(4-chlorophenyl)-1-piperazinyl]propanol (500 mg; 2.0 mmol) in toluene (10 ml) and refluxed for 16 h. The reaction mixture was then concentrated and submitted to flash chromatography on silica gel 60 eluting with toluene graduated to toluene/ethyl acetate (1:1). The product was taken up in ethyl acetate, which was treated with hydrogen chloride in ether. Recrystallization from methanol/ether afforded 440 mg of the title compound. M.p. 243°-244° C. MS (70 eV): m/z 431 (31%, M+), 254 (34), 209 (100), 177 (75), 121 (31), 70 (38).