Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]1[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:27]=[CH:26][NH:25][N:24]=2)=[CH:19][CH:18]=1>>[CH2:9]([N:4]1[CH2:5][CH2:6][CH2:7][CH2:8][CH:3]1[CH2:2][N:25]1[CH:26]=[CH:27][C:23]([C:20]2[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=2)=[N:24]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: BrCC1CCCCN1Cc1ccccc1
Reactant: Fc1ccc(-c2cc[nH]n2)cc1
Product: Fc1ccc(-c2ccn(CC3CCCCN3Cc3ccccc3)n2)cc1
Yield: 22.9 %

Procedure:
The title compound (0.8 g) was prepared from 2-bromomethyl-N-benzylpiperidine (2.68 g) and 3-(4-fluoro-phenyl)-1H-pyrazole (1.62 g) according to the method of example 93.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[N:9]=[C:8]([CH2:10][CH2:11][C:12]2[CH:13]=[C:14]([NH:18][C:19]3[C:24]([F:25])=[CH:23][N:22]=[C:21](Cl)[N:20]=3)[CH:15]=[CH:16][CH:17]=2)[CH:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C)C=O.O1CCOCC1>[F:25][C:24]1[CH:23]=[N:22][C:21]2[NH:3][C:4]3[CH:5]=[CH:6][CH:7]=[C:8]([N:9]=3)[CH2:10][CH2:11][C:12]3[CH:13]=[C:14]([NH:18][C:19]=1[N:20]=2)[CH:15]=[CH:16][CH:17]=3
Reactant: Nc1cccc(CCc2cccc(Nc3nc(Cl)ncc3F)c2)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CN(C)C=O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Fc1cnc2nc1Nc1cccc(c1)CCc1cccc(n1)N2
Yield: 24.8 %

Procedure:
To a mixture of N-{3-[2-(6-aminopyridin-2-yl)ethyl]phenyl}-2-chloro-5-fluoropyrimidin-4-amine dihydrochloride (35.0 mg, 0.084 mmol) and triethylamine (0.035 mL, 0.25 mmol) in a mixed solvent of 1,4-dioxane (0.70 mL) and N,N-dimethylformamide (0.70 mL) was added (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (5.8 mg, 0.01 mmol), palladium acetate (2.3 mg, 0.01 mmol) and cesium carbonate (54.7 mg, 0.17 mmol). The mixture was degassed by bubbling N2 through the solution. The sealed tube was then microwaved at 160° C. for 1 hour. The reaction mixture was diluted with THF/MeOH, filtered and concentrated to give a residue, which was purified by silica gel column chromatography to provide the desired product as a white powder (6.4 mg, 25%). LCMS for C17H15FN5 (M+H)+: m/z=308.1.
Reaction SMILES: [OH:1][C@H:2]1[C@H:7]([OH:8])[C@@H:6]([OH:9])[CH:5]([OH:10])[O:4][C@@H:3]1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12].[O:21]=[S:22]1(=[O:69])[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][NH:30][C@:31]23[CH2:65][CH2:64][C@@H:63]([C:66]([CH3:68])=[CH2:67])[C@@H:32]2[C@@H:33]2[C@@:46]([CH3:49])([CH2:47][CH2:48]3)[C@@:45]3([CH3:50])[C@@H:36]([C@:37]4([CH3:62])[C@@H:42]([CH2:43][CH2:44]3)[C:41]([CH3:52])([CH3:51])[C:40]([C:53]3[CH:61]=[CH:60][C:56]([C:57](O)=[O:58])=[CH:55][CH:54]=3)=[CH:39][CH2:38]4)[CH2:35][CH2:34]2)[CH2:24][CH2:23]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>O1CCOCC1>[O:69]=[S:22]1(=[O:21])[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][NH:30][C@:31]23[CH2:65][CH2:64][C@@H:63]([C:66]([CH3:68])=[CH2:67])[C@@H:32]2[C@@H:33]2[C@@:46]([CH3:49])([CH2:47][CH2:48]3)[C@@:45]3([CH3:50])[C@@H:36]([C@:37]4([CH3:62])[C@@H:42]([CH2:43][CH2:44]3)[C:41]([CH3:52])([CH3:51])[C:40]([C:53]3[CH:54]=[CH:55][C:56]([C:57]([O:10][C@H:5]5[O:4][C@H:3]([C:11]([O:13][CH2:14][C:15]6[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=6)=[O:12])[C@@H:2]([OH:1])[C@H:7]([OH:8])[C@H:6]5[OH:9])=[O:58])=[CH:60][CH:61]=3)=[CH:39][CH2:38]4)[CH2:35][CH2:34]2)[CH2:24][CH2:23]1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: O=C(OCc1ccccc1)[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1COCCO1
Solvent: CN1CCOCC1
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O[C@H]7O[C@H](C(=O)OCc8ccccc8)[C@@H](O)[C@H](O)[C@H]7O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.4 %

Procedure:
A mixture of (2S,3S,4S,5R)-benzyl 3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-carboxylate (61.7 mg, 0.217 mmol), 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid (100 mg, 0.145 mmol), HATU (88 mg, 0.232 mmol) and N-methylmorpholine (0.048 mL, 0.434 mmol) in dioxane (3 mL) was stirred overnight at room temperature. The reaction mixture was filtered, the clear solution was purified by prep HPLC with acetonitrile/water/ammonium acetate to provide the desired product as white solid (20 mg, 14%). LCMS: m/e 957.7 (M+H)+, 2.36 min (method 6). 1H NMR (500 MHz, Acetic) δ 8.05 (d, J=8.2 Hz, 2H), 7.58-7.14 (m, 7H), 5.95 (d, J=7.6 Hz, 1H), 5.38 (d, J=4.6 Hz, 1H), 5.26 (s, 2H), 4.84 (s, 1H), 4.74 (s, 1H), 4.30 (d, J=9.5 Hz, 1H), 4.05-3.78 (m, 3H), 3.46 (d, J=11.9 Hz, 1H), 3.38-3.22 (m, 6H), 3.20-3.11 (m, 3H), 3.07 (br. s., 2H), 2.95 (dt, J=10.8, 5.5 Hz, 1H), 2.42-1.01 (m, 22H), 1.77 (s, 3H), 1.30 (s, 3H), 1.15 (s, 3H), 1.12 (s, 3H), 1.03 (s, 3H), 1.00 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[C:8]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:9]=3[S:10][CH:11]=2)=[CH:4][CH:3]=1.[C:20]([O:24][CH3:25])(=[O:23])[CH:21]=[CH2:22].C(N(CC)CC)C>CN(C=O)C.C(Cl)Cl.O>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:8]2[C:7]([O:6][C:5]3[CH:18]=[CH:19][CH:2]=[CH:3][C:4]=3/[CH:22]=[CH:21]/[C:20]([O:24][CH3:25])=[O:23])=[CH:11][S:10][C:9]=2[CH:12]=1
Reactant: COc1ccc2c(Oc3ccc(Br)cc3)csc2c1
Reactant: C=CC(=O)OC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)/C=C/c1ccccc1Oc1csc2cc(OC)ccc12
Temperature: 120 °C
Yield: 61.1 %

Procedure:
To a microwave vial, 3-(4-bromophenoxy)-6-methoxybenzo[b]thiophene (500 mg, 1.49 mmol), methyl acrylate (770 mg, 8.95 mmol), and Pd(PPh3)2C2 (157 mg, 0.22 mmol) were suspended in DMF (12 mL) and triethylamine (1.039 mL, 7.46 mmol). The reaction was heated for 60 min at 120° C. under microwave irradiation. The reaction mixture was diluted with DCM and water. The organic layer was collected (phase separator) and concentrated to obtain the crude product. The crude material was purified by column chromatography (SiO2, 1-20% EtOAc/Heptane) to afford (E)-methyl 3-(((6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (311 mg, 0.91 mmol, 61% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm=1.46 (s, 3 H), 3.73 (s, 3 H), 6.28 (d, J=16.17 Hz, 1 H), 6.59 (s, 1 H), 6.90 (dd, J=8.59, 2.02 Hz, 1 H), 7.00 (d, J=8.59 Hz, 2 H), 7.21 (d, J=2.02 Hz, 1 H), 7.37-7.48 (m, 3 H), 7.59 (d, J=16.17 Hz, 1 H), LC/MS (m/z, MH+): 341.1.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].[Br-:12].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)(Cl)Cl>[Br:12][C:7]1[CH:6]=[CH:5][C:4]([OH:9])=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:8]=1
Reactant: [Br-]
Reactant: Oc1ccccc1C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClC(Cl)Cl
Product: Oc1ccc(Br)cc1C(F)(F)F
Yield: 153.8 %

Procedure:
First, 41.33 g of 2-trifluoromethylphenol and 1800 ml of chloroform were charged into a reaction vessel, and 129.16 g of tetra-n-butylammonium tribromide was slowly added at room temperature over about one hour with stirring. After stirring at room temperature for 72 hours, the reaction solution was concentrated. Then, 500 ml of 10% hydrochloric acid was added to the resultant residue, and the mixture was extracted four times with 200 ml of diethyl ether. The ether layers were combined, washed with water, dried over anhydrous magnesium sulfate and then concentrated to give 49.5 g of 4-bromo-2-trifluoromethylphenol as a crude product (yield, 81%).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].F[C:17]1[CH:18]=[C:19]([CH3:26])[CH:20]=[CH:21][C:22]=1[N+:23]([O-:25])=[O:24]>CS(C)=O>[CH3:26][C:19]1[CH:18]=[CH:17][C:22]([N+:23]([O-:25])=[O:24])=[C:21]([CH:20]=1)[NH:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)c1c(N)sc2ccccc12
Reactant: Cc1ccc([N+](=O)[O-])c(F)c1
Solvent: CS(C)=O
Product: CCOC(=O)c1c(Nc2cc(C)ccc2[N+](=O)[O-])sc2ccccc12
Yield: 111.9 %

Procedure:
In the same manner as in Starting Material Synthesis Example 4 and using ethyl 2-aminobenzo[b]thiophene-3-carboxylate (3 g), 3-fluoro-4-nitrotoluene (2.1 g) and dimethyl sulfoxide (25 ml), ethyl 2-(5-methyl-2-nitroanilino)benzo[b]thiophene-3-carboxylate (5.4 g) was obtained. Without purification, in the same manner as in Starting Material Synthesis Example 19 and using 10% palladium-carbon (1.5 g), ethyl 2-(2-amino-5-methylanilino)benzo[b]thiophene-3-carboxylate (1.6 g) was obtained.
Reaction SMILES: C([O:8][CH2:9][C:10]([N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[O:11])C1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[CH2:13]([N:12]([CH2:15][CH3:16])[C:10](=[O:11])[CH2:9][OH:8])[CH3:14]
Reactant: CCN(CC)C(=O)COCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCN(CC)C(=O)CO
Reaction time: 24 h

Procedure:
2.20 g (9.9 mmol) of 2-(benzyloxy)-N,N-diethylacetamide were dissolved in 45 ml of ethyl acetate, and 200 mg of Pd/C (10%) were added. The reaction mixture was stirred under an atmosphere of hydrogen for 24 hours and then filtered through kieselguhr. The filtrate was evaporated to dryness, and N,N-diethyl-2-hydroxyacetamide was obtained as a colorless residue.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[C:18]2[CH:19]=[N:20][CH:21]=[CH:22][C:23]=2[NH:24]C(OC(C)(C)C)=O)[CH2:9]1)=O)(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[CH2:9]1[C:10]2[C:15](=[C:14]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][C:23]=3[NH2:24])[CH:13]=[CH:12][CH:11]=2)[CH2:16][CH2:17][NH:8]1
Reactant: CC(C)(C)OC(=O)Nc1ccncc1-c1cccc2c1CCN(C(=O)OC(C)(C)C)C2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccncc1-c1cccc2c1CCNC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.3 %

Procedure:
5-(4-tert-Butoxycarbonylamino-pyridin-3-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (0.18 g, 0.42 mmol) was dissolved at room temperature in 20 mL of 10% trifluoroacetic acid in dichloromethane and stirred to room temperature for 18 h. The volatiles were evaporated, the residue was suspended in toluene and evaporated again. The residue was purified by flash chromatography eluting with 7% methanol in dichloromethane containing 0.7% of ammonium hydroxide to yield 0.075 g of 3-(1,2,3,4-tetrahydro-isoquinolin-5-yl)-pyridin-4-ylamine.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[CH:6][CH:5]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([S:10][CH:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH2:16]2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Sc2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(Sc2ccc(N)cc2)CC1
Reaction time: 2 h
Yield: 108.3 %

Procedure:
tert-Butyl 4-(4-nitrophenylthio)piperidine-1-carboxylate (8.56 mmol, 2.8973 g) and palladium (3.77 mmol, 0.401 g) were combined in ethanol (30 mL) and the reaction mixture hydrogenated at 5 bar for 2 hours. The reaction mixture was filtered and concentrated under vacuum, reaction incomplete. Hydrogenation resumed with fresh palladium and left overnight. The reaction mixture was filtered and concentrated under vacuum to afford the title compound (2.86 g).
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][O:14][N:15]=[C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][CH2:18][CH:17]2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:7]1)=[O:5])C.[OH-].[Na+].Cl.[Cl:35]CCl>C(O)C>[ClH:35].[C:26]1([CH:17]2[CH2:18][CH2:19][C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:16]2=[N:15][O:14][CH2:13][CH2:12][N:8]2[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)[C@@H]1CCCN(CCON=C2c3ccccc3CCC2c2ccccc2)C1
Reactant: ClCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)[C@@H]1CCCN(CCON=C2c3ccccc3CCC2c2ccccc2)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The above ester (0.6 g, 1.5 mmol) was dissolved in ethanol (10 ml) and 4N sodium hydroxide (1.1 ml) was added. The mixture was stirred at ambient temperature for 4 h and excess concentrated hydrochloric acid was added followed by dichloromethane (300 ml). The mixture was dried (MgSO4) and the solvent evaporated in vacuo to give a residue which was re-evaporated with acetone and recrystallised from acetone. This afforded 0.5 g of the title compound as a solid.
Reaction SMILES: [N:1]1([C:10]2[N:18]=[C:17](Cl)[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH2:20][C@H:21]1[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23][CH2:22]1>CS(C)=O>[N:1]1([C:10]2[N:18]=[C:17]([NH:20][C@H:21]3[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23][CH2:22]3)[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: Clc1nc(-n2cnc3ccccc32)c2nc[nH]c2n1
Solvent: CS(C)=O
Product: O[C@H]1CC[C@H](Nc2nc(-n3cnc4ccccc43)c3nc[nH]c3n2)CC1
Temperature: 120 °C

Procedure:
200 mg of product obtained in stage 1 above are mixed with 3 ml of DMSO and 586 mg (5 equivalents) of trans-4-aminocyclohexanol, and the mixture is then heated at 120° C. for approximately 4 days. The mixture is allowed to return to ambient temperature. Purification is carried out by chromatography on silica with a CH2Cl2-MeOH—NH4OH: 85-15-1.5 mixture for eluent. 45 mg of expected product are obtained.
Reaction SMILES: CO[C:3](=O)[NH:4][C:5]1[NH:9][C:8]2[CH:10]=[C:11]([C:14]3[CH:15]=[CH:16][C:17]4[O:23][CH2:22][CH2:21][N:20]([C:24]5[C:33]6[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=6)[N:27]=[CH:26][CH:25]=5)[CH2:19][C:18]=4[CH:34]=3)[CH:12]=[CH:13][C:7]=2[N:6]=1.F[P-](F)(F)(F)(F)F.Cl[C:44](N(C)C)=[N+](C)C.CN1CCOCC1>CN(C)C=O.C(OCC)(=O)C>[CH3:44][N:4]([CH3:3])[C:5]1[NH:9][C:8]2[CH:10]=[C:11]([C:14]3[CH:15]=[CH:16][C:17]4[O:23][CH2:22][CH2:21][N:20]([C:24]5[C:33]6[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=6)[N:27]=[CH:26][CH:25]=5)[CH2:19][C:18]=4[CH:34]=3)[CH:12]=[CH:13][C:7]=2[N:6]=1
Reactant: CN(C)C(Cl)=[N+](C)C
Reactant: COC(=O)Nc1nc2ccc(-c3ccc4c(c3)CN(c3ccnc5ccccc35)CCO4)cc2[nH]1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C)c1nc2ccc(-c3ccc4c(c3)CN(c3ccnc5ccccc35)CCO4)cc2[nH]1
Yield: 47.7 %

Procedure:
A solution of 4-(4-quinolin-4-yl-2,3,4,5-tetrahydrobenzoxazepin-7-yl)benzene-1,2-diamine (example 2) (50 mg, 0.13 mmol), N-(chloro(dimethylamino)methylene)-N-methylmethanaminium hexafluorophosphate (44 mg, 0.16 mmol) and N-methylmorpholine (0.20 g, 1.9 mmol) in N,N-dimethylformamide (10 mL) was heated to 140° C. for 1 hour. After cooling the reaction was diluted with ethyl acetate (80 mL), and washed twice with water (2×20 mL) and brine (20 mL). The solution was dried over anhydrous sodium sulfate, filtered and concentrated to a solid residue. The residue was then taken into N,N-dimethylformamide (3 mL), then diluted with chloroform (15 mL). The resulting solid was collected by filtration and the filter cake was precipitated once more using the same technique to give N,N-dimethyl-6-(4-quinolin-4-yl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1H-benzimidazol-2-amine (27 mg, 48% yield) as a gray powder. 1H NMR (400 MHz, d6-DMSO): 8.56 (d, 1H), 8.30 (d, 1H), 8.06-7.97 (m, 2H), 7.90 (br s, 1H), 7.72 (t, 1H), 7.62 (br s, 1H), 7.56 (m, 2H), 7.48 (d, 1H), 6.99 (dd, 2H), 5.28 (s, 2H), 4.61 (s, 2H), 4.38 (s, 2H), 3.28 (s, 6H); MS (EI) for C27H25N5O: 436 (MH+).
Reaction SMILES: [CH2:1]([N:5]([CH2:28][CH:29]([CH3:31])[CH3:30])[CH2:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18]C2NC3C=CC=CC=3N=2)[CH2:11][CH2:10]1)[CH:2]([CH3:4])[CH3:3].[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([N:40]=[C:41]=[S:42])=[C:36]([N+:43]([O-:45])=[O:44])[CH:35]=1.[OH-].[Na+]>C(Cl)Cl>[CH2:28]([N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[CH2:6][CH2:7][CH2:8][N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:41]([NH:40][C:37]2[CH:38]=[CH:39][C:34]([O:33][CH3:32])=[CH:35][C:36]=2[N+:43]([O-:45])=[O:44])=[S:42])[CH2:13][CH2:14]1)[CH:29]([CH3:31])[CH3:30]
Reactant: COc1ccc(N=C=S)c([N+](=O)[O-])c1
Reactant: CC(C)CN(CCCN1CCN(CCCNc2nc3ccccc3[nH]2)CC1)CC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1ccc(NC(=S)NCCCN2CCN(CCCN(CC(C)C)CC(C)C)CC2)c([N+](=O)[O-])c1

Procedure:
A solution of N4-(3-{4-[3-(diisobutylamino)propyl]piperizano}propyl)-amine (intermediate of example 16) (103 mg, 0.33 mmol) and 4-methoxy-2-nitrophenyl isothiocyanate (139 mg, 0.66 mmol) in CH2Cl2 (10 mL) has been stirred for 4 h at room temperature. NaOH 1M is added until alkaline pH. Organic layer was washed with NaOH 0.5M and dried over MgSO4. Crude compound is purified by thick-layer chromatography (CH2Cl2/MeOH: 90/10).
Reaction SMILES: Cl.Cl.[N:3]1([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][C@H:18]([CH2:20][O:21][C:22]4[CH:26]=[CH:25][O:24][N:23]=4)[O:17][C:16]3=[O:27])=[CH:11][C:10]=2[F:28])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C(N(CC)CC)C.Cl[C:37]([O:39][CH3:40])=[O:38]>ClCCl>[CH3:40][O:39][C:37]([N:6]1[CH2:5][CH2:4][N:3]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][C@H:18]([CH2:20][O:21][C:22]4[CH:26]=[CH:25][O:24][N:23]=4)[O:17][C:16]3=[O:27])=[CH:11][C:10]=2[F:28])[CH2:8][CH2:7]1)=[O:38]
Reactant: O=C1O[C@@H](COc2ccon2)CN1c1ccc(N2CCNCC2)c(F)c1
Reactant: COC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N1CCN(c2ccc(N3C[C@H](COc4ccon4)OC3=O)cc2F)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.9 %

Procedure:
3-(4-(piperazin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one dihydrochloride (866 mg, 2 mmol) was suspended in dichloromethane (40 ml) under nitrogen at ambient temperature. Triethylamine (707 mg, 7 mmol) was added, followed by methyl chloroforrnate (190 mg, 2 mmol). The mixture was stirred for 2 hours at ambient temperature, washed with water (2×50 ml), saturated brine (50 ml), and dried (magnesium sulfate). After filtration and evaporation, the residue was triturated with diethyl ether to give the desired product (689 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][N:19]4[C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[NH:21][C:20]4=[O:28])[CH2:12][CH2:11]3)[C:7](=[S:9])[NH:8][C:4]=2[CH:3]=1.I[CH3:32].C[O-].[Na+]>CO>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][N:19]4[C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[NH:21][C:20]4=[O:28])[CH2:12][CH2:11]3)[C:7]([S:9][CH3:32])=[N:8][C:4]=2[CH:3]=1
Reactant: O=c1[nH]c2ccccc2n1CCCN1CCC(n2c(=S)[nH]c3cc(Cl)ccc32)CC1
Reactant: CI
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CSc1nc2cc(Cl)ccc2n1C1CCN(CCCn2c(=O)[nH]c3ccccc32)CC1
Reaction time: 8 h

Procedure:
A mixture of 2.21 parts of 1-{3-[4-(5-chloro-2,3-dihydro-2-thioxo-1H-benzimidazol-1-yl)-1-piperidinyl]propyl}-1,3-dihydro-2H-benzimidazol-2-one, 0.71 parts of iodomethane, 0.28 parts of sodium methanolate and 40 parts of methanol is stirred overnight at room temprature. The reaction mixture is evaporated. The residue is stirred with water and the product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is crystallized from 4-methyl-2-pentanone. The product is filtered off and dried, yielding 1.1 parts of 1-[3-{4-[5-chloro-2-(methylthio)-1H-benzimidazol-1-yl]-1-piperidinyl}propyl]-1,3-dihydro-2H-benzimidazol-2-one; mp. 196.1° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[C:7]([S:11](Cl)(=[O:13])=[O:12])=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.[NH3:15].[OH-].[NH4+].Cl>[Cl-].[Na+].O.O1CCCC1>[CH3:1][N:2]1[C:6]2[C:7]([S:11]([NH2:15])(=[O:13])=[O:12])=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1
Reactant: N
Reactant: Cn1nnc2cccc(S(=O)(=O)Cl)c21
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1nnc2cccc(S(N)(=O)=O)c21
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a stirred solution of 1.5 g of 1-methyl-1H-benzotriazole-7-sulfonyl chloride and 75 mL of tetrahydrofuran at 0° C. was added 5 mL of ammonia under an inert atmosphere. The resulting suspension was stirred at ambient temperature for 15 hours. Concentrated ammonium hydroxide (10 mL) and brine (10 mL) were added. The aqueous layer was adjusted to pH 7 with concentrated hydrochloric acid and was extracted with ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered, and stripped to afford 1.38 g of the title compound as a white solid, m.p. 198°-200° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[C:5](C(O)=O)=[CH:4][N:3]=1.Cl.[CH3:16][NH:17][O:18][CH3:19].CN1CCOCC1.C(Cl)CCl>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([N:17]([CH3:16])[O:18][CH3:19])=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:10]=1
Reactant: CNOC
Reactant: O=C(O)c1cnc(Cl)cc1C(F)(F)F
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCCl
Solvent: ClCCl
Product: CON(C)c1cnc(Cl)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 2 h
Yield: 85.8 %

Procedure:
To a solution of 6-chloro-4-trifluoromethyl-nicotinic acid (0.9 g, 3.99 mmol) in methylene chloride were added N,O-dimethylhydroxylamine HCl (0.39 g, 1.0 eq), NMM (0.44 ml), and EDC (0.768 g) at 0° C. and the reaction mixture was stirred at 0° C. for 2 hrs. The reaction mixture was extracted with methylene chloride, and washed with water and brine. The organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure. The resulting residue was purified by column chromatography (Hex/EtOAc=4/1) to give the product (0.824 g, 76.9%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17](=O)[CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=4)[CH2:22][CH2:21]3)[CH2:13][CH2:12]2)=[CH:6][C:5]=1[C:39]([F:42])([F:41])[F:40])([O-:3])=[O:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:52])=CC=1>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17](=[S:52])[CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=4)[CH2:22][CH2:21]3)[CH2:13][CH2:12]2)=[CH:6][C:5]=1[C:39]([F:42])([F:41])[F:40])([O-:3])=[O:2]
Reactant: O=C(CCN1CCC(OCc2ccc(C(F)(F)F)cc2)CC1)N1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: O=[N+]([O-])c1ccc(NC2CCN(C(=S)CCN3CCC(OCc4ccc(C(F)(F)F)cc4)CC3)CC2)cc1C(F)(F)F

Procedure:
1-[4-(4-Nitro-3-trifluoromethyl-phenylamino)-piperidin-1-yl]-3-[4-(4-fluoromethyl-benzyloxy)-piperidin-1-yl]-propan-1-one (26 mg; 0.043 mmol, prepared in accordance with Example 57) is reacted with Lawesson's reagent (9 mg; 0.022 mmol) according to the general conditions described in Example 109. The desired product is obtained following purification by preparative HPLC (7 mg; 0.011 mmol). The structure was confirmed using Protocol I-B. Calculated mass=619; observed mass=619; HPLC retention time=4.79 min.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([O:10][CH3:11])=[C:5]([CH3:9])[C:6]=1[C:7]#[N:8].[C:12]([N:20]=[C:21]=[O:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:7]([C:6]1[C:5]([CH3:9])=[C:4]([O:10][CH3:11])[S:3][C:2]=1[NH:1][C:21]([NH:20][C:12](=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:22])#[N:8]
Reactant: O=C=NC(=O)c1ccccc1
Reactant: COc1sc(N)c(C#N)c1C
Product: COc1sc(NC(=O)NC(=O)c2ccccc2)c(C#N)c1C

Procedure:
Prepared as in Example 1a from 2-amino-5-methoxy-4-methylthiophene-3-carbonitrile (example 13b) and benzoyl isocyanate as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 2.03 (s, 3H), 3.86 (s, 3H), 7.54 (t, J=7.2 Hz, 2H), 7.67 (t, J=7.6 Hz, 1H), 8.01-8.03 (d, J=8.4 Hz, 2H), 11.60 (s, 1H), 12.03 (s, 1H). MS 316 (MH+).