Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10](Cl)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:13][C:14]1[CH:19]=[C:18]([C:20]2[N:24]=[C:23]([C:25]3[S:26][C:27]([CH2:31][N:32]([CH2:35][CH3:36])[CH2:33][CH3:34])=[C:28]([CH3:30])[CH:29]=3)[O:22][N:21]=2)[CH:17]=[C:16]([CH3:37])[C:15]=1[NH2:38]>C(Cl)Cl.C(OCC)C>[CH2:1]([O:8][CH2:9][C:10]([NH:38][C:15]1[C:16]([CH3:37])=[CH:17][C:18]([C:20]2[N:24]=[C:23]([C:25]3[S:26][C:27]([CH2:31][N:32]([CH2:33][CH3:34])[CH2:35][CH3:36])=[C:28]([CH3:30])[CH:29]=3)[O:22][N:21]=2)=[CH:19][C:14]=1[Cl:13])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)Cc1sc(-c2nc(-c3cc(C)c(N)c(Cl)c3)no2)cc1C
Reactant: O=C(Cl)COCc1ccccc1
Solvent: CCOCC
Solvent: ClCCl
Product: CCN(CC)Cc1sc(-c2nc(-c3cc(C)c(NC(=O)COCc4ccccc4)c(Cl)c3)no2)cc1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 28.9 %

Procedure:
A solution of benzyloxyacetyl chloride (142 mg, 767 μmol) in DCM (2 mL) is added to a solution of 2-chloro-4-[5-(5-diethylaminomethyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenylamine (30 mg, 77 μmol) in DCM (2 mL). The mixture is stirred at rt for 15 h. The mixture is diluted with diethyl ether and washed with 1 N aq. HCl. The organic extract is washed with 33% aq. KOH solution, dried over MgSO4, filtered and concentrated. The crude product is purified by reverse phase MPLC to give 2-benzyloxy-N-{2-chloro-4-[5-(5-diethylaminomethyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenyl}-acetamide (12 mg) as a pale yellow oil; LC-MS: tR=0.68 min; [M+1]+=529.18. The material is dissolved in THF:ethanol 1:1 (5 mL) and Pd/C (10 mg, 10% Pd) is added. The mixture is stirred at rt for 15 h under 5 bar of H2. The catalyst is removed by filtration and the filtrate is concentrated. The crude product is purified on prep. TLC plates with DCM containing 4% of methanol to give the title compound (4 mg) as a white solid; LC-MS: tR=0.50 min; [M+1]+=448.98; 1H NMR (CD3OD): δ 1.13 (t, J=7.0 Hz, 6H), 2.29 (s, 3H), 2.39 (s, 3H), 2.66 (q, J=6.8 Hz, 4H), 3.80 (s, 2H), 4.24 (s, 2H), 7.75 (s, 1H), 8.00 (s, 1H), 8.06 (s, 1H).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][NH:8][C:9]2[N:14]=[C:13]([C@@H:15]([NH:25]C(=O)OC(C)(C)C)[CH2:16][C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=3)[C:12]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[C:35]([C:40](=[O:42])[NH2:41])[CH:34]=3)=[CH:11][N:10]=2)[CH:5]=[CH:4][N:3]=[N:2]1.[ClH:43]>O1CCOCC1>[ClH:43].[N:1]1([CH2:6][CH2:7][NH:8][C:9]2[N:14]=[C:13]([C@@H:15]([NH2:25])[CH2:16][C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=3)[C:12]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[C:35]([CH:34]=3)[C:40]([NH2:41])=[O:42])=[CH:11][N:10]=2)[CH:5]=[CH:4][N:3]=[N:2]1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)c1nc(NCCn2ccnn2)ncc1-c1ccc(F)c(C(N)=O)c1
Agent: Cl
Solvent: C1COCCO1
Product: NC(=O)c1cc(-c2cnc(NCCn3ccnn3)nc2[C@@H](N)Cc2cc(F)cc(F)c2)ccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Compound 23D was dissolved in 2 mL of 4N HCl in dioxane and stirred at ambient temperature for overnight. The solvent was removed to afford the title product. (m/z) 483.08 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[CH:3]=1.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([CH:21]=O)=[CH:13]1.Cl>C(O)C>[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](/[CH:21]=[C:7]2\[O:8][C:4]3[CH:3]=[C:2]([OH:1])[CH:11]=[CH:10][C:5]=3[C:6]\2=[O:9])=[CH:13]1
Reactant: O=C1COc2cc(O)ccc21
Reactant: O=Cc1c[nH]c2ccccc12
Agent: Cl
Solvent: CCO
Product: O=C1/C(=C/c2c[nH]c3ccccc23)Oc2cc(O)ccc21
Temperature: 75 °C
Reaction time: 5 h
Yield: 105.4 %

Procedure:
The synthesis was performed with reference to the known literature (International Patent Publication WO1998/30556). A solution of 6-hydroxybenzofuran-3(2H)-one (2.0 g, 13 mmol) and 1H-indole-3-carboxaldehyde (2.3 g, 16 mmol) in ethanol (100 mL) was added with concentrated hydrochloric acid (10 mL), and the mixture was stirred at 75° C. for 5 hours. The reaction mixture was cooled to room temperature, and then the solid was collected by filtration, and washed with methanol and water to obtain (Z)-2-[(1H-indol-3-yl)methylene]-6-hydroxybenzofuran-3(2H)-one (3.8 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:27])[C:6]=1[C:7]1[CH:8]=[C:9]([NH:14][C:15](=[O:26])[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)[CH:10]=[CH:11][C:12]=1[OH:13].C(=O)([O-])[O-].[K+].[K+].Br[CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:27])[C:6]=1[C:7]1[CH:8]=[C:9]([NH:14][C:15](=[O:26])[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:23])([F:24])[F:25])[CH:17]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Cn1ncc(Cl)c1-c1cc(NC(=O)c2cccc(C(F)(F)F)c2)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cn1ncc(Cl)c1-c1cc(NC(=O)c2cccc(C(F)(F)F)c2)ccc1OCC(=O)OC(C)(C)C
Temperature: 65 °C
Reaction time: 1 h

Procedure:
To a solution of N-(3-(4-chloro-1-methyl-1H-pyrazol-5-yl)-4-hydroxyphenyl)-3-(trifluoromethyl)benzamide (0.396 g, 1.00 mmol) and potassium carbonate (0.207 g, 1.50 mmol) in acetone (10 mL) was added tert-butyl bromoacetate (0.215 g, 1.10 mmol). The reaction was stirred at 65° C. for 1 hour and then cooled to room temperature and partitioned between ethyl acetate and water. The organic layer was washed with water (×2) and brine, dried over magnesium sulfate and concentrated to a white solid (0.464 g, 91.0%). LCMS m/z (%)=510 (M+H, 35Cl, 30), 512 (M+H, 37Cl, 10), 454 (M-tBu+H, 35Cl, 100). 1H NMR (400 MHz, CDCl3) δ 1.47 (s, 9H) 3.80 (s, 3H) 4.52 (s, 2H) 6.87 (d, J=9.09 Hz, 1H) 7.45 (d, J=2.78 Hz, 1H) 7.50 (s, 1H) 7.64 (t, J=7.71 Hz, 1H) 7.78-7.89 (m, 2H) 7.94 (s, 1H) 8.07 (d, J=7.83 Hz, 1H) 8.14 (s, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][N:10]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][C:18]=3[CH3:19])[C:9]2=[O:20])[CH:5]=[CH:4][N:3]=1.[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1.C1(C(C2C=CC=CC=2)(P)CC)C=CC=CC=1.CC(C)([O-])C.[K+]>CC([O-])=O.CC([O-])=O.[Pd+2].CO.C1(C)C=CC=CC=1>[CH3:19][C:18]1[CH:17]=[CH:16][N:15]=[CH:14][C:13]=1[N:10]1[CH2:11][CH2:12][N:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:7]=2)[C:9]1=[O:20]
Reactant: Cc1ccncc1N1CCN(c2ccnc(Cl)c2)C1=O
Reactant: C1CCNC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: CO
Product: Cc1ccncc1N1CCN(c2ccnc(N3CCCC3)c2)C1=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 40.2 %

Procedure:
1-(2-Chloro-pyridin-4-yl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (58A: 100 mg, 0.3463 mmol) and pyrrolidine (0.145 mL, 1.7317 mmol) were added to toluene previously degassed for 10 minutes. The resulting mixture was stirred for 5 minutes. This was followed by the addition of Pd(OAc)2 (4 mg, 0.01732 mmol), diphenyl-phosphino-propane (14.3 mg, 0.03463 mmol) and potassium tertiary butoxide (66 mg, 0.6926 mmol) and stirring was continued for a further 10 minutes. The reaction mixture was heated to reflux for 16 hours. The reaction was monitored by TLC (10% MeOH in CHC13). The reaction mixture was cooled to room temperature, filtered and the filtrate was concentrated. Purification by column chromatography on silica gel (8% MeOH in chloroform) afforded 45 mg of the product (40% yield).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:11][OH:12])[CH:5]=[CH:4][N:3]=1.[CH3:13][O:14][C:15]1[CH:31]=[CH:30][C:18]([CH2:19][NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[CH:17][CH:16]=1>>[CH3:29][O:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][N:20]([CH2:19][C:18]2[CH:30]=[CH:31][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)[C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:11][OH:12])[CH:5]=[CH:4][N:3]=2)=[CH:27][CH:26]=1
Reactant: O=[N+]([O-])c1c(NO)ccnc1Cl
Reactant: COc1ccc(CNCc2ccc(OC)cc2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nccc(NO)c2[N+](=O)[O-])cc1

Procedure:
In step (2) of Reaction Scheme IV, an N-(2-chloro-3-nitropyridin-4-yl)hydroxylamine of Formula XXXVIII is reacted with bis-(4-methoxybenzyl)amine to provide an N-{2-[bis-(4-methoxybenzyl)amino]-3-nitropyridin-4-yl}hydroxylamine of Formula XXXIX. The reaction can be carried out by adding the bis-(4-methoxybenzyl)amine to a solution of a compound of Formula XXXVIII in a suitable solvent such as toluene in the presence of a base such as triethylamine. The reaction can be carried out at an elevated temperature (about 90° C.).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.S(Cl)(Cl)=O.[C:21]([O:25][C:26]([N:28]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])[CH:35]=2)[C:30]([NH2:45])=[N:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].CCN(C(C)C)C(C)C>C1COCC1.CN(C=O)C.C(Cl)Cl.CO>[C:21]([O:25][C:26]([N:28]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:39])[CH3:40])[CH:35]=2)[C:30]([NH:45][C:12](=[O:14])[C:11]2[CH:10]=[CH:9][C:8]([N:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]3)=[CH:16][CH:15]=2)=[N:29]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CN1CCN(c2ccc(C(=O)O)cc2)CC1
Reactant: CC(C)(C)OC(=O)n1nc(N)c2ccc(O[Si](C)(C)C(C)(C)C)cc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CN1CCN(c2ccc(C(=O)Nc3nn(C(=O)OC(C)(C)C)c4cc(O[Si](C)(C)C(C)(C)C)ccc34)cc2)CC1
Temperature: 50 °C
Reaction time: 5 h
Yield: 66.7 %

Procedure:
To a suspension of 4-(4-methyl-piperazin-1-yl)-benzoic acid (1.64 g, 7.48 mmol) in dry THF (50 ml), under argon atmosphere, at r.t., was added thionyl chloride (1.37 ml, 18.9 mmol) and 3 drops of dry DMF. The reaction mixture was heated to 50° C. and stirred for 5 h then the volatiles were removed under reduced pressure. The residue was taken up in dry toluene (50 ml), re-evaporated and the solid residue dried under high vacuum. The resultant crude 4-(4-methyl-piperazin-1-yl)-benzoyl chloride hydrochloride was suspended in 20 ml of dry THF and treated dropwise at r.t., under argon atmosphere, with a solution of 3-amino-6-(tert-butyl-dimethyl-silanyloxy)-indazole-1-carboxylic acid tert-butyl ester (1.81 g, 4.98 mmol) in 20 ml of dry THF and 2.56 ml of DIPEA (14.96 mmol). The reaction mixture was heated to 50° C. and stirred for 22 h. The volatiles were removed under reduced pressure, the residue diluted with DCM (100 ml) and washed with a saturated solution of NaHCO3 (75 ml). The organic layer was separated, dried over sodium sulfate and evaporated to dryness. The crude residue was purified by flash chromatography over silica gel eluting with DCM/MeOH/30% NH3 95:5:0.5 affording 1.88 g (yield: 67%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]2[C:9]([C:10](C)([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([Br:24])[CH:15]=3)[C:11]=1[C:12]#[N:13])=[CH:8][CH:7]=[C:6]1[N:26](C3CO3)[CH:27]=[CH:28][C:5]=21.[O:32]1[CH2:34][CH:33]1[CH2:35]N1C2C(=C(O)C=CC=2)C=C1.BrC1C(OC)=C(OC)C=C(C=1)C=O.C(#N)CC#N.N1CCCCC1>>[NH2:1][C:2]1[O:3][C:4]2[C:9]([CH:10]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([Br:24])[CH:15]=3)[C:11]=1[C:12]#[N:13])=[CH:8][CH:7]=[C:6]1[N:26]([CH2:35][CH:33]3[CH2:34][O:32]3)[CH:27]=[CH:28][C:5]=21
Reactant: Oc1cccc2c1ccn2CC1CO1
Reactant: COc1cc(C2(C)C(C#N)=C(N)Oc3c2ccc2c3ccn2C2CO2)cc(Br)c1OC
Agent: COc1cc(C=O)cc(Br)c1OC
Solvent: N#CCC#N
Solvent: C1CCNCC1
Product: COc1cc(C2C(C#N)=C(N)Oc3c2ccc2c3ccn2CC2CO2)cc(Br)c1OC

Procedure:
2-Amino-4-(3-bromo-4,5-dimethoxyphenyl)-3-cyano-7-oxiranyl-methyl-4H-pyrrolo[2,3-h]chromene: The title compound was prepared from 1-oxiranylmethyl-4-hydroxy-indole (70 mg, 0.37 mmol), 5-bromoveratraldehyde (91 mg, 0.37 mmol), malononitrile (25 mg, 0.37 mmol) and piperidine (0.01 mL, 0.18 mmol), similar to Example 16, to yield 80 mg (45%) of a white solid. 1H NMR (CDCl3): 7.15 (dd, J=1.5 Hz, 1H), 7.10 (dd, J=2.7 Hz, 1H), 6.92-6.91 (m, 1H), 6.78-6.75 (m, 2H), 6.62 (dd, J=0.9 Hz, 1H), 4.77 (s, 1H), 4.70 (brs, 2H), 4.48-4.43 (m, 1H), 4.15-4.13 (m, 1H), 3.83 (s, 3H), 3.82 (s, 3H), 3.28-3.27 (m, 1H), 2.84-2.81 (m, 1H), 2.48-2.44 (m, 1H).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[Br:16][C:17]1([C:20]([OH:22])=O)[CH2:19][CH2:18]1.O[N:24]1[C:28](=[O:29])[CH2:27][CH2:26][C:25]1=O.NC(CC)CO>C(Cl)Cl>[Br:16][C:17]1([C:20]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][OH:29])=[O:22])[CH2:19][CH2:18]1
Reactant: O=C1CCC(=O)N1O
Reactant: O=C(O)C1(Br)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCC(N)CO
Solvent: ClCCl
Product: O=C(NCCCCO)C1(Br)CC1
Yield: 76 %

Procedure:
7.45 g of N,N′-dicyclohexylcarbodiimide is added at 0° C. under nitrogen to a solution of 5.0 g of 1-bromocyclopropanecarboxylic acid 4 and 4.18 g of N-hydroxysuccinimide in 87 ml of methylene chloride, and it is stirred for 1.5 more hours. Then, 7.46 ml of 2-amino-1-butanol is added, and it is stirred for 2 hours at room temperature. After dilution with methylene chloride, it is filtered, concentrated by evaporation, and the residue is chromatographed on silica gel with ethyl acetate/hexane. 5.44 g of 1-bromo-N-[(1-hydroxymethyl)propyl]-cyclopropane-1-carboxamide 78 is obtained as a yellowish oil.
Reaction SMILES: [CH2:1]([C@H:3]1[C@@H:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][NH:17][C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:6]/[C:5](=[CH:20]/[C:21]([O:23][CH2:24][CH3:25])=[O:22])/[CH2:4]1)[CH3:2]>C1COCC1.[OH-].[OH-].[Pd+2]>[CH2:1]([C@H:3]1[C@@H:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][NH:17][C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:6][C@H:5]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:4]1)[CH3:2]
Reactant: CCOC(=O)/C=C1\C[C@@H](CC)[C@@H](c2nnc3cnc4[nH]ccc4n23)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOC(=O)C[C@@H]1C[C@@H](CC)[C@@H](c2nnc3cnc4[nH]ccc4n23)C1
Reaction time: 72 h
Yield: 30.6 %

Procedure:
To a slurry of 20 wt % Pd(OH)2 on carbon (0.134 g, 0.192 mmol) in THF (20 mL) was added a solution of (E)-ethyl 2-((cis)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylidene)acetate (1.3 g, 3.83 mmol, Example #38, Step G) in THF (5 mL). The reaction mixture was sparged with hydrogen and an atmosphere of hydrogen was maintained via balloon. After about 3 days, the reaction mixture was filtered through Celite®, concd under reduced pressure and purified by flash chromatography on silica gel eluting with EtOAc to afford a dark brown/black solid. The compound was further by purified by chiral chromatography (Table 2, Method 47) to afford ethyl 2-((1R,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)acetate [W.1.1](Rt=12.0 min, or =negative) (0.400 g, 31%): LC/MS (Table 1, Method a) Rt=1.85 min; MS m/z: 342 (M+H)+ and ethyl 2-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)acetate [W.1.2](Rt=13.7 min, or =negative) (0.420 g, 32%) as a white solid: LC/MS (Table 1, Method a) Rt=1.85 min; MS m/z: 342 (M+H)+.
Reaction SMILES: F[C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:16])[C:8]3[N:9]2[C:12](=[O:15])[NH:13][N:14]=3)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].[CH:20]([C:23]1[NH:24][CH:25]=[CH:26][N:27]=1)([CH3:22])[CH3:21]>>[CH:20]([C:23]1[N:24]([C:2]2[CH:11]=[C:10]3[C:5]([NH:6][C:7](=[O:16])[C:8]4[N:9]3[C:12](=[O:15])[NH:13][N:14]=4)=[CH:4][C:3]=2[N+:17]([O-:19])=[O:18])[CH:25]=[CH:26][N:27]=1)([CH3:22])[CH3:21]
Reactant: CC(C)c1ncc[nH]1
Reactant: O=c1[nH]c2cc([N+](=O)[O-])c(F)cc2n2c(=O)[nH]nc12
Product: CC(C)c1nccn1-c1cc2c(cc1[N+](=O)[O-])[nH]c(=O)c1n[nH]c(=O)n12

Procedure:
The title compound was prepared from 8-fluoro-7-nitro[1,2,4]triazolo[4,3-a]quinoxaline-1,4(2H,5H)-dione and 2-isopropylimidazole by a method analogous to the method described in example 11. M.p. 240° C. decomp.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12](O)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH3:63][N:64]([CH2:66][CH:67]1[CH2:72][CH2:71][CH2:70][NH:69][CH2:68]1)[CH3:65]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:69]1[CH2:70][CH2:71][CH2:72][CH:67]([CH2:66][N:64]([CH3:65])[CH3:63])[CH2:68]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Reactant: CN(C)CC1CCCNC1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2cc(C(=O)N3CCCC(CN(C)C)C3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and 3-(dimethylamino-methyl)-piperidine.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:11]([O:22][CH3:23])=[CH:12][C:13]2[O:18][C:17](=[O:19])[CH:16]=[C:15]([CH3:20])[C:14]=2[CH:21]=1)(=O)=O.[C:24]1([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(O)(C)C.C([O-])(=O)/C=C/C([O-])=O>CC(C)=O.C(O)C>[CH3:23][O:22][C:11]1[C:10]([O:9][CH2:8][CH2:7][CH2:6][N:33]2[CH2:34][CH2:35][N:30]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:31][CH2:32]2)=[CH:21][C:14]2[C:15]([CH3:20])=[CH:16][C:17](=[O:19])[O:18][C:13]=2[CH:12]=1
Reactant: COc1cc2oc(=O)cc(C)c2cc1OCCCOS(C)(=O)=O
Reactant: c1ccc(N2CCNCC2)cc1
Agent: O=C([O-])/C=C/C(=O)[O-]
Solvent: CC(C)=O
Solvent: CCO
Solvent: CC(C)O
Product: COc1cc2oc(=O)cc(C)c2cc1OCCCN1CCN(c2ccccc2)CC1
Yield: 77 %

Procedure:
Method B (32 h at 50° C.); starting materials: 6-[3-(methanesulfonyloxy)propoxy]-7-methoxy-4-methyl-2H-1-benzopyran-2-one (example 74) and 1-phenylpiperazine; yield 77%; fusion point 137°-140° C. (from isopropanol and ethanol). Fumarate: method E; yield 79%; fusion point 195°-200° C. (from ethanol and acetone).
Reaction SMILES: [Sn](Cl)Cl.[N+:4]([C:7]1[CH:8]=[C:9]([CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=1)[C:10]([O:12][CH3:13])=[O:11])([O-])=O>C(O)C>[NH2:4][C:7]1[CH:8]=[C:9]([CH:14]=[C:15]([C:17]([F:18])([F:19])[F:20])[CH:16]=1)[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Agent: Cl[Sn]Cl
Solvent: CCO
Product: COC(=O)c1cc(N)cc(C(F)(F)F)c1
Temperature: 60 °C
Yield: 56.6 %

Procedure:
Tin (II) chloride (60 g) was added to a solution of methyl 3-nitro-5-(trifluoromethyl)benzoate (25 g, 100 mmol) in ethanol (600 ml) and the mixture was heated to 60° C. for 2 hours. The mixture was cooled and concentrated under reduced pressure to approximately one third volume. The mixture was added slowly to saturated aqueous sodium hydrogen carbonate (1000 ml) and the resulting mixture was filtered through celite. The filter cake was washed with ethyl acetate (500 ml). The organic layer was dried (MgSO4) and the solvent was evaporated under reduced pressure to give methyl 3-amino-5-(trifluoromethyl)benzoate as an orange solid (12.4 g), 1H NMR (360 MHz,CDCl3) δ 3.95 (3H, s), 7.08 (1H, br s), 7.51 (1H, s), and 7.66 (1H, s).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10](OC)=[O:11])=[N:8][CH:9]=1)([O-:3])=[O:2].CC(C[AlH]CC(C)C)C.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C(Cl)Cl.O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]=[O:11])=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: COC(=O)c1ccc([N+](=O)[O-])cn1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: O=Cc1ccc([N+](=O)[O-])cn1
Temperature: -78 °C
Yield: 59.7 %

Procedure:
To a suspension of methyl 5-nitropicolinate (LIX) (1.282 g, 7.03 mmol) in DCM (25 mL) stirred at −78° C. under argon was slowly added DIBAL (1M in toluene) (9.14 mL, 9.14 mmol). The solution was allowed to warm to room temperature over 3 h. An aqueous solution of potassium sodium tartrate was added, diluted further with water and DCM. The solution was stirred at room temperature for another 30 min before the organic layer was separated. The aqueous layer was extracted 2×DCM, combined with the organic layer, dried over MgSO4, filtered and evaporated under reduced pressure. The residue was purified by column chromatography to produce 5-nitropicolinaldehyde (LX) as a brown oil (0.64 g, 4.2 mmol, 60% yield). 1H NMR (DMSO-d6) δ ppm 8.17 (d, J=9 Hz, 1H), 8.81 (dd, J=9 Hz, J=2 Hz, 1H), 9.56 (d, J=2 Hz, 1H), 10.08 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:28][CH2:29][N:30]3[C@H:35]4[CH2:36][CH2:37][C@@H:31]3[CH2:32][CH:33]([N:38]3[C:42]5[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=5[N:40]=[C:39]3[CH3:47])[CH2:34]4)[CH2:13][CH2:12][N:11]([C:14]([C@@H:16]3[CH2:20][CH2:19][CH2:18][N:17]3C(OC(C)(C)C)=O)=[O:15])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Cl>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:28][CH2:29][N:30]3[C@H:35]4[CH2:36][CH2:37][C@@H:31]3[CH2:32][CH:33]([N:38]3[C:42]5[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=5[N:40]=[C:39]3[CH3:47])[CH2:34]4)[CH2:13][CH2:12][N:11]([C:14](=[O:15])[C@@H:16]3[CH2:20][CH2:19][CH2:18][NH:17]3)[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCN(C(=O)[C@@H]2CCCN2C(=O)OC(C)(C)C)CC1
Agent: Cl
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCN(C(=O)[C@@H]2CCCN2)CC1
Yield: 99.2 %

Procedure:
1-((1R,5S)-8-{2-[1-[1-(dichloroacetyl)-L-prolyl]-4-(3-fluorophenyl)-4-piperidinyl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole was obtained from treating 1,1-dimethylethyl (2S)-2-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]-1-pyrrolidinecarboxylate (0.645 g, 1.01 mmol) with HCl as outlined in the procedure for Example 890 to form 1-((1R,5S)-8-{2-[4-(3-fluorophenyl)-1-L-prolyl-4-piperidinyl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole (0.545 g, 99%). 1-((1R,5S)-8-{2-[4-(3-fluorophenyl)-1-L-prolyl-4-piperidinyl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole (0.050 g, 0.09 mmol), Dichloro-acetyl chloride (0.013 g, 0.09 mmol) and DIEA (0.034 g, 0.534 mmol) were reacted following the procedure outlined in Example 890 to give the title compound, 1-((1R,5S)-8-{2-[1-[1-(dichloroacetyl)-L-prolyl]-4-(3-fluorophenyl)-4-piperidinyl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole (0.029 g, 49%) as an oil. ES-LCMS m/z 654 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][N:6]=[C:5]([N:11]2[C:16](=[O:17])[NH:15][C:14]3[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=3[S:12]2(=[O:23])=[O:22])[N:4]=1.[F:24][C:25]1[CH:32]=[C:31]([F:33])[CH:30]=[C:29]([F:34])[C:26]=1[CH2:27]Br.C([O-])([O-])=O.[K+].[K+].COC1C(C)=CC(N2C(=O)N(CC3C(F)=CC(F)=CC=3F)C3C=CC=CC=3S2(=O)=O)=CC=1C>CN(C=O)C>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][N:6]=[C:5]([N:11]2[C:16](=[O:17])[N:15]([CH2:27][C:26]3[C:25]([F:24])=[CH:32][C:31]([F:33])=[CH:30][C:29]=3[F:34])[C:14]3[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=3[S:12]2(=[O:23])=[O:22])[N:4]=1
Reactant: Fc1cc(F)c(CBr)c(F)c1
Reactant: COc1cnc(N2C(=O)Nc3ccccc3S2(=O)=O)nc1OC
Agent: COc1c(C)cc(N2C(=O)N(Cc3c(F)cc(F)cc3F)c3ccccc3S2(=O)=O)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cnc(N2C(=O)N(Cc3c(F)cc(F)cc3F)c3ccccc3S2(=O)=O)nc1OC
Yield: 13.3 %

Procedure:
The title compound was prepared from 2-(4,5-dimethoxypyrimidin-2-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide (IntA32) (50 mg, 0.15 mmol), 2,4,6-trifluorobenzyl bromide (41 mg, 0.18 mmol) and K2CO3 (62 mg, 0.45 mmol) in DMF (1.5 mL) using the methods of (115). After purification by gradient column chromatography further purification by preparative HPLC (method C) yielded the title compound (8 mg, 0.02 mmol).