Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH3:11])[N:5]=[C:4]([N:12]2[CH2:17][CH2:16][S:15][CH2:14][CH2:13]2)[N:3]=1.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.O>C(O)C>[C:8]([C:7]1[C:2]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[N:3][C:4]([N:12]2[CH2:17][CH2:16][S:15][CH2:14][CH2:13]2)=[N:5][C:6]=1[O:10][CH3:11])#[N:9]
Reactant: C1CNCCN1
Reactant: COc1nc(N2CCSCC2)nc(Cl)c1C#N
Solvent: CCO
Solvent: O
Product: COc1nc(N2CCSCC2)nc(N2CCNCC2)c1C#N
Temperature: 130 °C

Procedure:
18 gm (0.067 mol) of 4-chloro-5-cyano-6-methoxy-2-thiomorpholino-pyrimidine (m.p. 218°-219°C) were admixed with 60.3 gm (0.7 mol) of piperazine, and the mixture was heated at 130°C for 3 hours. After cooling, water was added, and the aqueous mixture was extracted with chloroform. The chloroform phase was dried, and the chloroform was removed in vacuo. The residue, the free base reaction product, was dissolved in hot ethanol, and the hydrochloride was precipitated by addition of ethanolic hydrochloric acid, suction-filtered off and washed with ethanol. Yield: 13 gm (54.8% of theory); m.p. 261°C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30](Cl)=[O:31])[C@H:13]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:33][CH:34]([CH3:36])[CH3:35])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:37][N:38]([CH3:48])[C:39](=[O:47])[CH2:40][N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1>>[ClH:22].[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30]([N:44]3[CH2:43][CH2:42][N:41]([CH2:40][C:39]([N:38]([CH3:48])[CH3:37])=[O:47])[CH2:46][CH2:45]3)=[O:31])[C@H:13]([C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[C@H:14]([C:16]3[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=3)[N:15]=2)=[C:7]([O:33][CH:34]([CH3:36])[CH3:35])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C(=O)CN1CCNCC1
Reactant: CC(C)Oc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Product: CC(C)Oc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N(C)C)CC1
Product: Cl

Procedure:
2-{4-[(4S,5R)-2-(4-tert-Butyl-2-isopropoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-N,N-dimethyl-acetamide hydrochloride was prepared from (4S,5R)-2-(4-tert-butyl-2-isopropoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 12i) and N,N-dimethyl-2-piperazin-1-yl-acetamide (Oakwood Products) in an analogous manner as described in example 25. LR-MS: 678.5 [(M+H)+]
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:14]=[C:15]3[CH2:21][C:20](=O)[N:19](COCC[Si](C)(C)C)[C:16]3=[N:17][CH:18]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[C:31](=[O:34])([O-])[O-].[Cs+].[Cs+].[CH3:37]I>CN(C=O)C>[CH3:20][C:21]1([CH3:37])[C:15]2[C:16](=[N:17][CH:18]=[C:13]([C:5]3[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:14]=2)[NH:19][C:31]1=[O:34]
Reactant: CI
Reactant: O=C([O-])[O-]
Reactant: COc1cc(-c2cnc3c(c2)CC(=O)N3COCC[Si](C)(C)C)cc(OC)c1OC
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cc(-c2cnc3c(c2)C(C)(C)C(=O)N3)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 73.1 %

Procedure:
To a solution of 5-(3,4,5-trimethoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)-methyl)-1H-pyrrolo[2,3-b]pyridin-2(3H)-one (43 mg, 0.10 mmol) in DMF (2 mL) was added cesium carbonate (0.17 g, 0.50 mmol) and methyl iodide (19 μL 0.30 mmol). The resulting solution was stirred for 48 hr at room temperature, after which it was partitioned between EtOAc and H2O. The organic layer was separated, dried over MgSO4, filtered, and concentrated in vacuo. The residue was dissolved in 6 N HCl (10 mL) and MeOH (5 mL), and the resulting mixture was stirred at room temperature overnight, after which it was partitioned between EtOAc and H2O. The organic layer was concentrated in vacuo, and the residue was dissolved in EtOH (2 mL). Potassium acetate (100 mg) was then added, and the reaction was stirred for 2 hr. The resulting solution was purified via preparatory HPLC to give the title compound (24 mg, 73%). 1H NMR (CDCl3, 300 MHz): δ 9.72 (s, 1H), 8.35 (d, J=2.1 Hz, 1H), 7.60 (d, J=1.8 Hz, 1H), 6.71 (s, 2H), 3.95 (s, 6H), 3.90 (s, 3H), 1.49 (s, 6H). HPLC retention time: 1.80 minutes; MS ESI (m/z): 329.4 (M+1)+, calc. 328.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH:10]([CH:11]=[CH2:12])[O:9][CH:8]=[N:7]1)=[O:5])[CH3:2].[OH2:13].C(N(CC)CC)C>O1CCCC1.ClCCl>[CH2:1]([O:3][C:4](=[O:5])[CH:6]([NH:7][CH:8]=[O:13])[CH:10]([OH:9])[CH:11]=[CH2:12])[CH3:2]
Reactant: C=CC1OC=NC1C(=O)OCC
Reactant: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: C=CC(O)C(NC=O)C(=O)OCC
Reaction time: 62 h

Procedure:
128 g of the 5-vinyl-2-oxazoline-4-carboxylic acid ethyl ester are dissolved in 70 ml of tetrahydrofuran, and 27.4 g of water and 3.5 g of triethylamine are added. The reaction mixture is stirred for 62 hours at 65°-70° and, having been cooled, is taken up in 200 ml of dichloromethane. The solution is dried over 200 g of magnesium sulphate, filtered and concentrated by evaporation in vacuo. Purification by column chromatography (silica gel;hexane/ethyl acetate 3:2) of the viscous oil that remains yields 2-formylamino-3-hydroxy-4-pentenoic acid ethyl ester in the form of a diastereoisomeric mixture, m.p. 50°-51°.
Reaction SMILES: [CH3:1][C:2](=[CH2:4])[CH3:3].[OH:5][C:6]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[OH:21])[CH2:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.O>C(Cl)(Cl)Cl.S(=O)(=O)(O)O>[C:2]([C:7]1[CH:8]=[CH:9][C:10]2[CH2:11][C:12]3[C:17](=[C:16]([OH:21])[CH:15]=[CH:14][CH:13]=3)[C:18](=[O:20])[C:19]=2[C:6]=1[OH:5])([CH3:3])([CH3:1])[CH3:4]
Reactant: C=C(C)C
Reactant: O=C1c2c(O)cccc2Cc2cccc(O)c21
Agent: O=S(=O)(O)O
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1ccc2c(c1O)C(=O)c1c(O)cccc1C2
Yield: 27.7 %

Procedure:
About 7 gm of isobutylene were introduced into a refluxing solution of 11.3 gm of 1,8-dihydroxy-9-(10H)anthracenone in 100 ml of chloroform and 6 ml of sulfuric acid. The resulting mixture was poured into water, and the organic phase was separated and worked up as described in Example 2. 3.9 gm of 2-tert. butyl-1,8-dihydroxy-9-(10H)anthracenone, m.p. 126°-127° C., corresponding to 27% of theory, were obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=C([CH:7]=[CH:8][C:9]=1[CH:10]1[CH2:13][O:12][CH2:11]1)C#N.[OH-:14].[Na+].[CH2:16]([OH:18])[CH3:17]>>[CH3:1][C:2]1[CH:3]=[C:17]([CH:7]=[CH:8][C:9]=1[CH:10]1[CH2:13][O:12][CH2:11]1)[C:16]([OH:14])=[O:18]
Reactant: CCO
Reactant: Cc1cc(C#N)ccc1C1COC1
Reactant: [OH-]
Agent: [Na+]
Product: Cc1cc(C(=O)O)ccc1C1COC1
Reaction time: 1 h
Yield: 14 %

Procedure:
To 3-methyl-4-(oxetan-3-yl)benzonitrile (500 mg, 2.89 mmol) in ethanol (7.5 mL) was added NaOH (3.0 mL of 5 M, 15 mmol) and the mixture immersed in a 85° C. oil bath. The mixture was heated and stirred for 1 h, concentrated, then diluted with ethyl acetate (20 mL). 6N HCl (˜3 mL) was added to adjust pH to 6. The aqueous layer was extracted with ethyl acetate (2×20 mL), then the combined organics washed with brine (10 mL), dried over MgSO4 and concentrated to give a white solid, which was triturated with ether to give a mixture (2:3 by NMR) of acid 3-methyl-4-(oxetan-3-yl)benzoic acid (500 mg, 14%) and amide. ESI-MS m/z calc. 192.2, found 193.3 (M+1)+; Retention time: 0.87 minutes (3 min run).
Reaction SMILES: [S:1]([N:11]1[C:15]2[N:16]=[CH:17][C:18]3[N:19]([CH:20]=[N:21][C:22]=3[C:23]3[CH:28]=[CH:27][C:26]([C:29]([OH:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=3)[C:14]=2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].C1C(=O)N([Br:40])C(=O)C1>CN(C=O)C.O>[Br:40][C:20]1[N:19]2[C:14]3[CH:13]=[CH:12][N:11]([S:1]([C:4]4[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=4)(=[O:2])=[O:3])[C:15]=3[N:16]=[CH:17][C:18]2=[C:22]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([OH:32])([CH3:30])[CH3:31])=[CH:25][CH:24]=2)[N:21]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2c(-c4ccc(C(C)(C)O)cc4)ncn23)cc1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2c(-c4ccc(C(C)(C)O)cc4)nc(Br)n23)cc1
Reaction time: 0.25 h
Yield: 85 %

Procedure:
2-(4-(6-Tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-3-yl)phenyl)propan-2-ol (0.285 g, 0.638 mmol, prepared using J.3 from Example #2, Step B with ethyl formate, L.2 with POCl3, AB and D with Preparation #H.1) was dissolved in DMF (3 mL) then treated with NBS (0.114 g, 0.638 mmol). The mixture was stirred for about 15 min then diluted with water (20 mL). The solid was collected by filtration then washed with water (5 mL). The material was dried under vacuum at about 70° C. to a constant weight to give 2-(4-(1-bromo-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-3-yl)phenyl)propan-2-ol (0.285 g, 85%): LC/MS (Table 2, Method b) Rt=2.58 min; MS m/z 527 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][SH:6].[H-].[Na+].Cl[C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[CH:12][CH:11]=1>CN(C=O)C.CCOCC>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][S:6][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[CH:12][CH:11]=1
Reactant: OCCCCS
Reactant: CC(=O)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(SCCCCO)cc1
Temperature: 110 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 4-hydroxybutanethiol (5.0 g, 47 mmol) in DMF (100 mL) was added NaH (60% dispersion in mineral oil, 2.1 g). After the effervescence had ceased, p-chloroacetophenone (4.3 mL, 33 mmol) was added. The solution was then stirred at 110° C. for 3 h. The mixture was cooled to RT and then diluted with ether (200 mL). The ethereal suspension was washed with 5% HCl (aq, 2×100 mL), water (100 mL), and then brine (50 mL). The ether extract was dried (MgSO4), filtered and concentrated to afford crude 1-[4-(4-hydroxybutylsulfanyl)phenyl]ethanone, which was used without purification. 1-[4-(4-hydroxybutylsulfanyl)phenyl]ethanone was taken up in dimethylformamide dimethylacetal (100 mL) and stirred at reflux for 12 h. The mixture was cooled and then concentrated to about one half of the original volume. Hexane was added to precipitate 3-Dimethylamino-1-[4-(4-hydroxybutylsulfanyl)phenyl]propenone. The mixture was filtered, washed with hexanes (50 mL), and dried to afford 3-Dimethylamino-1-[4-(4-hydroxy-butylsulfanyl)phenyl]propenone (6.4 g, 23 mmol): HPLC Retention Time; 5.58 min. (Method B) M+1; 279.8.
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([S:16][C:17](=S)OCC)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-:22].[K+].[Cl-].[NH4+]>C(O)C.O>[N:1]1([S:7]([C:10]2[CH:11]=[CH:12][C:13]([S:16][CH2:17][C:2](=[O:22])[CH2:3][CH2:4][CH2:5][CH3:6])=[CH:14][CH:15]=2)(=[O:8])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=S)Sc1ccc(S(=O)(=O)N2CCCCC2)cc1
Reactant: [OH-]
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CCCCC(=O)CSc1ccc(S(=O)(=O)N2CCCCC2)cc1
Temperature: 111 °C

Procedure:
Dithiocarbonic acid O-ethyl ester S-[4-(piperidine-1-sulfonyl)-phenyl]ester (1.24 g, 3.6 mmol) in ethanol (5 mL) and water (0.5 mL) was heated to 60° C. to form a solution. The flask was removed from the oil bath and KOH (561 mg, 10 mmol) added portionwise (exothermic reaction). The mixture was heated to 111° C. for one hour and 33 was added (553 mg, 4.13 mmol)The reaction mixture was then heated to 110° C. for 3 hours. The mixture was allowed to cool to r.t. and a saturated aqueous solution of ammonium chloride added (20 mL). The aqueous phase was extracted with EtOAc, the combined organics dried, and the solvent evaporated in vacuo. The resultant crude product 35 was taken on without purification. Mass Spectrum m/e=356.0 (M+1)
Reaction SMILES: [CH2:1]([C:5]1[C:14]([CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[C:13]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:31]3[S:32][CH:33]=[C:34]([C:36](N(OC)C)=[O:37])[N:35]=3)[CH:11]=2)[N:6]=1)[CH:2]([CH3:4])[CH3:3].[CH3:42][Mg]Br.O>O1CCCC1>[C:36]([C:34]1[N:35]=[C:31]([C:10]2[CH:11]=[C:12]3[C:7](=[CH:8][CH:9]=2)[N:6]=[C:5]([CH2:1][CH:2]([CH3:3])[CH3:4])[C:14]([CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[C:13]3[C:24]2[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=2)[S:32][CH:33]=1)(=[O:37])[CH3:42]
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1csc(-c2ccc3nc(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c4ccc(C)cc4)c3c2)n1
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1csc(-c2ccc3nc(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c4ccc(C)cc4)c3c2)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.4 %

Procedure:
To a suspension of tert-butyl {[2-isobutyl-6-(4-{[methoxy(methyl)amino]carbonyl}-1,3-thiazol-2-yl)-4-(4-methylphenyl)quinolin-3-yl]methyl}carbamate (0.23 g, 0.4 mmol) in tetrahydrofuran (10 ml) was added dropwise 3.0 M methylmagnesium bromide (0.4 ml, 1.2 mmol) at 0° C. After the completion of the dropwise addition, the mixture was stirred at 0° C. for 1 hr. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give tert-butyl [6-(4-acetyl-1,3-thiazol-2-yl)-2-isobutyl-4-(4-methylphenyl)-3-quinolinyl]methylcarbamate (0.20 g, yield 95%) as white crystals.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#N)[C:3]=1S(C(F)(F)F)=O.S(=O)(=O)(O)[OH:28].[OH-:32].[Na+]>>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]([OH:28])=[O:32])[CH:3]=1
Reactant: [OH-]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(=O)C(F)(F)F
Reactant: O=S(=O)(O)O
Agent: [Na+]
Product: Nc1cc(C(=O)O)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 135 °C
Yield: 77 %

Procedure:
A stirred mixture of 5-amino-1 -(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylsulfinyl-1 H-pyrazole-3-carbonitrile (5.00 g, 11.4 mmol) and sulfuric acid (50%, 100 ml) was heated to 135° C. for 3 hours. The cooled mixture was added to ice water and the pH adjusted to 4 by the addition of aqueous sodium hydroxide (6 N, approx. 230 ml), and then extracted with ethyl acetate. The organic phase was dried over magnesium sulfate, evaporated to dryness and purified by flash chomatography (silica, chloroform/ethanol) with subsequently trituration with tetrachloromethane to give the title compound (3.00 g, yield 77%) as off-white crystals, mp 213° C., 1H NMR (DMSO-d6): 5.69 (bs, 2H, NH2), 5.76 (s, 1H, pyrazole-H), and 8.20 (s, 2H, Ar—H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([OH:11])=[C:4]([CH3:10])[C:5]([CH3:9])=[C:6]([CH:8]=1)[OH:7].B(F)(F)F.[Cl:16][CH2:17][C:18]([CH3:22])(O)[CH:19]=[CH2:20]>ClC1C=CC=CC=1.CCCCCC.C(OCC)C>[Cl:16][CH2:17][C:18]([CH3:22])=[CH:19][CH2:20][C:8]1[C:2]([CH3:1])=[C:3]([OH:11])[C:4]([CH3:10])=[C:5]([CH3:9])[C:6]=1[OH:7]
Reactant: C=CC(C)(O)CCl
Reactant: Cc1cc(O)c(C)c(C)c1O
Agent: FB(F)F
Solvent: CCCCCC
Solvent: Clc1ccccc1
Solvent: CCOCC
Product: CC(=CCc1c(C)c(O)c(C)c(C)c1O)CCl
Reaction time: 0.5 h
Yield: 44 %

Procedure:
Trimethylhydroquinone (2.00 g, 14 mol) was suspended at room temperature in a mixture of chlorobenzene (10 ml) and hexane (5 ml). Boron trifluoride diethyl ether complex (3.60 ml of a 48 percent strength solution of boron trifluoride in diethyl ether, 1.95 g of boron trifluoride, 28 mmol) was then added in the course of 15 min. 1-Chloro-2-methylbut-3-en-2-ol (2.42 g, 20 mmol) was then added dropwise in the course of 15 min. After 30 min.,, the reaction mixture was filtered, and the filtrate was washed with chlorobenzene (10 mol) and dried at 40° C./20 mbar for 8 hours. 2.24 g (62.9 percent) of 2-(1-chloro-2-methylbut-2-en-4-yl)-1,4-dihydroxy-3,5,6-trimethylbenzene were obtained. The melting point of the product was 118° to 122° C. (decomposition). Other data regarding the product was:
Reaction SMILES: Cl[CH2:2]/[CH:3]=[C:4]1/[C:5]2[CH:18]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[CH:16]=[CH:15][C:6]=2[O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]/1=2.[N:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[NH:25][CH:24]=1.N1C2C(=CC=CC=2)C=C1>>[N:25]1([CH2:2]/[CH:3]=[C:4]2/[C:5]3[CH:18]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[CH:16]=[CH:15][C:6]=3[O:7][CH2:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]/2=3)[C:24]2[C:30](=[CH:29][CH:28]=[CH:27][N:23]=2)[CH:31]=[CH:26]1
Reactant: COC(=O)c1ccc2c(c1)/C(=C/CCl)c1ccccc1CO2
Reactant: c1ccc2[nH]cnc2c1
Agent: c1ccc2[nH]ccc2c1
Product: COC(=O)c1ccc2c(c1)/C(=C/Cn1ccc3cccnc31)c1ccccc1CO2

Procedure:
In Examples 40 through 49, the products were prepared in a manner similar to Example 23, using Compound h and the corresponding benzimidazole or indole derivatives.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4](O)[CH:3]=1.[C:13](=[O:16])([O-])[O-].[K+].[K+].S(OC)(O[CH3:23])(=O)=O.[OH-].[Na+]>CC(C)=O>[CH3:23][O:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([O:16][CH3:13])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: COS(=O)(=O)OC
Reactant: Oc1cc(O)c2ccccc2c1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: COc1cc(OC)c2ccccc2c1
Yield: 85.1 %

Procedure:
To 1,3-Dihydroxynaphthalene (15 g, 93.6 mmol) and potassium carbonate (20 g, 144.7 mmol) in acetone (200 ml) was added dimethyl sulfate (21 ml, 222 mmol). After stirring over-night the reaction mixture was mixed with 10% sodium hydroxide (100 ml) and extracted with ethyl acetate (200 ml×2) The organic layer was washed with water (100 ml×2), evaporated, and the residue stirred with ammonium hydroxide (50 ml) for 2 hrs to quench any unreacted dimethyl sulfate. Product was extracted with ethyl acetate (200 ml) and was washed with water (100 ml×2) and brine (100 ml). The solvent was evaporated yielding 15 g (85%) of 6.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([C:10]([OH:12])=O)=[CH:7][C:6]=2[CH:13]=1.[ClH:14].Cl.[NH2:16][C@@H:17]1[CH:22]2[CH2:23][CH2:24][N:19]([CH2:20][CH2:21]2)[CH2:18]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[ClH:14].[N:19]12[CH2:24][CH2:23][CH:22]([CH2:21][CH2:20]1)[C@@H:17]([NH:16][C:10]([C:8]1[S:9][C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:13][C:6]=3[CH:7]=1)=[O:12])[CH2:18]2
Reactant: N[C@H]1CN2CCC1CC2
Reactant: O=C(O)c1cc2cc(Br)ccc2s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2cc(Br)ccc2s1

Procedure:
133.7 mg (0.52 mmol) of 5-bromo-1-benzothiophene-2-carboxylic acid (Example 13A), 155.4 mg (0.78 mmol) of (R)-3-aminoquinuclidine dihydrochloride, 296.7 mg (0.78 mmol) of HATU, 369.8 mg (2.86 mmol) of N,N-diisopropylethylamine and 1.5 ml of DMF are reacted by general method C. The reaction mixture is purified by preparative HPLC. The product is dissolved in acetonitrile, and an excess of 1N hydrochloric acid is added. Finally, the solvent is removed. 175 mg (84% of theory) of the title compound are isolated.
Reaction SMILES: [C@H:1]1([C:9]([OH:11])=O)[C:3]2([CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2)[CH2:2]1.C1(C(O)=O)C2(CCCCC2)C1.[NH2:23][CH2:24][C@@H:25]([OH:27])[CH3:26].Cl.NCC(N)=O>>[OH:27][C@@H:25]([CH3:26])[CH2:24][NH:23][C:9]([C@H:1]1[C:3]2([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:2]1)=[O:11]
Reactant: O=C(O)[C@@H]1CC12CCCCC2
Reactant: C[C@H](O)CN
Agent: Cl
Agent: NCC(N)=O
Agent: O=C(O)C1CC12CCCCC2
Product: C[C@H](O)CNC(=O)[C@@H]1CC12CCCCC2

Procedure:
The title compound was prepared as described in Example 3 substituting the product from Example 9 for the product from Example 1B and substituting (S)-1-amino-2-propanol, purchased from Aldrich, for 2-aminoacetamide hydrochloride. 1H NMR (400 MHz, CD3OD) δ 3.80 (m, 1H), 3.16 (m, 2H), 1.20-1.70 (m, 11H), 1.13 (d, 3H), 1.02 (dd, 1H), 0.69 (dd, 1H); MS (CI) m/z 212 (M+H)+.
Reaction SMILES: [F-:1].[K+].I([C:6]1[CH:7]=[C:8]([CH:23]=[CH:24][C:25]=1[N+:26]([O-:28])=[O:27])[C:9]([NH:11][CH2:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])=[O:10])(=O)=O.C1OCCOCCOCCOCCOCCOC1.C(#N)C>CCOC(C)=O>[F:1][C:6]1[CH:7]=[C:8]([CH:23]=[CH:24][C:25]=1[N+:26]([O-:28])=[O:27])[C:9]([NH:11][CH2:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])=[O:10]
Reactant: [F-]
Reactant: O=C(CNC(=O)c1ccc([N+](=O)[O-])c(I(=O)=O)c1)OCc1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C(CNC(=O)c1ccc([N+](=O)[O-])c(F)c1)OCc1ccccc1
Yield: 61 %

Procedure:
A mixture of spray-dried KF (614 mg, 10.59 mmol), intermediate 7 (1 g, 2.12 mmol), 18-crown-6 (40 mg) and dry acetonitrile (20 mL) was refluxed for 40 min. After completion of reaction (TLC), the mixture was diluted with EtOAc (75 mL). The solution was successively washed with water (50 mL) and brine (50 mL) and dried over anhyd Na2SO4. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel column using chloroform:hexane (75:25) as eluents to give the product as a colorless solid (430 mg, 61%), mp 118-120° C. 1H NMR (400 MHz, CDCl3): δ 8.13 (1H, t, J=7.8 Hz), 7.75 (1H, d, J=10.8 Hz), 7.68 (1H, d, J=8.0 Hz), 7.38 (5H, br s), 6.68 (1H, br s), 5.25 (2H, s), 4.29 (2H, d, J=4.8 Hz); LC-MS negative ion mode): m/z 331 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[C:6]([NH2:8])[CH:7]=1.[F:17][C:18]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:19]=1[C:20]([NH:22][C:23]1[C:24]([C:28](O)=[O:29])=[N:25][NH:26][CH:27]=1)=[O:21].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[C:6]([NH:8][C:28]([C:24]2[C:23]([NH:22][C:20](=[O:21])[C:19]3[C:18]([F:17])=[CH:34][CH:33]=[CH:32][C:31]=3[F:35])=[CH:27][NH:26][N:25]=2)=[O:29])[CH:7]=1
Reactant: O=C(O)c1n[nH]cc1NC(=O)c1c(F)cccc1F
Reactant: CN1CCC(Oc2ccc(F)cc2N)CC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CN1CCC(Oc2ccc(F)cc2NC(=O)c2n[nH]cc2NC(=O)c2c(F)cccc2F)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
5-fluoro-2-(1-methyl-piperidin-4-yloxy)-phenylamine) (0.049 g, 0.22 mmol) was combined with 4-(2,6-difluoro-benzoylamino)-1H-pyrazole-3-carboxylic acid (0.053 g, 0.20 mmol), EDC (0.048 g, 0.25 mmol), HOBt (0.034 g, 0.25 mmol) and DMF (1 ml) and the resulting reaction mixture was stirred at ambient temperature for 18 hours. The reaction mixture was reduced in vacuo and purified by preparative LC/MS to give 4-(2,6-Difluoro-benzoylamino)-1H-pyrazole-3-carboxylic acid[5-fluoro-2-(1-methyl-piperidin-4-yloxy)-phenyl]amide as a buff solid. (0.010 g, 11%) (LC/MS: Rt 2.19, [M+H]+ 474.27).
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:21])[NH:8][C:9]1([C:12](=[O:20])[NH:13][C:14]2([C:17](=[NH:19])[NH2:18])[CH2:16][CH2:15]2)[CH2:11][CH2:10]1)([CH3:5])([CH3:4])[CH3:3].CN(C)[CH:24]=[C:25]([I:28])[CH:26]=O.CNC.C1COCC1>CCO.CCOCC>[C:2]([O:6][C:7](=[O:21])[NH:8][C:9]1([C:12](=[O:20])[NH:13][C:14]2([C:17]3[N:18]=[CH:26][C:25]([I:28])=[CH:24][N:19]=3)[CH2:16][CH2:15]2)[CH2:10][CH2:11]1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CN(C)C=C(I)C=O
Reactant: CC(C)(C)OC(=O)NC1(C(=O)NC2(C(=N)N)CC2)CC1
Agent: CNC
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1(C(=O)NC2(c3ncc(I)cn3)CC2)CC1
Temperature: 70 °C
Reaction time: 18 h
Yield: 18.4 %

Procedure:
To a solution of [1-(1-carbamimidoyl-cyclopropylcarbamoyl)-cyclopropyl]-carbamic acid tert-butyl ester hydrochloride (1.65 g, 5.2 mmol) in anhydrous EtOH (21 mL), was added 3-dimethylamino-2-iodo-propenal (1.3 g, 5.63 mmol) and 2M dimethylamine in THF (3.36 mL, 6.7 mmol). The vessel was capped and heated at 70° C. overnight. After 18 h, EtOH was removed in-vacuo and the dark orange residue was triturated with 5% iPrOH in EtOAc. A yellow solid was filtered off. The filtrate was concentrated in vacuo and purified by normal phase flash chromatography on silica gel (0→5% MeOH/CH2Cl2) to yield a black oil. This oil was treated with Et2O to precipitate a white solid. The solid was filtered off and the filtrate was reprocessed to give another crop of slightly darker solids. A total of 426 mg of {1-[1-(5-iodo-pyrimidin-2-yl)-cyclopropylcarbamoyl]-cyclopropyl}-carbamic acid tert-butyl ester was isolated, m/z 445.5 [M+H]+.