Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:21]([O-:23])=[O:22])=[C:6]([NH:8][CH:9]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13]([O:19][CH3:20])[CH:12]=2)[CH3:10])[CH:7]=1.[N:24]1([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:20][O:19][C:13]1[CH:12]=[C:11]([CH:9]([NH:8][C:6]2[CH:7]=[C:2]([N:27]3[CH2:26][CH2:25][N:24]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:29][CH2:28]3)[CH:3]=[CH:4][C:5]=2[N+:21]([O-:23])=[O:22])[CH3:10])[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=1
Reactant: COc1cc(OC)cc(C(C)Nc2cc(F)ccc2[N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1cc(OC)cc(C(C)Nc2cc(N3CCN(C(=O)OC(C)(C)C)CC3)ccc2[N+](=O)[O-])c1
Yield: 40.2 %

Procedure:
5-Fluoro-N-(1-(3,5-dimethoxyphenyl)ethyl)-2-nitrobenzenamine (762 mg, 2.4 mmol), t-butyl piperazine-1-carboxylate (443 mg, 2.4 mmol), N,N-diisopropylethylamine (614 mg, 4.8 mmol) were stirred at 80° C. in dry acetonitrile (50 mL) for 48 h. The solvent was evaporated and the residue was dissolved in dichloromethane and washed with water. The dichloromethane was evaporated and the crude compound was purified by silica chromatography using 25% ethyl acetate in hexanes to afford the title compound (469 mg, 41% yield). 1H NMR (400 MHz, CDCl3): δ 8.68 (s, 1H), 8.05 (d, 1H), 6.49 (s, 2H), 6.33 (s, 1H), 6.14 (d, 1H), 5.70 (s, 1H), 4.47 (m, 1H), 3.76 (s, 6H), 3.43 (m, 4H), 3.23 (m, 2H), 3.15 (m, 2H), 1.62 (d, 3H), 1.46 (s, 9H); MS (ESI) m/z: Calculated for C25H34N4O6: 486.25; Observed: 509.3 (M++Na).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH2:14][C:15]([OH:17])=O)[CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])(=[O:3])[CH3:2].C(Cl)(=O)C([Cl:21])=O>ClCCl.CN(C)C=O>[C:1]([O:4][C:5]1[CH:6]=[C:7]([CH2:14][C:15]([Cl:21])=[O:17])[CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc(CC(=O)O)ccc1[N+](=O)[O-]
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)Oc1cc(CC(=O)Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of (3-acetoxy-4-nitro-phenyl)acetic acid (2.0 g, Reference Example 18) in dichloromethane (20 mL) was treated with a solution of oxalyl chloride in dichloromethane (4.4 mL, 2M) and then with dry dimethylformamide (1 drop). After a vigorous effervescence the mixture was stirred at room temperature for 4 hours, then evaporated to give the title compound as a viscous oil which was used immediately without further purification.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[OH-].[Na+].[CH2:12](Br)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].Cl>CN(C)P(N(C)C)(N(C)C)=O>[C:1]([O:9][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1
Reactant: O=C(O)c1cccnc1
Reactant: CCCCCCCCCCCCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCCCCCCCCCOC(=O)c1cccnc1
Reaction time: 24 h
Yield: 77.2 %

Procedure:
In 100 ml of hexamethylphosphoramide was dissolved 4.9 g (0.04 mol) of nicotinic acid, and a 25% aqueous solution of sodium hydroxide (0.06 mol) was added thereto, followed by stirring using a magnetic stirrer at room temperature for 1 hour. To the mixture was further added 29.8 g (0.12 mol) of lauryl bromide, and the stirring was continued for an additional 24 hours. The reaction mixture was added to 200 ml of a 5% aqueous solution of hydrochloric acid and extracted with diethyl ether. The extract was washed with water, dried over sodium sulfate and distilled to remove the solvent. The residue was purified by column chromatography (Wakogel C-300, benzene:ethyl acetate=6:1 v/v) and recrystallized from methyl alcohol at 1° C. to obtain 9 g of n-dodecyl nicotinate as a colorless liquid in a yield of 77%, based on the nicotinic acid.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[N+:7]([C:10]1[C:18]2[NH:17][C:16](=[O:19])[NH:15][C:14]=2[CH:13]=[CH:12][CH:11]=1)([O-:9])=[O:8].Br[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>CN(C=O)C>[N+:7]([C:10]1[C:18]2[NH:17][C:16](=[O:19])[N:15]([CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:14]=2[CH:13]=[CH:12][CH:11]=1)([O-:9])=[O:8]
Reactant: O=c1[nH]c2cccc([N+](=O)[O-])c2[nH]1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Cn1c(=O)[nH]c2c([N+](=O)[O-])cccc21
Reaction time: 18 h

Procedure:
Cesium carbonate (1.75 g, 5.4 mmol) was added to a solution of 4-nitro-1,3-dihydro-2H-benzimidazol-2-one (800 mg, 4.5 mmol, described in Intermediate 31) and tert-butyl bromoacetate (0.791 mL, 5.4 mmol) in DMF (15 mL). After 18 h, the reaction was quenched with H2O (100 mL) and the solid precipitate was collected by filtration. The crude product was purified by silica gel chromatography, eluting with CH2Cl2:MeOH—95:5, to give the title compound. MS: m/z=294 (M+1).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[CH3:21])[C:11]([N:22]([CH3:42])[C:23](=[O:41])[C:24]([C:27]3[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[C:29]([C:37]([F:40])([F:39])[F:38])[CH:28]=3)([CH3:26])[CH3:25])=[CH:10][N:9]=2)[CH2:4][CH2:3]1.C(N(CC)C(C)C)(C)C.[C:52](Cl)(=[O:54])[CH3:53]>ClCCl>[C:52]([NH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[CH3:21])[C:11]([N:22]([CH3:42])[C:23](=[O:41])[C:24]([C:27]3[CH:28]=[C:29]([C:37]([F:39])([F:40])[F:38])[CH:30]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:32]=3)([CH3:26])[CH3:25])=[CH:10][N:9]=2)[CH2:4][CH2:3]1)(=[O:54])[CH3:53]
Reactant: Cc1cc(F)ccc1-c1cc(N2CCC(N)CC2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NC1CCN(c2cc(-c3ccc(F)cc3C)c(N(C)C(=O)C(C)(C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cn2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.8 %

Procedure:
To a solution of 80 mg (0.13 mmol) N-[4-amino-4′-(4-fluoro-2-methyl-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide and 26 mg (0.20 mmol) N,N-diisopropylethylamine in 3 ml dichloromethane were added 12 mg (0.15 mmol) acetyl chloride at 0° C. The reaction mixture was stirred at room temperature for 18 h. The mixture was diluted with 10 ml dichloromethane and washed with 10 ml of a saturated aqueous solution of sodium carbonate. The combined organic layers were dried over sodium sulfate, concentrated and purified by flash chromatography to give 82 mg (95%) of the title compound as a white foam.
Reaction SMILES: [OH:1][CH2:2][CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4]([OH:6])=O.C(Cl)(=O)OCC.[NH2:19][C:20]1[C:39]([Cl:40])=[CH:38][C:23]([C:24]([NH:26][C@H:27]2[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][NH2:35])[CH2:29][C@H:28]2[O:36][CH3:37])=[O:25])=[C:22]([O:41][CH3:42])[CH:21]=1>ClC(Cl)Cl.C(N(CC)CC)C>[NH2:19][C:20]1[C:39]([Cl:40])=[CH:38][C:23]([C:24]([NH:26][C@H:27]2[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][NH:35][C:4](=[O:6])[CH:3]([CH2:2][OH:1])[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:29][C@H:28]2[O:36][CH3:37])=[O:25])=[C:22]([O:41][CH3:42])[CH:21]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCN)C[C@H]1OC
Reactant: O=C(O)C(CO)c1ccccc1
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCNC(=O)C(CO)c2ccccc2)C[C@H]1OC
Reaction time: 0.75 h
Yield: 10 %

Procedure:
To a stirred suspension of 2.99 parts of α-(hydroxymethyl)benzeneacetic acid in 60 parts of trichloromethane were added dropwise first 1.82 parts of N,N-diethylethanamine and then 1.95 parts of ethyl carbonochloridate at a temperature below 5° C. Upon completion, stirring was continued for 45 minutes at this low temperature. The thus obtained solution was added dropwise to a solution of 5.35 parts of cis-4-amino-N-[1-(2-aminoethyl)-3-methoxy-4-piperidinyl]-5-chloro-2-methoxybenzamide in 45 parts of trichloromethane while the temperature was kept below 10° C. Upon completion, the whole was stirred for 20 hours at room temperature. The organic layer was washed with a sodium carbonate solution in water and with water, dried, filtered and evaporated. The residue was purified by column chromatography over silicia gel using a mixture of trichloromethane and methanol, saturated with ammonia, (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile and a few drops of water. The product was filtered off and dried in vacuo at 30° C., yielding 0.76 parts (10.0%) of cis-N-[2-[4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxy-1-piperidinyl]ethyl]-α-(hydroxymethyl)benzeneacetamide; mp. 114.0° C. (compound 87).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:10]([O-])=O)=[C:7]([OH:9])[CH:8]=1>[Pd].C(OCC)(=O)C.C(O)C>[NH2:10][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][C:7]=1[OH:9]
Reactant: COc1ccc([N+](=O)[O-])c(O)c1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc(N)c(O)c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 98.1 %

Procedure:
Subsequently, a mixture of 5-methoxy-2-nitrophenol (7.47 g) and 10% Pd/C (1.87 g) was prepared in an ethyl acetate/ethanol (100 mL, 1:1 v/v) mixture. The resulting slurry was stirred under an H2 atmosphere for 3.5 h at room temperature. Hydrogen was subsequently purged from the reaction flask and the reaction mixture was filtered through Celite. After washing the celite pad with additional solvent, volatiles in the resultant filtrate were removed in vacuo to give 2-amino-5-methoxyphenol (6.03 g, 98%).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[C:13]([CH2:15][N:16]=[N+]=[N-])[CH:12]=[CH:11][C:10]=1[C:19]([O:21][CH3:22])=[O:20])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[C:13]([CH2:15][NH2:16])[CH:12]=[CH:11][C:10]=1[C:19]([O:21][CH3:22])=[O:20])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(CN=[N+]=[N-])cc1S(=O)(=O)NC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(CN)cc1S(=O)(=O)NC(C)(C)C
Yield: 74.6 %

Procedure:
16.3 g (50 mmol) of N-tert-butyl-5-azidomethyl-2-methoxycarbonylbenzenesulfonamide are dissolved in 300 ml of methanol and hydrogenated over Pd/C (5%). The mixture is filtered and evaporated to dryness. The crude product obtained is purified by elution through a silica gel column using ethyl acetate/methanol 4:1. 11.2 g (74%) of N-tert-butyl-5-aminomethyl-2-methoxycarbonylbenzenesulfonamide are obtained as a viscous oil.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[N:6][CH:5]=[N:4]1.[Br:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([N:15]2[CH2:19][CH2:18][CH2:17][C@H:16]2[CH2:20]Cl)[CH:14]=1.C([O-])(O)=O.[Na+]>CN(C=O)C.C(Cl)Cl>[Br:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([N:15]2[CH2:19][CH2:18][CH2:17][C@H:16]2[CH2:20][N:3]2[CH:7]=[N:6][CH:5]=[N:4]2)[CH:14]=1
Reactant: ClC[C@@H]1CCCN1c1cncc(Br)c1
Reactant: c1nc[nH]n1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Brc1cncc(N2CCC[C@H]2Cn2cncn2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.7 %

Procedure:
To a solution of NaH (0.011 g, 0.272 mmol) in DMF (1 mL) was added 1H-1,2,4-triazole (0.016 g, 0.236 mmol) and the reaction mixture was stirred at room temperature for 30 min. Then, 3-bromo-5-((S)-2-chloromethyl-pyrrolidin-1-yl)-pyridine (0.05 g, 0.181 mmol) in DMF (0.5 mL) was added to the reaction mixture which was heated to 80° C. over night. The mixture was diluted with DCM, poured into aq. NaHCO3 (5 mL) and the aqueous layer was extracted with DCM (2×10 mL). Combined organics were dried over Na2SO4, filtered and evaporated to dryness to give the title compound (0.04 g, 72%) as a yellow oil. MS: 308.0, 310.0 (M+H+).
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:17])[C:6]2[C:14](=[CH:15][CH:16]=1)[C:13]1[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH:7]=2)(=[O:3])[CH3:2].[Se](=O)=[O:19]>O1CCOCC1>[C:5]1(=[O:17])[C:6]2[C:14]([C:13]3[C:8]([CH:7]=2)=[CH:9][CH:10]=[CH:11][CH:12]=3)=[CH:15][CH:16]=[C:4]1[C:1](=[O:3])[CH:2]=[O:19]
Reactant: CC(=O)C1=CC=C2C(=Cc3ccccc32)C1=O
Reactant: O=[Se]=O
Solvent: C1COCCO1
Product: O=CC(=O)C1=CC=C2C(=Cc3ccccc32)C1=O

Procedure:
The thus-isolated 2-acetylfluorenon is oxidized by selenium dioxide in dioxane medium at 98°-100° C during 22 hours to obtain 2-fluorenonyl-glyoxal isolated as semiacetal, the yield being equal to 31.2 weight percent. The thus-obtained intermediate product is subjected to treatment with sodium bisulfite in 60-percent ethanol to obtain the final product crystallizable with a molecule of water. The yield of the final product amounts to 57 weight percent when calculated for the semiacetal of 2-fluorenonyl-glyoxal and to 55 weight percent when calculated for the parent fluorene (of.Sintez organicheskikh preparatov/synthesis of organic preparations/, v.4, P.77, 1953 /in Russian/; Zhurnal organicheskoy khimii /Journal of organic chemistry/, 33, 3053, 1963 (in Russian).
Reaction SMILES: [C:1]1(=[N:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][C:26](OCC)=O)[CH2:19][CH2:18]1>>[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH:17]1[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][CH2:25][C:26]2[O:9][N:8]=[C:1]3[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]=23)[CH2:21][CH2:22]1
Reactant: ON=C1CCCCCC1
Reactant: CCOC(=O)CCCN1CCC(c2ccccc2Cl)CC1
Product: Clc1ccccc1C1CCN(CCCc2onc3c2CCCCC3)CC1

Procedure:
By the same reaction and treatment as in Example 48 using cycloheptanone oxime and ethyl 4-(4-(2-chlorophenyl)piperidin-1-yl)-n-butyrate, 3-(3-(4-(2-chlorophenyl)piperidin-1-yl)propyl)-5,6,7,8-tetrahydro-4H-cyclohepta[c]isoxazole is obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16]Br)[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].[BH4-].[Na+]>CS(C)=O.O>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1oc2cccc(CBr)c2c1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1oc2cccc(C)c2c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.7 %

Procedure:
To a solution of 0.291 g (0.98 mmol) of 4-bromomethyl-3-methylbenzofuran-2-carboxylic acid ethyl ester in 5 mL of DMSO was added 0.074 g (1.96 mmol) of sodium borohydride and the reaction was stirred at room temperature for 2 h. The reaction was diluted with water and extracted with ether. The organics were washed with water and brine, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate/hexanes (1:10) to provide 0.209 g of 4-methyl-3-methylbenzofuran-2-carboxylic acid ethyl ester.
Reaction SMILES: [CH:1]1[C:6]2[C:7](=O)[NH:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[S:11][C:5]=2[CH:4]=[C:3]([C:17]([O:19][CH3:20])=[O:18])[CH:2]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:22].P(Cl)(Cl)(Cl)=O>>[Cl:22][C:7]1[C:6]2[CH:1]=[CH:2][C:3]([C:17]([O:19][CH3:20])=[O:18])=[CH:4][C:5]=2[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[N:8]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: COC(=O)c1ccc2c(c1)Sc1ccccc1NC2=O
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1ccc2c(c1)Sc1ccccc1N=C2Cl
Reaction time: 0.5 h

Procedure:
At room temperature, add 14.25 gm. (50 mmole) of methyl 10,11-dihydrodibenzo[b,f][1,4]-thiazepin-11-one-3-carboxylate to a stirred mixture of 10.425 gm. (50 mmole) of phosphorous pentachloride in 50 ml. of phosphorous oxychloride. Stir for 30 minutes, add an additional 1 gm. of phosphorous pentachloride and continue stirring for one hour. Partition the reaction mixture between a mixture of 400 ml. of methylene chloride, 350 gm. of ice and 150 ml. of water. Separate the aqueous layer and extract with 50 ml. of methylene chloride. Wash the combined organic extracts with a mixture of 100 gm. of ice and 100 ml. of water. Dry the methylene chloride solution over magnesium sulfate, charcoal and filter. Evaporate the solution, take-up in 50 ml. of dry toluene and again evaporate. Take up the residue in 25 ml. of acetonitrile, cool in an ice bath and separate the precipitate by filtration to obtain the title product. (m.p. 134°-135.5° C.)
Reaction SMILES: [F:1][C:2]1[C:14]([F:15])=[C:13]([F:16])[CH:12]=[CH:11][C:3]=1[NH:4][CH:5]([CH3:10])[C:6]([O:8]C)=[O:7].[OH-].[Li+]>CO>[F:1][C:2]1[C:14]([F:15])=[C:13]([F:16])[CH:12]=[CH:11][C:3]=1[NH:4][CH:5]([CH3:10])[C:6]([OH:8])=[O:7]
Reactant: COC(=O)C(C)Nc1ccc(F)c(F)c1F
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC(Nc1ccc(F)c(F)c1F)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.7 %

Procedure:
Methyl 2-(2,3,4-trifluoroanilino)propionate (46.64 g) was dissolved in methanol (130 ml) and an aqueous solution (3 mol/l; 100 ml) of lithium hydroxide was slowly added thereto at 0° C. After stirring at room temperature for 3 hours, the solvent was evaporated. After adding water, the residue was washed with chloroform. Next, hydrochloric acid (6 mol/l) was slowly added to the aqueous layer until pH value reached 1. Then the aqueous layer was extracted with diisopropyl ether (IPE). The organic layer was dried over anhydrous magnesium sulfate and then the solvent was evaporated to give the title compound (43.7 g) as colorless crystals.
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][O:7][CH2:8][CH2:9][N:10]1[C:22]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[C:14]([NH2:23])[C:13]=2[N:12]=[C:11]1[CH3:24])(=[O:4])=[O:3].[H][H].[OH-].[Na+]>FC(F)(F)C(O)=O.O.[Pt]=O>[CH3:1][S:2]([CH2:5][CH2:6][O:7][CH2:8][CH2:9][N:10]1[C:22]2[C:21]3[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=3[N:15]=[C:14]([NH2:23])[C:13]=2[N:12]=[C:11]1[CH3:24])(=[O:3])=[O:4]
Reactant: [H][H]
Reactant: Cc1nc2c(N)nc3ccccc3c2n1CCOCCS(C)(=O)=O
Agent: O=[Pt]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc2c(N)nc3c(c2n1CCOCCS(C)(=O)=O)CCCC3
Yield: 76.4 %

Procedure:
Solid platinum oxide (0.5) was added to a solution of 1-{2-[2-(methylsulfonyl)ethoxy]ethyl}-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine (0.9 g, 2.6 mmol) in trifluoroacetic acid (7 mL) in a Parr vessel. The vessel was placed on a shaker and then pressurized with hydrogen to 50 psi (3.4×105 Pa). Hydrogen was added periodically to maintain the pressure. After 55 hours the reaction mixture was purged with nitrogen and then filtered through a layer of CELITE filter agent. The filter cake was washed with dichloromethane (˜200 mL). The filtrate was concentrated under reduced pressure to provide an oil. The oil was dissolved in water (50 mL). The pH of the solution was adjusted to pH 12 by the addition of aqueous 50% sodium hydroxide and then the solution was extracted with dichloromethane (2×100 mL). The combined extracts were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide crude product as a white foam. This material was recrystallized from ethyl acetate. The resulting off white plates were isolated by filtration, washed with ethyl acetate and dried under vacuum at 65° C. for 4 hours to provide 0.7 g of 1-{2-[2-(methylsulfonyl)ethoxy]ethyl}-2-methyl-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine, mp 173-175° C. 1H NMR (300 MHz, DMSO-d6) δ 5.65 (bs, 2H), 4.40 (t, J=5.0 Hz, 2H), 3.73 (t, J=5.6 Hz, 2H), 3.32 (t, J=5.6 Hz, 2H), 2.91 (m, 2H), 2.78 (s, 3H) 2.65 (m, 2H), 2.47 (s, 3H), 1.75 (m, 4H); MS (APCI) m/z 353 (M+
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[O:6][CH2:7][CH:8]([OH:11])[CH2:9][OH:10].[CH3:12][S:13](Cl)(=[O:15])=[O:14]>N1C=CC=CC=1>[OH:11][CH:8]([CH2:7][O:6][C:2]1[S:1][CH:5]=[CH:4][N:3]=1)[CH2:9][O:10][S:13]([CH3:12])(=[O:15])=[O:14]
Reactant: OCC(O)COc1nccs1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)OCC(O)COc1nccs1
Reaction time: 0.17 h

Procedure:
This example illustrates steps 3 and 4 of the generic process, of the invention, and further illustrates the preparation of the compounds of formula II of the invention. In this example 50 grams of 3-(thiazol-2-oxy)-1,2-propanediol is dissolved in 200 ml. of pyridine at 20°C and then 22.5 ml. of methylsulfonyl chloride is added. The mixture is allowed to stand for 10 minutes and then separated into two portions (1/10 portion and one 9/10 portion). The 1/10 portion is diluted with water, then filtered and the resulting filter cake dried affording 2-hydroxy-1-methylsulfonyloxy-3-(thiazol-2-oxy)-propane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][N:3]=1.[Br:9][C:10]1[CH:11]=[CH:12][C:13]([OH:23])=[C:14]([CH:22]=1)[C:15]([N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[O:16].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([O:23][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=2)=[C:14]([CH:22]=1)[C:15]([N:17]([CH2:18][CH3:19])[CH2:20][CH3:21])=[O:16]
Reactant: CCN(CC)C(=O)c1cc(Br)ccc1O
Reactant: Fc1ccnc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCN(CC)C(=O)c1cc(Br)ccc1Oc1ccnc(Cl)c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
2-Chloro-4-fluoropyridine (0.242 g, 1.837 mmol) was added to a mixture of 5-bromo-N,N-diethyl-2-hydroxybenzamide (0.500 g, 1.837 mmol) and cesium carbonate (1.197 g, 3.67 mmol) in acetonitrile (10.0 mL). The mixture stirred at 100° C. for 8 h. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was separated and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford a brown oil. This oil was purified via column chromatography on silica gel (RediSep 80 g column, gradient elution with 0-50% ethyl acetate-hexane) to afford 5-bromo-2-(2-chloropyridin-4-yloxy)-N,N-diethylbenzamide as a thick, yellow oil. MS m/z=383.0 [M+H]+. Calcd for C16H16BrClN2O2: 382.0.
Reaction SMILES: [CH:1]1([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:9]2[CH:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:3][NH:2]1.[CH3:16][C:17]1[S:18][C:19]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:20]([C:22](O)=[O:23])[N:21]=1>>[CH3:16][C:17]1[S:18][C:19]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:20]([C:22]([N:2]2[CH2:3][CH:4]3[CH:9]([CH2:8][CH2:7][CH2:6][CH2:5]3)[CH:1]2[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:23])[N:21]=1
Reactant: CCOC(=O)CC1NCC2CCCCC21
Reactant: Cc1nc(C(=O)O)c(-c2ccccc2)s1
Product: CCOC(=O)CC1C2CCCCC2CN1C(=O)c1nc(C)sc1-c1ccccc1

Procedure:
Ethyl 2-(2-(2-methyl-5-phenylthiazole-4-carbonyl)octahydro-1H-isoindol-1-yl)acetate was prepared according to general procedure A using ethyl 2-(octahydro-1H-isoindol-1-yl)acetate and 2-methyl-5-phenylthiazole-4-carboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[N:9]=[CH:8][C:7]([Br:10])=[CH:6][C:3]=1[C:4]#[N:5].[CH2:11](OC(OCC)CBr)[CH3:12]>>[Br:10][C:7]1[CH:6]=[C:3]([C:4]#[N:5])[C:2]2[N:9]([CH:11]=[CH:12][N:1]=2)[CH:8]=1
Reactant: N#Cc1cc(Br)cnc1N
Reactant: CCOC(CBr)OCC
Product: N#Cc1cc(Br)cn2ccnc12
Yield: 32 %

Procedure:
Prepared from 2-amino-5-bromo-nicotinonitrile (example C.23 step 1) (26 g, 131 mmol) and bromoacetaldehyde diethyl acetal (90%, 45 mL, 263 mmol) as described in example C.20 step 1. Obtained the title compound as a light brown solid (9.3 g, 32%). MS (ISP) 222.1 [(M+H)+], 224 [(M+2+H)+].