Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:19][CH2:20][CH2:21][CH:22]1[CH2:26][CH2:25][CH2:24][O:23]1.N#N>CN(C=O)C>[F:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH:4][CH2:19][CH2:20][CH2:21][CH:22]1[CH2:26][CH2:25][CH2:24][O:23]1
Reactant: Nc1ccc([N+](=O)[O-])cc1F
Reactant: ClCCCC1CCCO1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(NCCCC2CCCO2)c(F)c1
Temperature: 140 °C
Reaction time: 48 h
Yield: 31 %

Procedure:
To a mixture of 2-fluoro-4-nitroaniline (7.02 g, 45.0 mmol), Cs2CO3 (29.3 g, 90.0 mmol), KI (16.6 g, 100 mmol) and DMF (100 mL) was added 2-(3-chloropropyl)tetrahydrofuran (7.43 g, 50.0 mmol) dropwise under N2 and the mixture was stirred at 140° C. for 48 h. The mixture was cooled to rt and filtered and the filtrate was concentrated in vacuo. To the residue was added water (30 mL) and the mixture was extracted with DCM (30 mL×4). The combined organic layers were washed with brine (40 mL×2), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=20:1) to give the title compound as a yellow solid (3.74 g, 31%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([CH:9]=[CH:10][O:11][CH3:12])[CH:3]=1.C([Mg]Cl)(C)C.C([Li])CCC.[CH:23](N1CCOCC1)=[O:24].[Cl-].[NH4+]>CC1CCCO1.C1COCC1.CCCCCC>[F:8][C:5]1[CH:6]=[CH:7][C:2]([CH:23]=[O:24])=[CH:3][C:4]=1[CH:9]=[CH:10][O:11][CH3:12]
Reactant: O=CN1CCOCC1
Reactant: COC=Cc1cc(Br)ccc1F
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC1CCCO1
Product: COC=Cc1cc(C=O)ccc1F
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
4-Bromo-1-fluoro-2-(2-methoxyvinyl)benzene (limiting reagent) (step c) was dissolved in 2-methyltetrahydrofuran (5 volumes) and the solution cooled to −10° C. Iso-propylmagnesium chloride (0.37 molar equivalents of a 2M solution in THF) was added dropwise, keeping the temperature at −7° C. (+ or −2° C.), over about 30 minutes, followed by Butyllithium (0.74 molar equivalents of a 1.5M solution in hexane), controlling the temperature at −6° C. (+ or −2° C.), over about 1 hour. Stirred for 45 minutes then added to a solution of 4-formylmorpholine (2 molar equivalents) in 2-methyltetrahydrofuran (7 volumes) at −5° C. This addition took about 90 minutes. The reaction was then stirred for 1 hour, during which time the internal temperature rose to 5° C. The reaction mixture was poured into saturated aq. ammonium chloride solution (10 volumes) and extracted with t-BME (2×3 volumes). Combined extracts were washed with sat'd aq. ammonium chloride (until the pH of the washing was approx 6) (2×3 volumes), water (5 volumes), dried (Na2SO4), filtered and evaporated to give a mobile orange oil.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=1)=[C:2]=[O:3].F.C(F)([F:17])=O.CCCCCCCCCCCCCCC.FC(F)(F)C1C=CC(N)=CC=1>>[F:13][C:10]([F:11])([F:12])[C:7]1[CH:6]=[CH:5][C:4]([NH:1][C:2]([F:17])=[O:3])=[CH:9][CH:8]=1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: O=C(F)F
Agent: CCCCCCCCCCCCCCC
Agent: F
Agent: *C(F)(F)C(*)(F)F
Product: O=C(F)Nc1ccc(C(F)(F)F)cc1
Temperature: 24 °C
Reaction time: 112 h

Procedure:
4-(Trifluoromethyl)phenyl carbamic fluoride was prepared in situ by the reaction of 224 parts of 1-isocyanato-4-(trifluoromethyl)benzene and 460 parts of hydrogen fluoride added over a period of about 35 minutes at about 3° C. The reaction mixture was then sealed in a polytetrafluoroethylene reaction vessel, heated to about 24° C., and maintained thereat, with agitation, for about 112 hours. Infra-red analysis of the gaseous phase, when the reaction vessel was opened to atmospheric pressure, indicated large quantities of carbonyl fluoride present. The remaining organic product was analyzed by gas chromatographic techniques, using n-pentadecane as an internal standard, indicating a yield of 114 parts of 4-(trifluoromethyl)benzenamine.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C@@H:7]([C:18]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)=[O:19])[CH2:6]2)[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[F:33][C:34]([F:45])([F:44])[C:35]1[CH:40]=[CH:39][C:38]([N:41]=[C:42]=[O:43])=[CH:37][CH:36]=1>ClCCl>[CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C@@H:7]([C:18]([N:20]3[CH2:21][CH2:22][N:23]([C:42]([NH:41][C:38]4[CH:37]=[CH:36][C:35]([C:34]([F:33])([F:44])[F:45])=[CH:40][CH:39]=4)=[O:43])[CH2:24][CH2:25]3)=[O:19])[CH2:6]2)[CH2:2][CH2:3][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCN(C2CCC2)C[C@@H]1C(=O)N1CCNCC1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C2CCC2)C[C@@H]1C(=O)N1CCN(C(=O)Nc2ccc(C(F)(F)F)cc2)CC1
Reaction time: 8 h

Procedure:
tert-Butyl (2R)-4-cyclobutyl-2-(piperazin-1-ylcarbonyl)piperazine-1-carboxylate (350 mg) was stirred at room temperature in dichloromethane (15 ml). Triethylamine (0.14 ml) was added followed by 4-(trifluoromethyl)phenyl isocyanate (0.14 ml) and the solution stirred overnight. The solvent was removed in vacuo and the residue adsorbed onto silica for purification by chromatography eluting with 0-7.5% methanol/dichloromethane. This gave tert-butyl (2R)-4-cyclobutyl-2-{[4-({[4-(trifluoromethyl)phenyl]amino}carbonyl)piperazin-1-yl]carbonyl}piperazine-1-carboxylate as a white glass (370 mg).
Reaction SMILES: [N:1]([CH2:4][Si:5]([CH3:8])([CH3:7])[CH3:6])=[N+:2]=[N-:3].[CH:9]#[C:10][CH2:11][CH2:12][CH3:13].O[C@H]([C@@H]1C([O-])=C(O)C(=O)O1)CO.[Na+].C(O)=CCC>S([O-])([O-])(=O)=O.[Cu+2].O>[CH2:11]([C:10]1[N:3]=[N:2][N:1]([CH2:4][Si:5]([CH3:8])([CH3:7])[CH3:6])[CH:9]=1)[CH2:12][CH3:13]
Reactant: C[Si](C)(C)CN=[N+]=[N-]
Reactant: C#CCCC
Agent: [Cu+2]
Agent: CCC=CO
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Solvent: O
Product: CCCc1cn(C[Si](C)(C)C)nn1
Reaction time: 96 h

Procedure:
(Azidomethyl)trimethylsilane, pent-1-yne, copper (II) sulfate and sodium (R)-2-((S)-1,2-dihydroxyethyl)-4-hydroxy-5-oxo-2,5-dihydrofuran-3-olate) were added to a 1:2 solution of water:buten-1-ol. The reaction was stirred for about 4 days and t-butanol and water were removed, producing a 4-propyl-1-((trimethylsilyl)methyl)-1H-1,2,3-triazole solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)[N:5]=[CH:4][N:3]=1.[NH:16]1[CH2:23][CH2:22][CH2:21][C@@H:17]1[C:18]([OH:20])=[O:19].C(=O)([O-])[O-].[K+].[K+].Cl>CC(N(C)C)=O.C(OCC)(=O)C.[Cu]I>[Cl:15][C:10]1[CH:9]=[C:8]([C:6]2[N:5]=[CH:4][N:3]=[C:2]([N:16]3[CH2:23][CH2:22][CH2:21][C@@H:17]3[C:18]([OH:20])=[O:19])[CH:7]=2)[CH:13]=[CH:12][C:11]=1[Cl:14]
Reactant: Clc1cc(-c2ccc(Cl)c(Cl)c2)ncn1
Reactant: O=C(O)[C@H]1CCCN1
Agent: [Cu]I
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: O=C(O)[C@H]1CCCN1c1cc(-c2ccc(Cl)c(Cl)c2)ncn1
Temperature: 90 °C
Yield: 41.9 %

Procedure:
4-Chloro-6-(3,4-dichloro-phenyl)-pyrimidine (0.3 g, 1.2 mmol) and D-proline (0.13 g, 1.2 mmol) were added in one portion to a pressure vessel containing a solution of copper (I) Iodide (0.02 g, 0.16 mmol) and potassium carbonate (0.24 g, 1.8 mmol) in DMA (5 ml). The vessel was sealed and heated at 90° C. for 16 hours before being cooled to room temperature. The mixture was cooled to room temperature, diluted with ethyl acetate (10 ml) and acidified to pH 1 with concentrated HCl. The mixture was extracted with ethyl acetate (3×30 ml) and the organic layers were combined, dried (MgSO4), filtered, concentrated and the resulting residue was purified by prep HPLC to give the title compound (0.17 g, 43% yield) as a white solid.
Reaction SMILES: C(OC(C1N(CC2C3C=C(F)C=CC=3SC=2)C2C(C=1C=O)=CC=CC=2)=O)C.C([O:30][C:31]([C:33]1[N:34]([CH2:48][C:49]2[C:50]3[CH:57]=[C:56]([F:58])[CH:55]=[CH:54][C:51]=3[S:52][CH:53]=2)[C:35]2[C:40]([C:41]=1[CH2:42][NH:43][C:44]([O:46][CH3:47])=[O:45])=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:32])C>>[F:58][C:56]1[CH:55]=[CH:54][C:51]2[S:52][CH:53]=[C:49]([CH2:48][N:34]3[C:35]4[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:41]([CH2:42][NH:43][C:44]([O:46][CH3:47])=[O:45])=[C:33]3[C:31]([OH:32])=[O:30])[C:50]=2[CH:57]=1
Reactant: CCOC(=O)c1c(CNC(=O)OC)c2ccccc2n1Cc1csc2ccc(F)cc12
Agent: CCOC(=O)c1c(C=O)c2ccccc2n1Cc1csc2ccc(F)cc12
Product: COC(=O)NCc1c(C(=O)O)n(Cc2csc3ccc(F)cc23)c2ccccc12

Procedure:
1-(5-Fluoro-benzo[b]thiophen-3-ylmethyl)-3-formyl-1H-indole-2-carboxylic acid ethyl ester (from Example 115.1.) was converted to 1-(5-fluoro-benzo[b]thiophen-3-ylmethyl)-3-(methoxycarbonylamino-methyl)-1H-indole-2-carboxylic acid ethyl ester as described in Example 77.1. which was hydrolyzed as described in the general procedure B (Exp. 2.2) to give the title compound as a white solid. MS: 411.3 ([M−H]−).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][C:6](=[O:8])[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[CH2:3]1.[BH4-].[Na+]>CCO>[CH3:1][C@@H:2]1[CH2:7][C@H:6]([OH:8])[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[CH2:3]1
Reactant: CC1CC(=O)C=C(c2ccncc2[N+](=O)[O-])C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: C[C@H]1CC(c2ccncc2[N+](=O)[O-])=C[C@@H](O)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
To a solution of 5-methyl-3-(3-nitropyridin-4-yl)cyclohex-2-enone (1.0 equiv.) in EtOH (0.3 M) was added CeCl3-7H2O (1.2 equiv.). The reaction was cooled to 0° C., then NaBH4 (1.2 equiv.) was added in portions. Stirred for 1 h at 0° C., then quenched by adding water, concentrated to remove the EtOH, added EtOAc, extracted the organics, washed with brine, then dried with Na2SO4, filtered and concentrated to yield cis-(+/−)-5-methyl-3-(3-nitropyridin-4-yl)cyclohex-2-enol (94%). LC/MS=235.2 (M+H), LC=2.62 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]2[NH:9][CH:10]=[CH:11][C:3]=12.C1C(=O)N([I:19])C(=O)C1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]2[NH:9][CH:10]=[C:11]([I:19])[C:3]=12
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1cc(Cl)c2cc[nH]c2n1
Solvent: ClCCl
Product: Cc1cc(Cl)c2c(I)c[nH]c2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.3 %

Procedure:
To a stirred solution of 4-chloro-6-methyl-1H-pyrrolo[2,3-b]pyridine (4.06 g, 24.37 mmol) in DCM (80 mL) at 0° C., was added NIS (6.22 g, 27.6 mmol). The reaction mixture was then warmed to RT and stirred for 18 hours. The reaction mixture was then filtered (washed with excess DCM) to give the title compound (4.01 g). LCMS (A): m/z (M+H)+ 293, C8H6ClIN2 requires 292 (acidic).
Reaction SMILES: [C:1]1([C:7]([N:9]2[CH2:13][CH2:12][C@H:11]([NH:14][CH:15]3[CH2:18][N:17]([C:19]([C:21]4[CH:26]=[CH:25][C:24]([C:27]5[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=5)=[CH:23][CH:22]=4)=[O:20])[CH2:16]3)[CH2:10]2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=C(Cl)C=C(C(OO)=[O:45])C=1>C(Cl)Cl.O>[OH:45][N:14]([CH:15]1[CH2:16][N:17]([C:19]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=3)=[CH:23][CH:22]=2)=[O:20])[CH2:18]1)[C@H:11]1[CH2:12][CH2:13][N:9]([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:8])[CH2:10]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(c1ccc(-c2cccc(C(F)(F)F)c2)cc1)N1CC(N[C@H]2CCN(C(=O)c3ccccc3)C2)C1
Solvent: O
Solvent: ClCCl
Product: O=C(c1ccc(-c2cccc(C(F)(F)F)c2)cc1)N1CC(N(O)[C@H]2CCN(C(=O)c3ccccc3)C2)C1
Reaction time: 0.5 h
Yield: 11.4 %

Procedure:
To a solution of Compound 16 (60 mg, 0.12 mmol) in dry CH2Cl2 (1 mL) was added mCPBA (77%, 33 mg, 0.146 mmol) at 0° C. and the resulting mixture was stirred at this temperature for 30 min. The reaction mixture was diluted with CH2Cl2 and water. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, 5% MeOH/EtOAc) gave compound 54 (7 mg). MS m/z (M+Na+) 510.0, MS m/z (M+Na+) 532.0.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:22])[CH2:10][C:11]1[CH:21]=[CH:20][C:14]([C:15]([O:17]CC)=[O:16])=[CH:13][CH:12]=1.Cl>O1CCOCC1>[OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:22])[CH2:10][C:11]1[CH:21]=[CH:20][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1
Reactant: CCOC(=O)c1ccc(CC(=O)c2ccc(O)cc2O)cc1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)c1ccc(CC(=O)c2ccc(O)cc2O)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 82.2 %

Procedure:
To a solution of ethyl 4-(2-(2,4-dihydroxyphenyl)-2-oxoethyl)benzoate (2 g, 6.7 mmol) in 1,4-dioxane (10 ml), was added conc. HCl (10 ml). The reaction mixture was stirred at 70° C. overnight. The volatiles were removed under reduced pressure. The residue was dissolved with water (20 ml) and extracted with EtOAc (20 ml×2). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated to afford product as a brown solid (1.5 g, 83.3%). MS (ESI): m/z 273.1 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl.[CH2:13](O)[CH3:14]>>[CH2:13]([O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([Br:11])[CH:9]=[CH:10][C:2]=1[NH2:1])[CH3:14]
Reactant: Nc1ccc(Br)cc1C(=O)O
Reactant: CCO
Agent: Cl
Product: CCOC(=O)c1cc(Br)ccc1N

Procedure:
As in scheme 1 step 1, from 2-amino-5-bromobenzoic acid, ethanol and HCl gas and heating under reflux for 16 h to afford an off-white solid, mp 83° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[F:11].C(Cl)(=O)C(Cl)=O.Cl.[CH3:19][NH:20][O:21][CH3:22].C(N(CC)CC)C>ClCCl.CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:20]([O:21][CH3:22])[CH3:19])=[O:7])=[CH:4][C:3]=1[F:11]
Reactant: O=C(O)c1ccc(Br)c(F)c1
Reactant: CNOC
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc(Br)c(F)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 95.9 %

Procedure:
To a suspension of 4-bromo-3-fluorobenzoic acid (1, 967.9 g, 4.4 mol) in dichloromethane (5.9 L) and DMF (21 mL) was slowly added a solution of oxalyl chloride ((COCl)2, 560 mL, 6.4 mol, 1.45 equiv) in dichloromethane (520 mL) at room temperature. The resulting reaction mixture was stirred at room temperature for 20 h and then cooled to 0° C. by ice-water bath. N,O-dimethyl hydroxylamine hydrochloride (826 g, 8.4 mol, 1.9 equiv) was added followed by slow addition of triethylamine (TEA, 2.5 L, 17.7 mol, 4.0 equiv) at 0° C. The reaction mixture was then gradually warmed to room temperature and stirred at room temperature overnight. Once the coupling reaction was complete, the reaction mixture was washed with saturated aqueous sodium bicarbonate solution (NaHCO3, 2 L). The aqueous phase was back extracted with dichloromethane (1 L). The combined organic phases were washed with water (1 L), brine (1 L), and concentrated under reduced pressure. The resulting solid residue was dissolved into methyl tert-butyl ether (MTBE, 5 L), washed sequentially with water (5×1 L), brine (1 L), and dried over anhydrous sodium sulfate (Na2SO4). The filtrated solution was concentrated under reduced pressure and the resulting solid was dried in a vacuum oven at 45° C. to afford 4-bromo-3-fluoro-N-methoxy-N-methylbenzamide (3, 1106 g, 1153 g theoretical, 95.9% yield) which was used for the subsequent reaction without further purification. For 3: 1H NMR (400 MHz, DMSO-d6) δ ppm 7.78 (t, 1H, J=7.47 Hz), 7.56 (dd, 1H, J=9.3, 1.6 Hz), 7.18 (d, 1H, J=8.1 Hz), 3.53 (s, 3H), 3.25(s, 3H); C9H9BrFNO2 (MW 262.08), LCMS (EI) m/e 262.0/264.0 (M++H).
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH:12]2[S:24][C:16]3=[N:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[N:15]3[CH2:14][CH2:13]2)(=O)=O)=CC=1.O.[NH3:27].O1CCOCC1>O>[NH2:27][CH2:11][CH:12]1[S:24][C:16]2=[N:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:15]2[CH2:14][CH2:13]1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCn3c(nc4ccccc43)S2)cc1
Reactant: N
Solvent: C1COCCO1
Solvent: O
Product: NCC1CCn2c(nc3ccccc32)S1
Temperature: 120 °C
Yield: 35.1 %

Procedure:
To 2.24 g of 3,4-dihydro-2-p-toluenesulfonyloxymethyl-2H-(1,3)-thiazino[3,2-a]benzimidazole, were added 5 g of 25% ammonia water and 40 ml of dioxane. The mixturewere heated in a sealed tube, at 120° C., for 75 hours. The reactionmixture was then condensed under reduced pressure. The residue was added with water and then extracted with chloroform, and dried over anhydrous magnesium sulfate. Chloroform was evaporated under reduced pressure. The residue was chromatographed on silica gel and eluted with chloroform to obtain 0.46 g (yield: 35.1%) of the intended product, m.p. 217°-222° C.; IR νmaxKBr cm-1 3300-2600, 1440; Anal. Calcd. for C11H13N3S: C, 60.25; H, 5.97; N, 19.16; S, 14.62; Found: C, 60.28; H, 5.99; N, 19.60; S, 14.13.
Reaction SMILES: C([O:8][C:9]1[CH:21]=[CH:20][C:12]([O:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][CH:10]=1)C1C=CC=CC=1>O1CCCC1.[C].[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:20][CH:21]=1
Reactant: CCOC(=O)COc1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(O)cc1
Yield: 93 %

Procedure:
Ethy 4-benzyloxyphenoxyacetate (21.78 g) was hydrogenated using 7.5% palladium carbon (3.2 g) in tetrahydrofuran (220 ml) at 3 atm over 7 hours. After completion of the reaction, the reaction mixture was filtered through celite, and the solvent was evaporated. The obtained solid was filtrated with diisopropyl ether and dried under reduced pressure to give the title compound (13.88 g) as a white solid.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:12]2[N:13]=[C:14]([CH2:19][O:20][CH2:21][CH3:22])[N:15]([CH2:16][CH2:17][CH3:18])[C:11]=2[C:10]2[CH:9]=[C:8]([O:23][CH2:24][CH2:25][NH:26]C(=O)OC(C)(C)C)[CH:7]=[CH:6][C:5]=2[N:4]=1>C(O)C>[NH2:26][CH2:25][CH2:24][O:23][C:8]1[CH:7]=[CH:6][C:5]2[N:4]=[C:3]([NH2:2])[C:12]3[N:13]=[C:14]([CH2:19][O:20][CH2:21][CH3:22])[N:15]([CH2:16][CH2:17][CH3:18])[C:11]=3[C:10]=2[CH:9]=1
Reactant: CCCn1c(COCC)nc2c(N)nc3ccc(OCCNC(=O)OC(C)(C)C)cc3c21
Agent: Cl
Solvent: CCO
Product: CCCn1c(COCC)nc2c(N)nc3ccc(OCCN)cc3c21
Temperature: 25 °C
Yield: 85.4 %

Procedure:
A solution of hydrogen chloride (55 mL of 1.2 M) in ethanol was added to tert-butyl 2-[(4-amino-2-ethoxymethyl-1-propyl-1H-imidazo[4,5-c]quinolin-8-yl)oxy]ethylcarbamate (3.98 g, 8.97 mmol), and the reaction was heated at reflux for one hour. The reaction mixture was allowed to cool to ambient temperature, and the solvent was removed under reduced pressure. The resulting yellow solid was dissolved in a small volume of water, and 10% aqueous sodium hydroxide was added to adjust to pH 13. The mixture was then extracted with dichloromethane (3×100 mL), and the combined extracts were washed sequentially with water and brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting solid was recrystallized from acetonitrile to provide 2.63 g of 8-(2-aminoethoxy)-2-ethoxymethyl-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine as fine, peach-colored needles, mp 157-159° C.
Reaction SMILES: FC(F)(F)S(O[CH2:7][C:8]([F:14])([F:13])[CH2:9][CH:10]1[CH2:12][CH2:11]1)(=O)=O.[N-:17]=[N+:18]=[N-:19].[Na+]>CN(C=O)C.O>[CH:10]1([CH2:9][C:8]([F:14])([F:13])[CH2:7][N:17]=[N+:18]=[N-:19])[CH2:12][CH2:11]1
Reactant: O=S(=O)(OCC(F)(F)CC1CC1)C(F)(F)F
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCC(F)(F)CC1CC1
Temperature: 25 °C

Procedure:
A solution of 1.68 g (6.3 mmol) of 3-cyclopropyl-2,2-difluoropropyl trifluoromethanesulfonate and 820 mg (12.6 mmol) of sodium azide in 6.0 mL of DMF was heated at 50° C. under Ar overnight. After cooling to rt, the mixture was diluted with 40 mL of water, and extracted with two 75 mL portions of ether. The combined organic layers were washed thrice with water, brine, and dried over MgSO4. The solvents were concentrated by distillation at atmospheric pressure to give a solution of the title compound in ether that was used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:16]=[CH:15][C:11]3N=CS[C:10]=3[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.BrC1C=CC2[S:25][CH:24]=[N:23]C=2C=1.ClC1C(B2OC(C)(C)C(C)(C)O2)=CC=CN=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[C:7]([C:8]2[CH:16]=[CH:15][C:11]3[S:25][CH:24]=[N:23][C:10]=3[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Brc1ccc2scnc2c1
Reactant: Clc1ncccc1-c1ccc2ncsc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC1(C)OB(c2cccnc2Cl)OC1(C)C
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Clc1ncccc1-c1ccc2scnc2c1
Yield: 70 %

Procedure:
5-(2-chloropyridin-3-yl)benzo[d]thiazole was prepared in the similar manner of 6-(2-chloropyridin-3-yl)benzo[d]thiazole by heating the mixture of 5-bromobenzothiazole (1.0 g, 4.67 mmol), 2-chloro-3-pyridine boronic acid pinacol ester (1.34 g, 5.6 mmol), Pd(PPh3)4 (250 mg, 0.22 mmol) and 2M aq.Na2CO3 (7 mL, 14 mmol) in 1,4-dioxane (50 mL). Upon work-up and purification protocol used in the preparation of 6-(2-chloropyridin-3-yl)benzo[d]thiazole provided 5-(2-chloropyridin-3-yl)benzo[d]thiazole as a white solid (820 mg, 70%). 1H NMR (DMSO-d6): δ 9.46 (s, 1H), 8.45 (dd, 1H, J=2.0 and 4.9 Hz), 8.27 (d, 1H, J=8.5 Hz), 8.17 (app s, 1H), 7.97 (dd, 1H, J=1.7 and 7.6 Hz), 7.58 (d, 1H, J=8.5 Hz), 7.53 (dd, 1H, J=4.7 and 7.6 Hz), LCMS: rt 6.73 min (A), purity 99%, MS (m/e) 247.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:13](=[O:14])[CH:12]=[CH:11][C:10]2[C:15]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:16]([C:18](O)=[O:19])[S:17][C:9]1=2.C(N1C=CN=C1)([N:29]1C=CN=C1)=O.N>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:13](=[O:14])[CH:12]=[CH:11][C:10]2[C:15]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:16]([C:18]([NH2:29])=[O:19])[S:17][C:9]1=2
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1sc2c(ccc(=O)n2-c2ccccc2Cl)c1-c1ccccc1
Agent: N
Solvent: CN(C)C=O
Product: NC(=O)c1sc2c(ccc(=O)n2-c2ccccc2Cl)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84.1 %

Procedure:
A mixture of the compound of Example 126 (125 mg, 0.328 mmol) and 1,1′-carbonyldiimidazole (80 mg, 0.49 mmol) in DMF (3 mL) was stirred at r.t. for 90 min. Concentrated ammonia solution (0.5 mL) was added and the mixture stirred for 1 h. Volatiles were removed in vacuo. The residue was treated with 2M HCl(aq) and the resulting solid filtered off and dried. Purification by column chromatography on silica (3% MeOH in DCM) gave the title compound as a pale brown solid (105 mg, 84%). δH (DMSO-d6) 7.91–7.89 (1H, m), 7.83–7.80 (1H, m), 7.76–7.69 (2H, m), 7.66–7.59 (3H, m), 7.56–7.53 (2H, m), 7.51 (1H, d, J 9.7 Hz), 6.62 (1H, d, J 9.6 Hz), 6.2 (2H, br s). LCMS (ES+) RT 3.120 minutes, 380.8 (M+H)+.