Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH2:8][CH2:9][CH:10]([C:14]([N:16]3[CH2:21][CH2:20][CH:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:18][CH2:17]3)=[O:15])[CH2:11][C:12](=[O:13])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:34](Br)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CCO>[CH2:34]([O:1][C:2]1[C:7]2[CH2:8][CH2:9][CH:10]([C:14]([N:16]3[CH2:21][CH2:20][CH:19]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:18][CH2:17]3)=[O:15])[CH2:11][C:12](=[O:13])[C:6]=2[CH:5]=[CH:4][CH:3]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: BrCc1ccccc1
Reactant: O=C1CC(C(=O)N2CCC(c3ccccc3)CC2)CCc2c(O)cccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=C1CC(C(=O)N2CCC(c3ccccc3)CC2)CCc2c(OCc3ccccc3)cccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.5 %

Procedure:
600 mg (0.00165 mol) of (±)-1-hydroxy-7-[(4-phenylpiperidin-1-yl)carbonyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one were dissolved in 100 mL of abs. EtOH under a nitrogen atmosphere, then 228 mg (0.00165 mol) of anhydrous K2CO3 and a catalytic amount of KI were added, followed by 0.216 mL (0.0018 mol) of benzylbromide. The reaction mixture was stirred 3 h at room temperature, then 0.216 mL of benzylbromide were added and the stirring continued overnight. Further 0.216 mL of benzylbromide was added and the reaction stirred overnight. The solvent was then evaporated, the residue was taken up in water, brought to pH 1 with 1N HCl and extracted with AcOEt. The organic phase was dried and the solvent was removed in vacuo, the resulting crude product was purified by flash chromatography, eluting with a mixture Et2O/Hexane 8:2 respectively, yielding 595 mg of the title compound.
Reaction SMILES: COC(OC)[N:4]([CH3:6])C.[NH:9]1[CH2:22][CH2:21][CH2:20][NH:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.CO.[OH-].[Na+].[C:27]1(C)C=CC=C[CH:28]=1>O>[C:6]([CH2:27][CH2:28][N:9]1[CH2:22][CH2:21][CH2:20][NH:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)#[N:4]
Reactant: C1CNCCNCCCNCCNC1
Reactant: COC(OC)N(C)C
Reactant: Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: N#CCCN1CCCNCCNCCCNCC1
Temperature: 25 °C
Reaction time: 9 h

Procedure:
13.68 g (114.8 mmol) of dimethylformamide-dimethylacetal (under nitrogen) is added to 20.0 g (99.83 mmol) of 1,4,8,11-tetraazacyclotetradecane in 200 ml of absolute toluene. It is refluxed slowly and the solvent is distilled off in this way. Then, it is concentrated by evaporation under reduced pressure. The residue is cooled to room temperature. 6.36 g (119.8 mmol) of acrylic acid nitrile is instilled under a nitrogen atmosphere and heated slowly to 75° C. It is stirred for 9 hours at this temperature. It is cooled to room temperature and a mixture of 120 ml of methanol/30 ml of water is added. It is stirred for 10 minutes at room temperature. Then, 11.98 g (299.5 mmol) of sodium hydroxide is added and it is stirred for 24 hours at 40° C. It is evaporated to dryness in a vacuum and the residue is extracted 3 times with hot toluene (80° C.). The organic phase is dried on potassium hydroxide and concentrated by evaporation in a vacuum.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:17][C:16]3[C:11](=[CH:12][C:13]([OH:18])=[CH:14][CH:15]=3)[CH:10]3[CH2:19]S[CH2:21][CH:9]23)=[CH:4][CH:3]=1.O[O:23][S:24]([O-:26])=O.[K+].[O-]S([O-])=O.[Na+].[Na+]>CO.O.CCOC(C)=O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[O:17][C:16]3[C:11](=[CH:12][C:13]([OH:18])=[CH:14][CH:15]=3)[C@@H:10]3[CH2:19][S:24](=[O:26])(=[O:23])[CH2:21][C@H:9]23)=[CH:6][CH:7]=1
Reactant: O=S([O-])OO
Reactant: Oc1ccc(C2Oc3ccc(O)cc3C3CSCC32)cc1
Agent: O=S([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: O=S1(=O)C[C@H]2[C@@H](C1)c1cc(O)ccc1O[C@H]2c1ccc(O)cc1
Yield: 75.8 %

Procedure:
To a solution of enantiomer A of 4-(4-hydroxy-phenyl)-1,3a,4,9b-tetrahydro-3H-5-oxa-2-thia-cyclopenta[a]naphthalen-8-ol 11d (10 mg, 0.033 mmol) in MeOH/H2O (1:1, 3 mL) add oxone (40 mg, 0.066 mmol). Stir the reaction at 50° C. for 2 hours. Add 1.0 M Na2SO3 and stir the reaction for 5 minutes. Dilute with EtOAc and wash with saturated sodium bicarbonate. Extract aqueous layer with EtOCAc (2×). Combine organic extracts, dry (Na2SO4), filter and concentrate to afford 4-(4-Hydroxy-phenyl)-2,2-dioxo-1,2,3,3a,4,9b-hexahydro-5-oxa-2λ6-thia-cyclopenta[a]naphthalen-8-ol 14 (8.5 mg, 0.025 mmol, 77%). 1H NMR (δ, 400 MHz, MeOD) 7.47 (d, 2H, J=8.3 Hz), 6.87-6.74 (m, 4H), 6.67 (dd, 1H, J=8.6, 2.4 Hz), 5.25 (s, 1H), 4.12-4.01 (m, 2H), 3.00 (m, 1H), 2.72 (dt, 1H, J=6.8, 12.8 Hz), 2.63-2.53 (m, 1H), 2.52-2.42 (m, 1H). HPLC (Zorbax C18 column; 10 to 100% CH3CN/H2O for 10 min then 100% CH3CN for 5 min; 1 mL/min; tr 7.68 min).
Reaction SMILES: [CH2:1]([O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][O:7]1)[CH2:2][C:3]#[CH:4].Cl[C:13]([O:15][CH2:16][CH3:17])=[O:14]>>[CH2:16]([O:15][C:13](=[O:14])[C:4]#[C:3][CH2:2][CH2:1][O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][O:7]1)[CH3:17]
Reactant: CCOC(=O)Cl
Reactant: C#CCCOC1CCCCO1
Product: CCOC(=O)C#CCCOC1CCCCO1

Procedure:
The title compound was prepared from 2-but-3-ynyloxy-tetrahydro-pyran and ethyl chloroformate in accordance with the procedures of G. Cai et al., Tetrahedron, 2006, (5697-5708).
Reaction SMILES: [NH4+:1].[Cl-].C[Al](C)C.[Br:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[CH2:15][C:16]#[N:17].CO>C1(C)C=CC=CC=1.ClCCl>[ClH:14].[Br:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[CH2:15][C:16]([NH2:1])=[NH:17]
Reactant: N#CCc1ccc(Cl)cc1Br
Reactant: [NH4+]
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Cl
Product: N=C(N)Cc1ccc(Cl)cc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 174.4 %

Procedure:
To a stirred suspension of NH4Cl (9.241 g, 169.565 mmol) in dry toluene (120 mL) was added tri-methyl aluminum (2M) (45.23 mL, 90.435 mmol) at 5° C. the reaction mixture was warmed to room temperature and the reaction mixture was stirred for 2 h. A solution of (2-bromo-4-chlorophenyl)-acetonitrile (374) (13 g, 56.522 mmol) in toluene (30 mL) was added to the above reaction mixture and the reaction mixture was stirred for 14 h at 80° C. while silica thin layer chromatography was performed (10% methanol in dichloromethane; Rf=0.2). After completion of the reaction, the reaction mixture was quenched with a suspension of silica gel (20 g) in chloroform (200 mL) and the reaction mixture was stirred for half an hour at room temperature and filtered. The silica gel was washed with methanol (100 mL) and the combined filtrate was concentrated under reduced pressure to get 2-(2-bromo-4-chlorophenyl)-acetamidine hydrochloride (375) (14.0 g, 87.68%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:24])[CH2:15][NH:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:9][CH:8]=2)[N:6]=1.CCN(CC)CC.[N:32]1([C:38](Cl)=[O:39])[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOC(C)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:24])[CH2:15][N:16]([CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:38]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[O:39])=[CH:9][CH:8]=2)[N:6]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: Nc1nc(-c2ccc(NC(=O)CNCc3ccccc3)cc2)cs1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Nc1nc(-c2ccc(NC(=O)CN(Cc3ccccc3)C(=O)N3CCOCC3)cc2)cs1
Reaction time: 0.5 h
Yield: 68.3 %

Procedure:
To a cooled (0°) suspension of N-{4-(2-amino-4-thiazolyl)phenyl}-2-{(phenylmethyl)amino}acetamide (1.02 g, 3.00 mmol, described in example 2) in CH2Cl2 (30 mL) and Et3N (836 μL, 6.00 mmol), were added DMAP (36.6 mg, 0.30 mmol) and 4-morpholinecarbonyl chloride (350 μL, 3.00 mmol). The reaction mixture was stirred at 0° for 30 min, and then at room temperature for 18 h. The reaction mixture was then dissolved in EtOAc (300 mL). The resulting solution was washed with saturated aqueous NaHCO3 (100 mL), brine (100 mL), then dried (MgSO4), and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, EtOAc) to afford the title compound (925 mg, 68% yield) as a white solid: M.p. 105° (decomp.); 1H NMR (400 MHz, DMSO-d6) δ9.94 (s, 1H), 7.71 (d, J=8.7 Hz, 2H), 7.55 (d, J=8.7 Hz, 2H), 7.25-7.39 (m, 5H), 6.99 (s, 2H), 6.88 (s, 1H), 4.47 (s, 2H), 3.84 (s, 2H), 3.59 (t, J=4.9 Hz, 4H), 3.19 (t, J=4.9 Hz, 4H); MS (FAB) m/z 452 (MH)+; Anal. Calcd for C23H25N5SO3: C, 61.18; H, 5.58; N, 15.51. Found: C, 60.61; H, 5.60; N, 15.35.
Reaction SMILES: [CH:1]1([NH:6][CH2:7][C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:13][C:14](Cl)([O:16]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[CH:1]1([N:6]([CH2:7][C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[C:14]([Cl:13])=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: c1csc(CNC2CCCC2)c1
Solvent: ClCCl
Product: O=C(Cl)N(Cc1cccs1)C1CCCC1
Temperature: 25 °C
Reaction time: 64 h
Yield: 147.5 %

Procedure:
To a solution of 5.0 g (27.58 mmol) of cyclopentylthiophen-2-ylmethylamine in 40 ml of methylene chloride at 10° C. was added slowly with stirring 4.09 g (13.79 mmol) of triphosgene in 35 ml of methylene chloride. The reaction was allowed to continue stirring at room temperature for 64 hours, refluxed for 4 hours and 25 hours more at room temperature. The solvent was evaporated and the residue extracted with n-hexane. The organic solution was concentrated to yield 4.96 g (20.34 mmol) of a brown oil (74%). 1H-NMR (CDCl3): δ 1.4 (m, 8H), 4.2 (bs, 1H), 4.5 (m, 2H), 6.8-7.3 (m, 3H).
Reaction SMILES: [H-].[Na+].C1COCC1.[C:8]([O:12][C:13](=[O:21])/[CH:14]=[CH:15]/[C:16]1[CH:20]=[CH:19][NH:18][CH:17]=1)([CH3:11])([CH3:10])[CH3:9].[Br:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>O>[C:8]([O:12][C:13](=[O:21])/[CH:14]=[CH:15]/[C:16]1[CH:20]=[CH:19][N:18]([S:29]([C:26]2[CH:27]=[CH:28][C:23]([Br:22])=[CH:24][CH:25]=2)(=[O:31])=[O:30])[CH:17]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)/C=C/c1cc[nH]c1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)/C=C/c1ccn(S(=O)(=O)c2ccc(Br)cc2)c1
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
A mixture of 0.85 g NaH with 70.0 ml THF is cooled to −30° C. and 5.0 g (E)-3-(1H-pyrrol-3-yl)-acrylic acid tert-butyl ester are added. During the addition there is liberated a gas. The solution is stirred at ambient temperature for 0.5 h. Then 7.9 g 4-bromobenzenesulfonylchloride is added by -30° C. The suspension is stirred at ambient temperature for 3 h. The mixture is treated with water and then it is extracted with ethyl acetate. The title compound is isolated by flash chromatography. By this method 7.0 g of a colorless solid are obtained.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:10]1[C:15]2[N:16]=[C:17]([NH:19][CH2:20][CH2:21][C:22]([O:24][C:25](C)(C)C)=[O:23])[O:18][C:14]=2[C:13]([N:29]2[CH2:33][CH2:32][C@H:31]([N:34]([CH3:36])[CH3:35])[CH2:30]2)=[C:12]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:11]=1[CH3:43])#[N:9].S(Cl)(Cl)=O>ClCCl>[C:8]([C:10]1[C:15]2[N:16]=[C:17]([NH:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[O:18][C:14]=2[C:13]([N:29]2[CH2:33][CH2:32][C@H:31]([N:34]([CH3:35])[CH3:36])[CH2:30]2)=[C:12]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:11]=1[CH3:43])#[N:9]
Reactant: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(NCCC(=O)OC(C)(C)C)nc2c1C#N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COC(=O)CCNc1nc2c(C#N)c(C)c(-c3ccccc3)c(N3CC[C@H](N(C)C)C3)c2o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 17.2 %

Procedure:
Trifluoroacetic acid (1 ml) was added to a dichloromethane (2 ml) solution of tert-butyl N-{4-cyano-7-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-5-methyl-6-phenyl-1,3-benzoxazol-2-yl)-β-alaninate (I-279) (51 mg, 0.104 mmol), followed by stirring at room temperature for 2 hours. The reaction liquid was concentrated under reduced pressure, the residue was dissolved in dichloromethane (1 ml), and at room temperature, thionyl chloride (10 μl, 0.138 mmol) was added, followed by stirring at room temperature for 1 hour. The reaction liquid was concentrated under reduced pressure, the then dissolved in chloroform, and washed with an aqueous saturated sodium hydrogencarbonate solution and saturated brine. After drying over anhydrous sodium sulfate and concentration, the insoluble matter was separated by filtration, the solvent was evaporated away, and the resulting residue was purified by preparative TLC (eluent, chloroform:methanol=20:1, v/v), the eluate was purified in slurry with diethyl ether to obtain the entitled compound (8.00 mg, 17%) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].C(O[O:14][C:15]([CH3:18])(C)C)(C)(C)C.[C]=O.[CH2:21]([OH:23])C>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:21]([O:14][CH2:15][CH3:18])=[O:23]
Reactant: CCO
Reactant: CC(C)(C)OOC(C)(C)C
Reactant: Cc1ccccc1Cl
Agent: [C]=O
Product: CCOC(=O)Cc1ccccc1Cl
Temperature: 120 °C
Reaction time: 16 h
Yield: 82.7 %

Procedure:
o-Chlorotoluene (1.89 g), ethanol (46 mg), di-tert-butyl peroxide (73 mg, 1 equivalent), and Pd(Xantphos)Cl2 (3.8 mg, 1 mol %) were added into a reaction kettle, into which 10 atm carbon monoxide was introduced. The reaction was heated to 120° C., and stirred at this constant temperature for 16 h. After the reaction was completed, carbon monoxide was discharged, and 82 mg ethyl o-chlorophenylacetate was obtained by column chromatography, in a yield of 83%. 1HNMR (400 MHz, CDCl3) δ 1.24 (t, J=7.2 Hz, 3H), 3.77 (s, 2H), 4.15 (q, J=7.2 Hz, 2H), 7.21-7.24 (m, 2H), 7.28-7.30 (m, 1H), 7.36-7.40 (m, 1H); 13CNMR (100 MHz, CDCl3) δ 14.2, 39.2, 61.0, 126.9, 128.6, 129.5, 131.4, 132.6, 134.6, 170.6; HRMS (ESI) calcd. for C10H11ClNaO2 [M+Na]: 221.0340. found: 221.0343. The ethyl o-chlorophenylacetate obtained was dissolved in 1,4-dioxane. 6 N sodium hydroxide solution was added, and the reaction was heated to 60° C. After 2 h of reaction, the pH value was adjusted to 1 by adding 2 N hydrochloric acid. After removing the organic solvent under reduced pressure, 66 mg product o-chlorophenylacetic acid was obtained by extraction with ethyl acetate, and the yield of hydrolysis was 94%.
Reaction SMILES: N1([C:6]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[S:9](=[O:17])(=[O:16])[CH2:8][C:7]=2[C:18]([O:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)=[O:19])CCCC1.Cl.C(O)(=[O:33])C>>[OH:33][C:6]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[S:9](=[O:17])(=[O:16])[CH2:8][C:7]=1[C:18]([O:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1)=[O:19]
Reactant: CC(=O)O
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)C1=C(N2CCCC2)c2ccccc2S(=O)(=O)C1
Agent: Cl
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)C1=C(O)c2ccccc2S(=O)(=O)C1
Temperature: 0 °C

Procedure:
A mixture of 7.0 g of p-nitrophenyl 4-(1-pyrrolidinyl)-2H-1-benzothiopyran-3-carboxylate 1,1-dioxide, 50 ml of glacial acetic acid, and 100 ml of 1N hydrochloric acid was heated on a steam bath for 20 min and diluted with ice-water. The resulting precipitate was collected and recrystallized from tetrahydrofuran-isopropyl ether to give 5.5 g of product, mp 206°-209° dec.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[N:7]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[C:30]2[C:29]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[N+:23]([O-])=[CH:22][C:21]=2[N:20]=[C:19]1[CH2:32][CH3:33])[CH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[OH-].[NH4+:47]>C(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:34])[N:7]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[C:30]2[C:29]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[N:23]=[C:22]([NH2:47])[C:21]=2[N:20]=[C:19]1[CH2:32][CH3:33])[CH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [NH4+]
Reactant: CCc1nc2c[n+]([O-])c3ccccc3c2n1CCCCN(C(=O)OC(C)(C)C)C1CCOCC1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCc1nc2c(N)nc3ccccc3c2n1CCCCN(C(=O)OC(C)(C)C)C1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl[4-(2-ethyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)butyl]tetrahydro-2H-pyran-4-ylcarbamate in chloroform was added p-toluene sulfonyl chloride (1.2 eq.) followed by aq.ammonium hydroxide solution. The resulting reaction mixture was stirred at room temperature for overnight. Reaction mixture was washed with saturated sodium bicarbonate solution. Organic layer separated, dried over anhydrous sodium sulphate and concentrated under reduced pressure to yield sticky solid, which was then purified using silica gel column chromatography to afford tert-butyl[4-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]tetrahydro-2H-pyran-4-ylcarbamate.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9](=[O:24])[C:10]([OH:23])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:4][CH2:3]1.[Br:25][CH2:26][C:27]([NH:29][C:30]1[CH:34]=[CH:33][O:32][N:31]=1)=[O:28].O>C(#N)C>[Br-:25].[OH:23][C:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:9]([O:8][CH:5]1[CH2:6][CH2:7][N+:2]([CH2:26][C:27](=[O:28])[NH:29][C:30]2[CH:34]=[CH:33][O:32][N:31]=2)([CH3:1])[CH2:3][CH2:4]1)=[O:24]
Reactant: O=C(CBr)Nc1ccon1
Reactant: CN1CCC(OC(=O)C(O)(c2ccccc2)c2ccccc2)CC1
Solvent: O
Solvent: CC#N
Product: C[N+]1(CC(=O)Nc2ccon2)CCC(OC(=O)C(O)(c2ccccc2)c2ccccc2)CC1
Product: [Br-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution comprising hydroxy-diphenyl-acetic acid 1-methyl-piperidin-4-yl ester (Intermediate F) (0.25 g, 0.77 mmol) in acetonitrile (5 ml) under an inert atmosphere of argon is added 2-bromo-N-isoxazol-3-yl-acetamide (Intermediate A). The reaction mixture is stirred overnight at room temperature and then water is added. Acetonitrile is removed in vacuo and the resulting mixture is decanted into a clean flask and left overnight. The solid that formed is filtered to yield the titled product.
Reaction SMILES: [C:1]([Cl:6])(=[O:5])[CH2:2][CH2:3][CH3:4].[C:7]([O:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][N:23]=2)[N:18]=[CH:17][C:16]=1[NH2:25])(=[O:9])[CH3:8]>ClCCl>[ClH:6].[C:7]([O:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][N:23]=2)[N:18]=[CH:17][C:16]=1[NH:25][C:1](=[O:5])[CH2:2][CH2:3][CH3:4])(=[O:9])[CH3:8]
Reactant: CCCC(=O)Cl
Reactant: CC(=O)OCCCNc1c(N)cnc2cccnc12
Solvent: ClCCl
Product: CCCC(=O)Nc1cnc2cccnc2c1NCCCOC(C)=O
Product: Cl
Reaction time: 1 h

Procedure:
Butyryl chloride (4.7 mL, 45.4 mmol) was added dropwise to a solution of 3-[(3-amino[1,5]naphthyridin-4-yl)amino]propyl acetate prepared in Part C in dichloromethane (160 mL) at 0° C. The solution was allowed to warm to room 3 temperature and stir for 1 hour, then was concentrated under reduced pressure to provide 3-{[3-(butyrylamino)[1,5]naphthyridin-4-yl]amino}propyl acetate hydrochloride as a dark orange foam that was used directly in the next step.
Reaction SMILES: [NH2:1][CH:2]([CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6]1)[CH2:3][CH3:4].Cl[C:16]1[C:21]([Cl:22])=[C:20]([CH2:23][CH3:24])[N:19]=[CH:18][N:17]=1.C(N(CC)CC)C>C(O)(C)C>[Cl:22][C:21]1[C:16]([NH:1][CH:2]([CH:5]2[CH2:14][CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6]2)[CH2:3][CH3:4])=[N:17][CH:18]=[N:19][C:20]=1[CH2:23][CH3:24]
Reactant: CCC(N)C1CCc2ccccc2N1
Reactant: CCc1ncnc(Cl)c1Cl
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CCc1ncnc(NC(CC)C2CCc3ccccc3N2)c1Cl
Temperature: 80 °C
Yield: 70.8 %

Procedure:
Example P-1:1.3 g of 2-(1-aminopropyl)-1,2,3,4-tetrahydro-quinoline, 1.4 g of 4,5-dichloro-6-ethylpyrimidine and 0.85 g of triethylamine in 60 ml of absolute isopropanol are placed in a sulfonation flask at room temperature. The internal temperature of the flask is increased to 80° C. and the reaction mixture is stirred under reflux for 12 hours. The solvent is then removed under a water-jet vacuum, the residue is taken up in a mixture of 200 ml of ethyl acetate and 70 ml of water andthe mixture is shaken well. The organic phase is removed and the aqueous phase is further extracted twice, each time with 100 ml of ethyl acetate. The organic phase is dried over Na2SO4 and the solvent is removed under a water-jet vacuum. The crude product which remains can thenbe further purified by flash chromatography on silica gel (eluant: ethyl acetate/n-hexane 1:3) to yield 1.6 g of 2-[1-(5-chloro-6-ethylpyrimidin-4-ylamino)propyl]-1,2,3,4-tetrahydro-quinoline in the form of a red oil (nD50 =1.5822).
Reaction SMILES: [Br-].[C:2]([NH:5][C:6]1[S:7][CH:8]=[C:9]([CH2:11][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:10]=1)(=[O:4])[CH3:3].[OH:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=1.CC(C)([O-])C.[K+].O>CN(C)C=O.C(OCC)(=O)C>[OH:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=[CH:11][C:9]2[N:10]=[C:6]([NH:5][C:2](=[O:4])[CH3:3])[S:7][CH:8]=2)=[CH:34][CH:33]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: CC(=O)Nc1nc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cs1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)Nc1nc(C=Cc2ccc(O)cc2)cs1
Temperature: 90 °C
Reaction time: 12 h
Yield: 64.4 %

Procedure:
{[2-(Acetylamino)-1,3-thiazol-4-yl]methyl}(triphenyl)phosphoniumbromide (261.1 mg, 0.525 mmol) and 4-hydroxybenzaldehyde (183.2 mg, 1.50 mmol) were dissolved in anhydrous N,N-dimethylformamide (2 ml), and potassium tert-butoxide (56.1 mg, 0.50 mmol) was added at 0° C. After stirring at 90° C. for 12 hr, the mixture was cooled to room temperature. Water and ethyl acetate were added, and the mixture was stirred, stood still and then partitioned. The aqueous layer was extracted with ethyl acetate, and the combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (FUJI SILYSIA CHEMICAL LTD. BW-300SP 25 g, ethyl acetate:hexane=4:6→5:5) to give N-{4-[2-(4-hydroxyphenyl)vinyl]-1,3-thiazol-2-yl}acetamide (87.9 mg, 0.338 mmol, yield 67.5%) as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][OH:5].[H-].[Na+].[H][H].[Cl:11][C:12]1[C:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1>CN(C)C=O>[ClH:11].[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][O:5][C:12]1[C:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1
Reactant: Clc1nc2ccccc2cc1-c1ccccc1
Reactant: [H][H]
Reactant: CN(C)CCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCOc1nc2ccccc2cc1-c1ccccc1
Product: Cl
Temperature: 25 °C

Procedure:
2-Dimethylaminoethanol (1.07 g.) was added dropwise to a suspension of sodium hydride (0.56 g. of a 50% w/w dispersion in mineral oil) in dimethylformamide (25 ml.) at 0°-5°. When all the hydrogen had evolved, 2-chloro-3-phenylquinoline (2.5 g.) was added and the mixture was stirred and heated at 75° for 12 hours. The mixture was then cooled to ambient temperature, poured into ice-water (500 ml.), and extracted with ethyl acetate (5×100 ml.). The ethyl acetate extract was washed successively with water (50 ml.) and saturated brine (50 ml.), and then dried (MgSO4). The solvent was evaporated under reduced pressure (approx. 15 mm.) and the residual oil was chromatographed on basic alumina (100 g.; Brockmann Grade III), eluted with increasing concentrations of chloroform in petroleum ether. The eluate obtained with 10% v/v chloroform in petroleum ether was evaporated. The residual oil was dissolved in diethyl ether (100 ml.), and ethereal hydrogen chloride was added until precipitation was complete The mixture was filtered and the solid residue was crystallised from ethanol-diethyl ether to give 2-(2-dimethylaminoethoxy)-3-phenylquinoline hydrochloride, m.p. 155°-7°.