Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:45]=[CH:44][CH:43]=[CH:42][C:7]=1[C:8]([NH:10][C:11]1[CH:41]=[CH:40][C:14]([C:15]([N:17]([CH3:39])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([N:32]2[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]2)=[O:31])=[O:16])=[CH:13][CH:12]=1)=[O:9].C(N(CC)CC)C.[C:53](OC(=O)C)(=[O:55])[CH3:54]>ClCCl>[C:53]([NH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:45]=[CH:44][CH:43]=[CH:42][C:7]=1[C:8]([NH:10][C:11]1[CH:41]=[CH:40][C:14]([C:15]([N:17]([CH3:39])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([N:32]2[CH2:33][CH2:34][N:35]([CH3:38])[CH2:36][CH2:37]2)=[O:31])=[O:16])=[CH:13][CH:12]=1)=[O:9])(=[O:55])[CH3:54]
Reactant: CN1CCN(C(=O)CCCCCOc2ccccc2N(C)C(=O)c2ccc(NC(=O)c3ccccc3OCCCN)cc2)CC1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCCCOc1ccccc1C(=O)Nc1ccc(C(=O)N(C)c2ccccc2OCCCCCC(=O)N2CCN(C)CC2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.1 %

Procedure:
To an ice bath cooled solution of 4-[2-[(3-aminoprop-1-yl)oxy]benzoyl]amino-N-methyl-N-[2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (200 mg) in dichloromethane (10 ml) were added triethylamine (36.2 mg) and acetic anhydride (36.5 mg) and the mixture was stirred at ambient temperature for 4 hours. The reaction mixture was washed successively with water (10 ml), saturated aqueous sodium hydrogen carbonate solution (10 ml) and brine (10 ml), and dried over magnesium sulfate. The solvent was evaporated to give 4-[2-[(3-acetylaminoprop-1-yl)oxy]benzoyl]amino-N-methyl-N-[2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (201 mg) as a colorless amorphous.
Reaction SMILES: C([O:14][C:15]([C:17]1([O:20]/[N:21]=[C:22](/[C:72]2[N:73]=[C:74]([NH:77]C(OC(C)(C)C)=O)[S:75][CH:76]=2)\[C:23]([NH:25][C@@H:26]2[C:29](=[O:30])[N:28]([S:31]([OH:34])(=[O:33])=[O:32])[C@@H:27]2[CH2:35][N:36]2[N:40]=[C:39]([CH2:41][N:42](C(OC(C)(C)C)=O)[C:43]([N:52]3[CH2:55][CH:54]([CH2:56][NH:57]C(OC(C)(C)C)=O)[CH2:53]3)=[N:44]C(OC(C)(C)C)=O)[CH:38]=[N:37]2)=[O:24])[CH2:19][CH2:18]1)=[O:16])(C1C=CC=CC=1)C1C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:57][CH2:56][CH:54]1[CH2:55][N:52]([C:43](=[NH:44])[NH:42][CH2:41][C:39]2[CH:38]=[N:37][N:36]([CH2:35][C@@H:27]3[C@H:26]([NH:25][C:23](=[O:24])/[C:22](=[N:21]\[O:20][C:17]4([C:15]([OH:16])=[O:14])[CH2:19][CH2:18]4)/[C:72]4[N:73]=[C:74]([NH2:77])[S:75][CH:76]=4)[C:29](=[O:30])[N:28]3[S:31]([OH:34])(=[O:33])=[O:32])[N:40]=2)[CH2:53]1
Reactant: CC(C)(C)OC(=O)N=C(N1CC(CNC(=O)OC(C)(C)C)C1)N(Cc1cnn(C[C@@H]2[C@H](NC(=O)/C(=N\OC3(C(=O)OC(c4ccccc4)c4ccccc4)CC3)c3csc(NC(=O)OC(C)(C)C)n3)C(=O)N2S(=O)(=O)O)n1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N=C(NCc1cnn(C[C@@H]2[C@H](NC(=O)/C(=N\OC3(C(=O)O)CC3)c3csc(N)n3)C(=O)N2S(=O)(=O)O)n1)N1CC(CN)C1
Yield: 26.8 %

Procedure:
Followed the general procedure for the acid mediated deprotection using (2R,3S)-3-((Z)-2-((1-((benzhydryloxy)carbonyl)cyclopropoxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-((4-((N,N′-bis(tert-butoxycarbonyl)-3-(((tert-butoxycarbonyl)amino)methyl)azetidine-1-carboximidamido)methyl)-2H-1,2,3-triazol-2-yl)methyl)-4-oxoazetidine-1-sulfonic acid (690 mg, 0.57 mmol), DCM (3 mL) and TFA (2.1 mL, 27.4 mmol). The crude residue was purified via reverse phase prep HPLC (XSelect CSH, 30×100 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 60 mL/min) affording the title compound (98 mg, 27%). LCMS: Rt=0.32 min, m/z=641.3 (M+1), Method 2m_acidic; 1H NMR (400 MHz, DMSO-d6) δ 10.73 (s, 1H), 8.06 (s, 1H), 7.72-7.54 (m, 3H), 7.18 (s, 2H), 6.74 (s, 1H), 5.25 (dd, J=8.9, 5.5 Hz, 1H), 4.88 (dd, J=14.2, 4.3 Hz, 1H), 4.65 (dd, J=14.2, 7.7 Hz, 1H), 4.53 (ddd, J=7.6, 5.6, 4.4 Hz, 1H), 4.46-4.31 (m, 2H), 4.15 (td, J=8.7, 5.0 Hz, 2H), 3.96-3.81 (m, 2H), 3.11 (d, J=7.3 Hz, 2H assumed; partially obscured by water), 2.91 (p, J=6.8 Hz, 1H), 1.26-1.11 (m, 2H), 1.08-0.95 (m, 2H).
Reaction SMILES: [Br:1]Br.[CH3:3][N:4]1[C:8]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([S:22](=[O:29])(=[O:28])[NH:23][CH2:24][CH2:25][O:26][CH3:27])=[CH:18][CH:17]=3)[N:10]=2)=[CH:7][N:6]=[C:5]1[CH3:30].C(=O)([O-])O.[Na+]>C(O)(=O)C.O>[Br:1][C:7]1[N:6]=[C:5]([CH3:30])[N:4]([CH3:3])[C:8]=1[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([S:22](=[O:29])(=[O:28])[NH:23][CH2:24][CH2:25][O:26][CH3:27])=[CH:20][CH:21]=2)[N:10]=1
Reactant: BrBr
Reactant: COCCNS(=O)(=O)c1ccc(Nc2nccc(-c3cnc(C)n3C)n2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COCCNS(=O)(=O)c1ccc(Nc2nccc(-c3c(Br)nc(C)n3C)n2)cc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 24 %

Procedure:
A 1M solution of bromine in acetic acid (8.49 ml, 8.49 mmol) was added to a solution of 4(1,2-dimethylimidazol-5-yl)-2-{4-[N-(2-methoxyethyl)sulphamoyl]anilino}pyrimidine (Example 35 in WO 02/20512; 3.1g, 7.71mmol) in acetic acid (24 ml) heated at 70° C. under nitrogen. The mixture was stirred at 70° C. for 1 hour, allowed to cool, diluted with water and carefully neutralised with saturated aqueous sodium hydrogen carbonate solution. The aqueous solution was extracted with EtOAc, the extracts combined, dried and the volatiles removed by evaporation. The residue was purified by chromatography on silica gel eluting with DCM/MeOH (95:5 increasing in polarity to 90:10) to give the title compound (1 g, 24%). NMR: 2.38 (s, 3H), 2.87 (s, 2H), 2.51 (q, 2H), 3.16 (s, 3H), 3.52 (s, 3H), 7.49 (s, 1H), 7.70 (d, 2H), 7.88 (d, 2H), 8.82 (s, 1H).
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([N+:16]([O-:18])=[O:17])[CH:8]=1.O.[C:20](=O)([O-])[O-].[Na+].[Na+]>CO>[Br:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([O:13][CH3:20])=[O:12])=[C:9]([N+:16]([O-:18])=[O:17])[CH:8]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1ccc(Br)cc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(Br)cc1[N+](=O)[O-]

Procedure:
Add concentrated sulfuric acid (7 mL) to a solution of commercially available 4-bromo-2-nitrobenzoic acid (25.0 g, 102 mmol) in methanol (150 mL), and heat at reflux for 16 hours. Cool the reaction to room temperature and pour into water (500 mL) and adjust the pH of the suspension to 9 with solid sodium carbonate. Extract the solution with ethyl acetate (2×250 mL), then combine the organic extracts and wash with brine (100 mL), dry over sodium sulfate, filter and remove the solvent under reduced pressure to afford the title compound as a pale amber oil, which crystallizes upon standing (20.5 g, 78%)
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][CH2:10][C:11]2[N:21]3[C:22]4[C:17]([CH:18]([OH:23])[CH2:19][CH2:20]3)=[CH:16][CH:15]=[CH:14][C:13]=4[N:12]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:24]I.O>O1CCCC1>[CH3:24][O:23][CH:18]1[C:17]2[C:22]3=[C:13]([N:12]=[C:11]([CH2:10][CH2:9][C:3]4[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=4)[N:21]3[CH2:20][CH2:19]1)[CH:14]=[CH:15][CH:16]=2
Reactant: CI
Reactant: OC1CCn2c(CCc3ccccc3)nc3cccc1c32
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC1CCn2c(CCc3ccccc3)nc3cccc1c32
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 49 %

Procedure:
A portion (115 mg) of 60% sodium hydride was added to anhydrous tetrahydrofuran (15 mL) under an argon atmosphere; 0.2 g of 5,6-dihydro-2-(2-phenylethyl)-4H-imidazo[4,5,1-ij]quinolin-6-ol obtained in Example 4 was dissolved in anhydrous tetrahydrofuran (4 mL) and the solution was added dropwise to the first mentioned solution at room temperature. After stirring for 35 min at room temperature, methyl iodide (1.02 g) was added dropwise and the mixture was stirred for 4 hrs. Water was added to the reaction solution and the mixture was stirred; thereafter, the reaction solution was extracted with dichloromethane, washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to yield the titled compound as a yellow oil (103 mg).
Reaction SMILES: [C:1]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[S:9]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[CH:10]1.N1C=CN=C1>CN(C=O)C.C(OCC)(=O)C>[C:1]([Si:5]([CH3:7])([CH3:6])[O:16][CH2:15][CH2:14][C:11]1[CH:12]=[CH:13][S:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCc1ccsc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCc1ccsc1
Reaction time: 16 h

Procedure:
tert-Butylchlorodimethylsilane (3.88 g) was added to a stirred solution of 2-(thiophen-3-yl)ethanol (3.00 g) and 1H-imidazole (4.78 g) in DMF (30 mL) cooled in ice bath. After 16 h, the reaction mixture was diluted with ethyl acetate (300 mL), washed with water (3×150 mL) and evaporated in vacuo. Purification was by silica gel chromatography eluting with isohexane and then 1:5 ethyl acetate:isohexane, to collect the subtitled compound as an oil. Yield 5.2 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:11](=[O:21])[N:10]([CH2:22][C:23](O)=[O:24])[N:9]=2)=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[F:40][C:41]([F:52])([F:51])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[CH2:48][CH2:49][NH2:50]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:11](=[O:21])[N:10]([CH2:22][C:23]([NH:50][CH2:49][CH2:48][C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=3[C:41]([F:40])([F:51])[F:52])=[O:24])[N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)Cn1nc(-c2ccc(Cl)cc2)n(Cc2ccccc2F)c1=O
Reactant: NCCc1ccccc1C(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(Cn1nc(-c2ccc(Cl)cc2)n(Cc2ccccc2F)c1=O)NCCc1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
The carboxylic acid from Example 156A (60 mg, 0.14 mmol) and HOBt (27.0 mg, 0.20 mmol) are placed in 0.86 ml DMF and treated at RT with 38.2 mg (0.20 mmol) of EDC. After 20 mins, 27 mg of 2-(2-trifluoromethyl-phenyl)ethylamine (0.14 mmol) are added and the mixture is stirred overnight at RT. The mixture is then directly separated by preparative HPLC (Method 20). 69 mg (91% of theory) of the title compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[CH3:11][O:12][C:13]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:14]=1[NH2:15]>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([NH:15][C:14]2[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:13]=2[O:12][CH3:11])=[O:7])=[CH:9][CH:10]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: COc1ccc(N)c(OC)c1
Product: COc1ccc(NC(=O)c2ccc(Cl)nc2)c(OC)c1
Yield: 59 %

Procedure:
The title compound was prepared from 6-chloronicotinoyl chloride and 2,4-dimethoxyaniline as described in Example 1. The reaction mixture was filtered to remove the precipitate and the filtrate was evaporated. The resulting solid was purified by CH2Cl2/hexane recrystallization to give a light purple solid in a yield of 59%. 1H NMR (DMSO-d6): 9.77 (s, 1H), 8.93 (s, 1H), 8.35-8.31 (m, 1H), 7.68 (d, J=7.8, 1H), 7.46 (d, J=9.0, 1H), 6.67 (d, J=2.4, 1H), 6.57-6.53 (m, 1H), 3.80 (s, 3H), 3.78 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:14]=[CH:13][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)=[O:7])=[CH:4][N:3]=1.[CH3:15][C:16]1[CH:29]=[CH:28][C:19]([C:20]([NH:22][N:23]2[NH:27][CH:26]=[CH:25][S:24]2)=[O:21])=[CH:18][C:17]=1B1OC(C)(C)C(C)(C)O1>>[CH:10]1([CH2:9][NH:8][C:6](=[O:7])[C:5]2[CH:13]=[CH:14][C:2]([C:17]3[CH:18]=[C:19]([C:20](=[O:21])[NH:22][N:23]4[NH:27][CH:26]=[CH:25][S:24]4)[CH:28]=[CH:29][C:16]=3[CH3:15])=[N:3][CH:4]=2)[CH2:12][CH2:11]1
Reactant: O=C(NCC1CC1)c1ccc(Cl)nc1
Reactant: Cc1ccc(C(=O)NN2NC=CS2)cc1B1OC(C)(C)C(C)(C)O1
Product: Cc1ccc(C(=O)NN2NC=CS2)cc1-c1ccc(C(=O)NCC2CC2)cn1

Procedure:
N-Cyclopropylmethyl-6-[5-(thiadiazol-2-ylcarbamoyl)-2-methyl-phenyl]-nicotinamide was prepared from 6-chloro-N-cyclopropylmethylnicotinamide (Intermediate 1) and 4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-N-(thiadiazol-2-yl)-benzamide (Intermediate 12) using General Method B. LCMS: retention time 2.79 min, MH+ 394. NMR: δH [2H6]-DMSO 13.14,(1H, b), 9.24, (1H, s), 9.14,(1H, s), 8.86,(1H, t), 8.35,(1H, d), 8.25,(1H, s), 8.10,(1H, d), 7.82,(1H, d), 7.54,(1H, d), 3.21,(2H, t), 2.46,(3H, s), 1.07,(1H, m), 0.47,(2H, m), 0.27, (2H, m).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=1.O.[NH2:13][NH2:14]>C(O)C>[F:9][C:8]([F:11])([F:10])[C:7]1[C:2]([NH:13][NH2:14])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: FC(F)(F)c1cccnc1Cl
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNc1ncccc1C(F)(F)F

Procedure:
A solution of 200 g of 2-chloro-3-trifluoromethylpyridine in 500 ml of ethanol and 300 ml of hydrazine hydrate is heated under reflux for 6 hours. The solution is then concentrated in vacuo and, after cooling, the crystalline residue is then taken up with water, filtered off, washed with water and dried to give 145 g of 3-trifluoromethyl-2-hydrazinopyridine in the form of crystals melting at 72° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([F:10])[C:3]=1[CH:11]([O:15][CH2:16][CH3:17])[C:12]([OH:14])=O.[NH2:18][CH2:19][C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][C:21]=1[O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[C:24]([C:23]1[CH:26]=[CH:27][C:20]([CH2:19][NH:18][C:12](=[O:14])[CH:11]([C:3]2[C:4]([F:10])=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=2[F:1])[O:15][CH2:16][CH3:17])=[C:21]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:22]=1)#[N:25]
Reactant: CCOC(C(=O)O)c1c(F)cc(OC)cc1F
Reactant: N#Cc1ccc(CN)c(Oc2ccccc2)c1
Product: CCOC(C(=O)NCc1ccc(C#N)cc1Oc1ccccc1)c1c(F)cc(OC)cc1F

Procedure:
(RS)-(2,6-Difluoro-4-methoxy-phenyl)-ethoxy-acetic acid (example 101.3) was coupled with 4-aminomethyl-3-phenoxy-benzonitrile (example 106.3) according to general procedure C to give (RS)-N-(4-cyano-2-phenoxy-benzyl)-2-(2,6-difluoro-4-methoxy-phenyl)-2-ethoxy-acetamide. Colorless foam. MS 453.1 ([M+H]+)
Reaction SMILES: [SH:1][C:2]1[O:3][C:4]([C:7]2[O:11][C:10]([CH3:12])=[N:9][N:8]=2)=[N:5][N:6]=1.O1CCOCC1.Br[CH2:20][CH2:21][C:22]([F:26])=[C:23]([F:25])[F:24]>CN(C)C=O>[F:26][C:22](=[C:23]([F:25])[F:24])[CH2:21][CH2:20][S:1][C:2]1[O:3][C:4]([C:7]2[O:11][C:10]([CH3:12])=[N:9][N:8]=2)=[N:5][N:6]=1
Reactant: Cc1nnc(-c2nnc(S)o2)o1
Reactant: FC(F)=C(F)CCBr
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: Cc1nnc(-c2nnc(SCCC(F)=C(F)F)o2)o1
Yield: 54.5 %

Procedure:
3.7 g of 2-mercapto-5-(2-methyl-1,3,4-oxadiazol-5-yl)-1,3,4-oxadiazole according to Example H1 are initially introduced into a mixture of 36 ml of dioxane and 4 ml of dimethylformamide, and 2.24 g of potassium t-butylate are added, while stirring. 4.2 g of 4-bromo-1,1,2-trifluorobut-1-ene are added dropwise and the mixture is stirred overnight at room temperature. After the salts have been filtered off, the solvents are distilled off in vacuo, the residue is taken up in methylene chloride, the solution is washed with water and 1-normal sodium hydroxide solution in succession and the solvent is evaporated off in vacuo. 3.2 g of the desired compound of melting point 77°-79° C. are obtained as the residue.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[C:10]([O:13][C:14]1[C:15]([CH3:27])=[C:16]([CH3:26])[C:17]2[O:21][CH:20]([CH2:22]Br)[CH2:19][C:18]=2[C:24]=1[CH3:25])(=[O:12])[CH3:11]>CN(C)C=O.O>[C:10]([O:13][C:14]1[C:15]([CH3:27])=[C:16]([CH3:26])[C:17]2[O:21][CH:20]([CH2:22][S:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:19][C:18]=2[C:24]=1[CH3:25])(=[O:12])[CH3:11]
Reactant: CC(=O)Oc1c(C)c(C)c2c(c1C)CC(CBr)O2
Reactant: Sc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)CC(CSc1ccccc1)O2
Reaction time: 0.33 h
Yield: 92.2 %

Procedure:
To a solution of thiophenol [425 mg (3.8 mmol)] in dimethylformamide (10 ml) was added, under ice-cooling, sodium hydride [167 mg (4.2 mmol, content:60%)]. To the reaction mixture was added, after stirring for 20 minutes, a solution of 5-acetoxy-2-bromomethyl-4,6,7-trimethyl-2,3-dihydrobenzofuran [1.2 g (3.8 mmol)] dimethylformamide (5 ml). The mixture was stirred for further 30 minutes. The reaction mixture was diluted with water, which was subjected to extraction with ethyl acetate. The extract solution was washed with water, dried and concentrated. The concentrate was crystallized from isopropylether-hexane to afford 5-acetoxy-4,6,7-trimethyl-2-phenylthiomethyl-2,3-dihydrobenzofuran (Compound 4) [1.2 g (yield : 91.3%)]. In a manner as above, compounds 2, 6, 8, 10, 12 and 18 were synthesized by employing the corresponding thio compounds (3-mercaptopropionic acid, 1-octanethiol, 2-mercaptopyridine, 4-fluorothiophenol, 2-naphthalene thiol and benzyl mercaptan). Incidentally, when 3-mercaptopropionic acid was employed as the starting compound, 2.2 equivalents of sodium hydride was used.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[N:6][C:7]=1[Cl:8].Br[CH:11]([CH2:21][CH3:22])[C:12]([NH:14][C:15]([CH3:20])([CH3:19])[C:16]#[C:17][CH3:18])=[O:13]>>[Cl:1][C:2]1[CH:3]=[C:4]([O:9][CH:11]([CH2:21][CH3:22])[C:12]([NH:14][C:15]([CH3:20])([CH3:19])[C:16]#[C:17][CH3:18])=[O:13])[CH:5]=[N:6][C:7]=1[Cl:8]
Reactant: Oc1cnc(Cl)c(Cl)c1
Reactant: CC#CC(C)(C)NC(=O)C(Br)CC
Product: CC#CC(C)(C)NC(=O)C(CC)Oc1cnc(Cl)c(Cl)c1

Procedure:
5,6-Dichloropyridin-3-ol was reacted with 2-bromo-N-(4methylpent-2-yn-4-yl)butyramide in a similar procedure to that described in Example 10, Stage 2 to give 2-(5,6-dichloro-3-pyridyloxy)-N-(4methylpent-2-yn-4-yl)butyramide, gum.
Reaction SMILES: [NH2:1][CH:2]([CH2:5][CH3:6])[CH2:3][CH3:4].Cl[C:8]1[N:13]2[N:14]=[C:15]([CH3:26])[C:16]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=3[CH3:25])=[C:12]2[N:11]=[C:10]([CH3:27])[C:9]=1[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30].O>C(#N)C>[CH2:3]([CH:2]([NH:1][C:8]1[N:13]2[N:14]=[C:15]([CH3:26])[C:16]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=3[CH3:25])=[C:12]2[N:11]=[C:10]([CH3:27])[C:9]=1[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:5][CH3:6])[CH3:4]
Reactant: CCC(N)CC
Reactant: CCOC(=O)Cc1c(C)nc2c(-c3c(C)cc(C)cc3C)c(C)nn2c1Cl
Solvent: CC#N
Solvent: O
Product: CCOC(=O)Cc1c(C)nc2c(-c3c(C)cc(C)cc3C)c(C)nn2c1NC(CC)CC

Procedure:
3-Aminopentane (0.6 mL) was added to a solution of ethyl 2-(7-chloro-3-mesityl-2,5-dimethylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (130 mg) in acetonitrile (5 mL), followed by heating under reflux overnight. After cooling the reaction solution, water was added thereto. The mixture was extracted twice with ethylacetate, and the organic layer was washed with an aqueous saturated solution of sodium bicarbonate, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography, to give the title compound (84 mg) as a green oil.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([CH3:14])([OH:13])[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15](OC(OCC)C)[CH3:16].C1(C)C=CC(S(O)(=O)=O)=CC=1>CCOCC>[CH2:1]([O:8][CH2:9][C:10]1([CH3:14])[CH2:11][O:12][CH:15]([CH3:16])[O:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(C)OCC
Reactant: CC(O)(CO)COCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Product: CC1OCC(C)(COCc2ccccc2)O1

Procedure:
3-Benzyloxy-2-methylpropane-1,2-diol (5.0g), 1,1-diethoxyethane (3.0g) and p-toluenesulphonic acid were heated at 110°-115° C with stirring until no more alcohol was evolved. The mixture was then heated at 140°-145° C for 15 minutes. After cooling, the mixture was dissolved in ether and the resulting solution was then washed with 5% potassium carbonate solution followed by water. The solution was dried over anhydrous magnesium sulphate and the solvent was removed under reduced pressure to yield a liquid which on distillation gave the desired product having a b.p. 81°-82° C at 0.3 mm Hg.
Reaction SMILES: [CH2:1]([NH:4][C:5](=[O:25])[CH2:6][CH2:7][CH2:8][N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[CH:13][C:12]=2[N:11]=[C:10]1[CH2:22][CH2:23][CH3:24])[CH2:2][CH3:3].C1C=C(Cl)C=C(C(OO)=O)C=1.[OH-].[NH4+:38].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C1(C)C=CC=CC=1.ClCCl>[NH2:38][C:13]1[C:12]2[N:11]=[C:10]([CH2:22][CH2:23][CH3:24])[N:9]([CH2:8][CH2:7][CH2:6][C:5]([NH:4][CH2:1][CH2:2][CH3:3])=[O:25])[C:21]=2[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:14]=1
Reactant: [NH4+]
Reactant: CCCNC(=O)CCCn1c(CCC)nc2cnc3ccccc3c21
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCCNC(=O)CCCn1c(CCC)nc2c(N)nc3ccccc3c21

Procedure:
N-Propyl-4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butanamide (5.6 g, 15 mmol) was treated with mCPBA (8.5 g, 38 mmol), concentrated ammonium hydroxide (100 mL), and p-toluenesulfonyl chloride (4.9 g, 26 mmol) according to the method described in Part F of Example 1. The crude product was dissolved in hot toluene (25 mL) and dichloromethane. A precipitate slowly formed, was isolated by filtration, and was washed with toluene (15 mL). The solid was recrystallized twice from 4:1 methanol:water (25 mL), and the crystals were heated at reflux in chloroform in the presence of charcoal (1 g). The mixture was filtered through a layer of CELITE filter agent, and the filtrate was concentrated under reduced pressure. The residue was recrystallized twice from methanol:water and twice from toluene (15 mL) and dried overnight in a vacuum even to provide 0.74 g of 4-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)-N-propylbutanamide as a grey solid, mp 161-163° C.
Reaction SMILES: [CH2:1]([CH:9]([C:18]#[N:19])[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[Cl:17])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.N1C=CC=CC=1.[CH2:26]=[O:27].[OH-].C([N+](CC)(CC)CC)C1C=CC=CC=1>O>[C:18]([C:9]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[Cl:17])([CH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH2:26][OH:27])#[N:19]
Reactant: C=O
Reactant: N#CC(CCc1ccccc1)c1ccc(Cl)cc1Cl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Product: N#CC(CO)(CCc1ccccc1)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To an ice cold stirred solution of α-phenethyl-2,4-dichlorobenzyl cyanide (26.5g., 0.09 mole) in 200 ml. of pyridine containing a suspension of paraformaldehyde (11g., 0.35 mole) is added 1 ml. of benzyl triethylammonium hydroxide. The mixture is stirred under nitrogen at room temperature for 24 hours. The reaction mixture is poured into 1 liter of water and extracted with ether. The combined ether extracts are washed with water, saturated sodium chloride solution and dried over magnesium sulfate. The solvent is evaporated to give 25.4g. of a thick oil, which is identified by nmr.