Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[CH:7]=[CH:6][C:3]=1[CH:4]=O.ClC1C=C(O)C=CC=1C=O.C(O)(=O)[CH2:28][C:29]([OH:31])=[O:30].N1CCCCC1>N1C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[CH:7]=[CH:6][C:3]=1[CH:4]=[CH:28][C:29]([OH:31])=[O:30]
Reactant: O=Cc1ccc(OC2CCCCO2)cc1Cl
Reactant: O=C(O)CC(=O)O
Agent: O=Cc1ccc(O)cc1Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)C=Cc1ccc(OC2CCCCO2)cc1Cl
Yield: 55 %

Procedure:
Using 4.8 g of 2-chloro-4-(2-tetrahydropyranyloxy)benzaldehyde derived from 2-chloro-4-hydroxybenzaldehyde by the introduction of tetrahydropyranyl group thereinto, 4.2 g of malonic acid, 80 ml of pyridine, and 0.5 ml of piperidine, a reaction similar to that performed in Example 99 was carried out. As a result, 3.1 g of 2-chloro-4-(2-tetrahydropyranyloxy)cinnamic acid was obtained as crystal, which had the following physiochemical properties:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].C(=O)([O-])[O-].[Na+].[Na+].[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>O>[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[CH3:11])(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1N
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(S(=O)(=O)Nc2ccc([N+](=O)[O-])cc2C)cc1
Reaction time: 3 h

Procedure:
152g (1 mole) of 4-amino-3-methyl-nitrobenzene, 80g of sodium carbonate and 500g of water are mixed, 230g (1.2 moles) of p-toluenesulfonyl chloride were added thereto while stirring, and the reaction was carried out for 3 hours at 70° C to obtain 290g of 4-(N-p-toluenesulfonyl)amino-3-methylnitrobenzene.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][CH:18]=1)[NH2:15].ON1C2C=CC=CC=2N=N1.C(Cl)CCl>CN(C=O)C.C(N(CC)CC)C>[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:15][C:14]1[CH:16]=[CH:17][CH:18]=[C:12]([CH3:11])[CH:13]=1)=[O:6]
Reactant: Cc1cccc(N)c1
Reactant: Nc1ccccc1C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cccc(NC(=O)c2ccccc2N)c1
Reaction time: 16 h

Procedure:
To a solution of 2-aminobenzoic acid (290 mg) and 3-methylaniline (215 mg) in 10 mL of DMF was added 1-hydroxybenzotriazole (300 mg), EDC (400 mg) and triethylamine (500 μL). The resulting solution was stirred for 16 h. The reaction solution was partitioned with ethyl acetate and water. The ethyl acetate layer was extracted w/50 mL each of 5% citric acid, saturated sodium bicarbonate, saturated sodium chloride, dried over magnesium sulfate and concentrated in vacuo to afford the title compound as a solid.
Reaction SMILES: Cl.[OH:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=N)=[CH:5][CH:4]=1.CN(C)[CH:14]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:15][O:16][C:17]([CH:19]=[CH2:20])=O.[CH3:28][O-].[Na+]>>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]2[CH:20]=[CH:19][C:17]([O:16][CH2:15][CH2:14][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:28][N:9]=2)=[CH:10][CH:11]=1
Reactant: N=C(N)c1ccc(O)cc1
Reactant: C=CC(=O)OCC(CCCCCC)N(C)C
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Product: CCCCCCCCOc1ccc(-c2ccc(O)cc2)nc1

Procedure:
The intended compound was synthesized from 4-hydroxybenzamidine hydrochloride and β-dimethylamino-α-octyloxyacrolein by customary procedures by using sodium methoxide.
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19].C(=O)([O-])O.[Na+]>CC(C)=O.O>[CH2:1]([O:8][C:9]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCCCCCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(NCCCCCCO)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
7.06 ml (47 mmol) of chloroformic acid benzyl ester are added dropwise to a solution of 5.52 g (47 mmol) of 6-aminohexan-1-ol and 3.95 g (47 mmol) of sodium hydrogen carbonate in 100 ml of acetone and 50 ml of water. The mixture is stirred at room temperature for 18 hours and concentrated to approximately 70 ml, and the white precipitate is filtered off, washed with approximately 20 ml of water, taken up in 250 ml of methylene chloride and dried over magnesium sulfate; the magnesium sulfate is filtered off and the residue is concentrated to dryness by evaporation. 6-(N-benzyloxycarbonylamino)hexan-1-ol is obtained in the form of white crystals having a melting point of 58°-60°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:26]2[C:31]([CH3:32])=[CH:30][C:29]([OH:33])=[CH:28][C:27]=2[CH3:34])=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.[CH3:35][S:36][CH2:37][CH2:38]O.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[CH3:34][C:27]1[CH:28]=[C:29]([O:33][CH2:38][CH2:37][S:36][CH3:35])[CH:30]=[C:31]([CH3:32])[C:26]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[C:10]2[C:6]=1[CH2:7][CH2:8][C@H:9]2[O:11][C:12]1[CH:25]=[CH:24][C:15]2[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=2[CH:13]=1
Reactant: CSCCO
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(O)cc5C)ccc(F)c43)ccc21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(OCCSC)cc5C)ccc(F)c43)ccc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of methyl 2-((S)-6-((R)-7-fluoro-4-(4-hydroxy-2,6-dimethylphenyl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate (280 mg) and 2-(methylthio)-ethanol (54 μL) in toluene (8 mL) are successively added 1,1′-(azodicarbonyl)-dipiperidine (240 mg) and tributylphosphine (240 mL). The mixture is stirred for 12 hours at room temperature, partitioned between saturated aqueous NaHCO3 solution and dichloromethane and stirred for 30 minutes. The phases are separated and the organic phase is dried (MgSO4). The solvents are evaporated and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 90:10→70:30) to give the title compound. Yield: 235 mg; LC (method 4): tR=1.97 min; Mass spectrum (ESI+): m/z=537 [M+H]+.
Reaction SMILES: Br[CH2:2][N:3]1[C:7](=[O:8])[C:6]2=[CH:9][CH:10]=[CH:11][CH:12]=[C:5]2[C:4]1=[O:13].[C:14]1([N:20]2[C:24]([SH:25])=[N:23][N:22]=[N:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Na].O>CN(C)C(=O)C>[C:7]1(=[O:8])[N:3]([CH2:2][S:25][C:24]2[N:20]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:21]=[N:22][N:23]=2)[C:4](=[O:13])[C:5]2=[CH:12][CH:11]=[CH:10][CH:9]=[C:6]12
Reactant: Sc1nnnn1-c1ccccc1
Reactant: O=C1c2ccccc2C(=O)N1CBr
Agent: [Na]
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CSc1nnnn1-c1ccccc1
Yield: 72 %

Procedure:
A solution of 2.40 g N-(bromomethyl)phthalimide (0.010 mol) and 2.00 g 1-phenyl-1H-tetrazole-5-thiol, sodium salt (0.010 mol) in 20 ml N,N-dimethylacetamide was stirred 0.5 hours. The slurry was then poured into water extracted with ethyl acetate, dried and concentrated in vacuo. The solid obtained was recrystallized from ethyl acetate/hexane to give 2.43 g (72.0%) of a colorless solid, m.p. 146°-7° C.
Reaction SMILES: [ClH:1].C([NH:5][C:6]1[CH:7]=[C:8]([C:12]2[N:13]=[C:14]3[N:18]([CH:19]=2)[C:17]2[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=2[S:15]3)[CH:9]=[CH:10][CH:11]=1)(=[O:4])C>CO>[OH2:4].[ClH:1].[ClH:1].[NH2:5][C:6]1[CH:7]=[C:8]([C:12]2[N:13]=[C:14]3[N:18]([CH:19]=2)[C:17]2[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=2[S:15]3)[CH:9]=[CH:10][CH:11]=1.[NH2:5][C:6]1[CH:7]=[C:8]([C:12]2[N:13]=[C:14]3[N:18]([CH:19]=2)[C:17]2[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=2[S:15]3)[CH:9]=[CH:10][CH:11]=1.[ClH:1].[ClH:1]
Reactant: CC(=O)Nc1cccc(-c2cn3c(n2)sc2ccccc23)c1
Agent: Cl
Solvent: CO
Product: Nc1cccc(-c2cn3c(n2)sc2ccccc23)c1
Product: O

Procedure:
To a mixture of 30 ml of a 2 normal hydrochloric acid solution and 20 ml of methanol was added 4 g of 2-(m-acetamidophenyl)imidazo[2,1-b]benzothiazole and the mixture was refluxed for 2 hours. The reaction mixture was concentrated under reduced pressure to form solid materials, which were recrystallized from ethanol to provide 4.2 g of 2-(m-aminophenyl)imidazo[2,1-b]benzothiazole di-hydrochloride hemihydrate.
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]3[C:13]4[CH2:30][CH2:29][NH:28][C:27](=[O:31])[C:14]=4[C:15]([O:16][S:17]([C:20]4[C:21]([CH3:26])=[CH:22][CH:23]=[CH:24][CH:25]=4)(=[O:19])=[O:18])=[C:9]3[C:8]2=[O:32])=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1.Br[CH2:51][C:52]1[CH:57]=[CH:56][N:55]=[CH:54][CH:53]=1>CN(C=O)C.C(OCC)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]3[C:13]4[CH2:30][CH2:29][N:28]([CH2:51][C:52]5[CH:57]=[CH:56][N:55]=[CH:54][CH:53]=5)[C:27](=[O:31])[C:14]=4[C:15]([O:16][S:17]([C:20]4[C:21]([CH3:26])=[CH:22][CH:23]=[CH:24][CH:25]=4)(=[O:19])=[O:18])=[C:9]3[C:8]2=[O:32])=[CH:33][CH:34]=1
Reactant: BrCc1ccncc1
Reactant: Cc1ccccc1S(=O)(=O)Oc1c2c(n3c1C(=O)N(Cc1ccc(F)cc1)CC3)CCNC2=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1ccccc1S(=O)(=O)Oc1c2c(n3c1C(=O)N(Cc1ccc(F)cc1)CC3)CCN(Cc1ccncc1)C2=O
Reaction time: 0.5 h

Procedure:
To a cold (0° C.) solution of 8-(4-fluorobenzyl)-10-toluenesulfonyloxy-3,4,7,8-tetrahydropyrido-[3′,4′:4,5]pyrrolo[1,2-a]pyrazine-1,9(2H,6H)-dione (60 mg, 0.12 mmol) in anhydrous DMF (1 mL), a solution of lithium bis(trimethylsilyl)amide in THF (1 M, 1.5 eq) was added. The mixture was stirred at the same temperature for 30 minutes. A solution of 4-bromomethylpyridine in diethyl ether (generated from the corresponding hydrobromide salt through partition between aq sodium carbonate and ether, and drying the solution by passing it through a plug of activated basic alumina). The reaction mixture was stirred at rt for one hour and concentrated under vacuum. The residue was subjected to reverse phase preparative HPLC purification. Collection and lyophilization of appropriate fractions provided the titled compounds.
Reaction SMILES: O1CCO[CH:2]1[C:6]1[C:11]([NH2:12])=[CH:10][CH:9]=[CH:8][N:7]=1.[NH2:13][NH:14][C:15]([NH2:17])=[S:16]>C(O)C.O.Cl>[NH2:12][C:11]1[C:6]([CH:2]=[N:13][NH:14][C:15]([NH2:17])=[S:16])=[N:7][CH:8]=[CH:9][CH:10]=1
Reactant: Nc1cccnc1C1OCCO1
Reactant: NNC(N)=S
Agent: Cl
Solvent: O
Solvent: CCO
Product: NC(=S)NN=Cc1ncccc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(1,3-dioxolanyl)-3-aminopyridine (0.80 g, 4.8 mmol) in 10 mL of ethanol, 8 mL of water and 2 mL of concentrated hydrochloric acid was added 0.48 g (5.3 mmol) of thiosemicarbazide. The mixture was stirred at room temperature overnight and refluxed for 1 h, cooled and filtered. The crude yellow hydrochloride salt was dissolved in 50 mL of hot water and filtered. To the hot filtrate was added 10 mL of 5% sodium bicarbonate solution. The mixture was stirred at room temperature for 1 h, filtered and washed with water, followed by ethanol to yield 3-amino-2-formylpyridine thiosemicarbazone. Yield: 0.72 g (77%); mp 240°-241° C. dec; MS m/e 194 (M+); 1H NMR (90 MHz, DMSO-d6) δ 6.48 (br s, 2H, 3-NH2, D2O exchangeable), 7.12 (m, 2H, 4-H and 6-H), 7.83 (dd, 1H, 5-H), 8.10 (br s, 2H, CSNH2, D2O exchangeable), 8.10 (s, 1H, 2-CH), 10.95 (s, 1H, NNH, D2O exchangeable). Anal. (C7H9N5S) C, H, N.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[NH2:8][C:9]1[CH:32]=[CH:31][C:12]([O:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[CH:20]=[C:21]([C:23]4[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=4)[S:22][C:15]=23)=[C:11]([F:33])[CH:10]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[F:33][C:11]1[CH:10]=[C:9]([CH:32]=[CH:31][C:12]=1[O:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]2[CH:20]=[C:21]([C:23]3[CH:30]=[CH:29][C:26]([CH2:27][N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)=[CH:25][CH:24]=3)[S:22][C:15]=12)[NH2:8]
Reactant: CN1CCNCC1
Reactant: Nc1ccc(Oc2ccnc3cc(-c4ccc(C=O)cc4)sc23)c(F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CN1CCN(Cc2ccc(-c3cc4nccc(Oc5ccc(N)cc5F)c4s3)cc2)CC1
Reaction time: 0.5 h
Yield: 69.8 %

Procedure:
A 20 mL vial was charged with 1-methylpiperazine (0.0457 mL, 0.412 mmol), 4-(7-(4-amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)benzaldehyde (Example 94, Step A; 0.150 g, 0.329 mmol) and CH2Cl2 (5 mL). The reaction mixture was stirred for 30 minutes and sodium triacetoxyborohydride (0.0977 g, 0.461 mmol) was added slowly over five minutes, and then the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into Na2CO3 (100 mL) and extracted with CH2Cl2 (2×100 mL). The organic layers were over sodium sulfate, filtered and concentrated to provide the product (103 mg, 64%) as a brown solid. LRMS (APCI+) 449 (M+1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:9](I)=[CH:10][C:3]=12.CC1(C)C(C)(C)OB([C:30]2[CH2:35][CH2:34][CH:33]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:32][CH:31]=2)O1.N#N>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOC.C(O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:9]([C:30]3[CH2:35][CH2:34][CH:33]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:32][CH:31]=3)=[CH:10][C:3]=12
Reactant: Cc1ccc(S(=O)(=O)n2c(I)cc3c(Cl)ccnc32)cc1
Reactant: CCOC(=O)C1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: N#N
Solvent: O
Solvent: CCO
Solvent: COCCOC
Product: CCOC(=O)C1CC=C(c2cc3c(Cl)ccnc3n2S(=O)(=O)c2ccc(C)cc2)CC1
Temperature: 100 °C

Procedure:
A solution of 4-chloro-2-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (2.0 g, 4.4 mmol), ethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-enecarboxylate (1.6 g, 5.5 mmol) and bis(triphenylphosphine)palladium(ii) chloride (324 mg, 0.5 mmol) in a mixed solvent of 1,2-dimethoxyethane/ethanol/water with ratio of 7/3/2 (200 mL) was purged with N2 and heated at 100° C. overnight. After cooling, the reaction mixture was partitioned between water and ethyl acetate. The organic phase was concentrated and purified by flash chromatography on silica gel using an ISCO Companion eluting with heptanes/ethyl acetate (50%) to give desired product. MS (ESI+) m/z 460 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]2[C:5]([O:7][C:8](=[O:9])[C:3]=12)=O.[CH3:13][C:14]1[CH:15]=[C:16]([CH:31]=[CH:32][C:33]=1[NH2:34])[CH2:17][N:18]1[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][C:20]([C:27]([F:30])([F:29])[F:28])=[N:19]1>C(O)(=O)C>[F:30][C:27]([F:28])([F:29])[C:20]1[CH:21]=[C:22]([C:23]([F:26])([F:24])[F:25])[N:18]([CH2:17][C:16]2[CH:31]=[CH:32][C:33]([N:34]3[C:8](=[O:9])[C:3]4[C:4](=[CH:10][CH:11]=[CH:12][C:2]=4[F:1])[C:5]3=[O:7])=[C:14]([CH3:13])[CH:15]=2)[N:19]=1
Reactant: O=C1OC(=O)c2c(F)cccc21
Reactant: Cc1cc(Cn2nc(C(F)(F)F)cc2C(F)(F)F)ccc1N
Solvent: CC(=O)O
Product: Cc1cc(Cn2nc(C(F)(F)F)cc2C(F)(F)F)ccc1N1C(=O)c2cccc(F)c2C1=O
Yield: 76.4 %

Procedure:
3-Fluorophthalic anhydride (4.98 g) and 1-(3-methyl-4-aminobenzyl)-3,5-bis(trifluoromethyl)-1H-pyrazole (9.70 g) were refluxed in acetic acid (43 ml) for 3 hours. After finishing the reaction, the acetic acid was distilled off under the reduced pressure and the obtained crude crystals were washed with t-butyl methyl ether to obtain the aimed 2-{4-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl-methyl]-2-methylphenyl}-4-fluoroisoindol-1,3-dione (10.80 g). mp. 158-159° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:39])[CH:5]=[C:6]([Cl:38])[C:7]=1[CH2:8][C@H:9]([O:20][C:21](=[O:37])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[Cl:36])[CH:23]=1)[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1.Cl.[C:41](Cl)(=[O:51])[O:42][C@@H:43]1[CH:48]2[CH2:49][CH2:50][N:45]([CH2:46][CH2:47]2)[CH2:44]1>CC#N>[Cl:38][C:6]1[CH:5]=[N+:4]([O-:39])[CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][C@H:9]([O:20][C:21](=[O:37])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:29]([C:41]([O:42][C@@H:43]2[CH:48]3[CH2:49][CH2:50][N:45]([CH2:46][CH2:47]3)[CH2:44]2)=[O:51])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[Cl:36])[CH:23]=1)[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1
Reactant: O=C(Cl)O[C@H]1CN2CCC1CC2
Reactant: COc1ccc([C@H](Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)c2cccc(CNc3ccccc3Cl)c2)cc1OC
Agent: Cl
Solvent: CC#N
Product: COc1ccc([C@H](Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)c2cccc(CN(C(=O)O[C@H]3CN4CCC3CC4)c3ccccc3Cl)c2)cc1OC
Temperature: 80 °C
Yield: 52.4 %

Procedure:
A suspension of [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl]3-[(2-chloroanilino)methyl]benzoate (72 mg, 0.123 mmol) and (R)-quinuclidin-3-yl carbonochloridate hydrochloride (138 mg, 0.612 mmol) in anhydrous CH3CN (1 mL) was heated at 80° C. for 3 minutes under microwave irradiation. After cooling to room temperature, the solvent was removed in vacuo. Purification of the crude material by preparative HPLC afforded the title compound as a yellow solid (47.8 mg, 53%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:20])[CH:5]=[C:6]([Cl:19])[C:7]=1[S:8][C:9]1[N:10]=[N:11][C:12](Cl)=[C:13]([CH:15]([CH3:17])[CH3:16])[CH:14]=1.[C:21]([O-])(=[O:23])[CH3:22].[Na+].[OH-:26].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:20][C:21](=[O:23])[CH3:22])[CH:5]=[C:6]([Cl:19])[C:7]=1[S:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12](=[O:26])[NH:11][N:10]=1
Reactant: [OH-]
Reactant: CC(C)c1cc(Sc2c(Cl)cc(N)cc2Cl)nnc1Cl
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)Nc1cc(Cl)c(Sc2cc(C(C)C)c(=O)[nH]n2)c(Cl)c1
Temperature: 95 °C
Yield: 99 %

Procedure:
A solution of 3,5-dichloro-4-(6-chloro-5-isopropyl-pyridazin-3-ylsulfanyl)-phenylamine (83) (1.23 g, 3.50 mmol) in glacial acetic acid (35 mL) was treated with sodium acetate (1.0 g, 12.25 mmol). This mixture was heated to 95° C. for 18 h. At this time, the reaction mixture was cooled to 25° C., poured onto water (200 mL) and neutralized with a 3N aqueous sodium hydroxide solution. This solution was then extracted with ethyl acetate (2×200 mL). The combined organics were washed with a saturated aqueous sodium chloride solution (1×100 mL), dried with magnesium sulfate, filtered and concentrated under vacuum to afford N-[3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-ylsulfanyl)-phenyl]-acetamide (84) (1.3 g, 99%) as an off-white solid. This material was used without further purification; ES(+)-HRMS m/e calcd for C15H15Cl2N3O2S (M+H)+ 372.0335, found 372.0335. Exact Mass=371.0262; Molecular weight=372.28
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[Cl-].[NH4+].[CH:13]1C=CC=CC=1.C(OCC)C>>[CH3:13][CH:4]([OH:5])[C:3]1[CH:6]=[CH:7][CH:8]=[C:9]([Cl:10])[C:2]=1[Cl:1]
Reactant: c1ccccc1
Reactant: O=Cc1cccc(Cl)c1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC(O)c1cccc(Cl)c1Cl
Yield: 90 %

Procedure:
Iodomethane (324.89 g, 2.288 mol) was added dropwise, with stirring, to magnesium turnings (54.88 g, 2.288 mol) in dry ether (1 liter), to form methyl-magnesium iodide. 2,3-Dichlorobenzaldehyde (200 g, 1.144 mol) dissolved in benzene/diethyl ether (1 liter, 50:50) solution was added dropwise, with stirring, to the Grignard. The reaction mixture was allowed to stir at room temperature overnight. The solution was refluxed for 2 hours, and then allowed to cool. The reaction mixture was poured into saturated ammonium chloride solution (5 liters) and the organic layer separated. The aqueous layer was extracted with ether (3×2 liters). The organic phases were combined, washed with brine (1×2 liters), dried over anhydrous magnesium sulphate, filtered and evaporated down. α-Methyl-2,3-dichlorobenzyl alcohol (196.4 g, 90% yield) was obtained as a yellow oil which crystallised on standing to give a pale-yellow solid. T.l.c. (SiO2 ;CHCl3) showed no impurities so no further purification was carried out. However, if necessary the alcohol may be recrystallised from 40-60° C. petroleum ether to afford white prisms of melting point 53° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:24][C:25]#[C:26][CH3:27].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:24][C:25]#[C:26][CH3:27])=[CH:18][CH:17]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC#CCBr
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC#CCOc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)OCC)cc1
Temperature: 60 °C
Reaction time: 6 h
Yield: 89.1 %

Procedure:
A commercially available reagent of ethyl (S)-2-tert-butoxycarbonylamino-3-(4-hydroxy-phenyl)-propionate (4.84 g, 15.6 mmol) was dissolved in N,N-dimethylformamide (39 mL), and 1-bromo-2-butyne (1.65 mL, 18.8 mmol) and potassium carbonate (3.25 g, 23.5 mmol) were then added at room temperature. After stirring at 60° C. for 6 hours, and the reaction solution was cooled to room temperature. 1-Bromo-2-butyne (0.55 mL, 6.28 mmol) was added at room temperature, and the mixture was then stirred at 60° C. for 5 hours. The reaction solution was cooled to room temperature, and potassium carbonate (0.433 g, 3.13 mmol) was then added. After stirring at 60° C. for 4.5 hours, the reaction solution was cooled to room temperature. Water (70 mL) was added, and the mixture was then extracted twice with ethyl acetate (70 mL). The organic layer was washed with saturated aqueous solution (30 mL) of sodium chloride, dried over anhydrous sodium sulfate, and filtered. The solvent was distilled off under reduced pressure. The residue was purified on Biotage (silica gel, n-hexane/ethyl acetate) to obtain 5.02 g (13.9 mmol, yield 89%) of ethyl (S)-2-tert-butoxycarbonylamino-3-(4-but-2-ynyloxy-phenyl)-propionate.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:4]=[CH:5][NH:6][C:7]=1[C:8]([NH2:10])=[O:9].C(N(CC)CC)C.[CH:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>C(O)C>[CH:18](=[N:2][C:3]1[N:4]=[CH:5][NH:6][C:7]=1[C:8]([NH2:10])=[O:9])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NC(=O)c1[nH]cnc1N
Reactant: O=Cc1ccccc1
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: CCN(CC)CC
Product: NC(=O)c1[nH]cnc1N=Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 97.1 %

Procedure:
16.3 g (100 mmol) of 4-amino-5-imidazolecarboxamide hydrochloride was suspended in 200 ml ethanol, and 27.8 ml (200 mmol) of triethylamine was added to the suspension and dissolved. To the solution, 10.2 ml (100 mmol) of benzaldehyde was added and the mixture was heated for 8 hours while refluxing. After the addition of 400 ml of distilled water, the reaction mixture was stirred for one hour at 0° C. A solid precipitate produced was collected by filtration, washed with distilled water, then with ethanol, and dried under reduced pressure to obtain 20.8 g of the title compound (yield 97%).