Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:6][C:7]1[CH:19]=[CH:18][C:10]([O:11][C:12]([CH3:17])([CH3:16])[C:13](Cl)=[O:14])=[CH:9][CH:8]=1.Cl>CC#N.[Cl-].[Na+].O>[Br:6][C:7]1[CH:19]=[CH:18][C:10]([O:11][C:12]([CH3:16])([CH3:17])[C:13]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:14])=[CH:9][CH:8]=1
Reactant: CC(C)(Oc1ccc(Br)cc1)C(=O)Cl
Reactant: C1CCNC1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(C)(Oc1ccc(Br)cc1)C(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.3 %

Procedure:
Pyrrolidine (1.54 g, 21.6 mmol) in anhydrous MeCN (10 mL) was added with stirring to 2-(4-bromophenoxy)-2-methylpropanoyl chloride (2 g, 7.2 mmol) in anhydrous MeCN (10 mL) at 0° C. The mixture was stirred at room temperature for 18 h and acidified with HCl (aq. 1M, 40 mL). Brine was added and the mixture was extracted with CH2Cl2. The combined extracts were washed with NaHCO3 (aq. sat) and brine, dried (Na2SO4), and concentrated to give the sub-title compound (2.12 g, 94%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH:19]1([NH2:24])[CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH:19]1([NH:24][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)[CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: NC1CCCC1
Reactant: Fc1ccc(-c2ccc3ncnc(Cl)c3c2)cc1
Product: Fc1ccc(-c2ccc3ncnc(NC4CCCC4)c3c2)cc1

Procedure:
This compound was synthesized from 4-chloro-6-(4-fluorophenyl)-quinazoline and cyclopentylamine in 78%, using the procedure described example 37 and was characterized by its mass spectrum as follows: MS (m/z): 308 ([M+H]+, 100).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[C:5]([Cl:21])=[CH:4][N:3]=1.[CH3:22][P:23]([C:26]1[N:31]=[C:30]([O:32][CH3:33])[C:29]([NH2:34])=[CH:28][CH:27]=1)([CH3:25])=[O:24].Cl.[OH-].[Na+]>COCCO.C(O)C>[Cl:21][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])=[N:7][C:2]([NH:34][C:29]2[C:30]([O:32][CH3:33])=[N:31][C:26]([P:23]([CH3:22])([CH3:25])=[O:24])=[CH:27][CH:28]=2)=[N:3][CH:4]=1
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: COc1nc(P(C)(C)=O)ccc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: COCCO
Solvent: CCO
Product: COc1nc(P(C)(C)=O)ccc1Nc1ncc(Cl)c(Nc2ccccc2S(=O)(=O)C(C)C)n1
Temperature: 90 °C
Yield: 13.1 %

Procedure:
To a solution of 2,5-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine (86.0 mg, 0.250 mmol) in 1 mL of 2-methoxyethanol was added 6-(dimethylphosphoryl)-2-methoxypyridin-3-ylamine (50.0 mg, 0.250 mmol) and 0.15 mL of 2.5 M HCl in ethanol. The mixture was heated in a sealed tube at 90° C. for 16 h. The mixture was basified with 1N NaOH solution, and extracted with ethyl acetate. The organic layers were combined, washed with saturated sodium chloride solution, dried with sodium sulfate, filtered and concentrated. The crude residue was purified by silica gel chromatography (0-10% 7N ammonia in methanol:dichloromethane) to afford the desired product (16.7 mg, 22% yield). MS/ES+: m/z=510.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[C:6]([N:8]1[CH2:28][CH2:27][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[CH2:14][N:13]([CH2:23][CH2:24]O)[C:12]2=[O:26])[CH2:10][CH2:9]1)=[O:7].[NH:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1>>[F:35][C:32]([F:34])([F:33])[C:30]1[CH:29]=[C:5]([CH:4]=[C:3]([C:2]([F:36])([F:1])[F:37])[CH:31]=1)[C:6]([N:8]1[CH2:28][CH2:27][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[CH2:14][N:13]([CH2:23][CH2:24][N:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)[C:12]2=[O:26])[CH2:10][CH2:9]1)=[O:7]
Reactant: C1CCNC1
Reactant: Cc1ccccc1N1CN(CCO)C(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2
Product: Cc1ccccc1N1CN(CCN2CCCC2)C(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2

Procedure:
The title compound, MS: m/e=583.2 (M+H+), was prepared in accordance with the general method of example 48 from 8-(3,5-bis-trifluoromethyl-benzoyl)-3-(2-hydroxy-ethyl)-1-o-tolyl-1,3,8-triaza-spiro[4.5]decan-4-one and pyrrolidine.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([NH:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:7][CH:8]=1)[CH3:2].[CH2:16]([O:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH:22]=O)[CH3:17].C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C>[CH2:16]([O:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH2:22][N:13]1[CH2:14][CH2:15][CH:10]([NH:9][C:6]2[N:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][N:7]=2)[CH2:11][CH2:12]1)[CH3:17]
Reactant: CCOc1cc(C=O)ccc1OC
Reactant: CCc1cnc(NC2CCNCC2)nc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOc1cc(CN2CCC(Nc3ncc(CC)cn3)CC2)ccc1OC
Temperature: 55 °C
Yield: 38 %

Procedure:
To a solution of (5-ethyl-pyrimidin-2-yl)-piperidin-4-yl-amine (30.9 mg, 0.15 mmol, 1.0 equiv; intermediate C1) and 3-ethoxy-4-methoxy-benzaldehyde (32.4 mg, 0.18 mmol, 1.2 equiv; commercially available) in ethanol (2 mL) was added acetic acid (27.0 mg, 0.45 mmol, 3.0 equiv) and the mixture stirred at 55° C. After 1 h sodium cyano borohydride (47.1 mg, 0.75 mmol, 5.0 equiv), dissolved in ethanol (0.5 mL), was added and the mixture stirred at 55° C. over night. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 21.0 mg (38%) of the title compound. MS (ESI): 371.5 [M+H]+.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:4]=[CH:5][N:6]2[CH2:11][CH:10]([OH:12])[CH2:9][CH2:8][C:7]=12.Cl[CH2:14][C:15]([N:17]1[CH2:36][CH2:35][C:20]2[N:21]=[C:22]([NH:25][CH:26]3[CH2:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:27]3)[N:23]=[CH:24][C:19]=2[CH2:18]1)=[O:16].O>CN(C)C=O>[CH2:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:34][CH:26]1[NH:25][C:22]1[N:23]=[CH:24][C:19]2[CH2:18][N:17]([C:15](=[O:16])[CH2:14][O:12][CH:10]3[CH2:11][N:6]4[CH:5]=[CH:4][N:3]=[C:7]4[CH2:8][CH2:9]3)[CH2:36][CH2:35][C:20]=2[N:21]=1
Reactant: O=C(CCl)N1CCc2nc(NC3Cc4ccccc4C3)ncc2C1
Reactant: OC1CCc2nccn2C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(COC1CCc2nccn2C1)N1CCc2nc(NC3Cc4ccccc4C3)ncc2C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 10.8 %

Procedure:
Add sodium hydride (0.054 g; 1.85 equiv; 1.35 mmoles) to a solution of 5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-6-ol (0.252 g; 2.0 equiv; 1.46 mmoles) in dimethylformamide (2 mL) and stir at room temperature for 10 minutes. Add this mixture to a 0° C. solution of 2-chloro-1-[2-(2,3-dihydro-1H-inden-2-ylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl]ethanone (0.25 g; 1.0 equiv; 0.729 mmoles) in dimethylformamide (2 mL). Stir the resulting solution at 0° C. for 1 hour, then add water and load onto a SCX ion exchange column. Elute off the crude product (methanol to 7N ammonia in methanol). Further purify the product by reverse phase chromatography to afford 1-[2-(2,3-dihydro-1H-inden-2-ylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl]-2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-6-yloxy)ethanone (0.035 g; 11%) as a white foam. MS (m/z): 445(M+1).
Reaction SMILES: [Br:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5](=[O:12])[O:4][C:3]=1[C@H:13]([OH:16])[CH2:14][OH:15].N1C=CN=C1.[C:22]([Si:26]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)Cl)([CH3:25])([CH3:24])[CH3:23].O>CN(C)C=O>[Br:1][C:2]1[C:7]2[C:6](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:5](=[O:12])[O:4][C:3]=1[C@H:13]([OH:16])[CH2:14][O:15][Si:26]([C:22]([CH3:25])([CH3:24])[CH3:23])([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=c1oc([C@H](O)CO)c(Br)c2ccccc12
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](OC[C@@H](O)c1oc(=O)c2ccccc2c1Br)(c1ccccc1)c1ccccc1
Reaction time: 0.33 h
Yield: 63.5 %

Procedure:
A solution of 4-bromo-3-[(1R)-1,2-dihydroxyethyl]-1H-2-benzopyran-1-one (145 mg, 0.509 mmol) and imidazole (51.9 mg, 0.763 mmol) in N,N-Dimethylformamide (DMF) (2.4 mL) was treated with tert-butyldiphenylchlorosilane (159 μl, 0.610 mmol). After 20 min, the reaction mixture was poured into water and extracted with EtOAc. The organic phase was dried with Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (ethyl acetate-hexanes 0-50%) to afford the title compound (169 mg, 0.323 mmol, 64% yield) as a white foam: Rt=1.24 min, ES+ MS: 546 (M+23).
Reaction SMILES: C(OC([NH:11][C:12]([C:14]1[CH:43]=[CH:42][C:17]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][N:26](CC3C=CC(OC)=CC=3OC)[C:25](=[O:40])[C:24]2=[O:41])=[CH:16][CH:15]=1)=[NH:13])=O)C1C=CC=CC=1.[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47]>C1(OC)C=CC=CC=1>[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47].[C:12]([C:14]1[CH:15]=[CH:16][C:17]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][NH:26][C:25](=[O:40])[C:24]2=[O:41])=[CH:42][CH:43]=1)(=[NH:11])[NH2:13]
Reactant: COc1ccc(CN2CCN(CCCCOc3ccc(C(=N)NC(=O)OCc4ccccc4)cc3)C(=O)C2=O)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: N=C(N)c1ccc(OCCCCN2CCNC(=O)C2=O)cc1
Reaction time: 0.5 h

Procedure:
In 3.4 ml of anisole was dissolved 1.7 g of 4-[4-(4-benzyloxycarbonylamidinophenoxy)butyl]-1-(2,4-dimethoxybenzyl)-2,3-dioxopiperazine, and 6.8 ml of trifluoroacetic acid was added to the solution, followed by refluxing for 5 hours. After cooling, the solvent was distilled off under reduced pressure. To the resulting residue was added 10 ml of ethyl acetate, and stirred for 30 minutes, after which the precipitate was collected by filtration and dried to obtain 1.2 g of 4-[4-(4-amidinophenoxy)butyl]-2,3-dioxopiperazine trifluoroacetate.
Reaction SMILES: [F:1][C:2]([C:5]1[CH:6]=[C:7]([N:11]=C(C2C=CC=CC=2)C2C=CC=CC=2)[CH:8]=[N:9][CH:10]=1)([F:4])[CH3:3].O.Cl.C1COCC1>CCOC(C)=O>[F:1][C:2]([C:5]1[CH:6]=[C:7]([NH2:11])[CH:8]=[N:9][CH:10]=1)([F:4])[CH3:3]
Reactant: CC(F)(F)c1cncc(N=C(c2ccccc2)c2ccccc2)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(F)(F)c1cncc(N)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.2 %

Procedure:
Add 5-(1,1-difluoroethyl)-N-(diphenylmethylene)pyridin-3-amine (296 mg, 0.92 mmol), water (1 mL) and hydrochloric acid (1N, 4 mL) to THF (10 mL), stir at room temperature for 3 hrs. TLC (PE:EtOAc=2:1) shows the reaction is complete. Extract the mixture with ethyl acetate, wash the organic layer with saturated sodium bicarbonate solution and brine sequentially, and dry over anhydrous sodium sulfate. Concentrate under reduced pressure to give the crude product. Purification by flash chromatography (silica gel, EtOAc:PE=1:1) yields the title compound (140 mg, 96.5%). MS: (M+1): 159.2.
Reaction SMILES: ClC1N2C(=O)NN=C2C(C2C=CC(Cl)=CC=2)=C(C2C=CC(Cl)=CC=2)N=1.[Cl-].Cl[CH2:28][C:29]1[CH:30]=[CH:31][C:32]([C:35]([F:38])([F:37])[F:36])=[N:33][CH:34]=1.[Cl:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]2[N:51]=[C:50]([N:52]3[CH2:55][C:54](NCC)(C(N)=O)[CH2:53]3)[N:49]3[C:62](=[O:67])[N:63](CC)[N:64]=[C:48]3[C:47]=2[C:68]2[CH:73]=[CH:72][C:71]([Cl:74])=[CH:70][CH:69]=2)=[CH:42][CH:41]=1>>[N:52]1([C:50]2[N:49]3[C:62](=[O:67])[N:63]([CH2:28][C:29]4[CH:34]=[N:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=4)[N:64]=[C:48]3[C:47]([C:68]3[CH:69]=[CH:70][C:71]([Cl:74])=[CH:72][CH:73]=3)=[C:46]([C:43]3[CH:44]=[CH:45][C:40]([Cl:39])=[CH:41][CH:42]=3)[N:51]=2)[CH2:53][CH2:54][CH2:55]1
Reactant: FC(F)(F)c1ccc(CCl)cn1
Reactant: CCNC1(C(N)=O)CN(c2nc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)c3nn(CC)c(=O)n23)C1
Agent: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)nc(Cl)n12
Agent: [Cl-]
Product: O=c1n(Cc2ccc(C(F)(F)F)nc2)nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)nc(N3CCC3)n12

Procedure:
The title compound was prepared in two steps from 5-chloro-7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one by nucleophilic displacement of chloride with the requisite amine, followed by alkylation with 5-(chloromethyl)-2-(trifluoromethyl)pyridine, in a manner analogous to that in which 1-(7,8-bis(4-chlorophenyl)-2-ethyl-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-3-(ethylamino)azetidine-3-carboxamide was prepared. HPLC/MS: retention time=4.483 min, [M+H]30 =571.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]2[C:11]([O:13][C:14](=[O:15])[C:2]=12)=O.[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[F:23]>>[F:16][C:17]1[C:18]([F:23])=[CH:19][C:20]2[C:14](=[O:15])[C:2]3[C:3](=[CH:4][C:5]4[C:10]([CH:1]=3)=[CH:9][CH:8]=[CH:7][CH:6]=4)[C:11](=[O:13])[C:21]=2[CH:22]=1
Reactant: O=C1OC(=O)c2cc3ccccc3cc21
Reactant: Fc1ccccc1F
Product: O=C1c2cc(F)c(F)cc2C(=O)c2cc3ccccc3cc21

Procedure:
Using the same procedure and naphthalene-2,3-dicarboxylic anhydride and 1,2-difluorobenzene gives 2,3-difluoronaphthacene-5,12-dione.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[C:25]([O:27]CC)=[O:26])[CH:5]=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].O.[OH-].[Li+]>CO.C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]([CH2:30][C:31]2[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=2)[C:25]([OH:27])=[O:26])[CH:5]=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:16][CH:15]=2)[C:7]=1[O:8][CH2:9][C:10]([F:12])([F:11])[F:13]
Reactant: CCOC(=O)C(Cc1ccc(F)cc1)c1cc(Cl)c(OCC(F)(F)F)c(-c2ccc(C(F)(F)F)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C(Cc1ccc(F)cc1)c1cc(Cl)c(OCC(F)(F)F)c(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 26.7 %

Procedure:
A mixture of ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-(4-fluorophenyl)propanoate (400 mg, 0.719 mmol) and lithium hydroxide monohydrate (0.306 g, 7.29 mmol) in a MeOH/THF/Water solvent mixture (10 ml/10 ml/10 ml) was stirred for 3 h at room temperature. After completion of reaction volatiles were removed under reduced pressure. The residue was diluted with water, acidified with 5% HCl solution and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by Flash Column Chromatography to give 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-(4-fluorophenyl)propanoic acid (0.1 g). 1H-NMR (CDCl3, 400 MHz): 7.55-7.78 (m, 4H); 7.42 (s, 1H), 7.18 (s, 1H); 6.92-7.16 (m, 4H); 3.98 (q, 2H); 3.84 (t, 1H); 3.41 (dd, 1H), 3.02 (dd, 1H).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=2[CH:6]=1.[C:13]1(=[O:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.O>CCOCC>[OH:19][C:13]1([C:2]2[S:3][C:4]3[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=3[CH:6]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COc1ccc2cc(Br)sc2c1
Reactant: O=C1CCCCC1
Solvent: CCOCC
Solvent: O
Product: COc1ccc2cc(C3(O)CCCCC3)sc2c1
Yield: 41.7 %

Procedure:
To Mg (0.22 g, 9.05 mmol) under argon in Et2O (20 ml) was added dropwise a solution of bromide (4) (2.00 g, 8.23 mmol) in Et2O (20 ml). The mixture was refluxed for 2 h, a solution of cyclohexanone (1.00 ml, 9.87 mmol) in Et2O (5 ml) was added and the mixture was refluxed for 2 h. It was poured into iced water. The solution was extracted with ethyl acetate, dried over Na2SO4, filtered, and concentrated under vacuum to give 8.00 g as an oil. Triturating from diisopropyl ether afforded 2-(1-hydroxycyclohexyl)-6-methoxybenzothiophene as a white powder (0.90 g, 65%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([C:10]2[N:14](C)[N:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)=[C:5]([CH3:20])[CH:4]=1.Cl.O1CCC[CH2:23]1>>[CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([C:10]2[CH:11]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:13]([CH3:23])[N:14]=2)=[C:5]([CH3:20])[CH:4]=1
Reactant: COc1cc(C)c(-c2cc(C(F)(F)F)nn2C)cc1C
Reactant: C1CCOC1
Agent: Cl
Product: COc1cc(C)c(-c2cc(C(F)(F)F)n(C)n2)cc1C

Procedure:
A mixture of 5-(4-methoxy-2,5-dimethyl-phenyl)-1-methyl-3-trifluoromethyl-1H-pyrazole (described in Reference preparation example 84) 3.2 g, 6N aqueous hydrochloric acid solution 5.3 ml and tetrahydrofuran 50 ml was stirred with heating under reflux for one hour. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium carbonate solution and saturated saline. The organic layer was dried over anhydrous magnesium sulfate, and was then concentrated under reduced pressure. The resulting residue was subjected to a silica gel column chromatography to give 3-(4-methoxy-2,5-dimethyl-phenyl)-1-methyl-5-trifluoromethyl-1H-pyrazole 3 g.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:18][C:19]1[CH:23]=[C:22]([CH3:24])[O:21][N:20]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CC(C)=O>[CH3:24][C:22]1[O:21][N:20]=[C:19]([CH2:18][O:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH:23]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: Cc1cc(CBr)no1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(C)=O
Product: Cc1cc(COc2ccc([N+](=O)[O-])cc2)no1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
To a dry reaction flask equipped with a reflux condenser, a magnetic stirring bar and a rubber septum with a N2 inlet was placed 4-nitrophenol (2, X═H) (1.57 g, 11.36 mmol), anhydrous K2CO3 (1.58 g, 12 mmol) and tetrabutylammonium iodide (200 mg) in dry acetone (100 mL). The reaction mixture was stirred at room temperature for 30 minutes. To this heterogeneous mixture was added 3-(bromomethyl)-5-methylisoxazole (2.0 g, 11.36 mmol) at room temperature and then the reaction mixture was refluxed for over night. After cooling it to room temperature, the reaction mixture was filtered, washed with acetone (50 mL) and the combined filtrates were concentrated under reduced pressure. The resulting solid was purified by silica gel column, eluted with hexanes then polarity was increased gradually up to 40% EtOAc in hexanes to give 2.59 g (97%) of the desired 5-methyl-3-(4-nitrophenoxymethyl)isoxazole (3, X═H). 1H NMR (CDCl3): δ 8.19 (d, 2H, J=9.3 Hz), 7.04 (d, 2H, J=9.6 Hz), 6.18 (s, 1H), 5.20 (s, 2H), 2.44 (s, 3H); LCMS (m/z): 235 (MH+).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][C:9](=[N:11][OH:12])[C:8]2[N:13]([CH3:16])[CH:14]=[CH:15][C:7]=2[S:6]1(=[O:18])=[O:17].Cl.[F:20][C:21]1[CH:34]=[CH:33][C:24]([C:25]([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[O:26])=[CH:23][CH:22]=1.C(=O)([O-])O.[Na+].[I-].[Na+]>C(#N)C>[F:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([CH:27]2[CH2:32][CH2:31][N:30]([CH2:2][CH2:3][CH2:4][N:5]3[CH2:10][C:9](=[N:11][OH:12])[C:8]4[N:13]([CH3:16])[CH:14]=[CH:15][C:7]=4[S:6]3(=[O:18])=[O:17])[CH2:29][CH2:28]2)=[O:26])=[CH:33][CH:34]=1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: Cn1ccc2c1C(=NO)CN(CCCCl)S2(=O)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: CC#N
Product: Cn1ccc2c1C(=NO)CN(CCCN1CCC(C(=O)c3ccc(F)cc3)CC1)S2(=O)=O
Yield: 48.6 %

Procedure:
A suspension of 116 mg (0.4 mmol) of Compound 19, 389 mg (0.6 mmol) of 4-(4-fluorobenzoyl)piperidine hydrochloride, 134 mg (1.6 mmol) of sodium hydrogencarbonate and 120 mg (0.8 mmol) of sodium iodide in 8 ml of acetonitrile was refluxed for 24 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (eluent: methanol/methylene chloride=1/15), whereby 90 mg of the title compound were obtained (yield: 49%).
Reaction SMILES: [NH:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][N:4]=1)[NH2:2].[CH:13](=O)[C:14]1[CH:24]=[C:21]([O:22][CH3:23])[C:19]([OH:20])=[C:16]([O:17][CH3:18])[CH:15]=1.Cl>>[CH3:23][O:22][C:21]1[CH:24]=[C:14]([CH:15]=[C:16]([O:17][CH3:18])[C:19]=1[OH:20])[CH:13]=[N:2][NH:1][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][N:4]=1
Reactant: NNC1=NCCc2ccccc21
Reactant: COc1cc(C=O)cc(OC)c1O
Agent: Cl
Product: COc1cc(C=NNC2=NCCc3ccccc32)cc(OC)c1O

Procedure:
In a manner similar to that of Example 4, condensation of 1-hydrazino-3,4-dihydroisoquinoline (10.0 g.) and syringaldehyde (12.5 g.) and treatment of the reaction mixture with hydrochloric acid gave a solid, which was recrystallized from N,N-dimethylformamide-ether, affording 1-[2-(3,5-dimethoxy-4-hydroxybenzylidene)hydrazino]-3,4-dihydroisoquinoline (I: X=3,5-(CH3O)2 -4-HOC6H2, X'=Y=Y'=Z=Z'=H) hydrochloride in two crops (total of 18 g., m.p. 232°-233° C.).
Reaction SMILES: C(O)C.[NH2:4][C:5]1[C:14]2[N:15]=[C:16]([CH2:25][CH3:26])[N:17]([CH2:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:13]=2[C:12]2[CH:11]=[CH:10][C:9](/[CH:27]=[CH:28]/[C:29]([N:31]([CH3:33])[CH3:32])=[O:30])=[CH:8][C:7]=2[N:6]=1>[Pd].CO>[NH2:4][C:5]1[C:14]2[N:15]=[C:16]([CH2:25][CH3:26])[N:17]([CH2:18][CH:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)[C:13]=2[C:12]2[CH:11]=[CH:10][C:9]([CH2:27][CH2:28][C:29]([N:31]([CH3:32])[CH3:33])=[O:30])=[CH:8][C:7]=2[N:6]=1
Reactant: CCc1nc2c(N)nc3cc(/C=C/C(=O)N(C)C)ccc3c2n1CC1CCOCC1
Agent: [Pd]
Solvent: CCO
Solvent: CO
Product: CCc1nc2c(N)nc3cc(CCC(=O)N(C)C)ccc3c2n1CC1CCOCC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 68.9 %

Procedure:
A glass Parr bottle was charged with 10% palladium on carbon (0.1 g) wetted with ethanol (10 mL) and a slurry of (2E)-3-[4-amino-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-7-yl]-N,N-dimethylprop-2-enamide (0.32 g, 0.78 mmol) in methanol (200 mL). The vessel was placed on Parr apparatus, evacuated and charged with hydrogen (55 psi). The mixture was shaken at ambient temperature for 48 hours. The reaction mixture was filtered through a 0.2 micron PTFE membrane filter and the filter was rinsed with methanol (100 mL). The filtrate was concentrated to dryness under reduced pressure. The resulting solid was recrystallized from acetonitrile to provide 220 mg of 3-[4-amino-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-7-yl]-N,N-dimethylpropanamide as a white crystalline solid, mp 219-220° C.
Reaction SMILES: C([NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]2[N:22]=[C:23]([NH:26][C:27](=[O:29])[CH3:28])[S:24][CH:25]=2)=[CH:15][CH:14]=1)=[S:11])(=O)C1C=CC=CC=1.[OH-].[Na+].Cl>C(O)C>[NH2:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]2[N:22]=[C:23]([NH:26][C:27](=[O:29])[CH3:28])[S:24][CH:25]=2)=[CH:15][CH:14]=1)=[S:11]
Reactant: CC(=O)Nc1nc(CCc2ccc(NC(=S)NC(=O)c3ccccc3)cc2)cs1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(=O)Nc1nc(CCc2ccc(NC(N)=S)cc2)cs1
Temperature: 60 °C
Reaction time: 2 h
Yield: 79.5 %

Procedure:
A mixture of N-{4-[2-(4-{[(benzoylamino)carbonothioyl]amino}phenyl)ethyl]-1,3-thiazol-2-yl}acetamide (200 mg), 6N aqueous sodium hydroxide (0.19 ml) and ethanol (2 ml) was stirred at 60° C. for 2 hours. The reaction mixture was cooled to ambient temperature and neutralized with 1N hydrochloric acid (1.2 ml). The precipitated crystals were filtered and washed with water to give N-[4-(2-{4-[(aminocarbonothioyl)amino]phenyl}ethyl)-1,3-thiazol-2-yl]acetamide (120 mg).
Reaction SMILES: [C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=CC=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([N:9]1[CH2:15][CH:14]2[CH:11]([CH2:12][NH:13]2)[CH2:10]1)=[O:8].C1(C2C=CC=CC=2)[C:23]([C:28](O)=[O:29])=CC=CC=1>>[CH:11]12[CH2:12][NH:13][CH:14]1[CH2:15][N:9]([C:7]([C:2]1[C:1]3[C:6](=[CH:19][CH:20]=[CH:21][CH:16]=3)[CH:5]=[CH:4][C:3]=1[O:29][CH2:28][CH3:23])=[O:8])[CH2:10]2
Reactant: O=C(c1ccccc1-c1ccccc1)N1CC2CNC2C1
Reactant: O=C(O)c1ccccc1-c1ccccc1
Product: CCOc1ccc2ccccc2c1C(=O)N1CC2CNC2C1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 19, substituting 2-ethoxy-naphthalene-1-carboxylic acid for biphenyl-2-carboxylic acid. MS (ESI) mass calcd. for C18H20N2O2, 296.37; m/z found, 297.2 [M+H]+.