Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH:7]1[CH:11]=[N:10][CH:9]=[N:8]1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH:20]2[O:22][CH2:21]2)=[CH:15][CH:14]=1>C(#N)C>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][CH:20]([OH:22])[CH2:21][N:7]2[CH:11]=[N:10][CH:9]=[N:8]2)=[CH:17][CH:18]=1
Reactant: Clc1ccc(CC2CO2)cc1
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: OC(Cc1ccc(Cl)cc1)Cn1cncn1

Procedure:
To a suspension of potassium carbonate (8.14 g) and 1,2,4-triazole (8.14 g) in acetonitrile (100 ml) was added 1-(4-chlorophenyl)-2,3-epoxypropane (9.0 g), and the resulting suspension was heated to 70° for 4.5 h. The excess acetonitrile was evaporated under reduced pressure, and the residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with water and dried, and the solvent was evaporated to give a colourless oil. Purification by column chromatography on silica, eluting with chloroform/methanol, 95:5 by volume, gave 1-(4-chlorophenyl)-3-(1,2,4-triazol-1-yl)-2-propanol as a colourless oil which crystallised on standing, m.p. 104°-6°.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.N1C=CC=CC=1.[Cl:16][CH2:17][C:18](Cl)=[O:19]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:16][CH2:17][C:18]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1)=[O:19]
Reactant: c1ccc2[nH]ccc2c1
Reactant: O=C(Cl)CCl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C(CCl)c1c[nH]c2ccccc12
Temperature: 55 °C
Reaction time: 2 h

Procedure:
According to the method of J. Bergman et al. Tet. 29, 971-976 (1973), combine indole (11.7 g, 100 mmol), pyridine (8.1 mL, 100 mmol), and toluene (250 mL). Heat to 55° C. Add dropwise a solution of chloroacetyl chloride (8 mL, 100 mmol) in toluene (10 mL). After 2 hours, cool to ambient temperature. Dilute the reaction mixture with ethyl acetate and extract with water. Dry the organic layer over MgSO4, filter and evaporate in vacuo to give a residue. Recrystallize the residue from ethanol to give the title compound.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:15]=[CH:14][C:8]([CH:9]=[CH:10][C:11](O)=[O:12])=[CH:7][C:6]=1[O:16][CH3:17])(=[O:3])[CH3:2].S(Cl)(Cl)=O.[N-:22]=[N+:23]=[N-:24].[Na+]>C1C=CC=CC=1>[C:1]([O:4][C:5]1[CH:15]=[CH:14][C:8]([CH:9]=[CH:10][C:11]([N:22]=[N+:23]=[N-:24])=[O:12])=[CH:7][C:6]=1[O:16][CH3:17])(=[O:3])[CH3:2]
Reactant: COc1cc(C=CC(=O)O)ccc1OC(C)=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: COc1cc(C=CC(=O)N=[N+]=[N-])ccc1OC(C)=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
34.0 g (0.145 mol) of 4-acetoxy-3-methoxy-cinnamic acid are suspended in 150 ml of benzene and 21 ml (0.290 ml) of thionyl chloride are added. The mixture is then heated to the boil, under a reflux condenser, for 30 minutes; thereafter, the solvent and excess thionyl chloride are removed by distillation under reduced pressure. The crude 4-acetoxy-3-methoxycinnamic acid chloride which remains is dissolved in 150 ml of absolute 1,2-dimethoxyethane, 28.3 g (0.435 mol) of sodium azide are added and the mixture is subsequently stirred for 48 hours at room temperature. The inorganic salts are then filtered off and the filtrate is concentrated under reduced pressure at 30° C., in the course of which colourless crystals separate out. The crystallisation is completed by adding ether. 4-Acetoxy-3-methoxy-cinnamic acid azide of melting point 93°-95° C. (decomposition) is obtained.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.I[C:44]1[CH:49]=[CH:48][C:47]([C:50]([N:52]2[CH2:57][CH2:56][N:55]([CH3:58])[CH2:54][CH2:53]2)=[O:51])=[CH:46][CH:45]=1.[NH2:59][C:60]1[N:61]=[CH:62][C:63]2[C:69](=[O:70])[N:68]([C:71]3[CH:76]=[C:75]([N+:77]([O-:79])=[O:78])[CH:74]=[CH:73][C:72]=3[CH3:80])[CH2:67][CH2:66][C:64]=2[N:65]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[CH3:80][C:72]1[CH:73]=[CH:74][C:75]([N+:77]([O-:79])=[O:78])=[CH:76][C:71]=1[N:68]1[CH2:67][CH2:66][C:64]2[N:65]=[C:60]([NH:59][C:44]3[CH:49]=[CH:48][C:47]([C:50]([N:52]4[CH2:57][CH2:56][N:55]([CH3:58])[CH2:54][CH2:53]4)=[O:51])=[CH:46][CH:45]=3)[N:61]=[CH:62][C:63]=2[C:69]1=[O:70]
Reactant: CN1CCN(C(=O)c2ccc(I)cc2)CC1
Reactant: Cc1ccc([N+](=O)[O-])cc1N1CCc2nc(N)ncc2C1=O
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: Cc1ccc([N+](=O)[O-])cc1N1CCc2nc(Nc3ccc(C(=O)N4CCN(C)CC4)cc3)ncc2C1=O

Procedure:
A mixture of 4,5-Bis(diphenylphos-phino)-9,9-dimethylxanthene (xanthopos) (8.6 mg, 0.0148 mmol) and Tris(dibenzylideneacetone)dipalladium(0)[Pd2(dba)3] (6.81 mg, 0.0074 mmol) in dry 1,4-dioxane (5 ml) was stirred vigorously and nitrogen was bubbled through the suspension for 30 minutes. (4-Iodo-phenyl)-(4-methyl-piperazin-1-yl)-methanone (41.1 mg, 0.1247 mmol), 2-Amino-6-(2-methyl-5-nitro-phenyl)-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one (37.3 mg, 0.1247 mmol) and dry cesium carbonate (100 mg, 0.31 mmol) was added. Nitrogen was bubbled through for another 30 minutes; the mixture was allowed to reflux overnight. The mixture was cooled, diluted with ethylacetate, water was added and the layers were separated. The aqueous layer was extracted with ethyl acetate and the two organic extracts were combined. The organics were washed with brine, then dried (sodium sulfate), filtered and concentrated. Silica gel chromatography using 5-10% ethyl acetate/hexane as eluent provided 6-(2-Methyl-5-nitro-phenyl)-2-[4-(4-methyl-piperazine-1-carbonyl)phenylamino]-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one [22] as a yellow solid [Yield: 12.3 mg, 19.7%]
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH2:16][C@:15]2([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C@@H:13]([O:14]2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:25]S(O)(=O)=O>C1COCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH2:16][C@:15]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([OH:14])[C@@H:13]([OH:25])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(O)O
Reactant: O=C(OCc1ccccc1)N1CC[C@@]2(Cc3ccccc3)O[C@H]2C1
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CC[C@@](O)(Cc2ccccc2)[C@@H](O)C1
Reaction time: 16 h

Procedure:
To a solution of 37.6 g (116 mmol) of (1R,6S) and (1S,6R)-6-benzyl-7-oxa-3-aza-bicyclo[4.1.0]heptane-3-carboxylic acid benzyl ester in 170 ml THF were added 37 ml H2SO4 (10%). The reaction mixture was stirred for 16 hours and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate and extracted with sat. NaHCO3. The aqueous phase was extracted twice with ethyl acetate and the combined organic layers were washed with sat. NaHCO3, dried over MgSO4 and the solvent was removed under reduced pressure to give 40.8 g (100%, purity ˜95%) of crude (3R,4R) and (3S,4S)-4-benzyl-3,4-dihydroxy-piperidine-1-carboxylic acid benzyl ester.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:9]([CH3:11])=O)[CH:3]=1.[C:12](=[O:15])([O-])[O-:13].[K+].[K+].[OH-].[K+]>S([O-])([O-])(=O)=O.[Cu+2].CO>[CH2:12]1[O:15][C:3]2[CH:4]=[CH:11][C:9]([NH:8][C:4]3[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][CH:5]=3)=[CH:1][C:2]=2[O:13]1
Reactant: CC(=O)Nc1cccc(C)c1
Reactant: O=C([O-])[O-]
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Cc1cccc(Nc2ccc3c(c2)OCO3)c1
Yield: 40.3 %

Procedure:
A mixture of 40.0 g (268.1 mol) of m-acetotoluidine, 45.0 g (223.9 mol) of 3,4-bromomethylenedioxybenzene, 8 g (50.1 mol) of copper sulfate, and 31 g (267.7 mmol) of potassium carbonate was reacted in the same manner as in Example 5 (2) to obtain a crude reaction product. A mixture of this crude product, 50 g (757.4 mmol) of 85% KOH, and 200 ml of methanol was refluxed overnight and then concentrated. Water was added thereto. The resultant mixture was extracted with toluene twice. The toluene phase was washed with water three times, dried, and then concentrated. The residue was distilled under vacuum to obtain 24.51 g of N-3,4-methylenedioxyphenyl-N-m-tolylamine.
Reaction SMILES: [CH2:1]([O:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH:23]([CH2:27][CH3:28])[C:24](O)=[O:25])(=[O:22])=[O:21])=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].S(Cl)([Cl:31])=O>C(OCC)(=O)C.CN(C)C=O>[CH2:1]([O:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH:23]([CH2:27][CH3:28])[C:24]([Cl:31])=[O:25])(=[O:22])=[O:21])=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCOc1ccc(S(=O)(=O)C(CC)C(=O)O)cc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCOc1ccc(S(=O)(=O)C(CC)C(=O)Cl)cc1
Temperature: 70 °C

Procedure:
2-[(4-Dodecyloxyphenyl)sulfonyl]butanoic acid (1.1 g, 26.92 mMole) was suspended in ethyl acetate (100 mL) to which was added several drops of dimethylformamide and thionyl chloride (10.0 mL, 134.6 mMole). The mixture was heated at 70° C. for 1.5 hours, cooled, concentrated under reduced pressure, co-evaporated with ethyl acetate (2×100 mL) and the oil so obtained used as such in the next step of the reaction sequence.
Reaction SMILES: CO[CH:3](OC)[C:4](=[N:7][OH:8])[C:5]#[N:6].[OH:11][CH2:12][CH2:13][NH:14][NH2:15].[ClH:16]>C(O)(C)C>[ClH:16].[NH2:6][C:5]1[N:14]([CH2:13][CH2:12][OH:11])[N:15]=[CH:3][C:4]=1[N:7]=[O:8]
Reactant: NNCCO
Reactant: COC(OC)C(C#N)=NO
Agent: Cl
Solvent: CC(C)O
Product: Nc1c(N=O)cnn1CCO
Temperature: 79.5 °C
Yield: 87 %

Procedure:
To a flask having an inner volume of 25 ml and equipped with a stirring device, a thermometer and a reflux condenser were charged 3.37 g (22 mmol) of 3,3-dimethoxy-2-hydroxyiminopropionitrile with a purity of 94.0% by weight synthesized in the same manner as in Example 1, 1.60 g (20 mmol) of 2-hydroxyethylhydrazine with a purity of 95% by weight, 9.6 ml of isopropyl alcohol and 2 ml (24 mmol) of conc. hydrochloric acid, and the mixture was reacted under reflux (79 to 80° C.) for one hour. After completion of the reaction, when the reaction mixture was analyzed by high performance liquid chromatography (absolute calibration curve method), it was found that 3.35 g of 5-amino-1-(2-hydroxyethyl)-4-nitrosopyrazole hydrochloride (Reaction yield: 86.9%) had been formed.
Reaction SMILES: [OH:1][CH:2]([C:5]1[N:6]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[S:8][CH:9]=1)[CH2:3][NH2:4].[C:16]([CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](=O)[CH3:30])=[CH:24][CH:23]=1)([O:18][CH3:19])=[O:17].C(O)(=O)C.C([BH3-])#N.[Na+].Cl.C(=O)(O)[O-].[Na+]>CO>[C:16]([CH2:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([CH2:28][CH:29]([NH:4][CH2:3][CH:2]([OH:1])[C:5]2[N:6]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[S:8][CH:9]=2)[CH3:30])=[CH:26][CH:27]=1)([O:18][CH3:19])=[O:17]
Reactant: NCC(O)c1csc(-c2ccccc2)n1
Reactant: COC(=O)COc1ccc(CC(C)=O)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)COc1ccc(CC(C)NCC(O)c2csc(-c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
1.32 g (0.006 mol) of 2-Hydroxy-2-(2-phenyl-thiazol-4-yl)ethanamine and 1.33 g (0.006 mol) of 1-(4-carbomethoxymethoxyphenyl)-propan-2-one are dissolved in 40 ml of absolute methanol, and 0.34 ml (0.006 mol) of glacial acetic acid and 0.37 g (0.006 mol) of sodium cyanoborohydride are added and the mixture is stirred at room temperature for 20 hours. It is then poured onto ice, and the mixture is acidified with hydrochloric acid, made alkaline with sodium bicarbonate solution and extracted with chloroform. The extract is dried over sodium sulphate, concentrated and purified on a silica gel column using ethyl acetate/methanol=9:1 as eluant.
Reaction SMILES: B1C2CCCC1CCC2.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH:24]=[CH2:25])=[CH:20][CH:19]=2)=[CH:13][C:12]=1[C:26]([F:29])([F:28])[F:27].[OH-:30].[Na+].OO>C1COCC1.O>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][OH:30])=[CH:22][CH:23]=2)=[CH:13][C:12]=1[C:26]([F:27])([F:28])[F:29]
Reactant: C=Cc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: OCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.7 %

Procedure:
9-BBN (158 mL, 79 mmol) was added to a solution of 1-chloro-2-(trifluoromethyl)-4-(4-vinylphenoxy)benzene (15.75 g, 52.7 mmol) in THF (160 mL) at 0° C. The resultant reaction mixture was stirred at room temperature overnight. To the mixture was added water (16 mL), 3M NaOH solution (80 mL) and 30% hydrogen peroxide (80 mL). It was stirred at 50° C. for 2 h, concentrated in vacuo, and diluted with ethyl acetate (200 mL). The organic phase was collected, washed with water (100 mL×2) & brine (100 mL), dried over sodium sulfate, and concentrated. Purification via a column chromatography then provided the title compound as a colorless oil (12.13 g, 71.7% yield). LCMS: rt=2.08 min, [M+H+]=299
Reaction SMILES: [CH:1]1([C:6]2[C:7]3[S:19][C:18]([C:20]([O:22]C)=[O:21])=[CH:17][C:8]=3[NH:9][C:10]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>C1COCC1.CO>[CH:1]1([C:6]2[C:7]3[S:19][C:18]([C:20]([OH:22])=[O:21])=[CH:17][C:8]=3[NH:9][C:10]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)c1cc2[nH]c(-c3ccccc3)c(C3CCCC3)c2s1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc2[nH]c(-c3ccccc3)c(C3CCCC3)c2s1
Reaction time: 0.15 h
Yield: 73 %

Procedure:
A solution (0.015 M) of methyl 6-cyclopentyl-5-phenyl-4H-thieno[3,2-b]pyrrole-2-carboxylate in THF/MeOH (1:1) was treated with aqueous NaOH (2 N solution, 20 eq.) then the mixture was heated to reflux for 45 min. After cooling down, the mixture was concentrated then the residue diluted with water and acidified to pH 2-3 with aqueous HCl (1 N) and extracted with AcOEt. The combined organic phase was dried and concentrated to give a residue that was purified by RP-HPLC (Conditions: Waters X-TERRA MS C18, 10 micron, 19×150 mm; flow: 20 mL/min; Gradient: A: H2O+0.05% TFA; B: MeCN+0.05% TFA; 90% A isocratic for 2 min then linear to 10% A in 9 min) to afford the title compound (73%) as a solid.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=4)[C:15]=3[O:14]2)(=O)=O)=CC=1.[N-:29]=[N+:30]=[N-:31].[Na+]>>[N:29]([CH2:12][CH:13]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)[C:15]=2[O:14]1)=[N+:30]=[N-:31]
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4cccc(Cl)c4)c3O2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: [N-]=[N+]=NCC1Cc2cccc(-c3cccc(Cl)c3)c2O1

Procedure:
Treatment of (±)-[7-(3-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (3.6 g, 8.66 mmol) with sodium azide (2.25 g, 34.65 mmol) generally according to the procedure described for Intermediate 98 gave (±)-2-(azidomethyl)-7-(3-chlorophenyl)-2,3-dihydro-1-benzofuran. Treatment of the azide with sulfided platinum on carbon (0.125 g, 5 wt. %) generally according to the procedure described for Example 1 provided 1.91 g (74%) of (±)-1-[7-(3-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a tan solid, hydrochloride salt. mp 150-154° C.; Anal. calcd. for C15H14ClNOHCl: C, 60.83; H, 5.1; N, 4.73. Found: C, 59.17; H, 5.12; N, 4.38.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[N:10]=[C:11]=S.[NH:13]([C:15](=[O:38])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([C@H:25]2[CH2:30][CH2:29][C@H:28]([C:31]([CH3:37])([CH3:36])[C:32]([O:34][CH3:35])=[O:33])[CH2:27][CH2:26]2)=[CH:21][CH:20]=1)=[O:17])[NH2:14].CCN=C=NCCCN(C)C>CC(N(C)C)=O.O>[CH3:37][C:31]([C@H:28]1[CH2:27][CH2:26][C@H:25]([C:22]2[CH:21]=[CH:20][C:19]([NH:18][C:16]([C:15]3[O:38][C:11]([NH:10][C:3]4[CH:4]=[C:5]([F:9])[C:6]([F:8])=[CH:7][C:2]=4[F:1])=[N:14][N:13]=3)=[O:17])=[CH:24][CH:23]=2)[CH2:30][CH2:29]1)([CH3:36])[C:32]([O:34][CH3:35])=[O:33]
Reactant: Fc1cc(F)c(N=C=S)cc1F
Reactant: COC(=O)C(C)(C)[C@H]1CC[C@H](c2ccc(NC(=O)C(=O)NN)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Solvent: CC(=O)N(C)C
Solvent: O
Product: COC(=O)C(C)(C)[C@H]1CC[C@H](c2ccc(NC(=O)c3nnc(Nc4cc(F)c(F)cc4F)o3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2,4,5-trifluorophenyl isothiocyanate (183 mg, 0.96 mmol) in DMA (1 mL) was added in one portion to a suspension of methyl 2-[trans-4-(4-{[hydrazino(oxo)acetyl]amino}-phenyl)cyclohexyl]-2-methylpropanoate (Intermediate 105, 290 mg, 0.80 mmol) in DMA (3 mL) and the reaction mixture was stirred at room temperature for 1 h 30 mins. EDCI (230 mg, 1.20 mmol) was added in one portion and the reaction mixture was heated to 90° C. for 10 mins in the microwave. The mixture was then cooled to room temperature, poured into H2O (20 mL) and stirred for 5 mins. The mixture was centrifuged and the aqueous layer decanted off to leave a solid residue. The solid residue was taken up in H2O (5 mL), stirred for 5 mins and then centrifuged and the aqueous layer decanted off to leave a solid residue. H2O (5 mL) was added and the mixture was filtered to give the title compound (398 mg, 96%) as a solid; 1H NMR δ 1.1 (6H, s), 1.12-1.26 (2H, m), 1.36-1.5 (2H, m), 1.57-1.7 (3H, m), 1.78-1.89 (2H, m), 2.39-2.49 (1H, m), 3.6 (3H, s), 7.2 (2H, d), 7.65-7.78 (1H, m), 7.68 (2H, d), 8.12-8.24 (1H, m), 11.0 (1H, s), 11.1 (1H, s); MS m/e MH+ 517.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].CC[O-].[Na+].[Na].[Cl:17][C:18]1[CH:19]=[C:20]([CH2:24][CH2:25][CH2:26]OS(C2C=CC(C)=CC=2)(=O)=O)[CH:21]=[CH:22][CH:23]=1>O.C(O)C>[CH2:1]([O:3][C:4](=[O:11])[CH:5]([CH2:26][CH2:25][CH2:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([Cl:17])[CH:19]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)OCCCc2cccc(Cl)c2)cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(CCCc1cccc(Cl)c1)C(=O)OCC
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 41.7 %

Procedure:
91.3 g of malonic acid diethyl ester are added dropwise, at 50° C., to a sodium ethylate solution freshly prepared from 13.11 g of sodium and 650 ml of ethanol. The mixture is kept at that temperature for 2.5 hours, and 185 g of p-toluenesulfonic acid [3-(3-chlorophenyl)propyl] ester are then added dropwise. When the addition is complete, the obtained mixture is stirred at 50° C. for 6 hours; 800 ml of water are then added, and the mixture is extracted 3 times with a total of 1 liter of diethyl ether. The combined organic phases are dried over sodium sulfate; the solvent is evaporated off, and the residue is distilled. 74.2 g of 3-(3-chlorophenyl)propylmalonic acid diethyl ester (b.p. 145° to 152° C. under 0.01 mm Hg) are obtained.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[CH:17][C:16]2[N:15]=[C:14](N)[C:13]3[N:20]=[C:21]([CH2:24][CH2:25][CH2:26][CH3:27])[N:22]([CH3:23])[C:12]=3[C:11]=2[CH:10]=1)C1C=CC=CC=1>C(O)C.[Pd]>[CH2:24]([C:21]1[N:22]([CH3:23])[C:12]2[C:11]3[CH:10]=[C:9]([OH:8])[CH:18]=[CH:17][C:16]=3[N:15]=[CH:14][C:13]=2[N:20]=1)[CH2:25][CH2:26][CH3:27]
Reactant: CCCCc1nc2c(N)nc3ccc(OCc4ccccc4)cc3c2n1C
Agent: [Pd]
Solvent: CCO
Product: CCCCc1nc2cnc3ccc(O)cc3c2n1C
Reaction time: 8 h
Yield: 86.8 %

Procedure:
A solution of 8-benzyloxy-2-butyl-1-methyl-1H-imidazo[4,5-c]quinolin-4-amine (14.65 g, 42.4 mmol), prepared as described in Parts A-C of Example 59, in ethanol (1.2 L) was added to 10% palladium on carbon (6.77 g, 63.6 mmol) and a small amount of ethanol in a Parr vessel. The reaction was placed under hydrogen pressure (50 psi, 3.4×105 Pa) for 3.5 hours. The catalyst was removed by filtration and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to a small volume. Hexanes were added, and the resulting mixture was allowed to stand overnight in a refrigerator. Crystals formed and were isolated by filtration, washed with hexanes (500 mL), and dried for three days under high vacuum to provide 9.40 g of 2-butyl-1-methyl-1H-imidazo[4,5-c]quinolin-8-ol as a white solid, mp 219-220.2° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([C:15]3[CH:20]=[CH:19][N:18]=[C:17](Cl)[CH:16]=3)[N:9]=2)=[CH:4][CH:3]=1.[C:22]([NH:26][S:27]([C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1)(=[O:29])=[O:28])([CH3:25])([CH3:24])[CH3:23]>>[C:22]([NH:26][S:27]([C:30]1[CH:31]=[CH:32][CH:33]=[C:34]([C:17]2[CH:16]=[C:15]([C:10]3[N:9]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[CH:13]=[C:12]([CH3:14])[N:11]=3)[CH:20]=[CH:19][N:18]=2)[CH:35]=1)(=[O:29])=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: Cc1cc(-c2ccc(Cl)cc2)nc(-c2ccnc(Cl)c2)n1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Product: Cc1cc(-c2ccc(Cl)cc2)nc(-c2ccnc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)c2)n1

Procedure:
3-{4-[4-(4-Chloro-phenyl)-6-methyl-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonic acid tert-butylamide was prepared from 4-(4-chloro-phenyl)-2-(2-chloro-pyridin-4-yl)-6-methyl-pyrimidine (example E.45) (0.32 g, 1.0 mmol) and commercially available 3-(tert.-butylsulfamoyl)-phenylboronic acid (0.31 g, 1.2 mmol) according to the general procedure VI. Obtained as a light brown solid (0.47 g), which was subsequently deprotected.
Reaction SMILES: [NH2:1][C:2]1[C:19]([Cl:20])=[CH:18][C:5]([C:6]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[CH:7][C:8]([OH:10])=O)=[CH:4][C:3]=1[Cl:21].C(N(CC)CC)C.ClC(OCC)=O.[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>C(Cl)(Cl)Cl>[NH2:1][C:2]1[C:3]([Cl:21])=[CH:4][C:5]([C:6]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[CH:7][C:8]([N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)=[O:10])=[CH:18][C:19]=1[Cl:20]
Reactant: C1COCCN1
Reactant: Nc1c(Cl)cc(C(=CC(=O)O)c2ccc(Cl)cc2)cc1Cl
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Nc1c(Cl)cc(C(=CC(=O)N2CCOCC2)c2ccc(Cl)cc2)cc1Cl
Temperature: -10 °C

Procedure:
20 g (0.058 mol) of 4-amino-β-(4-chlorophenyl)-3,5-dichloro-cinnamic acid (mixture of isomers A and B in the ratio 1:1.5) were dissolved in 700 ml of dry chloroform. 5.93 g (0.058 mol) of triethylamine were added while cooling with ice and stirring, and the mixture was cooled to -10° C. and combined with 6.35 g (0.058 mol) of ethyl chloroformate. After the addition had ended, 25.5 g (0.29 mol) of morpholine were added while further stirring and cooling. The resulting mixture was stirred for 4 hours more at room temperature and then extracted three times with water, and the organic phase was dried over sodium sulfate and concentrated to dryness in vacuo. The residue was chromatographed on a silica gel column (silica gel: substance=10:1, eluant: chloroform/ethyl acetate=1:1). The eluates containing substance were combined and evaporated to dryness in vacuo. Colorless crystals were obtained, melting point 140°-144° C., which contained the cis/trans isomer mixture in a proportion of 3:2.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2([CH:11]3[CH2:12][C:8]4([C:13]([OH:15])=[O:14])[CH:9]([CH2:10]3)[CH:7]24)[C:4](=[O:16])[NH:3]1.[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][O:14][C:13]([C:8]23[CH2:12][CH:11]4[C:5]5([C:4](=[O:16])[N:3]([CH2:22][C:21]6[CH:24]=[CH:25][C:18]([F:17])=[CH:19][CH:20]=6)[C:2](=[O:1])[N:6]5[CH2:22][C:21]5[CH:24]=[CH:25][C:18]([F:17])=[CH:19][CH:20]=5)[CH:7]2[CH:9]3[CH2:10]4)=[O:15])=[CH:20][CH:19]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: O=C1NC(=O)C2(N1)C1CC3C2C3(C(=O)O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1N(Cc2ccc(F)cc2)C(=O)C2(C3CC4C2C4(C(=O)OCc2ccc(F)cc2)C3)N1Cc1ccc(F)cc1
Temperature: 25 °C
Yield: 98.8 %

Procedure:
A solution of 1.1 g (5.0 mmole) of 2′,5′-dioxo-spiro{tricyclo[2.2.1.02,6]heptane-3,4′-imidazoline}-1-carboxylic acid in 30 mL of N,N-dimethylformamide was treated with an excess of p-fluorobenzyl bromide (4.73 g, 25 mmole) and potassium carbonate (3.45 g, 25 mmole) at 60° C. for 36 hours. After cooling to room temperature, the mixture was diluted to 500 mL with water and extracted with 2×250 mL of ethyl acetate. The extracts were washed with water, dried over sodium sulfate and concentrated in vacuum to give 2.7 g of the title compound, again as a mixture of diastereomers.