Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([C:8]2[CH:30]=[CH:29][C:11]([CH2:12][N:13]3[CH:21]=[C:20]4[C:15]([N:16]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:17](=[O:24])[N:18]([CH3:23])[C:19]4=[O:22])=[CH:14]3)=[CH:10][CH:9]=2)[CH:5]=[CH:4][CH:3]=1.[Cl:31]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.CN(C=O)C>[Cl:31][C:14]1[N:13]([CH2:12][C:11]2[CH:29]=[CH:30][C:8]([C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([F:1])[N:7]=3)=[CH:9][CH:10]=2)[CH:21]=[C:20]2[C:19](=[O:22])[N:18]([CH3:23])[C:17](=[O:24])[N:16]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:15]=12
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2cn(Cc3ccc(-c4cccc(F)n4)cc3)cc21
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)Cn1c(=O)n(C)c(=O)c2cn(Cc3ccc(-c4cccc(F)n4)cc3)c(Cl)c21
Temperature: 100 °C
Yield: 56.7 %

Procedure:
6-(4-(6-fluoropyridin-2-yl)benzyl)-1-isobutyl-3-methyl-1H-pyrrolo [3,4-d]pyrimidine-2,4(3H,6H)-dione (81 mg, 0.2 mmol) is dissolved in a mixture of CCl4 and DMF (3/1, v/v), and then N-chlorosuccinimide (27 mg, 0.2 mmol) is added. The reaction mixture is heated in a Biotage microwave at 100° C. for 30 minutes. Solvents are removed under vacuum, and the residue is purified by a semi-preparative HPLC to give pure product as off white solids (50 mg, yield 70%). MS (ESI) m/z 441.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:10]2[O:20][C:19]3[CH:18]=[C:17]([OH:21])[CH:16]=[C:15]([OH:22])[C:14]=3[C:12](=[O:13])[CH:11]=2)=[CH:7][C:8]=1[OH:9].[CH2:23](Br)[CH:24]=[CH2:25]>CO.[K]>[OH:22][C:15]1[C:14]2[C:12](=[O:13])[CH:11]=[C:10]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[C:8]([O:9][CH2:25][CH:24]=[CH2:23])[CH:7]=3)[O:20][C:19]=2[CH:18]=[C:17]([OH:21])[CH:16]=1
Reactant: C=CCBr
Reactant: COc1ccc(-c2cc(=O)c3c(O)cc(O)cc3o2)cc1O
Agent: [K]
Solvent: CO
Product: C=CCOc1cc(-c2cc(=O)c3c(O)cc(O)cc3o2)ccc1OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 83.8 %

Procedure:
20 g of diosmetin are dissolved in a mixture of 400 ml of anhydrous methanol and 13.3 g of potassium pellets. The reaction mixture is maintained at room temperature and then 16 g of allyl bromide dissolved in 40 ml of methanol are added dropwise with stirring. Stirring is then continued for 48 hours, and the solvents and volatile products are subsequently distilled off under reduced pressure at room temperature. The residue is taken up in 400 ml of CH2Cl2, and the insoluble material is collected by filtration and then recrystallised from 440 ml of isopropanol to yield 19 g of the expected compound, m.p.: 219° C.
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.[NH3:19]>CO>[NH2:19][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
Reactant: N
Reactant: Fc1ccc(-c2ccc3ncnc(Cl)c3c2)cc1
Solvent: CO
Product: Nc1ncnc2ccc(-c3ccc(F)cc3)cc12

Procedure:
This compound was synthesized from 4-chloro-6-(4-fluorophenyl)-quinazoline and a 7 N ammonia solution in methanol in 84%, using the procedure described for example 37. The product was characterized by its mass spectrum as follows: MS (m/z): 240 ([M+H]+, 100).
Reaction SMILES: C(=O)(O)[O-].[Na+].[NH2:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1[OH:14].[Cl:15][CH2:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1.Cl>COCCO.O>[Cl:15][CH2:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH:6][C:7]2[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=2[OH:14])=[O:22])=[CH:19][CH:18]=1
Reactant: O=C(Cl)c1ccc(CCl)cc1
Reactant: Cc1ccc(O)c(N)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCO
Solvent: O
Product: Cc1ccc(O)c(NC(=O)c2ccc(CCl)cc2)c1

Procedure:
With stirring, 37.52 g (446.6 mmol) of sodium bicarbonate were added to 50 g (406 mmol) of 2-amino-4-methylphenol in 250 ml of 2-methoxyethanol. 84.4 g (446.6 mmol) of 4-chloromethylbenzoyl chloride, dissolved in 250 ml of 2-methoxyethanol, were then added dropwise to the solution over 15 min. During this time, an increase in reaction temperature of from room temperature to 40° C. was observed. After 4 hours of stirring, 1 liter of water and 10 ml of concentrated hydrochloric acid were added to the reaction mixture. The crystals formed were filtered off and dried under reduced pressure. This gave 116 g of the target compound which were reacted further without further purification.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[CH:5][C:6]([CH3:10])=[C:7]([CH:9]=1)[NH2:8].[H+].[B-:14]([F:18])([F:17])([F:16])[F:15].[N:19]([O-])=O.[Na+]>O>[F:15][B-:14]([F:18])([F:17])[F:16].[F:1][C:2]([F:11])([F:12])[C:3]1[CH:4]=[CH:5][C:6]([CH3:10])=[C:7]([N+:8]#[N:19])[CH:9]=1
Reactant: O=N[O-]
Reactant: Cc1ccc(C(F)(F)F)cc1N
Agent: F[B-](F)(F)F
Agent: [H+]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(C(F)(F)F)cc1[N+]#N
Reaction time: 0.25 h

Procedure:
Seventeen and one-half grams of 5-trifluoromethyl-2-methylaniline was melted and the melted material added to 100 ml. of a cold 48 percent HBF4 solution. 7.9 g. of sodium nitrite in 10 ml. of water were added thereto in dropwise fashion. The temperature of the diazotization reaction was maintained below 15° C. during the addition. The diazotization mixture was stirred in the cold for about 15 minutes and then poured onto a sintered glass funnel. 5-Trifluoromethyl-2-methylphenyldiazonium fluorborate formed in the above reaction was collected thereon as a solid precipitate. The filter cake was washed once with cold HBF4 solution, twice with cold ethanol and several times with cold ether; weight = 20.2 g.; m.p. above 250° C.
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][NH:18][CH:19]1[C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21][CH2:20]1)=O)(C)(C)C.C(N(CC)C(C)C)(C)C.Br[CH2:39][CH2:40][CH2:41][C:42]#[N:43]>CC#N>[NH:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:8]=[C:9]1[CH2:17][N:18]([CH:19]1[C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21][CH2:20]1)[CH2:39][CH2:40][CH2:41][CH2:42][NH2:43]
Reactant: N#CCCCBr
Reactant: CC(C)(C)OC(=O)n1c(CNC2CCCc3cccnc32)nc2ccccc21
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: NCCCCN(Cc1nc2ccccc2[nH]1)C1CCCc2cccnc21
Temperature: 25 °C
Yield: 68.5 %

Procedure:
To a solution of (1-tert-butoxycarbonyl-1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine (0.169 g, 0.451 mmol) in CH3CN (5 mL) was added N,N-diisopropylethylamine (0.25 mL, 1.44 mmol) followed by 4-bromobutyronitrile (0.10 mL, 1.01 mmol). The resultant mixture was heated to 80° C. for 5 d then cooled to room temperature. The mixture was concentrated and the residue was partitioned between CH2Cl2 (20 mL) and brine (10 mL). The phases were separated and the aqueous phase was extracted with CH2Cl2 (3×10 mL). The combined organic extracts were dried (Na2SO4) and concentrated. Purification of the crude material by column chromatography on silica gel (30:1:1 CH2Cl2—CH3OH—NH4OH) provided 108 mg (54%) of a yellow foam.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:24])[C:11]([C:17]1[CH:22]=[CH:21][N:20]=[C:19](Cl)[CH:18]=1)([OH:16])[C:12]([F:15])([F:14])[F:13].[I-:25].[Na+].I>C(C(C)=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:24])[C:11]([C:17]1[CH:22]=[CH:21][N:20]=[C:19]([I:25])[CH:18]=1)([OH:16])[C:12]([F:15])([F:14])[F:13]
Reactant: [I-]
Reactant: COc1ccc(C(C)C(O)(c2ccnc(Cl)c2)C(F)(F)F)c(Cl)c1
Agent: I
Agent: [Na+]
Solvent: CCC(C)=O
Product: COc1ccc(C(C)C(O)(c2ccnc(I)c2)C(F)(F)F)c(Cl)c1
Yield: 79.5 %

Procedure:
3-(2-Chloro-4-methoxy-phenyl)-2-(2-chloro-pyridin-4-yl)-1,1,1-trifluoro-butan-2-ol (Example 132, 0.38 g) in ethyl-methyl ketone (5 mL) was treated with sodium iodide (600 mg) and HI-57% (0.132 mL) and heated for 2.5 h under reflux. The reaction mixture was then concentrated in vacuo, diluted with water, and pH adjusted to 7 with a saturated aqueous NaHCO3 solution. The mixture was extracted twice with ethyl acetate. The combined organic phases were washed with 0.5M sodium-thiosulfate and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (20 g silica gel, ethyl acetate/heptane 20:80) to give the title compound as white solid (375 mg). MS (m/e)=471.9 (MH+).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14].[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([CH2:2][C:3]2[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=2[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])[CH2:22][CH2:21]1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1ccc(C(F)(F)C(F)(F)F)c(CBr)c1
Product: CN1CCN(Cc2cc([N+](=O)[O-])ccc2C(F)(F)C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-Bromomethyl-4-nitro-1-pentafluoroethyl-benzene (2.6 g) was added to N-methylpiperazine (5 ml) and stirred at RT for 3 h. The mixture was filtered and the filtrate was treated with 1-chlorobutane, extracted with 2N HCl (100 ml). The acidic solution was treated with 5N NaOH (6 ml) then extracted with EtOAc. The organic layer was removed, dried over MgSO4 and concentrated to give the compound as an oil.
Reaction SMILES: S([O-])([O-])(=O)=O.S([O-])([O-])(=O)=O.[Al+3].S([O-])([O-])(=O)=O.S([O-])([O-])(=O)=[O:18].[Al+3].[F:23][C:24]1[C:29]([B:30](C2C(F)=C(F)C(F)=C(F)C=2F)[C:31]2[C:36]([F:37])=[C:35]([F:38])[C:34]([F:39])=[C:33]([F:40])[C:32]=2[F:41])=[C:28]([F:53])[C:27]([F:54])=[C:26]([F:55])[C:25]=1[F:56]>C1(C)C=CC=CC=1>[F:23][C:24]1[C:29]([B:30]([C:31]2[C:36]([F:37])=[C:35]([F:38])[C:34]([F:39])=[C:33]([F:40])[C:32]=2[F:41])[OH:18])=[C:28]([F:53])[C:27]([F:54])=[C:26]([F:55])[C:25]=1[F:56]
Reactant: O=S(=O)([O-])[O-]
Reactant: Fc1c(F)c(F)c(B(c2c(F)c(F)c(F)c(F)c2F)c2c(F)c(F)c(F)c(F)c2F)c(F)c1F
Agent: [Al+3]
Solvent: Cc1ccccc1
Product: OB(c1c(F)c(F)c(F)c(F)c1F)c1c(F)c(F)c(F)c(F)c1F

Procedure:
Moreover, that patent also discloses a method in which alminium sulfate 18 hydrate is used instead of water. Specifically, aluminium sulfate 18 hydrate is added to a toluene solution of tris (pentafluorophenyl) borane. After the solution is refluxed, insoluble alminium sulfate is separated from the reaction mixture. A solvent of a filtrate is removed in vacuo. Toluene is added to the thus obtained residue. After stirring, the insoluble matter passes through a G4 sintered-glass so as to be separated. The solvent of the filtrate is again removed in vacuo. Heptane is added to the residue. The solution is stirred and filtered so that a cake is obtained. Finally, the thus obtained cake is washed with heptane, and dried in vacuo so as to isolate bis (pentafluorophenyl) borinic acid. However, this method has such a problem that it is necessary to remove the by-product alminium sulfate and its process is so complicated.
Reaction SMILES: [CH3:1][N:2]([CH3:34])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([NH:12][C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[N:31]=[C:30]([CH3:32])[O:29][N:28]=4)=[CH:23][C:22]=3[CH3:33])=[CH:17][CH:16]=2)=[O:14])[CH:9]=[CH:10][CH:11]=1.[Cl:35]N1C(=O)CCC1=O>ClCCl>[CH3:1][N:2]([CH3:34])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:35])=[C:8]([NH:12][C:13]([C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[N:31]=[C:30]([CH3:32])[O:29][N:28]=4)=[CH:23][C:22]=3[CH3:33])=[CH:19][CH:20]=2)=[O:14])[CH:7]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1nc(-c2ccc(-c3ccc(C(=O)Nc4cccc(OCCN(C)C)c4)cc3)c(C)c2)no1
Solvent: ClCCl
Product: Cc1nc(-c2ccc(-c3ccc(C(=O)Nc4cc(OCCN(C)C)ccc4Cl)cc3)c(C)c2)no1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of N-[3-(2dimethylaminoethoxy)phenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-carboxamide (E13) (200 mg) in dichloromethane (10 ml) was treated with N-chlorosuccinimide (64 mg) and the mixture stirred at room temperature overnight. The reaction mixture was evaporated under reduced pressure, and the residue triturated with diethyl ether and the precipitated succinimide was removed by filtration. The filtrate was evaporated under reduced pressure and flash column chromatographed on silica gel, eluting with dichloromethane, then chloroform and methanol to give the title compound. (77 mg, 36%). Mp 101°-2° C.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:6](=[O:15])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:14])[CH3:3].Cl[C:23]1[C:24]2[C:31]([C:32]#[N:33])=[CH:30][NH:29][C:25]=2[N:26]=[CH:27][N:28]=1.CCN(CC)CC>CCCCO>[CH3:14][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]=1[C:6](=[O:15])[N:5]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:4]([C@@H:2]([NH:1][C:23]1[C:24]3[C:31]([C:32]#[N:33])=[CH:30][NH:29][C:25]=3[N:26]=[CH:27][N:28]=1)[CH3:3])=[CH:13]2
Reactant: Cc1cccc2cc([C@H](C)N)n(-c3ccccc3)c(=O)c12
Reactant: N#Cc1c[nH]c2ncnc(Cl)c12
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: Cc1cccc2cc([C@H](C)Nc3ncnc4[nH]cc(C#N)c34)n(-c3ccccc3)c(=O)c12
Temperature: 150 °C
Reaction time: 16 h
Yield: 23.8 %

Procedure:
(S)-3-(1-Aminoethyl)-8-methyl-2-phenylisoquinolin-1(2H)-one (compound 4704) (208 mg, 0.75 mol), 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (compound 5505) (160 mg, 0.90 mmol) and Et3N (228 mg, 2.25 mmol) were dissolved in n-BuOH (20 mL) in a sealed tube, and the resulting mixture stirred at 150° C. for 16 h. The reaction mixture was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with 50% Hex/EA) to afford the desired product, (S)-4-(1-(8-methyl-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethylamino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (5506, compound 264 in Table 4) (90 mg, 28% yield) as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:14]=[CH:13][C:8]2[NH:9][C:10](=[O:12])[O:11][C:7]=2[CH:6]=1)(=[O:4])[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CC(C)=O>[CH2:21]([N:9]1[C:8]2[CH:13]=[CH:14][C:5]([C:1](=[O:4])[CH2:2][CH3:3])=[CH:6][C:7]=2[O:11][C:10]1=[O:12])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: CCC(=O)c1ccc2[nH]c(=O)oc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCC(=O)c1ccc2c(c1)oc(=O)n2Cc1ccccc1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
94 g (492 mmol) 6-propionyl-3H-benzoxazol-2-one is placed in 1000 mL acetone and 160 g (1.157 mol) potassium carbonate and then 65 ml (546 mol) benzylbromide are added and the mixture is stirred for 4 h at 50° C. The reaction mixture is suction filtered hot and then the filtrate is slowly cooled. The solid is suction filtered and washed with acetone/diethyl ether.
Reaction SMILES: [OH-].[K+].CCO.[CH3:6][O:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=2)[N:10](C(OCC)=O)[N:9]=1.Cl>O>[CH3:6][O:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=2)[NH:10][N:9]=1
Reactant: CCOC(=O)n1nc(OC)c2cc([N+](=O)[O-])ccc21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1n[nH]c2ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.4 %

Procedure:
Potassium hydroxide (0.6 g) was added to an EtOH (20 ml) solution containing ethyl 3-methoxy-5-nitro-1H-indazol-1-carboxylate (1.24 g) obtained in the 3rd step, followed by stirring at room temperature for 0.5 hours. Water and concentrated hydrochloric acid (1 ml) were added dropwise to the reaction solution. A solid precipitate was collected by filtration and washed with water. A light yellow solid of 3-methoxy-5-nitro-1H-indazole (636 mg) was thus obtained.
Reaction SMILES: C([O:9][CH2:10][CH2:11][N:12]1[C:24]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]=[C:16]([Cl:25])[C:15]=2[N:14]=[CH:13]1)(=O)C1C=CC=CC=1.N>CO>[Cl:25][C:16]1[C:15]2[N:14]=[CH:13][N:12]([CH2:11][CH2:10][OH:9])[C:24]=2[C:23]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N:17]=1
Reactant: O=C(OCCn1cnc2c(Cl)nc3ccccc3c21)c1ccccc1
Agent: N
Solvent: CO
Product: OCCn1cnc2c(Cl)nc3ccccc3c21
Temperature: 20 °C
Reaction time: 72 h

Procedure:
A mixture of 25.3 g (0.072 mole) of 1-(2-benzoyloxyethyl)-4-chloro-1H-imidazo[4,5-c]quinoline (from Example 117) and 500 ml of 10% ammonia in methanol was stirred at about 20° C. for three days, and was then filtered and finally evaporated to low volume. The slurry was mixed with diethyl ether, and the solid was separated by filtration, washed with ether and recrystallized from methanol to provide white crystals of 4-chloro-1-(2-hydroxyethyl)-1H-imidazo[4,5-c]quinoline, m.p. 185°-187° C. Analysis: Calculated for C12H10ClN3O: % C, 58.2; % H, 4.1; N, 17.0; Found: % C, 58.0; % H, 4.0; % N, 17.3.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]=[C:12]([S:15][CH3:16])SC)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:17]([N:24]1[CH2:33][CH2:32][C:27]2([CH2:31][N:30]=[N:29][CH2:28]2)[CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>N1C=CC=CC=1>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]=[C:12]([N:30]2[N:29]=[CH:28][C:27]3([CH2:32][CH2:33][N:24]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH2:25][CH2:26]3)[CH2:31]2)[S:15][CH3:16])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CCC3(CC2)CN=NC3)cc1
Reactant: CSC(=NS(=O)(=O)c1ccc(N)cc1)SC
Solvent: c1ccncc1
Product: CSC(=NS(=O)(=O)c1ccc(N)cc1)N1CC2(C=N1)CCN(Cc1ccccc1)CC2
Temperature: 180 °C

Procedure:
In a 25 mL microwave vial, 1.50 g 4-amino-N-(bis-methylsulfanyl-methylene) benzenesulfonamide and 1.37 g 8-benzyl-2,3,8-triaza-spiro[4.5]dec-2-ene were suspended in 20 mL pyridine. The vial was capped and heated for 1 hour at 180° C. (6 bar) in the microwave. The reaction mixture was concentrated on silica. Purification with flash column chromatography (DCM→DCM/MeOH 99:1→DCM/MeOH 98:2) yielded 1.03 g (41%) of a beige amorph. 1H NMR (400 MHz, CDCl3) δ 1.57-1.72 (m, 2H), 1.78-1.92 (m, 2H), 2.17-2.32 (m, 5H), 2.66-2.81 (m, 2H), 3.51 (s, 2H), 4.04 (s, 2H), 4.28 (s, 2H), 6.64-6.71 (m, 2H), 6.98 (s, 1H), 7.20-7.37 (m, 5H), 7.72-7.79 (m, 2H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[C:17]1([SH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)C>[C:5]1([C:3](=[O:4])[CH2:2][S:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=C(CSc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 98 %

Procedure:
To a suspension of 2-bromoacetophenone (10 g) and potassium carbonate (7.1 g) in ethanol (150 mL) was added thiophenol (5.2 mL) under ice-cooling, and the mixture was stirred at room temperature for 12 hr. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine in this order, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=15:1) to give the title compound as yellow crystals (yield 11 g, 98%).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]([CH3:12])[C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:16]1[N:21]=[C:20]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[S:29]([NH:32][CH3:33])(=[O:31])=[O:30])[C:19]([Cl:34])=[CH:18][N:17]=1.Cl.O1CCOCC1>COCCO>[Cl:34][C:19]1[C:20]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[S:29]([NH:32][CH3:33])(=[O:31])=[O:30])=[N:21][C:16]([NH:1][C:2]2[CH:14]=[CH:13][C:5]3[N:6]([CH3:12])[C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:17][CH:18]=1
Reactant: CNS(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CN1C(=O)CCCc2cc(N)ccc21
Agent: Cl
Solvent: COCCO
Solvent: C1COCCO1
Product: CNS(=O)(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCCC(=O)N3C)ncc1Cl
Temperature: 120 °C
Yield: 14 %

Procedure:
7-Amino-1-methyl-1,3,4,5-tetrahydrobenzo[b]azepin-2-one (160 mg, 0.84 mmol), 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzenesulfonamide (280 mg, 0.84 mmol) and 4N HCl in dioxane (0.21 ml, 0.84 mmol) were dissolved in 2-methoxyethanol (4 ml) and heated to 120° C. for 5 hours. The mixture was concentrated to a brown solid. Preparative TLC (5% MeOH/CH2Cl2) gave a brown residue which was triturated with MeOH/CH2Cl2 to 2-[5-Chloro-2-(1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzenesulfonamide as a white solid, 58 mg. (14% yield) 1H NMR (400 MHz, DMSO-d6) δ 9.58 (s, 1H), 9.23 (s, 1H), 8.32-8.58 (m, 1H), 8.27 (s, 1H), 7.45-7.90 (m, 5H), 7.23-7.37 (m, 1H), 7.14-7.22 (m, 1H), 3.22 (s, 3H), 2.39-2.60 (m, 5H), 1.92-2.18 (m, 4H); MS (m/e) 487 (M+1); retention time 7.65 minute; mp 175-177° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:22][C@H:23]([CH2:27][O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH:24]([CH3:26])[CH3:25])[C@@H:10]([OH:21])CC(=C)C(NCCCC)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:36]([O:40]C(N[C@@H](C[C@H](COCC1C=CC=CC=1)C(C)C)[C@H](O)CC(=C)C(NCCCC)=O)=O)(C)(C)C>>[CH3:36][O:40][C:10](=[O:21])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:22][C@@H:23]([CH2:27][O:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[CH:24]([CH3:25])[CH3:26]
Reactant: C=C(C[C@H](O)[C@H](C[C@H](COCc1ccccc1)C(C)C)NC(=O)OC(C)(C)C)C(=O)NCCCC
Reactant: C=C(C[C@@H](O)[C@H](C[C@H](COCc1ccccc1)C(C)C)NC(=O)OC(C)(C)C)C(=O)NCCCC
Product: COC(=O)[C@H](C[C@@H](COCc1ccccc1)C(C)C)NC(=O)OC(C)(C)C

Procedure:
(2S,3S,5R)-2-[3-(tert-Butoxycarbonyl)amino-5-(benzyloxymethyl)-2-hydroxy-6-methylheptyl]-N-(butyl)acrylamide (A) and (2R,3S,5R)-2-[3-(tert-butoxycarbonyl)amino-5-(benzyloxymethyl)-2-hydroxy-6-methylheptyl]-N-(butyl)acrylamide (B): In a manner analogous to that described in Example 1g), there is obtained first, by reduction of (2S,4R)-2-(tert-butoxycarbonyl)amino-4-(benzyloxymethyl)-5-methyl-hexanoic acid methyl ester (8.0 g), dissolved in anhydrous toluene (120 ml), with a 1.2M diisobutylaluminium hydride solution in toluene (34.9 ml), (2S,4R)-2-(tert-butoxycarbonyl)amino-4-(benzyloxymethyl)-5-methyl-hexanal in the form of a pale-yellow oil (Rf (N)=0.6). The crude aldehyde is reacted in a manner analogous to that described in Example 1g) without being purified further. The crude product (14.8 g) obtained after aqueous working-up is chromatographed over 1.0 kg of silica gel using an eluant gradient from B to E, with separation of the two (2S,3S,5R)- and (2R,3S,5R)-diastereoisomers. There are obtained title compound A (2.52 g, 24%) in the form of a light-yellow oil, Rf (E)=0.55, HPLC Rt =19.8 min, MS(FAB) m/e 491 (M+ +1), and title compound B (3.76 g, 35%) in the form of a light-yellow oil, Rf (E)=0.42, HPLC Rt =19.6 min. MS(FAB) m/e 491 (M+ +1).