Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10](Cl)[C:9]2[C:4](=[C:5]([C:13]3[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=3[CH3:21])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[O:22]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][NH2:30])[CH2:24][CH2:23]1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][C:2]1[CH:11]=[C:10]([NH:30][CH2:29][CH2:28][N:25]2[CH2:26][CH2:27][O:22][CH2:23][CH2:24]2)[C:9]2[C:4](=[C:5]([C:13]3[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=3[CH3:21])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1cc(C)c(-c2cccc3c(Cl)cc(C)nc23)c(C)c1
Reactant: NCCN1CCOCC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: Cc1cc(C)c(-c2cccc3c(NCCN4CCOCC4)cc(C)nc23)c(C)c1
Temperature: 100 °C
Yield: 39.8 %

Procedure:
Part C: To a solution of 5.1 g (17.1 mmol) of 2-methyl-4-chloro-8-(2,4,6-trimethylphenyl)-quinoline and 2.68 g (20.6 mmol) of 2-morpholinoethylamine in 150 ml of toluene, after bubbling through nitrogen gas for 30 minutes, a quantity of 2.29 g (23.9 mmol) sodium tertiary butoxide, 0.16 g (0.26 mmol) of 2,2′-bis(diphenylphosphino)-1,1′-binaphtyl (BINAP) and 0.082 g (0.09 mmol) Pd2(dibenzylideneacetone)3 were subsequently added. After heating to 100° C. for 16 hours and subsequent cooling, the reaction mixture was filtered and concentrated in vacuo. The product was purified on a silicagel column using CH2Cl2/MeOH/NH4OH 93:7:0.5 as the eluent. A total of 2.65 g of 2-methyl-4-(N-2-morpholinoethyl)amino-8-(2,4,6-tri-methylphenyl)-quinoline was obtained (40% yield).
Reaction SMILES: [N:1](=[C:3]1[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:19]([CH2:20][CH2:21][C@:4]12[CH3:5])[C@:17]1([CH3:18])[C:12]([CH2:13][C@@H:14]([OH:22])[CH2:15][CH2:16]1)=[CH:11][CH2:10]3)[OH:2].C1(N=C=NC2CCCCC2)CCCCC1.[C:38](O)(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>ClCCl>[C:38]([O:22][C@H:14]1[CH2:15][CH2:16][C@@:17]2([CH3:18])[C:12](=[CH:11][CH2:10][C@@H:9]3[C@@H:19]2[CH2:20][CH2:21][C@@:4]2([CH3:5])[C@H:6]3[CH2:7][CH2:8][C:3]2=[N:1][OH:2])[CH2:13]1)(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=NO)CC[C@@H]12
Reactant: O=C(O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: C[C@]12CC[C@H](OC(=O)c3ccccc3)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=NO)CC[C@@H]12
Yield: 49.1 %

Procedure:
17-Oximino-5-androsten-3β-ol (9) (0.5 g, 1.6 mmol) and dicyclohexylcarbodiimide (DCC) (0.34 g, 1.6 mmol) was dissolved in anhydrous dichloromethane (30.0 ml) and stirred. To this was added benzoic acid (0.2 g, 1.6 mmol). The reaction mixture was stirred for 48 hr at room temperature (20-25°) and completion of the reaction was monitored by TLC. The precipitated material was filtered, solvent removed under reduced pressure to give residue which was crystallized from ethyl acetate:petroleum ether (60:80) to get 17-oximino-5-androsten-3β-yl benzoate (13) (0.32 g, 64.0%) mp 165-170° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:14][C:15](=[O:32])[C:16]([NH:18][C:19]([CH3:31])([CH3:30])[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][CH:22]=2)=[O:17])[CH:6]=[CH:7][C:8]=1[C:9]1[O:13][CH:12]=[N:11][CH:10]=1.[Sn](Cl)Cl.O1CCOCC1>C(O)C.C(OCC)(=O)C>[NH2:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][C:19]([NH:18][C:16](=[O:17])[C:15]([NH:14][C:5]2[CH:6]=[CH:7][C:8]([C:9]3[O:13][CH:12]=[N:11][CH:10]=3)=[C:3]([O:2][CH3:1])[CH:4]=2)=[O:32])([CH3:30])[CH3:31])=[CH:22][CH:23]=1
Reactant: COc1cc(NC(=O)C(=O)NC(C)(C)Cc2ccc([N+](=O)[O-])cc2)ccc1-c1cnco1
Agent: Cl[Sn]Cl
Solvent: C1COCCO1
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1cc(NC(=O)C(=O)NC(C)(C)Cc2ccc(N)cc2)ccc1-c1cnco1
Yield: 75.9 %

Procedure:
A mixture of 44 mg (0.1 mmol) of N-[3-methoxy-4-(5-oxazolyl)phenyl]-N′-[1,1-dimethyl-2-(4-nitrophenyl)ethyl]oxalamide and 90 mg (0.5 mmol) of tin(II) chloride were stirred and heated at 85° C. in 2 ml of ethanol and 1 ml of 1,4-dioxane for 5 hours. The resulting solution was cooled, diluted with ethyl acetate and washed with 2M sodium hydroxide. The organic phase was dried over magnesium sulphate, evaporated to dryness and the residue chromatographed on silica gel using ethyl acetate/petrol (2:1) for the elution. After trituration with petrol there was obtained 31 mg of N-[2-(4-aminophenyl)-1,1-dimethylethyl]-N′-[3-methoxy-4-(5-oxazolyl)phenyl]oxalamide as a white solid. MS: m/e 409 M+H]+.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:2]=1.[OH2:18]>>[CH:6]1[CH:5]=[C:4]([OH:18])[C:3]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:2][CH:1]=1.[CH:15]1[C:14]([OH:17])=[CH:13][CH:12]=[C:11]([S:8]([C:3]2[CH:4]=[CH:5][C:6]([OH:7])=[CH:1][CH:2]=2)(=[O:10])=[O:9])[CH:16]=1
Reactant: O
Agent: O=S(=O)(c1ccc(O)cc1)c1ccc(O)cc1
Product: O=S(=O)(c1ccc(O)cc1)c1ccccc1O

Procedure:
Since almost no water is contained in the reaction mixture, it is preferable that 4,4′-dihydroxydiphenylsulfone is separated by crystallization by adding phenol to the reaction mixture. The amount of the crystallized 4,4′-dihydroxydiphenylsulfone to provide the content of 2,4′-dihydroxydiphenylsulfone greater than the content of 4,4′-dihydroxydiphenylsulfone in the filtrate obtained by the crystallization of 4,4′-dihydroxydiphenylsulfone, followed by the filtration, can be calculated, and the amount of the added phenol can be obtained based on the solubility using the amount obtained by the calculation. The filtrate having a content of 2,4′-dihydroxydiphenylsulfone greater than the content of 4,4′-dihydroxydiphenylsulfone can be obtained as follows: phenol is added to the reaction mixture; the resultant mixture is heated until the entire fluid becomes homogeneous; the heated fluid is cooled, and crystals of 4,4′-dihydroxydiphenylsulfone are allowed to grow sufficiently and then separated by filtration. Since the crystals of 4,4′-dihydroxydiphenylsulfone separated by the filtration contains phenol and phenolsulfonic acid, it is preferable that the crystals are washed with hot water and dried. The obtained 4,4′-dihydroxydiphenylsulfone has a purity of 95% by weight or greater.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([F:11])[C:5]([C:6]([OH:8])=O)=[C:4]([F:12])[CH:3]=1.[CH3:13][C:14]1[C:15]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[N:16][CH:17]=[C:18]([CH3:20])[CH:19]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.[Cl-].[Na+].O>[Br:1][C:2]1[CH:3]=[C:4]([F:12])[C:5]([C:6]([N:24]2[CH2:25][CH2:26][N:21]([C:15]3[C:14]([CH3:13])=[CH:19][C:18]([CH3:20])=[CH:17][N:16]=3)[CH2:22][CH2:23]2)=[O:8])=[C:9]([F:11])[CH:10]=1
Reactant: O=C(O)c1c(F)cc(Br)cc1F
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cnc(N2CCN(C(=O)c3c(F)cc(Br)cc3F)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
4-Bromo-2,6-difluorobenzoic acid (2.88 g), 1-(3,5-dimethylpyridin-2-yl)piperazine (2.32 g) described in Preparation Example 79 and 1-hydroxybenzotriazole 1 hydrate (1.64 g) were dissolved in N,N-dimethylformamide (50 mL), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (2.32 g) was added, and the mixture was stirred at room temperature overnight. To the reaction mixture was added saturated brine, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (chloroform:methanol) to give the title compound (4.33 g).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[N:25]=[C:24]([C:29]#[C:30][C:31]2[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=2)[CH:23]=[CH:22]3)=[CH:15][CH:14]=1.[NH:39]1[CH2:43][CH2:42][CH2:41][CH2:40]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])([O-])=O.[K+].[K+]>C1COCC1.O.C(O)(=O)C>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[N:25]=[C:24]([C:29]#[C:30][C:31]2[CH:38]=[CH:37][C:34]([CH2:35][N:39]4[CH2:43][CH2:42][CH2:41][CH2:40]4)=[CH:33][CH:32]=2)[CH:23]=[CH:22]3)=[CH:15][CH:14]=1
Reactant: O=Cc1ccc(C#Cc2ccc3cc(-c4ccc(Cl)cc4)ccc3n2)cc1
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Clc1ccc(-c2ccc3nc(C#Cc4ccc(CN5CCCC5)cc4)ccc3c2)cc1
Reaction time: 0.5 h

Procedure:
3 mg p-toluenesulphonic acid and 100 μL glacial acetic acid are added to a solution of 290 mg (0.78 mmol) 4-[6-(4-chloro-phenyl)-quinoline-2-ylethynyl]-benzaldehyde and 56 mg (0.78 mmol) pyrrolidine in 10 mL THF at RT and stirred for 30 minutes. Then 334 mg (1.57 mmol) NaBH(OAc)3 are added batchwise and the reaction mixture is stirred for 14 h. A few drops of water are added dropwise to the reaction mixture and this is stirred for 15 minutes. The reaction mixture is then combined with K2CO3 and filtered. The filtrate is evaporated down. The purification is carried out by column chromatography on silica gel (DCM/MeOH/NH3 90:10:1).
Reaction SMILES: [C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][C:4]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)#[N:2].N(C1C2CCCCC=2C(C#N)=CC=1)=C=O.[OH:33][C@H:34]1[C@@H:41]2[N:37]([C:38](=[O:55])N(C3C4CCCCC=4C(C#N)=CC=3)[C:40]2=[O:42])[CH2:36][CH2:35]1>>[OH:33][C@H:34]1[C@@H:41]2[N:37]([C:38](=[O:55])[N:7]([C:6]3[CH:5]=[C:4]([C:10]4[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=4)[C:3]([C:1]#[N:2])=[CH:9][CH:8]=3)[C:40]2=[O:42])[CH2:36][CH2:35]1
Reactant: COc1ccc(-c2cc(N)ccc2C#N)cc1
Reactant: N#Cc1ccc(N2C(=O)[C@@H]3[C@H](O)CCN3C2=O)c2c1CCCC2
Agent: N#Cc1ccc(N=C=O)c2c1CCCC2
Product: COc1ccc(-c2cc(N3C(=O)[C@@H]4[C@H](O)CCN4C3=O)ccc2C#N)cc1

Procedure:
The title compound was prepared from compound 49A by procedures analogous to those described in Experiment 2E and 2F. HPLC: 96% at 3.24 min (retention time) (Conditions: YMC S5 C18 (4.6×50 mm); Eluted with 0% to 100% B, 8 min gradient, 3 min hold. (A=90% H2O—10% MeOH—0.1% H3PO4 and B=10% H2O—90% MeOH—0.1% H3PO4); Flow rate at 2.5 mL/min UV detection at 220 nm). LC/MS m/z 364 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:38])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([NH:11][C:12]3[N:17]4[N:18]=[CH:19][C:20]([C:21](O)=[O:22])=[C:16]4[N:15]=[CH:14][C:13]=3[C:24]([N:26]3[CH2:31][CH2:30][CH:29]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH2:28][CH2:27]3)=[O:25])[C:4]=2[O:3]1.[CH2:39]([S:41]([NH2:44])(=[O:43])=[O:42])[CH3:40]>>[CH3:38][C:2]1([CH3:1])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([NH:11][C:12]3[N:17]4[N:18]=[CH:19][C:20]([C:21]([NH:44][S:41]([CH2:39][CH3:40])(=[O:43])=[O:42])=[O:22])=[C:16]4[N:15]=[CH:14][C:13]=3[C:24]([N:26]3[CH2:31][CH2:30][CH:29]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH2:28][CH2:27]3)=[O:25])[C:4]=2[O:3]1
Reactant: CCS(N)(=O)=O
Reactant: CC1(C)Cc2cccc(Nc3c(C(=O)N4CCC(c5ccccc5)CC4)cnc4c(C(=O)O)cnn34)c2O1
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3cccc4c3OC(C)(C)C4)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Yield: 44.8 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(2,2-dimethyl-2,3-dihydrobenzofuran-7-ylamino)-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.05 g, 0.10 mmol) obtained in step 2 and ethanesulfonamide (0.063 g, 0.58 mmol), the title compound (0.027 g, 44%) was obtained.
Reaction SMILES: [CH3:1][C:2]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:13])=[CH2:3].CS(O[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])(=O)=O.O>CN(C)C=O>[CH3:3][C:2]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[C:5]1=[O:13])=[CH2:1]
Reactant: CC(C)(C)OC(=O)NCCCCCCOS(C)(=O)=O
Reactant: C=C(C)n1c(=O)[nH]c2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: C=C(C)n1c(=O)n(CCCCCCNC(=O)OC(C)(C)C)c2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.8 %

Procedure:
5.9 g (135 mmol) of a 55% sodium hydride dispersion in mineral oil are washed oil-free with hexane and subsequently covered with 100 ml of dimethylformamide. To this suspension are added dropwise at room temperature 22.3 g (128 mmol) of 1-(1-methylvinyl)benzimidazolin-2-one in 100 ml of dimethylformamide. After stirring at room temperature for 2 hours 55.0 g of tert.-butyl [6-[(methylsulphonyl)oxy]hexyl]carbamate in 100 ml of dimethylformamide are added dropwise and the reaction mixture is stirred at room temperature for 18 hours. Thereafter. the reaction mixture is poured into 1 l of water and extracted with 750 ml of methylene chloride. The organic extract is washed with water, dried over potassium carbonate and evaporated. The thus-obtained residue is chromatographed on 950 g of silica gel with methylene chloride/hexane, methylene chloride and a 95:5 mixture of methylene chloride and isopropanol as the elution agent, whereby there are obtained 45.3 g of tert.-butyl [6-[3-(1-methylvinyl)-2-oxo-1-benzimidazolinyl]hexyl]carbamate as an oil.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[CH:2]([CH:4]([C:6]([OH:8])=O)[OH:5])[OH:3]>C1(C)C=CC=CC=1>[C:6]1(=[O:8])[O:10][C:1](=[O:9])[CH:2]([OH:3])[CH:4]1[OH:5]
Reactant: O=C(O)C(O)C(O)C(=O)O
Solvent: Cc1ccccc1
Product: O=C1OC(=O)C(O)C1O

Procedure:
In the first step, a chiral tartaric anhydride is prepared by reaction of three equivalents of an acid chloride with tartaric acid according to the description in JACS 1933, 55, 2605, and is subsequently reacted with alkenamines at temperatures between 120° C. and 160° C. in suitable inert solvents, such as toluene.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:33][CH:34]=[CH2:35])[CH:8]=[C:9]([C:11]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[N:21]=[CH:20]3)([OH:16])[C:12]([F:15])([F:14])[F:13])[CH:10]=1)=O)C.[H-].C([Al+]CC(C)C)C(C)C.Cl.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH2:33]([N:7]1[C:6]([CH2:4][OH:3])=[CH:10][C:9]([C:11]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[N:21]=[CH:20]3)([OH:16])[C:12]([F:15])([F:14])[F:13])=[CH:8]1)[CH:34]=[CH2:35]
Reactant: C=CCn1cc(C(O)(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(F)(F)F)cc1C(=O)OCC
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Product: C=CCn1cc(C(O)(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(F)(F)F)cc1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 3.5 %

Procedure:
To a chilled (0° C.) solution of 250 mg (0.51 mmol) 1-allyl-4-{2,2,2-trifluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-1-hydroxyethyl}-1H-pyrrole-2-carboxylic acid ethyl ester in anhydrous CH2Cl2 was added 1.5 mL (1.5 mmol) of a 1 M solution of diisobutylaluminum hydride (DIBAL) in CH2Cl2. The reaction was warmed to reflux and stirred overnight. The reaction was cooled to room temperature, poured into 100 mL of 1N aqueous HCl, then made basic with saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by HPLC using CH3CN—H2O buffered with 0.1% TFA (5-90% gradient). The fractions from the column were concentrated in vacuo to remove CH3CN and then the resulting aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate. The solvent was concentrated in vacuo to afford 8.0 mg (4%) of the title compound. MS m/z 446.41 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].[S:11]1[CH2:17][C:15](=[O:16])[NH:14][C:12]1=S.CCN(C(C)C)C(C)C>C(#N)C>[Cl:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH:5][C:12]1[S:11][CH2:17][C:15](=[O:16])[N:14]=1
Reactant: NCc1ccc(F)cc1Cl
Reactant: O=C1CSC(=S)N1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C1CSC(NCc2ccc(F)cc2Cl)=N1
Temperature: 0 °C
Reaction time: 72 h
Yield: 16.5 %

Procedure:
To a solution of 2-chloro-4-fluoro-benzylamine (4.5 g, 28.19 mmol) and Rhodanine (3.75 g, 28.2 mmol) in acetonitrile (170 mL) was added DIPEA (9.82 mL, 56.4 mmol) at room temperature. Then, this solution was cooled to 0° C. and mercuric chloride (8.42 g, 31.02 mmol) was added in two portions within 10 min. After addition, the suspension was allowed to warm to room temperature and stirred for 3 days. The resulting black solids were filtered through a plug of celite and washed with acetonitrile (1.0 L) and ethyl acetate (500 mL). The combined filtrates were removed under the vacuum and the crude residue was dissolved in ethyl acetate (150 mL) and washed with water and brine solution. After drying over magnesium sulfate, the filtrate was removed under the vacuum and the residue was dissolved in ethyl acetate (50 mL) at hot condition. After cooling in the refrigerator overnight, the solids were collected by filtration and washed with hexanes. After drying in air, 1.2 g (16.5% yield) of 2-(2-chloro-4-fluoro-benzylamino)-thiazol-4-one was isolated as a white amorphous solid: EI-HRMS m/e calcd for C10H8FN2OS2 (M+) 258.0030, found 258.0027.
Reaction SMILES: O[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:13]2[NH:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][C:17]([O:26][CH3:27])=[CH:18][C:19]=3[O:24][CH3:25])[N:14]=2)[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1.C(Br)(Br)(Br)[Br:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C>[Br:29][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:13]2[NH:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][C:17]([O:26][CH3:27])=[CH:18][C:19]=3[O:24][CH3:25])[N:14]=2)[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1
Reactant: COc1cc(OCCO)cc(-c2nc3cc(OC)cc(OC)c3c(=O)[nH]2)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COc1cc(OCCBr)cc(-c2nc3cc(OC)cc(OC)c3c(=O)[nH]2)c1
Temperature: 40 °C
Reaction time: 7 h

Procedure:
To a solution of 2-[3-(2-hydroxy-ethoxy)-5-methoxy-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one (8.00 g, 21.5 mmol) in anhydrous DMF (30 mL) was added carbon tetrabromide (9.80 g, 29.5 mmol) and triphenylphosphine (7.78 g, 29.5 mmol). The reaction mixture was stirred at 40° C. for 7 hours. DMF was removed under vacuum and dichloromethane (200 mL) was added. The organic phase was washed with water (150 mL), then brine (100 mL), and dried over anhydrous sodium sulfate. Solvent was removed and the residue was washed three times with a mixture of ether and dichloromethane (20:1, 200 mL) to give 2-[3-(2-bromo-ethoxy)-5-methoxy-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one as a white solid. Yield: 8.9 g (95%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7](/[CH:10]=[CH:11]/[C:12]([OH:14])=O)[CH:8]=2)[CH:3]=[CH:2]1.Cl.C[N:17](C)[CH2:18][CH2:19][CH2:20]N=C=NCC.C(N)CC.N=C=N>CN(C)C1C=CN=CC=1.C(Cl)Cl.CN(C)C=O>[CH2:18]([NH:17][C:12](=[O:14])/[CH:11]=[CH:10]/[C:7]1[CH:8]=[C:9]2[C:4]([CH:3]=[CH:2][NH:1]2)=[CH:5][CH:6]=1)[CH2:19][CH3:20]
Reactant: O=C(O)/C=C/c1ccc2cc[nH]c2c1
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: N=C=N
Solvent: CN(C)C=O
Solvent: CCCN
Solvent: ClCCl
Product: CCCNC(=O)/C=C/c1ccc2cc[nH]c2c1
Reaction time: 18 h
Yield: 61.2 %

Procedure:
A mixture of E-indole-6-acrylic acid (0.96 g), 4-dimethylaminopyridine (0.635 g), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.96 g) was dissolved in methylene chloride (50 ml) and N,N-dimethylformamide (60 ml) and stirred for 1 hour. Propylamine (0.591 g) was added and stirring continued for 18 hr. Further quantities of 4-dimethylaminopyridine (0.635 g), the carbodiimide (0.96 g) and propylamine (0.591 g) were added; and the mixture stirred for a further 30 hr. The solvents were evaporated; the residue partitioned between ethyl acetate and 1M hydrochloric acid; and the organic phase washed with water and brine; dried (MgSO4); and evaporated. The residue was purified by flash chromatography, eluting with 1:10 methanol:chloroform, to give E-N-propylindole-6-acrylamide (0.7 g, 60%) as an off-white solid; partial NMR (250 MHz, DMSO-d6): 0.89(t, 3H, CH2CH2CH3, 1.48(m, 2H, CH2CH2CH3), 3.15(m, 2H, CH2CH2CH3); 6.44(d, J=2.8 Hz H3 -indole), 6.55(d, J=15.7 Hz, 1H, olefinic H), 8.00(br t, 1H, NHCO), 11.28(br s, 1H, H1 -indole).
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]#[N:12])=[CH:10][C:5]=2[S:4][CH:3]=1.C(C1C=C2C(=CC=1)C([N:25]1[CH2:30][CH2:29][NH:28][C@H:27]([CH3:31])[CH2:26]1)=CC=C2)#N>>[C:11]([C:9]1[CH:8]=[CH:7][C:6]2[C:2]([N:25]3[CH2:30][CH2:29][NH:28][C@H:27]([CH3:31])[CH2:26]3)=[CH:3][S:4][C:5]=2[CH:10]=1)#[N:12]
Reactant: N#Cc1ccc2c(Br)csc2c1
Reactant: C[C@@H]1CN(c2cccc3cc(C#N)ccc23)CCN1
Product: C[C@@H]1CN(c2csc3cc(C#N)ccc23)CCN1

Procedure:
3-Bromo-1-benzothiophene-6-carbonitrile was coupled with (2R)-methylpiperazine, as described above for (3R)-1-(6-cyano-1-naphthyl)-3-methylpiperazine, to yield (3R)-1-(6-cyano-1-benzothien-3-yl)-3-methylpiperazine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]([CH2:15][CH2:16][CH2:17][O:18][CH:19]([CH3:21])[CH3:20])[C:13]([CH2:22][O:23][CH2:24][CH3:25])=[N:12][C:7]=3[CH:8]=[N:9][C:10]=2[CH:11]=1.C(OO)(=[O:28])C.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]([CH2:15][CH2:16][CH2:17][O:18][CH:19]([CH3:20])[CH3:21])[C:13]([CH2:22][O:23][CH2:24][CH3:25])=[N:12][C:7]=3[CH:8]=[N+:9]([O-:28])[C:10]=2[CH:11]=1
Reactant: CCOCc1nc2cnc3cc(Br)ccc3c2n1CCCOC(C)C
Reactant: CC(=O)OO
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCOCc1nc2c[n+]([O-])c3cc(Br)ccc3c2n1CCCOC(C)C
Temperature: 50 °C
Reaction time: 2 h
Yield: 80.2 %

Procedure:
A slurry of 7-bromo-2-ethoxymethyl-1-(3-isopropoxypropyl)-1H-imidazo[4,5-c]quinoline (6.6 g, 16.2 mmol) in ethyl acetate (55 mL) was heated to 50° C. Peroxyacetic acid (5.12 mL, 24.4 mmol, of 32% in dilute acetic acid) was added dropwise over a period of 2 minutes. The reaction was allowed to stir at 50° C. for 2 hours. Additional peroxyacetic acid (1 mL) was added and the reaction mixture was stirred for an additional 2 hours. A solution of sodium metabisulfite (4.01 g, 21.1 mmol) in water (8 mL) was added. Following the addition of the sodium metabisulfite, the pH of the reaction mixture was adjusted to pH 10 with aqueous saturated sodium bicarbonate. The layers were separated and the aqueous layer was extracted with dichloromethane (2×50 mL). The combined organics were washed sequentially with water and brine, dried over sodium sulfate, filtered, and then concentrated under reduced pressure to provide a yellow solid. This material was purified by flash chromatography (150 g of silica gel eluting with a gradient of 1-12% CMA in chloroform) to provide 5.49 g of 7-bromo-2-ethoxymethyl-1-(3-isopropoxypropyl)-1H-imidazo[4,5-c]quinoline-5-oxide.
Reaction SMILES: [C:1]([CH2:9][C:10](=[O:12])[CH3:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:15].C(N(CC)CC)C>C(OCC)C>[CH2:17]([O:16][C:14]([O:12][C:10]([CH3:11])=[CH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:15])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CC(=O)CC(=O)c1ccccc1
Reactant: CCCCCCCCCCCCCCCCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCOC(=O)OC(C)=CC(=O)c1ccccc1
Yield: 80.6 %

Procedure:
The preparation is carried out as described in Example 1, using 17.8 g (0.11 mole) of benzoylacetone, 30.5 g (0.1 mole) of n-hexadecyl chloroformate and 100 ml of diethyl ether as well as 11 g (0.11 mole) of triethylamine. The crude product (34.7 g) obtained is recrystallised from a mixture of 85 ml of isopropanol and 10 ml of water. The white crystals melt at 31° C.