Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[N:9][OH:10])([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.[OH-].[Na+].[S:31]1[CH:35]=[CH:34][CH:33]=[C:32]1[C:36](Cl)=O>CC1CCCO1.O>[C:2]1([C:1]2[N:8]=[C:36]([C:32]3[S:31][CH:35]=[CH:34][CH:33]=3)[O:10][N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1cccs1
Reactant: NC(=NO)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: CC1CCCO1
Solvent: O
Product: c1ccc(-c2noc(-c3cccs3)n2)cc1
Temperature: 70 °C
Yield: 95 %

Procedure:
A 39.45% solution of benzamide oxime in 2-methyltetrahydrofuran (33.34 g) was charged to a 100 mL flask, followed by water (9.0 g), 40% aqueous solution of tetrabutylammonium hydroxide (1.02 g), and 51% sodium hydroxide (3.52 g, 0.045 moles). To this mixture was added 2-thiophenecarbonyl chloride (13.83 g, 0.0936 moles) and 51% sodium hydroxide (7.33 g, 0.0935 moles) simultaneously over a 30 minute period while heating to about 70° C. The reaction was complete in less than 80 minutes. The aqueous salt phase was removed, water was added (30 g), and the 2-methyltetrahydrofuran partly removed by atmospheric distillation (13.5 mL). An additional amount (32 g) of hot water was added, and the remainder of the 2-methyltetrahydrofuran was distilled out, during which time the product, 3-phenyl-5-(2-thienyl)-1,2,4-oxadiazole, precipitated. The aqueous slurry of 3-phenyl-5-(2-thienyl)-1,2,4-oxadiazole was filtered, washed with water and dried overnight in a vacuum oven to yield 3-phenyl-5-(2-thienyl)-1,2,4-oxadiazole, 20.47 g, 99.1% pure, 95.0% yield.
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[CH:7]=[C:6]([CH3:17])[C:3]=1[C:4]#[N:5].[N:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][NH2:27])=[CH:20][CH:19]=1.C(=O)([O-])O.[Na+].CS(C)=O>O>[N:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][NH:27][C:2]2[N:9]=[C:8]([NH:10][C:11]3[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=3)[CH:7]=[C:6]([CH3:17])[C:3]=2[C:4]#[N:5])=[CH:20][CH:19]=1
Reactant: NCCOc1ccncc1
Reactant: Cc1cc(Nc2cc(C)c(C#N)c(Cl)n2)n[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(Nc2cc(C)c(C#N)c(NCCOc3ccncc3)n2)n[nH]1
Temperature: 100 °C
Reaction time: 27 h

Procedure:
Compound A (400 mg, 1.63 mmol), 2-(pyridin-4-yloxy)ethylamine (540 μl) and sodium hydrogencarbonate (1.32 g) were added to DMSO (12 ml), and the mixture was stirred at 100° C. for 27 hr. After stirring, the reaction mixture was added to cold water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and concentrated, and the residue was washed by suspending in ethyl acetate to give the object compound of 2-(2-(pyridin-4-yloxy)ethylamino)-6-(5-methyl-1H-pyrazol-3-ylamino)-4-methylnicotinonitrile (23 mg).
Reaction SMILES: [OH-].[K+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[CH:5]=[CH:4]1.[CH2:12]([O:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][C:21]=1[O:28][CH3:29])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:30]O>>[CH2:12]([O:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]([O:25][CH3:30])[C:5]2[C:6]3[C:11](=[N:10][CH:9]=[CH:8][CH:7]=3)[NH:3][CH:4]=2)=[CH:22][C:21]=1[O:28][CH3:29])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COc1cc(C=O)ccc1OCc1ccccc1
Reactant: c1cnc2[nH]ccc2c1
Reactant: CO
Agent: [K+]
Agent: [OH-]
Product: COc1cc(C(OC)c2c[nH]c3ncccc23)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Methanol (125 mL) and potassium hydroxide (4.4 g, 79 mmol) were mixed with 1H-pyrrolo[2,3-b]pyridine (94, 3.1 g, 26.6 mmol) and 4-benzyloxy-3-methoxy-benzaldehyde (564, 12.9 g, 53.2 mmol). The reaction was stirred at room temperature for 2 days. The resulting white solid was filtered and washed with water. Crude material was carried forward without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17](=[O:18])[C:16]3[C:15]4[C:10](=[CH:11][C:12]([C:19]#[N:20])=[CH:13][CH:14]=4)[NH:9][C:8]=3[C:7]([CH3:22])([CH3:21])[C:6]=2[CH:23]=1.[C:24]([O:28][C:29](=[O:36])[N:30]([CH2:34][CH3:35])[CH2:31][CH2:32]O)([CH3:27])([CH3:26])[CH3:25]>>[C:24]([O:28][C:29](=[O:36])[N:30]([CH2:31][CH2:32][O:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17](=[O:18])[C:16]3[C:15]4[C:10](=[CH:11][C:12]([C:19]#[N:20])=[CH:13][CH:14]=4)[NH:9][C:8]=3[C:7]([CH3:21])([CH3:22])[C:6]=2[CH:23]=1)[CH2:34][CH3:35])([CH3:26])([CH3:27])[CH3:25]
Reactant: CC1(C)c2cc(O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Reactant: CCN(CCO)C(=O)OC(C)(C)C
Product: CCN(CCOc1ccc2c(c1)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O)C(=O)OC(C)(C)C

Procedure:
Under the same conditions as the method for synthesizing Compound A7-1, the title compound was prepared from Compound A6 and ethyl-(2-hydroxy-ethyl)-carbamic acid tert-butyl ester.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:11][C:10]2[C:12]([N+:18]([O-])=O)=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:9]=2[NH:8][C:7](=[O:21])[CH2:6]1)(=[O:4])=[O:3].CN(C)C=O>>[NH2:18][C:12]1[C:10]2[CH2:11][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][C:7](=[O:21])[NH:8][C:9]=2[CH:15]=[CH:14][C:13]=1[O:16][CH3:17]
Reactant: COc1ccc2c(c1[N+](=O)[O-])CN(S(C)(=O)=O)CC(=O)N2
Solvent: CN(C)C=O
Product: COc1ccc2c(c1N)CN(S(C)(=O)=O)CC(=O)N2
Yield: 97.4 %

Procedure:
4-Methanesulfonyl-7-methoxy-6-nitro-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (0.57 g, 0.0018 mol) was hydrogenated in N,N-Dimethylformamide (40 mL, 0.5 mol) 10% Pd/C (10:90, Palladium:carbon black, 0.057 g) for 5 days. After the reaction was filtered and the filtrate evaporated. the residue was triturated with ether giving 6-Amino-4-methanesulfonyl-7-methoxy-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one as a grey solid (0.50 g, 97%). Mp 232-233° C.; LCMS (m/e) 285 (M); 1H-NMR (DMSO, 400 MHz) δ 1H-NMR (DMSO, 400 MHz) δ 9.93 (s, 1H), 6.84-6.82 (d, 1H, J=8.59 Hz), 6.38-6.36 (d, 2H, J=8.33 Hz), 4.85 (s, 2H), 4.35 (s, 2H), 3.77 (s, 3H), 3.68 (s, 2H), 2.98 (s, 3H).
Reaction SMILES: C([Li])CCC.[CH3:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Cl:14][C:15]1[CH:16]=[C:17]([N+:22]([O-:24])=[O:23])[CH:18]=[CH:19][C:20]=1F>O1CCCC1>[Cl:14][C:15]1[CH:16]=[C:17]([N+:22]([O-:24])=[O:23])[CH:18]=[CH:19][C:20]=1[N:7]([CH3:6])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Reactant: CNc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN(c1ccccc1)c1ccc([N+](=O)[O-])cc1Cl
Temperature: 25 °C

Procedure:
n-Butyl lithium (12.3 mL of a 2.5 M solution in hexanes) is added dropwise to a solution of N-methyl aniline (3.0 g) in tetrahydrofuran (75 mL) at 0° C. The mixture is allowed to warm slowly to room temperature and is then re-cooled to 0° C. and added by cannula to a solution of 3-chloro-4-fluoronitrobenzene (4.9 g) in tetrahydrofuran (35 mL) that is kept at −78° C. Following the addition, the reaction mixture is permitted to warm to room temperature over the course of 1 hour, and is then concentrated under reduced pressure, quenched by addition of saturated aqueous ammonium chloride, and extracted three times with ethyl acetate. The pooled organic layers are washed three times with 5% aqueous hydrochloric acid, once with water, once with saturated aqueous sodium bicarbonate, once with saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. Following removal of the solvent under reduced pressure the residue is chromatographed over silica gel (5% diethyl ether in hexanes is used as the eluant) to provide the desired product as a clear colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([CH:12]=[CH2:13])=[N:9][C:8]=2[CH:14]=1)([O-:3])=[O:2].[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>C(O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([CH2:12][CH2:13][N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)=[N:9][C:8]=2[CH:14]=1)([O-:3])=[O:2]
Reactant: C1CCNC1
Reactant: C=Cc1nc2cc([N+](=O)[O-])ccc2o1
Solvent: CCO
Product: O=[N+]([O-])c1ccc2oc(CCN3CCCC3)nc2c1

Procedure:
A solution of 1 g (5.25 mmol) of 5-nitro-2-vinylbenzoxazole and 0.66 mL (8 mmol) of pyrrolidine in 8 mL of ethanol is stirred for 2 hours at ambient temperature. Then the reaction solution is evaporated down. The purification is carried out by column chromatography on silica gel (eluant: dichloromethane/ethanol/ammonia (20:1:0.1)). Yield: 0.74 g (53.9% of theory); C13H15N3O3 (M=261.28); calc.: molecular ion peak (M+H)+: 262; found: molecular ion peak (M+H)+: 262; Rf value: 0.2 (silica gel, dichloromethane/ethanol/ammonia (20:1:0.1)).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][NH:13][CH2:12][CH:11]([C:15]([O:17][CH3:18])=[O:16])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].C(N(CC)CC)C.Cl[C:27]([O:29][C:30]1[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=1)=[O:28]>ClCCl>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:14][N:13]([C:27]([O:29][C:30]3[CH:31]=[CH:32][C:33]([N+:36]([O-:38])=[O:37])=[CH:34][CH:35]=3)=[O:28])[CH2:12][CH:11]([C:15]([O:17][CH3:18])=[O:16])[CH2:10]2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCc1ccc(C2CNCC(C(=O)OC)C2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1ccc(C2CC(C(=O)OC)CN(C(=O)Oc3ccc([N+](=O)[O-])cc3)C2)cc1
Temperature: 0 °C

Procedure:
10.0 g (40.4 mmol) of the compound from Example 2A were initially charged in 135 ml of dichloromethane and cooled to 0° C., and 11.2 ml (8.2 g, 80.9 mmol) of triethylamine and 8.5 g (40.4 mmol) of 4-nitrophenyl chloroformate were added. The reaction mixture was allowed to warm to room temperature over a period of 2 h. For work-up, the mixture was twice washed with water, and the organic phase was dried over sodium sulphate. The solvent was removed under reduced pressure and the residue was dried under high vacuum. Yield: 16.5 g (83% of theory)
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH3:15][C:16]([CH3:26])([CH2:19][C:20]1([CH3:25])[O:24][CH2:23][CH2:22][O:21]1)[CH2:17][NH2:18].C(N(CC)CC)C>ClCCl>[CH3:15][C:16]([CH3:26])([CH2:19][C:20]1([CH3:25])[O:21][CH2:22][CH2:23][O:24]1)[CH2:17][NH:18][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: CC(C)(CN)CC1(C)OCCO1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(CNc1c([N+](=O)[O-])cnc2ccccc12)CC1(C)OCCO1
Yield: 99.9 %

Procedure:
The general method described in Step 1 of Example 1 was used to react 4-chloro-3-nitroquinoline (21.8 g, 104 mmol), 2,2-dimethyl-3-(2-methyl-[1,3]dioxolan-2-yl)propylamine (19.8 g, 114 mmol) and triethylamine (15.2 g, 150 mmol) in dichloromethane for 75 hours to provide [2,2-dimethyl-3-(2-methyl-[1,3]dioxolan-2-yl)propyl]-(3-nitroquinolin-4-yl)amine (35.9 g) as a yellow solid that was used directly in the next step without further purification.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1)[CH3:2].[C:10](=[S:12])=[S:11].[CH2:13](N(CC)CC)C.CCCCCC>C(OCC)C>[CH2:1]([C:3]1[CH:9]=[CH:8][C:6]([NH:7][C:10](=[S:12])[S:11][CH3:13])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCN(CC)CC
Reactant: S=C=S
Reactant: CCc1ccc(N)cc1
Solvent: CCCCCC
Solvent: CCOCC
Product: CCc1ccc(NC(=S)SC)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.8 %

Procedure:
To a solution of 4-ethylaniline (7.8 g) in diethyl ether (40 ml) were added carbon disulfide (6 g) and triethylamine (13 g). After stirring at room temperature for 2 hours, the precipitated crystals were collected by filtration and dried. The crystals (16 g) were dissolved in methanol (100 ml) and methyl iodide (7.6 g) was added dropwise thereto. The mixture was stirred at room temperature for 2 hours, acidified (pH =about 2) with in HCl and extracted with ethyl acetate. The organic phase was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a solid. The solid was treated with hexane, triturated, filtered and dried to give the desired methyl 4-ethylphenyldithiocarbamate (9.5 g, yield: 67%), m.p. 78° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH:3]=1.[CH3:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20]>>[OH:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:4]2[CH:3]=[C:2]([NH:20][C:19]3[CH:21]=[CH:22][CH:23]=[C:17]([CH3:16])[CH:18]=3)[N:7]=[CH:6][N:5]=2)=[CH:10][CH:11]=1
Reactant: Cc1cccc(N)c1
Reactant: Oc1ccc(Nc2cc(Cl)ncn2)cc1
Product: Cc1cccc(Nc2cc(Nc3ccc(O)cc3)ncn2)c1

Procedure:
Using an analogous reaction procedure to that described in Example 6, 6-chloro-4-(4'-hydroxyanilino)pyrimidine (3.2 g) was reacted with 3-methylaniline (5 ml). The product so obtained was triturated under methylene chloride. The solid so obtained was filtered off and extracted with hot water. On cooling a solid precipitated from the aqueous solution. The solid was extracted from the aqueous solution with ethyl acetate, washed with water and with brine, dried (MgSO4) and recrystallised from a mixture of ethyl acetate and hexane to give 4-(4'-hydroxyanilino)-6-(3'-methylanilino)pyrimidine (0.15 g), m.p. 242°-245° C.;
Reaction SMILES: FC(F)(F)C1C=CC(CBr)=CC=1.Br[CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:24]=1[N:23]=[CH:22][CH:21]=[CH:20]2.[CH3:25][C:26]1[N:27]=[C:28]([N:36]2[CH2:40][CH2:39][NH:38][C:37]2=[O:41])[S:29][C:30]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32]>>[CH3:25][C:26]1[N:27]=[C:28]([N:36]2[CH2:40][CH2:39][N:38]([CH2:14][C:15]3[CH:16]=[CH:17][CH:18]=[C:19]4[C:24]=3[N:23]=[CH:22][CH:21]=[CH:20]4)[C:37]2=[O:41])[S:29][C:30]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32]
Reactant: BrCc1cccc2cccnc12
Reactant: CCOC(=O)c1sc(N2CCNC2=O)nc1C
Agent: FC(F)(F)c1ccc(CBr)cc1
Product: CCOC(=O)c1sc(N2CCN(Cc3cccc4cccnc34)C2=O)nc1C
Yield: 82 %

Procedure:
Following the procedure as described in Example 13, making variations as required to replace 4-(trifluoromethyl)benzyl bromide with 8-(bromomethyl)quinoline to react with ethyl 4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained as a colorless solid in 82% yield: MS (ES+) m/z 397.3 (M+1)
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[C:7](O)[N:6]=[C:5]([CH:10]([CH3:12])[CH3:11])[N:4]=1.P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:7]1[N:6]=[C:5]([CH:10]([CH3:12])[CH3:11])[N:4]=[C:3]([CH2:2][Cl:1])[CH:8]=1
Reactant: CC(C)c1nc(O)cc(CCl)n1
Reactant: O=P(Cl)(Cl)Cl
Product: CC(C)c1nc(Cl)cc(CCl)n1
Temperature: 80 °C

Procedure:
12.1 g (0.065 mol) of 4-chloromethyl-6-hydroxy-2-isopropyl-pyrimidine are suspended in 50 ml of phosphorus oxychloride and the suspension is heated to 80° C. for 30 minutes under nitrogen, the crystalline starting material dissolving gradually. The excess phosphorus oxychloride is then distilled off at 40°-60° C. under reduced pressure. The residue is poured on to ice-water, the pH-value of the mixture is brought to 7 by the addition of sodium hydroxide and the mixture is extracted three times with diethyl ether. The combined organic extracts are dried over anhydrous sodium sulphate and evaporated under reduced pressure. The dark coloured oily residue is taken up in hot n-hexane and the solution is treated with active carbon. After filtration of the hot mixture through Celite there is obtained 6-chloro-4-chloromethyl-2-isopropyl-pyrimidine as an orange oil which is pure in accordance with thin-layer chromatography. By distillation of this oil under reduced pressure there is obtained a colourless liquid, b.p. 75° C./0.05 mmHg, nD20 1.5226.
Reaction SMILES: CO[CH2:3][CH2:4]OC.Br[C:8]1[C:20]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:19][C:18]2[C:17]3[C:12](=[CH:13][C:14](Br)=[C:15]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:16]=3)[CH2:11][C:10]=2[CH:9]=1.[C:30]1(OB(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(O)C>[C:25]([C:15]1[C:14]([C:4]2[CH:3]=[CH:10][CH:9]=[CH:8][CH:20]=2)=[CH:13][C:12]2[CH2:11][C:10]3[C:18]([C:17]=2[CH:16]=1)=[CH:19][C:20]([C:21]([CH3:24])([CH3:22])[CH3:23])=[C:8]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH:9]=3)([CH3:27])([CH3:26])[CH3:28]
Reactant: CC(C)(C)c1cc2c(cc1Br)Cc1cc(Br)c(C(C)(C)C)cc1-2
Reactant: COCCOC
Reactant: OB(O)Oc1ccccc1
Solvent: CCO
Product: CC(C)(C)c1cc2c(cc1-c1ccccc1)Cc1cc(-c3ccccc3)c(C(C)(C)C)cc1-2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 54 %

Procedure:
Under a nitrogen atmosphere, 120 mL of anhydrous DME was added to 8.15 g (18.7 mmol) of 2,7-dibromo-3,6-di-tert-butylfluorene and 1.08 g (0.93 mmol) of Pd(PPh3), and the mixture was stirred at room temperature for 20 minutes. To this solution, 20 mL of an ethanol solution in which 5.01 g (41.1 mmol) of phenylboric acid was dissolved was added. The flask that had contained the phenylboric acid was washed two times with 4 mL of ethanol, and this was also added to the solution. The mixture was then stirred at room temperature for 20 minutes. Thereafter, 37.4 mL (74.8 mmol) of a 2.0 mol/L aqueous solution of sodium carbonate was added. Subsequently, the mixture was heated to reflux for 18 hours, and left to be naturally cooled, and the reaction was terminated with 1N hydrochloric acid in an ice bath. Thereafter, ether was added to extract the soluble fraction, and the aqueous layer was subjected to extraction with diethyl ether twice. The resultant extract was then combined with the organic layer obtained earlier. The resulting liquid was washed two times with a saturated aqueous solution of sodium hydrogen carbonate, two times with water, and once with saturated brine, and then dried over magnesium sulfate. The solvent was distilled off, and the residue was subjected to separation by silica gel chromatography. To the thus obtained whitish yellow powder, a mixture solution of hexane and a small amount of dichloromethane was added, and the mixture was heated to 60° C. to dissolve the powder completely. The resultant solution was left to stand for 1 hour at room temperature and then left to stand for 13 hours at −20° C. Crystals precipitated were washed 3 times with 10 mL of hexane to give a target product as a white powder (yield 4.36 g (54%)).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7](=[S:17])[NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([Br:16])[CH:10]=2)=[N:4][S:5][N:6]=1.F[C:19](F)(F)S(OC)(=O)=O.C(N(CC)C(C)C)(C)C>ClCCl>[NH2:1][C:2]1[C:3]([C:7]([S:17][CH3:19])=[N:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([Br:16])[CH:10]=2)=[N:4][S:5][N:6]=1
Reactant: COS(=O)(=O)C(F)(F)F
Reactant: Nc1nsnc1C(=S)Nc1ccc(F)c(Br)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CSC(=Nc1ccc(F)c(Br)c1)c1nsnc1N
Reaction time: 1 h
Yield: 95.8 %

Procedure:
A solution of 4-amino-N-(3-bromo-4-fluorophenyl)-1,2,5-thiadiazole-3-carbothioamide (130 mg, 0.4 mmol) in dichloromethane (5.2 mL) was treated with methyl trifluoromethanesulfonate (64 μL, 0.6 mmol) followed by N,N-diisopropylethylamine (102 μL, 0.6 mmol) and stirred for 1 h. The reaction mixture was diluted with dichloromethane (100 mL), washed with water (50 mL) and brine (50 mL), dried with sodium sulfate, filtered, and concentrated to give the desired product (133 mg, 98%). LCMS for C10H9BrFN4S2 (M+H)+: m/z=346.8, 348.8.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][Cl:15])[CH2:10][CH2:11][C:5]=2[CH:4]=1.[CH3:21][NH:22][CH:23]([CH3:34])[CH2:24][C:25]1[CH:30]=[C:29]([Cl:31])[C:28]([NH2:32])=[C:27]([Cl:33])[CH:26]=1>>[ClH:15].[CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][N:22]([CH3:21])[CH:23]([CH3:34])[CH2:24][C:25]3[CH:26]=[C:27]([Cl:33])[C:28]([NH2:32])=[C:29]([Cl:31])[CH:30]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: CNC(C)Cc1cc(Cl)c(N)c(Cl)c1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCCl)CC2
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)C(C)Cc1cc(Cl)c(N)c(Cl)c1)CC2
Product: Cl

Procedure:
This compound was prepared analogous to Example 5(b) from 1-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-chloro-propane and N-methyl-N-[2-(4-amino-3,5-dichloro-phenyl)-1-methyl-ethyl]-amine.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[S:11])[O:8][CH:7]2[CH3:12].[H-].[Na+].[H][H].Cl[C:18]1[N:23]=[C:22]([O:24][CH3:25])[N:21]=[C:20]([O:26][CH3:27])[N:19]=1>CN(C)C=O>[CH3:27][O:26][C:20]1[N:21]=[C:22]([O:24][CH3:25])[N:23]=[C:18]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:10]=2[C:9](=[S:11])[O:8][CH:7]3[CH3:12])[N:19]=1
Reactant: COc1nc(Cl)nc(OC)n1
Reactant: CC1OC(=S)c2c(O)cccc21
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1nc(OC)nc(Oc2cccc3c2C(=S)OC3C)n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
1.0 g of 7-hydroxy-3-methyl-isobenzofuran-1(3H)-thione is introduced into a suspension of 0.15 g of sodium hydride in absolute dimethylformamide and, when the evolution of hydrogen has ceased, 1.0 g of 2-chloro-4,6-dimethoxy-1,3,5-triazine is added thereto. The reaction mixture is subsequently stirred at room temperature for 5 hours, ice-water is then added and the whole is extracted with ethyl acetate and washed with sodium chloride solution. The crude product, having been concentrated by evaporation, is purified by chromatography (eluant: 45% ethyl acetate in n-hexane) and recrystallised from acetone/n-hexane to yield 7-[(4,6-dimethoxy-1,3,5-triazin-2-yl)oxy]-3-methyl-isobenzofuran-1(3H)-thione in the form of yellow crysals, m.p. 177°-178° C.; IR spectrum (CHCl3): 1590, 1560, 1366, 1304, 1140 cm-1 ; 1H-NMR (CDCl3): 5.81 ppm (q, 1H), 1.73 ppm (d, 3H).
Reaction SMILES: [CH:1]1([C:6]2[C:14]3[C:9](=[CH:10][C:11]([C:15]([NH:17][C:18]4([C:22]5[N:26]([CH3:27])[C:25]6[CH:28]=[CH:29][C:30](/[CH:32]=[CH:33]/[C:34](O)=[O:35])=[CH:31][C:24]=6[N:23]=5)[CH2:21][CH2:20][CH2:19]4)=[O:16])=[CH:12][CH:13]=3)[N:8]([CH3:37])[C:7]=2[C:38]2[CH:43]=[N:42][CH:41]=[CH:40][N:39]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C[N:45](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(=O)([O-])O.[NH4+].CCN(CC)CC>CS(C)=O.C(O)(=O)C>[C:34](/[CH:33]=[CH:32]/[C:30]1[CH:29]=[CH:28][C:25]2[N:26]([CH3:27])[C:22]([C:18]3([NH:17][C:15]([C:11]4[CH:10]=[C:9]5[C:14]([C:6]([CH:1]6[CH2:5][CH2:4][CH2:3][CH2:2]6)=[C:7]([C:38]6[CH:43]=[N:42][CH:41]=[CH:40][N:39]=6)[N:8]5[CH3:37])=[CH:13][CH:12]=4)=[O:16])[CH2:21][CH2:20][CH2:19]3)=[N:23][C:24]=2[CH:31]=1)(=[O:35])[NH2:45]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cn1c(C2(NC(=O)c3ccc4c(C5CCCC5)c(-c5cnccn5)n(C)c4c3)CCC2)nc2cc(/C=C/C(=O)O)ccc21
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cn1c(C2(NC(=O)c3ccc4c(C5CCCC5)c(-c5cnccn5)n(C)c4c3)CCC2)nc2cc(/C=C/C(N)=O)ccc21
Yield: 34 %

Procedure:
A solution of (E)-3-(2-{1-[(3-cyclopentyl-1-methyl-2-pyrazin-2-yl-1H-indole-6-carbonyl)amino]cyclobutyl}-1-methyl-1H-benzimidazol-5-yl)acrylic acid 5-2 (compound 4003, Table 4; 60 mg, 0.087 mmol), TBTU (68 mg, 0.18 mmol), ammonium hydrogen carbonate (20 mg, 0.26 mmol) and Et3N (36 μL, 0.26 mmol) in DMSO (3 mL) was stirred at RT for 3 h. The reaction mixture was neutralized with the addition of a few drops of acetic acid, and purified on a reversed phase C18, semi-preparative HPLC column (using a solvent gradient from 5% to 100% MeCN in H2O (all solvents contain 0.1% trifluoroacetic acid)) to isolate the inhibitor 3-cyclopentyl-1-methyl-2-pyrazin-2-yl-1H-indole-6-carboxylic acid {1-[5-((E)-2-carbamoylethenyl)-1-methyl-1H-benzoimidazol-2-yl]cyclobutyl}amide 5-3 (compound 1005, Table 1) as a pale yellow amorphous solid in >95% homogeneity (17 mg, 34% yield).