Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[O:13][CH2:14][CH2:15][O:16][CH3:17].CC(OC(C)=O)=O.[N+:25]([O-])([OH:27])=[O:26]>CC(O)=O>[CH3:1][O:2][C:3]1[C:4]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[CH:5][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:11]([N+:25]([O-:27])=[O:26])[CH:12]=1
Reactant: COCCOc1cc(C(=O)OC)ccc1OC
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: COCCOc1cc(C(=O)OC)c([N+](=O)[O-])cc1OC
Temperature: 50 °C
Yield: 56 %

Procedure:
According to the procedure described in Example 6A Step 2, to a solution of methyl 4-methoxy-3-(2-methoxyethoxyl)benzoate (5.6 g, 23.3 mmol) and Ac2O (12 mL) in AcOH (60 mL) was dropped fuming nitric acid (90%, 4 mL). The reaction was heated at 50° C. for 3 hours, and the residue was purified by silica gel chromatography with 0-15% EtOAc/hexane as eluants to afford methyl 4-methoxy-5-(2-methoxyethoxy)-2-nitrobenzoate as a solid (3.67 g, 56%). 1H NMR (300 MHz, DMSO-d6) δ 7.64 (s, 1H), 7.34 (s, 1H), 4.26 (m, 2H), 3.91 (s, 3H), 3.82 (s, 3H), 3.68 (m, 2H), 3.33 (s, 3H).
Reaction SMILES: [Cl-].[CH2:2]([Si@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][Zn+])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)[CH2:3][CH3:4].[F:20][C:21]1[C:26]([F:27])=[C:25]([O:28][CH2:29][CH2:30]I)[CH:24]=[CH:23][CH:22]=1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCCC1>[CH2:2]([Si@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[C:18][C:22]3[CH:23]=[CH:24][C:25]([O:28][CH2:29][CH3:30])=[C:26]([F:27])[C:21]=3[F:20])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)[CH2:3][CH3:4]
Reactant: Fc1cccc(OCCI)c1F
Reactant: CCC[Si@H]1CC[C@H](c2ccc(CC[Zn+])cc2)CC1
Agent: [Pd]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCC[Si@H]1CC[C@H](c2ccc(C#Cc3ccc(OCC)c(F)c3F)cc2)CC1

Procedure:
10.0 ml (10.0 mmol) of a tetrahydrofuran solution of 1.0M 4-(trans-4-n-propyl-4-silacyclohexyl) phenylethyl zinc chloride was dripped into a mixture of 4.20 g (14.8 mmol) of 2,3-difluoro-4-iodoethoxybenzene, 70 mg of tetrakis (triphenylphosphine) palladium (0) and 15 ml of tetrahydrofuran. The reaction mixture was reacted for 2 hours at 50° C. After a conventional after treatment, purification was conducted by means of silica-gel column chromatography to obtain 3.25 g (yield 88%) of the target product.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:41])[N:6]2[CH2:16][CH2:17][CH2:18][CH2:19][N:20]([CH2:29][C:30]1[CH:31]=[C:32]([CH2:36][C:37]([O:39]C)=[O:38])[CH:33]=[CH:34][CH:35]=1)[CH2:21][C:22]([CH3:28])([CH3:27])[CH2:23][N:24]([CH3:26])[CH3:25].[OH-].[Li+]>>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:41])[N:6]2[CH2:16][CH2:17][CH2:18][CH2:19][N:20]([CH2:29][C:30]1[CH:31]=[C:32]([CH2:36][C:37]([OH:39])=[O:38])[CH:33]=[CH:34][CH:35]=1)[CH2:21][C:22]([CH3:27])([CH3:28])[CH2:23][N:24]([CH3:26])[CH3:25]
Reactant: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCN(Cc3cccc(CC(=O)OC)c3)CC(C)(C)CN(C)C)c2n1
Agent: [Li+]
Agent: [OH-]
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCN(Cc3cccc(CC(=O)O)c3)CC(C)(C)CN(C)C)c2n1

Procedure:
Using the compound obtained in Example 2-31 (50 mg) and lithium hydroxide (15 mg), the same manner to Example 2-12 was conducted to give the titled compound as a white solid. Yield: 10 mg (21%); mp 189-190° C., MS APCI+ve 556 (M+H).
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:24]([O:26]C)=[O:25])=[CH:12][C:13]=3[N:14]3[CH2:23][CH2:22][C:21]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>O1CCCC1.CO>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:24]([OH:26])=[O:25])=[CH:12][C:13]=3[N:14]3[CH2:23][CH2:22][C:21]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[C:15]=23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCc1ccccc1-3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCc1ccccc1-3
Temperature: 25 °C
Reaction time: 15 h
Yield: 92.8 %

Procedure:
To a solution of methyl 12-cyclohexyl-5,6-dihydroindolo[2,1-a]isoquinoline-9-carboxylate (337 mg, 0.93 mmol) in tetrahydrofuran (3 ml) and methanol (3 ml) was added 4N aqueous sodium hydroxide solution (3.0 ml), and the mixture was stirred at room temperature for 15 hr. The reaction mixture was acidified with 2N hydrochloric acid. The precipitated solid was collected by filtration and dried in vacuo to give 12-cyclohexyl-5,6-dihydroindolo[2,1-a]isoquinoline-9-carboxylic acid (298 mg, yield 92.3%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[F:47][C:48]([F:60])([F:59])[CH2:49][C:50]1[N:54]2[CH2:55][CH2:56][NH:57][CH2:58][C:53]2=[N:52][N:51]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([N:57]1[CH2:56][CH2:55][N:54]2[C:50]([CH2:49][C:48]([F:47])([F:59])[F:60])=[N:51][N:52]=[C:53]2[CH2:58]1)=[O:5]
Reactant: FC(F)(F)Cc1nnc2n1CCNC2
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCn2c(nnc2CC(F)(F)F)C1
Reaction time: 12 h
Yield: 22 %

Procedure:
2-Fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoic acid 1a (801 mg, 2.69 mmol) was dissolved in 25 mL of N,N-dimethylformamide, followed by addition of O-(1-benzotriazolyl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.27 g, 3.36 mmol), crude 3-(2,2,2-trifluoro ethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine 26b (460 mg, 2.24 mmol) and N, N-diisopropylethylamine (0.8 mL, 4.48 mmol). After stirring for 12 hours, the reaction mixture was concentrated under reduced pressure, added with 30 mL of H2O and extracted with ethyl acetate (30 mL×3). The organic phase was combined, concentrated under reduced pressure, added with 30 mL of ethyl acetate, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography with elution system A to obtain 4-[[4-fluoro-3-[3-(2,2,2-trifluoroethyl)-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazine-7-carbonyl]phenyl]methyl]-2H-phthalazin-1-one 26 (240 mg, yield 22.1%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)CC)C.[CH3:23][CH:24]([CH3:27])[CH2:25][NH2:26].Cl>CN(C)C=O>[Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10]([NH:26][CH2:25][CH:24]([CH3:27])[CH3:23])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=[N+]([O-])c1c(Cl)nc2ccccc2c1Cl
Reactant: CC(C)CN
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)CNc1c([N+](=O)[O-])c(Cl)nc2ccccc12
Temperature: 0 °C
Yield: 90 %

Procedure:
A mixture of 2,4-dichloro-3-nitroquinoline (100g) and N,N-dimethylformamide (180 mL) was stirred, and triethylamine (42 g, 4 eq) was added dropwise, followed by dropwise addition of 2-methylpropylamine (21.5 g, 0.7 eq). The mixture was stirred at room temperature until the reaction was completed as determined by gas chromatography. Aqueous hydrochloric acid (250 mL, 4N) was added with stirring. The resulting mixture was stirred and cooled to about 0° C. to precipitate the product. The precipitate was filtered, washed with water, and dried at reduced pressure to afford the product 2-chloro-N-(2-methylpropyl)-3-nitro-4-quinolinamine in about 90% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([SH:9])[CH:5]=[CH:6][C:7]=1[F:8].I[CH2:11][CH3:12].C(N(CC)CC)C>C(#N)C>[CH2:11]([S:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=1)[CH3:12]
Reactant: Fc1ccc(S)cc1F
Reactant: CCI
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCSc1ccc(F)c(F)c1
Temperature: 80 °C

Procedure:
To thick-walled reaction pressure tube was added 3,4-difluorobenzenethiol (1500 mg, 10.26 mmol), iodoethane (1.095 mL, 13.34 mmol), acetonitrile (20 mL), and triethylamine (1.860 mL, 13.34 mmol). The vessel was capped and heated at 80° C. for 2 hours. After cooling to room temperature, the reaction mixture was concentrated. Methylene chloride was added and the mixture was washed with water three times. The organic layer was concentrated to provide crude 4-(ethylthio)-1,2-difluorobenzene which was used without further purification. This material was combined with 2-propanol (20 mL) and water (10 mL). To the mixture was added OXONE® (8388 mg, 13.7 mmol). After stirring at room temperature overnight, the reaction mixture was evaporated in vacuo and the residue was extracted with ethyl acetate. The ethyl acetate was washed with water three times followed by saturated aqueous sodium bicarbonate and then brine. The organic layer was dried with sodium sulfate, filtered, and concentrated. The resulting residue was purified by flash chromatography (silica gel, 0-100% ethyl acetate/hexane) to give Intermediate 8 (2 g, 99% yield) as white solid. 1H NMR (CDCl3, 500 MHz) δ 7.67-7.82 (m, 2H), 7.38 (dd, J=16.22, 9.07 Hz, 1H), 3.13 (q, J=7.70 Hz, 2H), 1.25-1.32 (m, 3H); MS (ESI) 207.1 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:24][C@H:23]([CH2:25][O:26][C:27](=[O:29])[CH3:28])[C@@H:17]([O:18][C:19](=[O:22])[CH2:20][CH3:21])[C@H:12]3[O:13][C:14](=[O:16])[CH3:15])[C:4]=2[N:5]=[CH:6][N:7]=1.[N+:30]([O-])([OH:32])=[O:31].S(=O)(=O)(O)O>ClCCl.O>[NH2:1][C:2]1[C:3]2[C:10]([N+:30]([O-:32])=[O:31])=[CH:9][N:8]([C@@H:11]3[O:24][C@H:23]([CH2:25][O:26][C:27](=[O:29])[CH3:28])[C@@H:17]([O:18][C:19](=[O:22])[CH2:20][CH3:21])[C@H:12]3[O:13][C:14](=[O:16])[CH3:15])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=[N+]([O-])O
Reactant: CCC(=O)O[C@H]1[C@@H](OC(C)=O)[C@H](n2ccc3c(N)ncnc32)O[C@@H]1COC(C)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: ClCCl
Product: CCC(=O)O[C@H]1[C@@H](OC(C)=O)[C@H](n2cc([N+](=O)[O-])c3c(N)ncnc32)O[C@@H]1COC(C)=O
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of the product from Step 4 (1.5 g, 3.69 mmol) in dichloromethane (25 mL) was cooled to 0° C. and a 1:1 mixture of fuming nitric acid and sulfuric acid (4 mL) was added dropwise and the reaction was vigorously stirred at 0° C. for 20 min. The reaction was quenched with ice cold saturated sodium bicarbonate solution. The quenched reaction was diluted with water and extracted with dichloromethane. The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by plating on silica gel with dichloromethane and eluded by ramping to 5% methanol in dichloromethane to give 600 mg (36%);
Reaction SMILES: C[O:2][C:3](=[O:38])[CH2:4][CH2:5][NH:6][C:7](=[O:37])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=3)=[C:22]([CH:35]=[O:36])[CH:21]=2)[CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:10][CH:9]=1.[BH4-].[Na+]>CO.C(OCC)(=O)C>[OH:36][CH2:35][C:22]1[CH:21]=[C:20]([O:19][CH:14]([C:11]2[CH:12]=[CH:13][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:38])=[O:2])=[O:37])=[CH:9][CH:10]=2)[CH2:15][CH:16]([CH3:18])[CH3:17])[CH:25]=[CH:24][C:23]=1[C:26]1[CH:27]=[CH:28][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:30][CH:31]=1
Reactant: COC(=O)CCNC(=O)c1ccc(C(CC(C)C)Oc2ccc(-c3ccc(C(C)C)cc3)c(C=O)c2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)CC(Oc1ccc(-c2ccc(C(C)C)cc2)c(CO)c1)c1ccc(C(=O)NCCC(=O)O)cc1
Reaction time: 2 h
Yield: 263.8 %

Procedure:
To the solution of 3-{4-[1-(2-formyl-4′-isopropyl-biphenyl-4-yloxy)-3-methyl-butyl]-benzoylamino}-propionic acid methyl ester (36 mg, 0.07 mmol) in methanol (5 ml) is added NaBH4 (3 mg, 0.07 mmol). After 2 h, the mixture is diluted with ethyl acetate, washed with 1N HCl, water, brine, dried over MgSO4, and concentrated. The residue is taken into methanol (20 mL), followed by the addition of sodium hydroxide (5 N aqueous, 1 mL), stirred for 4 h. The reaction mixture is concentrated and acidified by 5 N HCl (1 mL), extracted with ethyl acetate. Combined organic layers are washed with water and brine, dried over sodium sulfate. Concentration gives the title compound (93 mg) as a white solid. MS (ES): 502.2 [M−H]−.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C[Si]([N:19]=[N+:20]=[N-:21])(C)C>>[CH2:12]([C:13]1[N:19]=[N:20][NH:21][CH:14]=1)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: C#CCCCCCCCCCCCC
Reactant: C[Si](C)(C)N=[N+]=[N-]
Product: CCCCCCCCCCCCc1c[nH]nn1
Reaction time: 14 h
Yield: 49.8 %

Procedure:
A mixture of 1-tetradecyne (6.6 g, 34 mmol) and trimethylsilyl azide (4.1 g, 35 mmol) was autoclaved at 135° C. for 14 hours and then at 150° C. for 14 hours. The resulting mixture was rinsed with ether and the ether solution was washed with water, dried over MgSO4, filtered, and concentrated to give a brown oil. Triturated with cold hexanes to give the title compound as a tan solid (4.02 g, 50%); mp 64°-67° C.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]([NH:13][C:14]([C:16]1[C:24]2[C:19](=[N:20][CH:21]=[C:22]([C:25]3[C:33]4[C:28](=[CH:29][C:30]([CH3:34])=[CH:31][CH:32]=4)[N:27]([CH2:35][CH2:36][CH2:37][N:38]([CH3:40])[CH3:39])[N:26]=3)[N:23]=2)[NH:18][CH:17]=1)=[O:15])([CH3:12])[CH3:11])(C(C)(C)C)(C)C.[ClH:41]>CO>[ClH:41].[CH3:40][N:38]([CH3:39])[CH2:37][CH2:36][CH2:35][N:27]1[C:28]2[C:33](=[CH:32][CH:31]=[C:30]([CH3:34])[CH:29]=2)[C:25]([C:22]2[N:23]=[C:24]3[C:16]([C:14]([NH:13][C:10]([CH3:11])([CH3:12])[CH2:9][OH:8])=[O:15])=[CH:17][NH:18][C:19]3=[N:20][CH:21]=2)=[N:26]1
Reactant: Cc1ccc2c(-c3cnc4[nH]cc(C(=O)NC(C)(C)CO[Si](C)(C)C(C)(C)C)c4n3)nn(CCCN(C)C)c2c1
Agent: Cl
Solvent: CO
Product: Cc1ccc2c(-c3cnc4[nH]cc(C(=O)NC(C)(C)CO)c4n3)nn(CCCN(C)C)c2c1
Reaction time: 3 h

Procedure:
To the solution of N-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-2-(1-(3-(dimethylamino)propyl)-6-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (1 g, 1.78 mmol) in 10 mL of methanol was added 1 mL of concentrated HCl, stirred for 3 hours, the precipitate was filtered and the filter cake was washed with 2-methoxy-2-methylpropane to give 25 mg of 2-(1-(3-(dimethylamino)propyl)-6-methyl-1H-indazol-3-yl)-N-(1-hydroxy-2-methylpropan-2-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide hydrochloride. LCMS: (M+H)+=450; 1H NMR (300 MHz, DMSO): δ 12.84 (s, 1H), 9.55 (s, 1H), 9.14 (s, 1H), 8.49 (d, 1H, J=8.1 Hz), 8.40 (s, 1H), 7.96 (s, 1H), 7.62 (s, 1H), 7.17 (d, 1H, J=8.4 Hz), 4.61-4.58 (m, 2H), 3.67 (s, 2H), 3.21 (s, 2H), 2.82 (s, 6H), 2.55 (s, 3H), 2.33 (brs, 2H), 1.49 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH:13]=[O:14])=[N:11][CH:12]=1.[OH:18]O>O=[Mn]=O.CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]([OH:18])=[O:14])=[N:11][CH:12]=1
Reactant: O=Cc1ccc(OCc2cccc(F)c2)cn1
Reactant: OO
Agent: O=[Mn]=O
Solvent: CC(C)=O
Product: O=C(O)c1ccc(OCc2cccc(F)c2)cn1
Yield: 97.7 %

Procedure:
A mixture of 5-(3-fluoro-benzyloxy)-pyridine-2-carbaldehyde (600 mg, 2.6 mmol), hydrogen peroxide (aq. 35%, 4 ml, 118 mmol) acetone (20 ml) and a catalytic amount of MnO2 was heated under reflux for 4 h. The solvent was evaporated and the residue was triturated with water. The precipitate was collected to give the title compound as a white solid (628 mg, 98%). MS: m/e =247.1 (M+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:20]=[CH:19][C:12]2[CH:13]=[C:14]([C:16](=[O:18])[CH3:17])[O:15][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].O>CO>[CH2:1]([O:8][C:9]1[CH:20]=[CH:19][C:12]2[CH:13]=[C:14]([CH:16]([OH:18])[CH3:17])[O:15][C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1cc2ccc(OCc3ccccc3)cc2o1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(O)c1cc2ccc(OCc3ccccc3)cc2o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.6 %

Procedure:
To a solution of 1-[6-(benzyloxy)-1-benzofuran-2-yl]ethanone (25.7 g, 96.6 mmol) in methanol (300 mL) was added sodium borohydride (3.67 g, 96.6 mmol) by small portions, and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the solvent was evaporated. Ethyl acetate was added thereto, and the mixture was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=5:1) to give the title compound (18.3 g, yield 71%).
Reaction SMILES: [NH2:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[Cl:11].OC1C(C)=CC(C([NH:19][OH:20])=N)=CC=1C>>[NH2:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([C:6]([NH:19][OH:20])=[NH:7])=[CH:4][C:3]=1[Cl:11]
Reactant: Cc1cc(C#N)cc(Cl)c1N
Reactant: Cc1cc(C(=N)NO)cc(C)c1O
Product: Cc1cc(C(=N)NO)cc(Cl)c1N

Procedure:
The title compound is prepared from commercially available 4-amino-3-chloro-5-methylbenzonitrile in analogy to 4,N-dihydroxy-3,5-dimethyl-benzamidine; LC-MS: tR=0.50 min; [M+1]+=200.01; 1H NMR (D6-DMSO): δ 2.15 (s, 3H), 5.20 (s, 2H), 5.61 (s, 2H), 7.28 (s, 1H), 7.40 (s, 1H), 9.33 (s, 1H).
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]([F:23])([F:22])[C:10]1[CH:11]=[C:12]([N:19]=[C:20]=[O:21])[CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17].[NH2:24][C:25]([C:28]#[N:29])([CH3:27])[CH3:26]>O1CCCC1>[F:8][C:9]([F:22])([F:23])[C:10]1[CH:11]=[C:12]([N:19]2[C:28](=[NH:29])[C:25]([CH3:27])([CH3:26])[NH:24][C:20]2=[O:21])[CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17]
Reactant: CC(C)(N)C#N
Reactant: O=C=Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1(C)NC(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C1=N
Temperature: 20 °C
Reaction time: 72 h
Yield: 40 %

Procedure:
1 ml of triethylamine was added to a mixture of 49.6g of 3-trifluoromethyl-4-nitrophenyl isocyanate in 500 ml of tetrahydrofuran and then 18 g of 2-amino-2-cyanopropane were rapidly added thereto. The mixture was stirred for 72 hours at 20° C and was evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with an 8-2 methylene chloride-acetone mixture to obtain 27 g of 1-(3'-trifluoromethyl-4'-nitrophenyl)-4,4 -dimethyl-5-imino-imidazoline-2-one melting at 168° C.
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([C:12]([NH:14][C:15]2[CH:16]=[C:17]([NH:21][C:22]3[N:27]=[C:26]([S:28][C:29]#[N:30])[C:25]([N+:31]([O-])=O)=[CH:24][N:23]=3)[CH:18]=[CH:19][CH:20]=2)=[O:13])[CH:9]=[CH:10][CH:11]=1)([CH3:5])[CH3:4])#[N:2].CN1CCCC1=O.Cl.[OH-].[Na+]>C(O)C>[NH2:30][C:29]1[S:28][C:26]2[N:27]=[C:22]([NH:21][C:17]3[CH:16]=[C:15]([NH:14][C:12](=[O:13])[C:8]4[CH:9]=[CH:10][CH:11]=[C:6]([C:3]([C:1]#[N:2])([CH3:5])[CH3:4])[CH:7]=4)[CH:20]=[CH:19][CH:18]=3)[N:23]=[CH:24][C:25]=2[N:31]=1
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Nc3ncc([N+](=O)[O-])c(SC#N)n3)c2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CN1CCCC1=O
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Nc3ncc4nc(N)sc4n3)c2)c1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 60.4 %

Procedure:
To a suspension of 2-{[3-({[3-(1-cyano-1-methylethyl)phenyl]carbonyl}amino)phenyl]amino}-5-nitropyrimidin-4-yl thiocyanate (844 mg, 1.84 mmol) and reduced iron (513 mg, 9.20 mmol) in ethanol (16 mL)/1-methylpyrrolidin-2-one (8 mL) was added 1N hydrochloric acid (4 mL), and the mixture was stirred at 100° C. for 1.5 hr. The reaction mixture was neutralized with 2N aqueous sodium hydroxide solution (3 mL), and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure. To the obtained residue was added saturated aqueous sodium hydrogen carbonate solution (50 mL), and the mixture was extracted with ethyl acetate (50 mL, 2×20 mL). The combined organic layer was washed with saturated brine (10 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=40/60→20/80), and the fractions containing the object product were concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate and hexane to give the title compound (477 mg, 60%) as pale-purple crystals.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[C:3]=1[C:4]([NH:6][C:7]1[S:18][C:10]2[C:11]([CH3:17])([CH3:16])[O:12][C:13]([CH3:15])([CH3:14])[C:9]=2[C:8]=1[C:19]([OH:21])=O)=[O:5].Cl.[CH2:31]([NH2:34])[C:32]#[CH:33]>>[F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:28])([F:29])[F:27])[C:3]=1[C:4]([NH:6][C:7]1[S:18][C:10]2[C:11]([CH3:17])([CH3:16])[O:12][C:13]([CH3:14])([CH3:15])[C:9]=2[C:8]=1[C:19]([NH:34][CH2:31][C:32]#[CH:33])=[O:21])=[O:5]
Reactant: C#CCN
Reactant: CC1(C)OC(C)(C)c2c1sc(NC(=O)c1c(F)cccc1C(F)(F)F)c2C(=O)O
Agent: Cl
Product: C#CCNC(=O)c1c(NC(=O)c2c(F)cccc2C(F)(F)F)sc2c1C(C)(C)OC2(C)C

Procedure:
The title compound was prepared from the product of Example 45A and commercially available propargylamine hydrochloride using the procedure described for Example 2B. 1H NMR (DMSO-d6, 300 MHz) δ 1.44 (s. 6H), 1.48 (s, 6H), 3.06-3.08 (m, 1H), 3.90-3.93 (m, 2H), 7.65-7.81 (m, 3H), 8.55 (t, J=5.6 Hz, 1H), 11.58 (br s, 1H). MS (ESI+) m/z 469 (M+H)+. Anal. calcd. for C22H20F4N2O3S: C, 56.40; H, 4.30; N, 5.98. Found: C, 56.36; H, 4.27; N, 5.94.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[C:10]([CH3:11])=[CH:9][S:8][C:7]=1[CH2:12]O.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[Cl:5][C:6]1[C:10]([CH3:11])=[CH:9][S:8][C:7]=1[CH2:12][Cl:3]
Reactant: O=S(Cl)Cl
Reactant: Cc1csc(CO)c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1csc(CCl)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Thionyl chloride (2.1 ml) was added dropwise to a chloroform (30 ml) solution of (3-chloro-4-methyl-2-thienyl)methanol (2.34 g), followed by stirring at room temperature for 30 minutes. The reaction solution and chloroform were added to a saturated aqueous sodium hydrogen carbonate solution and then the organic layer was separated. Furthermore, the organic layer washed with brine and, after drying over anhydrous sodium sulfate and filtration, the solvent was removed by evaporation under reduced pressure to obtain 3-chloro-2-(chloromethyl)-4-methylthiophene. Sodium cyamide (1.06 g) and water (15 ml) were added to an acetone (9 ml) solution of 3-chloro-2-(chloromethyl)-4-methylthiophene, followed by stirring at 60° C. for 1 hour. After water and ether were added to the reaction solution, the organic layer was separated. Furthermore, the organic layer washed with brine and, after drying over anhydrous sodium sulfate and filtration, the solvent was removed by evaporation under reduced pressure. The resulting crude product was purified by column chromatography (hexane:ethyl acetate=9:1) to obtain 1.33 g of (3-chloro-4-methyl-2-thienyl)acetonitrile (yellow oil).