Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].C([N:12]1[CH2:16][CH2:15][CH:14]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[CH:19]=2)[CH2:13]1)C1C=CC=CC=1>C1C=CC=CC=1>[Br:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[O:17][CH:14]1[CH2:15][CH2:16][N:12]([C:1]([Cl:4])=[O:2])[CH2:13]1
Reactant: O=C(Cl)Cl
Reactant: Brc1cccc(OC2CCN(Cc3ccccc3)C2)c1
Solvent: c1ccccc1
Product: O=C(Cl)N1CCC(Oc2cccc(Br)c2)C1
Temperature: 0 °C
Reaction time: 6 h
Yield: 188.6 %

Procedure:
To a benzene solution of 5.05 g (0.051 mole) of phosgene in 50 ml of benzene at 10° C. under nitrogen gas was added dropwise 15.5 g (0.047 mole) of 1-benzyl-3-(3-bromophenoxy)pyrrolidine in 50 ml of dry benzene. The reaction mixture was stirred for 6 hr, diluted with ice-water mixture. The benzene layer which developed was separated and dried over magnesium sulfate and concentrated in vacuo to give 27 g of oil. The oil was triturated with hot 30/60 petroleum ether and the mixture stirred overnight. The petroleum layer was decanted and the oil again treated with fresh petroleum ether. The oil was again separated to give 20 g of oil crude product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=O)[C:10]1[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][N:11]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:22]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]=[C:9]([Cl:22])[C:10]1[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][N:11]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CS(=O)(=O)c1ccc(C(=O)Nc2ccccc2Cl)nc1
Solvent: c1ccccc1
Product: CS(=O)(=O)c1ccc(C(Cl)=Nc2ccccc2Cl)nc1

Procedure:
N-(2-chlorophenyl)-5-(methylsulfonyl)picolinamide 5 (1.26 g, 0.0040 mol) in anhydrous benzene (20 mL) was added to PCl5 (1.26 g, 6.0 mmol) and the mixture was heated to reflux overnight. The solvent was removed and the residue was further dried under high vacuum. Crude N-(2-chlorophenyl)-5-(methylsulfonyl)picolinimidoyl chloride 6 was obtained as a yellow solid (1.60 g). The N-(2-chlorophenyl)-5-(methylsulfonyl)picolinimidoyl chloride 6 was dissolved into THF anhydrous (30 mL) and the reaction was cooled down to 0° C. and hydrazine monohydrate (9.0 mL) was added. The reaction was kept at 0° C. for 10 min and warmed to ambient temperature in 0.5 h. The solvent was removed and the residue was purified by column chromatography (eluting with hexane and ethyl acetate 1:1) to give N′-(2-chlorophenyl)-5-(methylsulfonyl) picolinimidohydrazide 7 as a yellow solid. Yield: 1.22 g, 92.0%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]#[N:13])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C(OCCCC)(=O)C.[C:22]1(=[O:28])[O:27][C:25](=[O:26])[CH:24]=[CH:23]1>CCCCCCC>[C:12]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:22]([CH:23]=[CH:24][C:25]([OH:27])=[O:26])=[O:28])=[CH:7][C:6]=1[C:8]([F:9])([F:10])[F:11])#[N:13]
Reactant: N#Cc1ccc(N)cc1C(F)(F)F
Reactant: O=C1C=CC(=O)O1
Solvent: CCCCCCC
Solvent: CCCCOC(C)=O
Product: N#Cc1ccc(NC(=O)C=CC(=O)O)cc1C(F)(F)F
Temperature: 60 °C
Yield: 100.2 %

Procedure:
5-amino-2-cyanobenzotrifluoride (210.6 mmoles; 40.00 g) and butyl acetate (80 mL) were added to a 250 mL round bottom flask, followed by the addition of maleic anhydride (231.9 mmoles, 23.20 g). The resulting suspension was heated to 60° C. for 3.5 h. The reaction mixture was cooled to 25° C. and then heptane (160 mL) was added dropwise over a period of 25 minutes. The resulting suspension was filtered and washed with a mixture of 4:1, hepatane:butyl acetate (30 mL) and heptane (45 mL). The cake was dried in vacuo to give 60 g (95% yield) of compound 516A.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][N:10]([CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9][CH2:8][N:7]1[C:25](=[O:40])[CH2:26][CH:27]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:5])C.O[Li].O>C1COCC1.CO.O>[CH:12]([N:10]1[CH2:9][CH2:8][N:7]([C:25](=[O:40])[CH2:26][CH:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:6]([C:4]([OH:5])=[O:3])[CH2:11]1)([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)C1CN(C(c2ccccc2)c2ccccc2)CCN1C(=O)CC(c1ccccc1)c1ccccc1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)C1CN(C(c2ccccc2)c2ccccc2)CCN1C(=O)CC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 95 %

Procedure:
A mixture of 4-Benzhydryl-1-(3,3-diphenyl-propionyl)-piperazine-2-carboxylic acid ethyl ester (0.51 g, 0.957 mmol), and LiOH.H2O (0.12 g, 2.87 mmol) in THF/MeOH/H2O (15:5:5) was stirred at room temperature for two days. The solvent was evaporated under reduced pressure, the residue was dissolved in water, acidified with 1N HCl to pH 3. The product was extracted with EtOAc, dried with MgSO4, and evaporated under reduced pressure. The product was purified by column chromatography (CH2Cl2:MeOH 15:1) to give the title compound in 95% yield.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:36]=[CH:35][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[C:15]([CH2:17][O:18][C:19]4[CH:32]=[CH:31][C:22]([CH2:23][CH:24]5[S:28][C:27](=[O:29])[NH:26][C:25]5=[O:30])=[CH:21][CH:20]=4)[N:14]([CH3:33])[C:13]=3[CH:34]=2)=[CH:6][CH:5]=1.[C:37]1([N:47]=[C:48]=[S:49])[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]=[CH:39][CH:38]=1.C(N(CC)CC)C>CN(C)C=O>[O:29]=[C:27]1[NH:26][C:25](=[O:30])[CH:24]([CH2:23][C:22]2[CH:31]=[CH:32][C:19]([O:18][CH2:17][C:15]3[N:14]([CH3:33])[C:13]4[CH:34]=[C:9]([O:8][C:7]5[CH:35]=[CH:36][C:4]([NH:3][C:48]([NH:47][C:37]6[C:46]7[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=7)[CH:40]=[CH:39][CH:38]=6)=[S:49])=[CH:5][CH:6]=5)[CH:10]=[CH:11][C:12]=4[N:16]=3)=[CH:20][CH:21]=2)[S:28]1
Reactant: S=C=Nc1cccc2ccccc12
Reactant: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(N)cc3)cc21
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(NC(=S)Nc4cccc5ccccc45)cc3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.4 %

Procedure:
A mixture of 5-[4-[6-(4-aminophenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione dihydrochloride (400 mg), 1-naphthyl isothiocyanate (148 mg), triethylamine (153 mg) and anhydrous N,N-dimethylformamide (8 ml) was stirred at room temperature for 1 hour and then allowed to stand overnight. The reaction mixture was concentrated and partitioned between ethyl acetate and water. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then concentrated. The residue was chromatographed on a silica gel column using ethyl acetate:n-hexane=3:2→2:1→4:1→1:0 as the eluant to afford the title compound (301 mg, mp 185.8-188.1° C.).
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[CH:13]1([NH2:18])[CH2:17][CH2:16][CH2:15][CH2:14]1.Cl.Cl.C([O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][N:35]1[C:43]2[C:42]([NH:44][C:45]3[CH:50]=[CH:49][C:48]([O:51][CH:52]4[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]4)=[C:47]([Cl:58])[CH:46]=3)=[N:41][CH:40]=[N:39][C:38]=2[CH:37]=[CH:36]1)(=O)C1C=CC=CC=1.C(N(CC)CC)C>O1CCCC1.O>[ClH:58].[Cl:58][C:47]1[CH:46]=[C:45]([NH:44][C:42]2[C:43]3[N:35]([CH2:34][CH2:33][O:32][CH2:31][CH2:30][OH:29])[CH:36]=[CH:37][C:38]=3[N:39]=[CH:40][N:41]=2)[CH:50]=[CH:49][C:48]=1[O:51][CH:52]1[CH2:53][CH2:54][N:55]([C:1]([NH:18][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:2])[CH2:56][CH2:57]1
Reactant: O=C(OCCOCCn1ccc2ncnc(Nc3ccc(OC4CCNCC4)c(Cl)c3)c21)c1ccccc1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NC1CCCC1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NC1CCCC1)N1CCC(Oc2ccc(Nc3ncnc4ccn(CCOCCO)c34)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 129.5 %

Procedure:
To a solution of 1,1′-carbonylbis(1H-imidazole) (162 mg) in tetrahydrofuran (5 mL) was added a solution of cyclopentylamine (85 mg) in tetrahydrofuran (1 mL), and the mixture was stirred at room temperature for 1 hr. A solution of 2-[2-(4-{[3-chloro-4-(piperidin-4-yloxy)phenyl]amino}-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethyl benzoate dihydrochloride (305 mg) and triethylamine (0.153 mL) in tetrahydrofuran (1 mL) was added, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was dissolved in methanol (8 mL) and tetrahydrofuran (2 mL). 1N Aqueous sodium hydroxide solution (1 mL) was added, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was subjected to basic silica gel column chromatography (eluent, methanol:ethyl acetate=0:100→10:90). The object fraction was concentrated under reduced pressure. The residue was dissolved in ethyl acetate-ethanol, and 1N hydrochloric acid/ethyl acetate solution (0.5 mL) was added. The solvent was evaporated under reduced pressure and the obtained residue was crystallized from ethanol-ethyl acetate to give the title compound (188 mg) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][C:8]([CH3:17])([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[CH2:19]([NH2:21])[CH3:20]>C1COCC1.CO>[Cl:1][C:2]1[N:3]=[C:4]([NH:21][CH2:19][CH3:20])[C:5]2[CH2:10][CH2:9][C:8]([CH3:17])([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: CC1(c2ccccc2)CCc2c(Cl)nc(Cl)nc21
Reactant: CCN
Solvent: C1CCOC1
Solvent: CO
Product: CCNc1nc(Cl)nc2c1CCC2(C)c1ccccc1
Temperature: 25 °C
Yield: 85.7 %

Procedure:
To a solution of 2,4-dichloro-7-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (Preparation V) (43.1 mg, 0.154 mmol) in THF (772 μL) at rt was added a solution of 2M Ethylamine (386 μL, 0.772 mmol) diluted with 390 uL MeOH (overall reaction is 0.1M in 1:1 THF/MeOH). Let stir at rt. Removed the solvent and subjected the residue to a Silica gel column with an EtOAc/Hex gradient to afford 2-chloro-N-ethyl-7-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (38.0 mg, 0.132 mmol, 86% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[C:5](C)=[CH:6][CH:7]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C(C2C=CC=CC=2)CC(Cl)=O)C=CC=CC=1>[OH:9][C:4]1[CH:3]=[C:2]([CH3:1])[C:7]([C:2]([CH3:1])([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:3][C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:9])=[CH:6][CH:5]=1
Reactant: Cc1ccc(C)c(O)c1
Reactant: Clc1ccccc1
Agent: O=C(Cl)CC(c1ccccc1)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1cc(O)ccc1C(C)(CC(=O)c1ccccc1)c1ccccc1

Procedure:
Twenty-four and four-tenths grams of 3,6-dimethylphenol and 26.6 grams of aluminum chloride are dissolved in 250 mls chlorobenzene and 48.9 grams of 3,3-diphenylpropionic acid chloride, dissolved in 150 mls chlorobenzene, are added while stirring. The stirring is continued for several days at 100° C. The chlorobenzene is evaporated in vacuo, the residue is mixed with ice and ether and washed several times with water. After drying with sodium sulfate, the ether is evaporated. Fifteen and one-tenth grams of 4-hydroxy-3,6-dimethyl-β,β-diphenylpropiophenone are obtained.
Reaction SMILES: [CH3:1][C@@H:2]([C:5]([N:7]1[C@H:11]([C:12]([OH:14])=[O:13])[CH2:10][CH2:9][CH2:8]1)=[O:6])[CH2:3][SH:4].C(N(CC)C(C)C)(C)C.[Cl:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30](Cl)=[O:31]>O.CC#N>[Cl:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30]([S:4][CH2:3][C@@H:2]([CH3:1])[C:5]([N:7]1[CH2:8][CH2:9][CH2:10][C@H:11]1[C:12]([OH:14])=[O:13])=[O:6])=[O:31]
Reactant: O=C(Cl)OCCCCCl
Reactant: C[C@H](CS)C(=O)N1CCC[C@H]1C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: O
Product: C[C@H](CSC(=O)OCCCCCl)C(=O)N1CCC[C@H]1C(=O)O
Temperature: 0 °C
Reaction time: 4 h
Yield: 104.2 %

Procedure:
Captopril (3.50 g, 0.0161 Mol) and N,N-diisopropyl ethylamine (6.80 ml, 0.039 Mol) were dissolved in H2O/CH3CN (80 ml, 1:1) and the mixture was cooled to 0° C. Then 4-chlorobutylchloroformate (2.70 ml, 0.0198 Mol) was added and the reaction was slowly warmed to room temperature and stirred for 4 h. The mixture was then partitioned between HCl (4%, 100 ml) and EtOAc (100 ml). The organic layer was separated and the aqueous phase was extracted with EtOAc (2×100 ml). The combined organic phases were washed with brine (3×60 ml), dried over sodium sulphate and evaporated under reduced pressure affording 1-[(2S)-3-(4-chlorobutoxycarbonyl)mercapto-2-methyl-1-oxopropyl]-L-proline (5.90 g) as a colourless oil that was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH2:13]([N:16]1[C:25](=[O:26])[C:24]2[NH:23][C:22]([C:27]3[N:31]([CH3:32])[N:30]=[C:29]([O:33][CH2:34][C:35](O)=[O:36])[CH:28]=3)=[N:21][C:20]=2[N:19]([CH2:38][CH2:39][CH3:40])[C:17]1=[O:18])[CH2:14][CH3:15]>>[CH3:40][CH2:39][CH2:38][N:19]1[C:17](=[O:18])[N:16]([CH2:13][CH2:14][CH3:15])[C:25](=[O:26])[C:24]2[C:20]1=[N:21]/[C:22](/[N:23]=2)=[C:27]1/[CH:28]=[C:29]([O:33][CH2:34][C:35]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=2)=[O:36])[NH:30][N:31]/1[CH3:32]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: CCCn1c(=O)c2[nH]c(-c3cc(OCC(=O)O)nn3C)nc2n(CCC)c1=O
Product: CCCn1c(=O)c2c(n(CCC)c1=O)=N/C(=C1/C=C(OCC(=O)Nc3ccc(C(=O)OCC)cc3)NN1C)N=2

Procedure:
Using ethyl 4-(amino)benzoate and 2-[5-(1,3-dipropyl-xanthin-8-yl)-1-methyl-pyrazol-3-yl)oxyacetic acid (Example 36), according to the method described in Example 36.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[C:11]3[N:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.[C:23](Cl)(=[O:25])[CH3:24].[CH3:27][Mg]Br.C(=O)(O)[O-].[Na+]>O1CCCC1>[C:23]([N:20]1[CH:21]=[CH:22][C:17]([C:16]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[N:9][N:10]3[CH:15]=[CH:14][CH:13]=[N:12][C:11]=23)=[CH:18][CH:19]1[CH3:27])(=[O:25])[CH3:24]
Reactant: C[Mg]Br
Reactant: CC(=O)Cl
Reactant: Fc1ccc(-c2nn3cccnc3c2-c2ccncc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)N1C=CC(c2c(-c3ccc(F)cc3)nn3cccnc23)=CC1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(4-fluorophenyl)-3-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidine (480 mg) in dry tetrahydrofuran (15 ml) was added acetyl chloride (0.89 ml) dropwise under ice cooling. The mixture was stirred at ambient temperature for 1 hour and to the mixture was added a solution of methyl magnesium bromide in tetrahydrofuran (1 mole solution, 12.42 ml) under ice cooling. The mixture was stirred at ambient temperature for 2 hours and to the mixture was added an aqueous saturated sodium bicarbonate solution. The separated oil was extracted with dichloromethane and the solution was washed with brine, dried and concentrated in vacuo. The residue was purified by column chromatography on silica gel to give 3-(1-acetyl-1,2-dihydro-2-methylpyridin-4-yl)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyrimidine (327 mg).
Reaction SMILES: CCCCCC.C([Li])CCC.N12CCN(CC1)CC2.[F:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1.CN([CH:30]=[O:31])C>C(OCC)C>[F:20][C:21]1[C:22]([CH:30]=[O:31])=[N:23][CH:24]=[CH:25][CH:26]=1
Reactant: Fc1cccnc1
Reactant: CN(C)C=O
Agent: C1CN2CCN1CC2
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: O=Cc1ncccc1F
Reaction time: 1 h
Yield: 42.7 %

Procedure:
To a mixture of a 1.6M n-butyl lithium hexane solution (35 ml) and diethyl ether (200 ml) was added, at -78° C. under argon atmosphere, a solution of 1,4-diazabicyclo[2,2,21octane (6.35 g) in diethyl ether (200 ml), which was stirred for one hour at temperatures ranging from -70° to -50° C. To the mixture was added 3-fluoropyridine (5.00 g) at -70° C., and the mixture was stirred for one hour at temperatures ranging from -70° to -60° C. To the reaction mixture was added at -70° C. DMF (9.41 g). The mixture was stirred for one hour at temperatures ranging from -70° to -50° C., which was then poured into a saturated aqueous saline solution, followed by extraction with ethyl acetate/chloroform (about 4:1). The extract solution was washed with a saturated aqueous saline solution, dried (anhydrous sodium sulfate), and concentrated. The concentrate was purified by means of a silica gel column chromatography (eluent: ethyl acetate/hexane) to give 3-fluoro-2-formylpyridine (2.75 g, m.p. 52°-53° C.). Reference Example 47 (Production of Compound D-6)
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.C(NC(C)C)(C)C.[Li].[F:18][C:19]([F:23])([F:22])[CH2:20]I>C1COCC1>[F:18][C:19]([F:23])([F:22])[CH2:20][CH2:1][C:2]1[N:3]=[CH:4][C:5]([C:6]#[N:7])=[CH:8][CH:9]=1
Reactant: FC(F)(F)CI
Reactant: Cc1ccc(C#N)cn1
Agent: [Li]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: N#Cc1ccc(CCC(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.4 %

Procedure:
To a solution of 6-methyl-nicotinonitrile (118 mg, 1.0 mmol) in anhydrous THF (20 mL) at −78 C under nitrogen was added lithium diisopropylamine (2M solution in THF/heptane/ethylbenzene, 550 μL, 1.1 mmol) drop-wise. The resulting solution was allowed to warm to room temperature for 5 min and then cooled back to −78 C. 1,1,1-Trifluoro-2-iodo-ethane (524 mg, 2.5 mmol) was then added to the solution drop-wise and the reaction mixture was allowed to warm to room temperature and stirred at this temperature for 2 h. The reaction mixture was cooled at 0 C and quenched with water; the resulting solution was extracted with EtOAc (3×25 mL). Combined organics were washed with brine (25 mL), dried over magnesium sulfate and purified by silica chromatography (25% EtOAc in heptane) to afford the title compound as a pale yellow oil (191 mg, 95%). Method C HPLC-MS: MH+ requires m/z=201. Found: m/z=201, Rt=1.22 min (86%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[NH:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][CH2:27][S:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)[CH2:21][CH2:20]2)=[CH:4][CH:3]=1.OO.[OH-:39].[Na+].[C:41]([OH:44])(=[O:43])[CH3:42]>>[C:41]([OH:44])(=[O:43])[C:42]([OH:35])=[O:39].[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[NH:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][CH2:27][S:28]([C:29]3[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=3)(=[O:43])=[O:39])[CH2:21][CH2:20]2)=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: COc1ccc(SCCCN2CCC(Nc3nc4ccccc4n3Cc3ccc(F)cc3)CC2)cc1
Reactant: CC(=O)O
Agent: OO
Agent: [Na+]
Product: COc1ccc(S(=O)(=O)CCCN2CCC(Nc3nc4ccccc4n3Cc3ccc(F)cc3)CC2)cc1
Product: O=C(O)C(=O)O
Yield: 16 %

Procedure:
A mixture of 3.7 parts of 1-(4-fluorophenylmethyl)-N-{1-[3-(4-methoxyphenylthio)propyl]-4-piperidinyl}-1H-benzimidazol-2-amine, 2.42 parts of hydrogen peroxide solution 30% and 20 parts of acetic acid is stirred and refluxed for 1 hour. The reaction mixture is cooled and poured onto ice-water. The whole is alkalized with sodium hydroxide solution 50% and the product is extracted with trichloromethane. The extract is washed with water, dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is converted into the ethanedioate salt in methanol and 2-propanol. The salt is filtered off and dried, yielding 0.8 parts (16%) of 1-(4-fluorophenylmethyl)-N-{1-[3-(4-methoxyphenylsulfonyl)propyl]-4-piperidinyl}-1H-benzimidazol-2-amine ethanedioate (1:2); mp. 213.1° C.
Reaction SMILES: [O:1]=[C:2]1[N:11]([C@@H:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:13]([OH:15])=O)[C:10](=[O:20])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[NH2:21][C:22]1[S:23][CH:24]=[CH:25][N:26]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>CN(C=O)C>[O:1]=[C:2]1[N:11]([C@@H:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:13]([NH:21][C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[O:15])[C:10](=[O:20])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1
Reactant: Nc1nccs1
Reactant: CC(C)C[C@@H](C(=O)O)n1c(=O)[nH]c2ccccc2c1=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)C[C@@H](C(=O)Nc1nccs1)n1c(=O)[nH]c2ccccc2c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of Compound 1 (187 mg, 0.7 mmol), 2-aminothiazole (70 mg, 0.7 mmol), HBTU (303 mg, 0.8 mmol) and 0.2 mL of Et3N in DMF (5 mL) was stirred at room temperature for 2 hours to provide the title compound, which purified by HPLC. 1H NMR (400 MHz, CD3OD) δ: 8.03 (dd, J=1.2, 8.0 Hz, 1H), 7.70-7.63 (m, 1H), 7.42 (d, J=4.0 Hz, 1H), 7.27-7.17 (m, 2H), 7.15 (d, J=4.0 Hz, 1H), 5.76 (dd, J=4.8, 9.2 Hz, 1H), 2.29-2.20 (m, 1H), 2.11-2.01 (m, 1H), 1.61-1.49 (m, 1H), 1.01 (d, J=6.8 Hz, 3H), 0.94 (d, J=6.8 Hz, 3H). [M+H] calc'd for C17H18N4O3S, 359; found, 359.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20](Cl)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:40]1[S:44][N:43]=[CH:42][CH:41]=1)CCC.O>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20]([C:40]3[S:44][N:43]=[CH:42][CH:41]=3)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccns1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(-c2ccns2)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O

Procedure:
A solution of tert-butyl 6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (60 mg, 0.120 mmol), 5-(tributylstannyl)isothiazole (67.2 mg, 0.180 mmol) and tetrakis(triphenylphosphine)palladium(0) (69.2 mg, 0.060 mmol) in toluene (2.0 mL) was heated to 120° C. for 45 minutes via microwave irradiation. The reaction mixture was subsequently poured into water and was extracted with EtOAc. The extracts were dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (Flash 60 column) eluting with hexane/EtOAc (1:1) to give the title compound as a yellow solid. ESI-MS m/z [M+H]+ calc'd for C25H32FN5O6S, 550. found, 550.
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:11]=[CH:12][C:6]=2[CH2:5][O:4]1.[CH2:17]([NH2:21])[CH2:18][CH2:19][CH3:20].CCO>C(CC(C)(C)C)(C)C>[CH3:16][S:13]([C:10]1[CH:11]=[CH:12][C:6]2[CH2:5][O:4][CH:3]([CH2:2][NH:21][CH2:17][CH2:18][CH2:19][CH3:20])[O:8][C:7]=2[CH:9]=1)(=[O:15])=[O:14]
Reactant: CS(=O)(=O)c1ccc2c(c1)OC(CBr)OC2
Reactant: CCCCN
Solvent: CCO
Solvent: CC(C)CC(C)(C)C
Product: CCCCNCC1OCc2ccc(S(C)(=O)=O)cc2O1
Temperature: 130 °C

Procedure:
A mixture of 2-(bromomethyl)-7-(methylsulfonyl)-4H-1,3-benzodioxine (30 mg, 0.10 mmol), n-butan-1-amine (0.50 ml, 5.1 mmol) and EtOH (1.0 ml) was heated under microwave radiation at 130° C. for 30 min. MS m/z (rel. intensity, 70 eV) 299 (M+, 1), 123 (8), 86 (bp), 77 (9), 72 (10).