Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[C:9]([CH3:18])[CH:8]=1.C[O:20][B:21](C)[O:22]C.Cl>CCCCCC.C1COCC1>[CH3:18][C:9]1[CH:8]=[C:7]([B:21]([OH:22])[OH:20])[CH:12]=[CH:11][C:10]=1[O:13][C:14]([F:17])([F:16])[F:15]
Reactant: Cc1cc(Br)ccc1OC(F)(F)F
Reactant: COB(C)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cc(B(O)O)ccc1OC(F)(F)F
Temperature: -78 °C
Reaction time: 2 h

Procedure:
At −78° C., 8.5 ml (1.4 g, 21.1 mmol) of a 2.5M solution of n-butyllithium in hexane were initially charged in 30 ml of THF. 4.9 g (19.2 mmol) of 4-bromo-2-methyl(trifluoromethoxy)benzene were dissolved in 15 ml of THF and slowly added dropwise. 3.0 g (28.8 mmol) of trimethylboronic acid were then added dropwise. The mixture was stirred at −78° C. for 2 h, and 11 ml of 2 N hydrochloric acid were then added. The mixture was allowed to warm to RT, and the organic phase was separated off. The solvent was removed under reduced pressure and the residue was recrystallized from n-heptane. Yield: 3.3 g (78% of theory)
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([O:13][CH3:14])[C:11]=1[OH:12])[CH:7]=[O:8])[CH:2]=[CH2:3].C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][CH2:23][CH2:24][CH3:25]>O>[CH2:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([O:13][CH3:14])[C:11]=1[O:12][CH2:22][CH2:23][CH2:24][CH3:25])[CH:7]=[O:8])[CH:2]=[CH2:3]
Reactant: CCCCBr
Reactant: C=CCc1cc(C=O)cc(OC)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: C=CCc1cc(C=O)cc(OC)c1OCCCC
Yield: 98.8 %

Procedure:
A mixture of 3-allyl-4-hydroxy-5-methoxybenzaldehyde (10.25 g, 0.053 mole), dimethylformanide (150 ml), potassium carbonate (8.29 g, 0.06 mole) and 1-bromobutane (8.22 g, 0.06 mole) was maintained at 40°-45° C. for three hours. The reaction mixture was plunged into iced water and the oil formed extracted with dichloromethane. After washing with water, drying and evaporation of the solvent, a brown oil was obtained which was passed through a bed of silica 60 to give a pale yellow oil, 3-allyl-4-butoxy-5-methoxybenzaldehyde (13 g, yield=91%).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2].[C:24]1([CH2:30][CH2:31][C:32](Cl)=[O:33])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)C(C)C)(C)C>O1CCCC1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:32](=[O:33])[CH2:31][CH2:30][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
Reactant: O=C(Cl)CCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1c2ccc(NC(=O)CCc3ccccc3)cc2C(C)(c2ccccc2)CC1(C)C

Procedure:
Acylation of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) with 3-phenylpropionyl chloride (11 mg) and N,N-diisopropylethylamine (22 l) in tetrahydrofuran (1 ml) was performed according to the method described in example 6.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9]C)[C:4]=1[N:11]1[C:23]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2.Cl.[NH+]1C=CC=CC=1>O>[CH:22]1[C:23]2[N:11]([C:4]3[C:5]([OH:9])=[CH:6][CH:7]=[CH:8][C:3]=3[OH:2])[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:18]=2[CH:19]=[CH:20][CH:21]=1
Reactant: COc1cccc(OC)c1-n1c2ccccc2c2ccccc21
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: O
Product: Oc1cccc(O)c1-n1c2ccccc2c2ccccc21
Temperature: 25 °C
Yield: 60.6 %

Procedure:
9-(2,6-Dimethoxyphenyl)-9H-carbazole (10.00 g) and pyridinium hydrochloride (50.0 g) were placed in the 250 ml round-bottom flask, equipped with magnetic stirrer and immersed in the pre-heated oil bath (230° C., 45 min). The reaction mixture was cooled down to room temperature, diluted with 400 ml water and extracted with ethyl acetate (3×150 ml). Organic fractions were combined, dried over sodium sulfate anhydrous, filtered and evaporated, providing 5.5 g of pure 2-carbazol-9-yl-benzene-1,3-diol. 2-Carbazol-9-yl-benzene-1,3-diol (5.5 g, 20 mmol) and pyridine (6.0 ml) were dissolved in 50 ml DCM (anhydrous) and cooled in the ice bath. Solution of triflic anhydride (6.0 ml) in 20 ml DCM was added dropwise upon intensive stirring, reaction mixture was warmed up to room temperature and stirred overnight. The reaction mixture was washed with water, dried over sodium sulfate, filtered and evaporated, providing crude triflate. Pure material (white solid, 6.0 g) was obtained by column chromatography on silica gel (eluent hexane/ethyl acetate 1/1 mixture).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][CH:7]([CH3:11])[C:8]([OH:10])=O)=[O:4].[CH2:12]([O:19][C:20](=[O:24])[C@H:21]([CH3:23])[NH2:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.OC1C2N=NNC=2C=CC=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[CH2:12]([O:19][C:20](=[O:24])[C@H:21]([CH3:23])[NH:22][C:8](=[O:10])[CH:7]([CH3:11])[CH2:6][CH2:5][C:3]([O:2][CH3:1])=[O:4])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C[C@H](N)C(=O)OCc1ccccc1
Reactant: COC(=O)CCC(C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Product: COC(=O)CCC(C)C(=O)N[C@@H](C)C(=O)OCc1ccccc1
Temperature: 0 °C

Procedure:
4-methoxycarbonyl-2-methylbutanoic acid (3.1 g.), L-alanine benzyl ester (3.58 g.) and hydroxybenzotriazole (2.7 g.) are dissolved in dichloromethane. The solution is chilled in the ice bath and dicyclohexylcarbodiimide (4.12 g.) is added. After stirring 15 minutes in the ice bath and 18 hours at room temperature the precipitate is filtered off and the filtrate is concentrated to dryness. The residue is dissolved in ethyl acetate and washed neutral. The organic phase is dried over magnesium sulfate and concentrated to dryness to yield N-(4-methoxycarbonyl-2-methylbutanoyl)-L-alanine benzyl ester.
Reaction SMILES: [CH2:1]([N:8]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:9][C:10]([C:12]1[CH:13]=[CH:14][C:15](OCCO)=[C:16]([CH:20]=1)[C:17]([NH2:19])=[O:18])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C(=O)(O)[O-:34].[Na+].[C:38]([O:41][C:42](=O)[CH3:43])(=[O:40])[CH3:39]>C(O)(=O)C>[CH2:1]([N:8]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:9][C:10]([C:12]1[C:20]([O:34][CH2:43][CH2:42][O:41][C:38](=[O:40])[CH3:39])=[C:16]([CH:15]=[CH:14][CH:13]=1)[C:17]([NH2:19])=[O:18])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])O
Reactant: CC(=O)OC(C)=O
Reactant: NC(=O)c1cc(C(=O)CN(Cc2ccccc2)Cc2ccccc2)ccc1OCCO
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)OCCOc1c(C(N)=O)cccc1C(=O)CN(Cc1ccccc1)Cc1ccccc1
Reaction time: 48 h

Procedure:
A solution of 5-(N,N-dibenzylglycyl)-2-(2-hydroxyethoxy)-benzamide (see Example 6(a)) (2.5 g) in acetic anhydride (10 ml) and acetic acid (10 ml) was heated at 100° for 1.25 hours, cooled, and poured into water. After being allowed to stand for 2 days at room temperature the aqueous solution was basified with sodium bicarbonate and extracted with ethyl acetate (3 × 100 ml). The dried extract was evaporated and the ether-soluble portion of the residue treated with ethereal hydrogen chloride. The precipitate (1.6 g) in water (50 ml) was basified with sodium bicarbonate solution and was extracted with ether (3 × 50 ml). The dried extracts were evaporated to give a solid m.p. 120°-128° (from ethyl acetate).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7].C(=O)([O-])[O-].[K+].[K+].[F:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26]Br>CC(C)=O>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([O:14][CH2:26][C:25]2[CH:28]=[CH:29][CH:30]=[C:23]([F:22])[CH:24]=2)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cccc(O)c1C(=O)OC
Reactant: Fc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cccc(OCc2cccc(F)c2)c1C(=O)OC
Yield: 112.5 %

Procedure:
To a stirred suspension of 3-hydroxyphthalic acid dimethyl ester (1.4 g, 6.7 mmol) in acetone (30 mL) and potassium carbonate (2.8 g, 20 mmol) was added 3-fluorobenzyl bromide (0.89 mL, 7.0 mmol) and refluxed overnight. The solvent was evaporated and the residue was partitioned between water (100 mL) and ethyl acetate (150 mL) and washed with water (2×100 mL). The combined organic phases was dried, concentrated and purified by flash column chromatography (EtOAc/Hexane) to give 3-(3-fluoro-benzyloxy)-phthalic acid dimethyl ester (2.4 g, 113% crude yield). The product was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:18]=[CH:17][S:16][C:5]=3[C:6](=[O:15])[NH:7][C:8]=2[C:9]([CH3:14])=[CH:10][C:11]=1[O:12][CH3:13].[F:19][C:20]1[CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=[CH:22][C:21]=1[CH:35]([CH3:45])[CH2:36][NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41]>>[F:19][C:20]1[CH:25]=[C:24]([C:2]2[C:3]3[C:4]4[CH:18]=[CH:17][S:16][C:5]=4[C:6](=[O:15])[NH:7][C:8]=3[C:9]([CH3:14])=[CH:10][C:11]=2[O:12][CH3:13])[CH:23]=[CH:22][C:21]=1[CH:35]([CH3:45])[CH2:36][NH:37][C:38](=[O:44])[O:39][C:40]([CH3:42])([CH3:41])[CH3:43]
Reactant: CC(CNC(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1F
Reactant: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1Br
Product: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1-c1ccc(C(C)CNC(=O)OC(C)(C)C)c(F)c1
Yield: 27 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxy-6-methylthieno[2,3-c]quinolin-4(5H)-one) (900 mg, 2.8 mmol) was reacted with ter-butyl 2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propylcarbamate (1.3 g, 3.3 mmol) to afford the desired product (200 mg, 27%) as a yellow solid: ESI MS m/z 497 [C27H29FN2O4S+H]+.
Reaction SMILES: [OH-].[K+].[SH:3][C:4]1[N:5]=[C:6]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=[C:7]2[N:8]=1.S(OC)(O[CH3:19])(=O)=O>CO>[CH3:14][C:11]1[CH:12]=[CH:13][C:6]2[C:7](=[CH:9][CH:10]=1)[N:8]=[C:4]([S:3][CH3:19])[N:5]=2
Reactant: Cc1ccc2nc(S)nc-2cc1
Reactant: COS(=O)(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CSc1nc2ccc(C)ccc-2n1
Temperature: 45 °C

Procedure:
First, 38 g of potassium hydroxide was dissolved in 800 ml of methanol, 108.5 g of 2-mercapto-6-methycycloheptimidazole was added, and the mixture was stirred with heating to the inner temperature of about 45° C. Then, 131.2 g of dimethyl sulfate was added dropwise thereto and stirred with heating to the inner temperature of about 45° C. for one hour. After the solvent was distilled away in some extent under reduced pressure, 1 l of water was added and extracted with chloroform (0.5 l×2). The chloroform layer was dried over anhydrous sodium sulfate and evaporated to 200 ml under reduced pressure to distil away the solvent. With the addition of 1 l of hexane, crystals were deposited, and they were collected by filtration and dried.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([C:17]#N)[CH:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[OH2:21].S(=O)(=O)(O)[OH:23]>C(O)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([C:17]([OH:23])=[O:21])[CH:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(O)O
Reactant: COc1cc2[nH]nc(-c3cccc(F)c3)c2cc1C#N
Reactant: O
Solvent: CC(=O)O
Product: COc1cc2[nH]nc(-c3cccc(F)c3)c2cc1C(=O)O
Temperature: 110 °C
Reaction time: 18 h

Procedure:
A total of 172 mg of 3-(3-fluoro-phenyl)-6-methoxy-1H-indazole-5-carbonitrile obtained in Production Example II-1-d was dissolved in 2 ml of acetic acid, 0.7 ml of water and 0.5 ml of sulfuric acid, followed by stirring at 110° C. for 18 hours. After cooling to room temperature, water was added to the reaction mixture. The resulting crystals were washed with water, to give 159 mg of the title compound as light pink crystals.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:8]([CH2:9][N:10]([CH3:21])[C@@H:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][CH2:13][CH2:12]2)=[C:7]([CH3:22])[N:6]=[C:5]([C:23]2[C:28]([CH2:29][CH3:30])=[CH:27][CH:26]=[CH:25][C:24]=2[CH2:31][CH3:32])[N:4]=1.[C:33](OC(=O)C)(=[O:35])[CH3:34]>C(Cl)(Cl)Cl>[CH2:29]([C:28]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:31][CH3:32])[C:23]=1[C:5]1[N:4]=[C:3]([CH2:2][NH:1][C:33](=[O:35])[CH3:34])[C:8]([CH2:9][N:10]([CH3:21])[C@@H:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][CH2:13][CH2:12]2)=[C:7]([CH3:22])[N:6]=1)[CH3:30]
Reactant: CC(=O)OC(C)=O
Reactant: CCc1cccc(CC)c1-c1nc(C)c(CN(C)[C@H]2CCCc3ccccc32)c(CN)n1
Solvent: ClC(Cl)Cl
Product: CCc1cccc(CC)c1-c1nc(C)c(CN(C)[C@H]2CCCc3ccccc32)c(CNC(C)=O)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a vial containing (1S)-N-{[4-(aminomethyl)-2-(2,6-diethylphenyl)-6-methylpyrimidin-5-yl]methyl}-N-methyl-1,2,3,4-tetrahydronaphthalen-1-amine (9 mg, 0.021 mmol) in CHCl3 (2.0 mL) is added acetic anhydride (0.05 mL, 25.0 eq., 0.53 mmol) and allowed to stir at room temperature for 2 h. All solvent is then removed and excess acetic anhydride is removed azeotropically with toluene (3×2 mL). The sample is re-dissolved in CHCl3 and eluted through a plug of SiO2, washing with CHCl3. Concentration affords the title compound as a colorless gum. [mass expected (470.65); mass found (470.34)].
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4](=[O:26])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[C:7]([F:25])[CH:6]=1.[OH-].[Na+]>CO.O1CCCC1.O>[F:25][C:7]1[CH:6]=[C:5]([C:4](=[O:26])[C:3]([OH:27])=[O:2])[CH:10]=[CH:9][C:8]=1[O:11][CH2:12][CH2:13][O:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1
Reactant: COC(=O)C(=O)c1ccc(OCCOc2ccc3ccccc3c2)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C(=O)c1ccc(OCCOc2ccc3ccccc3c2)c(F)c1
Yield: 87.3 %

Procedure:
A solution of 3-fluoro-4-[2-(2-naphthalenyloxy)ethoxy]-alpha-oxobenzeneacetic acid methyl ester (0.5 g) in warm methanol (10 mL) and tetrahydrofuran (10 mL) was treated with 1N sodium hydroxide (2 mL) and after 10 minutes the mixture was diluted with water and concentrated to remove the organic solvents. The residue was acidified with excess hydrochloric acid and extracted with dichloromethane containing a little tetrahydrofuran. The organic layer was washed with water, dried (Na2SO4), filtered and evaporated to give crude product. Crystallization from acetone-hexane provided 0.42 g of purified 3-fluoro-4-[2-(2-naphthalenyloxy)ethoxy]-alpha-oxobenzeneacetic acid as a yellow solid, mp 168°-169° C.
Reaction SMILES: [CH:1](=[N+:8]([O-:16])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:17]([P:19](=[O:26])([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22])=[CH2:18]>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:18][CH:17]([P:19]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])=[O:26])[O:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [O-][N+](=Cc1ccccc1)Cc1ccccc1
Reactant: C=CP(=O)(OCC)OCC
Solvent: Cc1ccccc1
Product: CCOP(=O)(OCC)C1CC(c2ccccc2)N(Cc2ccccc2)O1
Yield: 30.6 %

Procedure:
A solution of 2.11 g (10 mmol) of N-benzylidenebenzylamine N-oxide and 1.64 g (10 mmol) of diethyl vinylphosphonate in 30 ml of toluene under a nitrogen blanket is heated at reflux temperature for 5 days. The solvent is removed under reduced pressure to give 4.45 g of crude product which is then purified by preparative HPLC (Waters Prep 500A, silica gel, 3:2 heptane:ethyl acetate eluent) to give 1.15 g (31% yield) of a caramel-colored liquid.
Reaction SMILES: F[C:2]1[N:25]=[C:24](F)[C:23]([I:27])=[CH:22][C:3]=1[C:4]([C:6](=[CH:12][NH:13][CH2:14][C@@H:15]1[CH2:19][CH2:18][CH2:17][N:16]1[CH2:20][CH3:21])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].C([O-])([O-])=O.[K+].[K+].[CH3:34][N:35]([CH3:39])[CH2:36][CH2:37][NH2:38]>CN(C=O)C>[CH3:34][N:35]([CH3:39])[CH2:36][CH2:37][NH:38][C:24]1[N:25]=[C:2]2[C:3]([C:4](=[O:5])[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:12][N:13]2[CH2:14][C@@H:15]2[CH2:19][CH2:18][CH2:17][N:16]2[CH2:20][CH3:21])=[CH:22][C:23]=1[I:27]
Reactant: CCOC(=O)C(=CNC[C@@H]1CCCN1CC)C(=O)c1cc(I)c(F)nc1F
Reactant: CN(C)CCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C[C@@H]2CCCN2CC)c2nc(NCCN(C)C)c(I)cc2c1=O
Temperature: 90 °C
Reaction time: 0.25 h

Procedure:
(S)-ethyl 2-(2,6-difluoro-5-iodonicotinoyl)-3-((1-ethylpyrrolidin-2-yl)methylamino)acrylate (Intermediate 38, 0.360 g, 0.73 mmol) was taken up in DMF (5 mL), K2CO3 (0.303 g, 2.19 mmol) was added and reaction mixture was heated to 90° C. for 15 min. The reaction mixture cooled to room temperature and N1,N1-dimethylethane-1,2-diamine (0.080 mL, 0.73 mmol) was added and stirred for 15 min. The reaction mixture was quenched with water and extracted with EtOAc 3 times. The combined organics were washed with brine two times, dried over Mg2SO4, and the solvent removed. Crude product was carried on without purification.
Reaction SMILES: [O:1]=[S:2]1(=[O:25])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([NH2:23])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:24])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1.[O:26]=[C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29](=[O:36])[N:28]1[CH:37]([C:42]([F:45])([F:44])[F:43])[CH2:38][C:39](Cl)=[O:40].C(N(CC)C(C)C)(C)C>CN(C)C=O.ClCCl>[O:25]=[S:2]1(=[O:1])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([NH:23][C:39](=[O:40])[CH2:38][CH:37]([N:28]3[C:29](=[O:36])[C:30]4[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:27]3=[O:26])[C:42]([F:45])([F:44])[F:43])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:24])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1
Reactant: O=C(Cl)CC(N1C(=O)c2ccccc2C1=O)C(F)(F)F
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(N)c2c1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NC(=O)CC(N3C(=O)c4ccccc4C3=O)C(F)(F)F)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
To a solution of 2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine (200 mg, 0.565 mmol, prepared in analogy to the one in Example 2-1) in N,N-dimethylformamide (6 mL) was added a solution of 3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4,4,4-trifluorobutanoyl chloride (670 mg, 2.3 mmol) in dichloromethane (4 mL) followed by N,N-diisopropylethylamine (0.3 mL). The resulting mixture was stirred at room temperature for 1 hour and heated at 85° C. for additional 2 hours. After being cooled to room temperature, the resulting mixture was evaporated in vacuo. The residue was diluted with water and extracted with ethyl acetate (20 mL×2). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography to afford 230 mg of the product as a solid (yield was 66%).
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]([C:22]2[CH:29]=[CH:28][C:25]([CH:26]=O)=[C:24]([N+:30]([O-:32])=[O:31])[CH:23]=2)[CH:17]=1.O>O1CCCC1>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]([C:22]2[CH:29]=[CH:28][C:25]([CH:26]=[CH:5][C:3]#[N:4])=[C:24]([N+:30]([O-:32])=[O:31])[CH:23]=2)[CH:17]=1
Reactant: COc1ccnc(-c2ccc(C=O)c([N+](=O)[O-])c2)c1
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccnc(-c2ccc(C=CC#N)c([N+](=O)[O-])c2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (60% dispersion in mineral oil, 192 mg) in tetrahydrofuran (10 ml) was added a solution of diethyl cyanomethylphosphonate (0.777 ml) dropwise at 0° C., and the mixture was stirred at ambient temperature for 30 minutes. Then to the resultant mixture was added a solution of 4-(4-methoxypyridin-2-yl)-2-nitrobenzaldehyde (1.03 g) in tetrahydrofuran (20 ml) dropwise at 0° C., and the mixture was stirred at ambient temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was triturated with diisopropyl ether, filtered and dried to give 4-(4-methoxypyridin-2-yl)-2-nitrocinnamonitrile (1.11 g) as a mixture of regioisomers.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([CH:20]4[CH2:22][CH2:21]4)[N:18]=3)[N:13]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:12]=2)=[O:10])[CH2:3]1.C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[CH3:38][S:39]([N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([CH:20]4[CH2:22][CH2:21]4)[N:18]=3)[N:13]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:12]=2)=[O:10])[CH2:3]1)(=[O:41])=[O:40]
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)NC2CCCNC2)c2nc(C3CC3)cnc21
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1cc(C(=O)NC2CCCN(S(C)(=O)=O)C2)c2nc(C3CC3)cnc21
Temperature: 0 °C
Reaction time: 6 h
Yield: 80.1 %

Procedure:
In a 15 mL round-bottomed flask, 2-cyclopropyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid piperidin-3-ylamide hydrochloride (200 mg, 0.44 mmol) was dissolved in CH2Cl2 (3 mL) and cooled to 0° C. Added triethylamine (0.12 mL, 0.88 mmol) followed by methanesulfonyl chloride (0.04 mL, 0.48 mmol). The reaction mixture was stirred at room temperature for 6 h then diluted with 30 mL of CH2Cl2 and washed with water (5 mL). The aqueous layer was extracted with CH2Cl2 (30 mL) and the combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography over 12 g SiO2 with EtOAc/Hexanes (gradient: 0-100% EtOAc) to provide 174 mg (89%) of 2-cyclopropyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1-methanesulfonyl-piperidin-3-yl)-amide as a white foam.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)[Cl:2].C([O-])(O)=O.[Na+].[CH2:11]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[C:12]1[CH:20]=[CH:19][C:18]2[O:17][CH2:16][O:15][C:14]=2[CH:13]=1>CCO>[Cl:2][CH2:1][CH:3]([OH:5])[CH2:4][N:24]1[CH2:25][CH2:26][N:21]([CH2:11][C:12]2[CH:20]=[CH:19][C:18]3[O:17][CH2:16][O:15][C:14]=3[CH:13]=2)[CH2:22][CH2:23]1
Reactant: ClCC1CO1
Reactant: c1cc2c(cc1CN1CCNCC1)OCO2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: OC(CCl)CN1CCN(Cc2ccc3c(c2)OCO3)CC1
Reaction time: 16 h
Yield: 24.6 %

Procedure:
To a mixture of epichlorohydrin (3.9 mL, 50 mmol) in EtOH (25 mL) and anhydrous NaHCO3 (4.2 g, 50 mmol), 1-piperonylpiperazine (11.0 g, 50 mmol) in EtOH (125 mL) was added dropwise over 45 min at 0° C., under nitrogen. After 16 h and removal of the EtOH in vacuo, the crude material was passed through silica gel (vacuum, 5% MeOH:CH2Cl2) to give pure product (3.85 g, 26.4%) as an amber oil. DCI/MS (M+1) 313. 400 MHz 1H NMR (CDCl3)δ: 7.25 (s, 1H), 6.7-6.8 (m, 2H), 5.9 (s, 2H), 4.6 (m, 1H),3.9 (m, 1H), 3.5 (m,2H), 3.4 (s, 2H), 2.4-2.7 (m, 10H).
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[CH3:7][C:8]([C:12]1[N:16]([CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:15]2[CH:24]=[CH:25][C:26]([S:28]([N:31]3[CH:35]=[C:34]([CH:36]=[O:37])[CH:33]=[N:32]3)(=[O:30])=[O:29])=[CH:27][C:14]=2[N:13]=1)([CH3:11])[CH2:9][CH3:10]>CN(C=O)C>[CH3:11][C:8]([C:12]1[N:16]([CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:15]2[CH:24]=[CH:25][C:26]([S:28]([N:31]3[CH:35]=[C:34]([C:36]([OH:1])=[O:37])[CH:33]=[N:32]3)(=[O:30])=[O:29])=[CH:27][C:14]=2[N:13]=1)([CH3:7])[CH2:9][CH3:10]
Reactant: O=S([O-])OO
Reactant: CCC(C)(C)c1nc2cc(S(=O)(=O)n3cc(C=O)cn3)ccc2n1CC1CCOCC1
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC(C)(C)c1nc2cc(S(=O)(=O)n3cc(C(=O)O)cn3)ccc2n1CC1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Oxone (534 mg, 0.869 mmol) was added to a solution of 1-{[2-(1,1-dimethylpropyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]sulfonyl}-1H-pyrazole-4-carbaldehyde (322 mg, 0.724 mmol) in DMF (8 mL). The resulting mixture was stirred overnight at room temperature and used directly for step A. MS (ESI) (M+H)+=460.92.