Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[S:8]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[O:9].ClC1C=C(C=CC=1)C(OO)=[O:20]>C(Cl)Cl>[Cl:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[S:8]([CH2:10][C:11]([O:13][CH3:14])=[O:12])(=[O:20])=[O:9]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)CS(=O)C1CCCCC1Cl
Solvent: ClCCl
Product: COC(=O)CS(=O)(=O)C1CCCCC1Cl
Temperature: 5 °C
Reaction time: 4 h

Procedure:
The compound of Example 24 (3.5 g, 0.0112 mole) was dissolved in methylene chloride and cooled to 5° C. with an ice bath. 3-Chloroperoxybenzoic acid (85%, 2.3 g 0.0112 mole) was added, and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was filtered and concentrated in a rotary evaporator to give the crude product as a solid. The product was purified by silica gel chromatography. The structure was supported by NMR.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:11][C:12]([Mg]Br)=[CH:13][CH3:14].[Cl-].[NH4+]>O1CCCC1>[Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:13]([CH3:14])=[C:12]([CH3:11])[NH:8][C:7]=12
Reactant: CC=C(C)[Mg]Br
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1[nH]c2c(Cl)nccc2c1C
Temperature: -20 °C
Reaction time: 2 h
Yield: 30 %

Procedure:
2-Chloro-3-nitropyridine (8 g, 50.46 mmol) was dissolved in anhydrous tetrahydrofuran (200 ml) at nitrogen atmosphere. 1-Methyl-1-propenyl magnesium bromide (0.5M in tetrahydrofuran solution, 252 ml, 126.15 mmol) was slowly added at −78° C. to the solution. The reaction mixture was stirred for 2 hours at −20° C. and 20% ammonium chloride solution was added thereto. The reaction mixture was extracted with ethyl acetate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/3, v/v) to give 2.73 g of the titled compound as a pale yellow solid. (Yield: 30%)
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[N:5][O:6][N:7]=1)#[N:2].N[NH:16][C:17]([NH2:19])=[S:18].C([O-])(O)=O.[Na+]>C(O)(C(F)(F)F)=O>[NH2:19][C:17]1[S:18][C:1]([C:3]2[C:4]([NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[N:5][O:6][N:7]=2)=[N:2][N:16]=1
Reactant: NNC(N)=S
Reactant: N#Cc1nonc1NC(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Nc1nnc(-c2nonc2NC(=O)C(F)(F)F)s1
Yield: 51 %

Procedure:
To a suspension of N-(4-cyano-1,2,5-oxadiazol-3-yl)-2,2,2-trifluoroacetamide (0.10 g, 0.49 mmol) in 2 mL of TFA was added thiosemicarbazide (0.044 g, 0.49 mmol). The reaction mixture was poured into ice and neutralized with sat. NaHCO3 to pH=7. The aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layer was washed with NaCl and concentrated. Trituration with diethyl ether afforded the title compound as a beige solid (0.070 g, 51%). 1H NMR (DMSO, 500 MHz) δ 7.93 (s, 2H), 6.55 (s, 1H). Mass Spec. FIA MS 281.1(M+1).
Reaction SMILES: [O:1]=[C:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:21](O)=[O:22])[NH:3]1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([NH2:35])([CH3:34])[CH3:33])=[CH:28][CH:27]=1>>[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([NH:35][C:21]([C@H:11]2[CH2:10][CH2:9][C@H:8]3[C@H:7]4[C@H:16]([CH2:15][CH2:14][C@:12]23[CH3:13])[C@:17]2([CH3:20])[C:4]([NH:3][C:2](=[O:1])[CH2:19][CH2:18]2)=[CH:5][CH2:6]4)=[O:22])([CH3:33])[CH3:34])=[CH:28][CH:27]=1
Reactant: COc1ccc(C(C)(C)N)cc1
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4NC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)O
Product: COc1ccc(C(C)(C)NC(=O)[C@H]2CC[C@H]3[C@@H]4CC=C5NC(=O)CC[C@]5(C)[C@H]4CC[C@]23C)cc1
Yield: 65 %

Procedure:
The title compound was prepared in a yield of 65% in a similar manner to that described in Example 37 by reacting 3-oxo-4-azaandrost-5-ene-17β-carboxylic acid and 1-(4-methoxyphenyl)-1-methylethylamine.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:19])([CH3:18])[CH2:10]/[CH:11]=[CH:12]/[C:13]([O:15]CC)=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>O1CCOCC1.O>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:19])([CH3:18])[CH2:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)/C=C/CC(C)(C)NC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C/C=C/C(=O)O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.1 %

Procedure:
Ethyl (2E)-5-(tert-butoxycarbonylamino)-5-methylhex-2-enoate (1.233 g, 4.54 mmol) was dissolved in dioxane (20 ml). Lithium hydroxide (0.120 g, 5.00 mmol) was added as a solid. Water (10 ml) was added. The solution was stirred 16 h at room temp. The solution was diluted with water (70 ml) and was extracted with tert-butylmethylether (2×100 ml). The aqueous phase was acidified with 1N sodium hydrogensulfate solution (pH =1) and was extracted with tert-butylmethylether (3×70 ml). These organic layers were combined and dried over magnesium sulfate. The solvent was removed in vacuo to give 1.05 g of (2E)-5-(tert-butoxycarbonylamino)-5-methylhex-2-enoic acid. The crude product was used for further synthesis.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:15]1[CH2:19][C@H:18]([OH:20])[CH2:17][C@H:16]1[C:21]([OH:24])([CH3:23])[CH3:22])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>ClCCl>[CH2:8]([N:15]1[CH2:19][C@H:18]([O:20][S:26]([CH3:25])(=[O:28])=[O:27])[CH2:17][C@H:16]1[C:21]([OH:24])([CH3:22])[CH3:23])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(O)[C@@H]1C[C@@H](O)CN1Cc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of triethylamine (4.32 ml) and (2S,4R)-1-benzyl-2-(1-hydroxy-1-methylethyl)-4-hydroxypyrrolidine (4.87 g) in dichloromethane (50 ml) was added methanesulfonyl chloride (2.4 ml) at 0° C. After stirring at room temperature for 4 hours, the mixture was quenched with water and extracted with ethyl acetate (×2). The combined extracts were washed with brine, dried over magnesium sulfate, evaporated under reduced pressure, and purified with column chromatography (silica gel, 500 ml, methanol:dichloromethane=4:96) to give (2S,4R)-1-benzyl-2-(1-hydroxy-1-methylethyl)-4-(methanesulfonyloxy)pyrrolidine (3.34 g) as a pale yellow solid.
Reaction SMILES: C1(P(=[CH:20][CH:21]=[O:22])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:23][C:24]1[CH:25]=[CH:26][C:27]([CH:30]=O)=[N:28][CH:29]=1>>[Br:23][C:24]1[CH:25]=[CH:26][C:27](/[CH:30]=[CH:20]/[CH:21]=[O:22])=[N:28][CH:29]=1
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(Br)cn1
Product: O=C/C=C/c1ccc(Br)cn1

Procedure:
818 mg of (triphenylphosphoranylidene)acetaldehyde and 500 mg of 5-bromopyridine-2-carbaldehyde are stirred at RT overnight. The volatile fractions are removed under reduced pressure, and the residue is purified by column chromatography (silica gel, MeOH:DCM=99:1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[CH2:10][CH:11]1[CH2:13][CH2:12]1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][CH:11]2[CH2:13][CH2:12]2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: ClCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccc(OCC2CC2)cc1
Temperature: 80 °C

Procedure:
5.0 g (28.9 mmol) 4-bromophenol, 3.93 g (43.4 mmol) (chloromethyl)cyclopropane and 7.99 g (57.8 mmol) K2CO3 are added to 10 mL DMF and stirred at 80° C. over night. Afterwards the reaction mixture is diluted with water and extracted with DCM. The organic layer is dried with MgSO4 and the solvent is removed in vacuo.
Reaction SMILES: B(Br)(Br)Br.[C:5]([C:7]1[CH:8]=[C:9]([C:17](=[O:27])[C:18]([O:20][CH2:21]CCCCC)=[O:19])[CH:10]=[C:11]([O:15]C)[C:12]=1[O:13]C)#[N:6].CO>C(Cl)Cl>[C:5]([C:7]1[CH:8]=[C:9]([C:17](=[O:27])[C:18]([O:20][CH3:21])=[O:19])[CH:10]=[C:11]([OH:15])[C:12]=1[OH:13])#[N:6]
Reactant: CCCCCCOC(=O)C(=O)c1cc(C#N)c(OC)c(OC)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C(=O)c1cc(O)c(O)c(C#N)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4.8 ml of boron tribromide dissolved in 20 ml of methylene chloride are added dropwise while cooling with ice within 20 minutes to 4.0 g of hexyl (3-cyano-4,5-dimethoxyphenyl)glyoxylate dissolved in 100 ml of methylene chloride and the reaction mixture is stirred at room temperature for 18 hours. 40 ml of methanol are subsequently added dropwise thereto at -60°, the mixture is stirred at room temperature for 1 hour and evaporated. The residue is taken up in methanol. It is heated under reflux for 10 minutes, evaporated to dryness and dried in a high vacuum. The thus-obtained crude product is recrystallized from acetonitrile. There is obtained methyl (3-cyano-4,5-dihydroxyphenyl)glyoxylate of m.p. 252°.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])([CH3:8])([CH3:7])[CH3:6].[C:16](Cl)(=[O:18])[CH3:17]>C1(C)C=CC=CC=1>[CH3:7][C:5]([C:9]1[CH:14]=[C:13]([C:16](=[O:18])[CH3:17])[CH:12]=[CH:11][C:10]=1[OH:15])([CH3:8])[CH3:6]
Reactant: CC(C)(C)c1ccccc1O
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(O)c(C(C)(C)C)c1
Temperature: -45 °C
Reaction time: 0.17 h

Procedure:
To a dry, round bottom flask was added aluminum chloride (4.402 g, 33.0 mmol). The flask was then cooled to −45° C. After 10 minutes, dry toluene (80 mL) was added followed by dropwise addition of 2-tert-butylphenol (5.00 mL, 32.7 mmol) (commercially available from Aldrich). The mixture was stirred and maintained at −4° C. After 1.5 hours, acetyl chloride (2.40 mL, 33.8 mmol) was carefully added dropwise. The mixture was allowed to warm to room temperature and monitored with TLC and LC-MS. After 18 hours, the mixture was slowly poured onto crushed ice. This mixture was stirred at room temperature and the crystals were collected by filtration. The light yellow solid was identified as T5.1 (4.2589 g, 68%). MS ESI (pos.) m/e: 193.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:8][CH2:7][CH2:6][N:5]([C:9]([C:11]2[CH:15]=[C:14]([C:16]3[CH:17]=[N:18][NH:19][CH:20]=3)[S:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][CH2:30][OH:31]>CN(C=O)C>[CH3:1][C:2]1([CH3:21])[CH2:8][CH2:7][CH2:6][N:5]([C:9]([C:11]2[CH:15]=[C:14]([C:16]3[CH:17]=[N:18][N:19]([CH2:29][CH2:30][OH:31])[CH:20]=3)[S:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1
Reactant: OCCBr
Reactant: CC1(C)CCCN(C(=O)c2csc(-c3cn[nH]c3)c2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)CCCN(C(=O)c2csc(-c3cnn(CCO)c3)c2)CC1
Temperature: 100 °C
Yield: 23 %

Procedure:
(4,4-Dimethyl-azepan-1-yl)-[5-(1H-pyrazol-4-yl)-thiophen-3-yl]-methanone (0.075 g, 0.25 mmol) was dissolved in DMF (1 mL) and potassium carbonate (44 mg, 0.32 mmol) was added followed by 2-bromoethanol (27 μL, 0.38 mmol). The reaction mixture was heated at 100° C. overnight then quenched by addition of ammonium chloride. The mixture was extracted with ethyl acetate (×2) then the organics were washed with lithium chloride (15% aqueous solution) and evaporated. The crude material was purified by chromatography on a silica II cartridge, eluting with 10-66% ethyl acetate in cyclohexane. The residue was purified by HPLC, eluting with 10%-98% acetonitrile in water (0.1% formic acid) over 20 minutes. The fractions containing the desired product were concentrated under vacuum and freeze-dried to give the title compound as a colourless oil (0.020 g). LCMS m/z 348.29 [M+H]+ R.T.=8.62 min (Analytical Method 2).
Reaction SMILES: [C:1]1([C@H:7]2[N:21]3[C:22]4[C:14]([C:15]5[C:20]3=[CH:19][CH:18]=[CH:17][C:16]=5[OH:23])=[CH:13][CH:12]=[CH:11][C:10]=4[O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][C:32]#[N:33]>CN(C=O)C>[C:1]1([C@H:7]2[N:21]3[C:22]4[C:14]([C:15]5[C:16]([O:23][CH2:31][C:32]#[N:33])=[CH:17][CH:18]=[CH:19][C:20]=53)=[CH:13][CH:12]=[CH:11][C:10]=4[O:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CCBr
Reactant: Oc1cccc2c1c1cccc3c1n2[C@H](c1ccccc1)CO3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCOc1cccc2c1c1cccc3c1n2[C@H](c1ccccc1)CO3
Temperature: 25 °C
Reaction time: 20 h
Yield: 89 %

Procedure:
To a mixture of (R)-(−)-1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-ol (5.9 g 19.6 mmol) in DMF (50 mL) is added potassium carbonate (8.1 g, 58.7 mmol) and bromoacetonitrile (4.1 mL, 58.7 mmol). The mixture is stirred at room temperature for 20 h. The mixture is partitioned between water and Et2O. The organic layer is washed twice with water (200 mL), dried over anhydrous sodium sulfate and concentrated. Column chromatography (800 mL silica) using CH2Cl2 eluent gave 5.94 g (89%) of (R)-(−)-2-[(1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-yl)oxy]acetonitrile.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[OH:15])=O)=[N:2]1.Cl.[NH2:17][OH:18].O>CN(C)C=O>[O:1]1[CH2:6][CH2:5][O:4][C:3]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[OH:15])=[N:17][OH:18])=[N:2]1
Reactant: O=C(C1=NOCCO1)c1ccccc1O
Reactant: NO
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: ON=C(C1=NOCCO1)c1ccccc1O
Yield: 60.8 %

Procedure:
At 80° C., 4.14 g (0.02 mol) of (5,6-dihydro-1,4,2-dioxazin-3-yl)-(2-hydroxy-phenyl)-methanone (III-1) in 20 ml of dimethylformamide are stirred with 2.1 g (0.03 mol) of hydroxylamine hydrochloride for 2 hours. The reaction mixture is poured into water and the resulting mixture is extracted with ethyl acetate, and the organic phase is dried over sodium sulphate and concentrated under reduced pressure. 4.7 g of crude product consisting of 15% E isomer and 57.5% Z isomer (HPLC) are obtained. The crude product is chromatographed over silica gel using a mixture of diethyl ether and petroleum ether (1:1). 2.7 g (60.8% of theory) of (5,6-dihydro-1,4,2-dioxazin-3-yl)-(2-hydroxy-phenyl)-methanone oxime (V-1) are obtained (content according to HPLC analysis: 93.4%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11](=[O:18])[C@@H:12]([OH:17])[CH2:13][O:14][CH2:15][CH3:16])=[N:8][CH:9]=1.[CH3:19][N:20]1[CH:24]=[CH:23][N:22]=[C:21]1[N:25]1[C:29]2=[N:30][CH:31]=[N:32][C:33](OC3C=CC=CC=3)=[C:28]2[CH:27]=[N:26]1>C1COCC1>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11](=[O:18])[C@@H:12]([O:17][C:33]2[N:32]=[CH:31][N:30]=[C:29]3[N:25]([C:21]4[N:20]([CH3:19])[CH:24]=[CH:23][N:22]=4)[N:26]=[CH:27][C:28]=23)[CH2:13][O:14][CH2:15][CH3:16])=[N:8][CH:9]=1
Reactant: Cn1ccnc1-n1ncc2c(Oc3ccccc3)ncnc21
Reactant: CCOC[C@H](O)C(=O)Nc1ccc(Cl)cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC[C@H](Oc1ncnc2c1cnn2-c1nccn1C)C(=O)Nc1ccc(Cl)cn1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (60% in oil) (29.2 mg, 0.73 mmol) was added to (S)—N-(5-chloropyridin-2-yl)-3-ethoxy-2-hydroxypropanamide (Intermediate H3) (149 mg, 0.61 mmol) in anhydrous THF (5 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then 1-(1-methyl-1H-imidazol-2-yl)-4-phenoxy-1H-pyrazolo[3,4-d]pyrimidine (Intermediate AV1) (196 mg, 0.67 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 4 hours. The reaction mixture was quenched with 1M citric (2 mL), extracted with EtOAc, the organic layer was washed with water ×2 and brine, dried (MgSO4), filtered and evaporated to afford orange oil. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 50 mm diameter, 150 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents to afford the product (111 mg, 41.2%, 95% ee). 1H NMR (400 MHz, CDCl3) δ 1.22 (3H, t), 3.56-3.72 (5H, m), 4.03-4.15 (2H, m), 6.05 (1H, t), 7.02 (1H, d), 7.17 (1H, d), 7.65-7.71 (1H, m), 8.19-8.26 (2H, m), 8.43 (1H, s), 8.65 (1H, s), 8.78 (1H, s); m/z (ES+) (M+H)+=443.40; HPLC tR=1.92 min.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]#[C:23][CH3:24])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)=[O:4].[CH3:25][C:26]1([CH3:36])[O:31][CH2:30][C:29]([C:33](O)=[O:34])([CH3:32])[CH2:28][O:27]1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1>CN(C)C=O>[CH2:21]([O:20][C:17]1[CH:16]=[CH:15][C:14]([S:11]([C:5]2([C:3]([O:2][CH3:1])=[O:4])[CH2:10][CH2:9][N:8]([C:33]([C:29]3([CH3:32])[CH2:28][O:27][C:26]([CH3:36])([CH3:25])[O:31][CH2:30]3)=[O:34])[CH2:7][CH2:6]2)(=[O:13])=[O:12])=[CH:19][CH:18]=1)[C:22]#[C:23][CH3:24]
Reactant: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OC)CCNCC2)cc1
Reactant: CC1(C)OCC(C)(C(=O)O)CO1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OC)CCN(C(=O)C3(C)COC(C)(C)OC3)CC2)cc1

Procedure:
Methyl 4-(4-but-2-ynyloxybenzenesulfonyl)-1-[(2,2,5-trimethyl-1,3-dioxan-5-yl)carbonyl]-4-piperidinecarboxylate was prepared following the procedure Example 64 (step 6). Starting from 4-(4-but-2-ynyloxy-benzenesulfonyl)-piperidine-4-carboxylic acid methyl ester (500 mg, 1.29 mmol) in dimethylformamide (10 ml), (2,2,5-trimethyl-1,3-dioxan-5-yl)carboxylic acid (224 mg, 1.29 mmol), 1-hydroxybenzotriazole (209 mg, 1.56 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (346 mg, 1.81 mmol), and N-methylmorpholine (0.212 ml, 1.94 mmol), to obtain 385 mg (59%) of the product as a solid. HR-MS: m/z Calculated for C25H33NO8S 508.2000; Found 508.1998.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([N:8]2[C:12]3=[C:13]4[S:19][CH:18]=[CH:17][C:14]4=[N:15][CH:16]=[C:11]3[N:10]=[C:9]2[C@H:20]([OH:22])[CH3:21])[CH2:3]1.C(N(CC)CC)C.[CH:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][C:38](Cl)=[O:39])=[CH:32][CH:31]=1>CN(C)C=O>[C:33]1([CH2:36][CH2:37][C:38]([N:2]2[CH2:7][CH2:6][CH2:5][C@H:4]([N:8]3[C:12]4=[C:13]5[S:19][CH:18]=[CH:17][C:14]5=[N:15][CH:16]=[C:11]4[N:10]=[C:9]3[CH:20]([OH:22])[CH3:21])[CH2:3]2)=[O:39])[CH:34]=[CH:35][CH:30]=[CH:31][CH:32]=1
Reactant: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CCCNC1
Reactant: O=C(Cl)CCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(O)c1nc2cnc3ccsc3c2n1[C@H]1CCCN(C(=O)CCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 34 %

Procedure:
To a mixture of (1R)-1-{1-[(3S)-piperidin-3-yl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl}ethanol hydrochloride (15 mg, 0.044 mmol) (Example 50, step 4) and triethylamine (24.7 μL, 0.177 mmol) in N,N-dimethylformamide (0.3 mL) was added benzenepropanoyl chloride (8.6 μL, 0.058 mmol). The resulting mixture was stirred for 90 min at room temperature. The mixture was purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give 6.5 mg (34%) of the desired product. LCMS calculated for C24H27N4O2S (M+H)+: m/z=435.2. Found: 435.1. 1H NMR (300 MHz, CDCl3) δ 9.07 (s, 1H), 7.71-7.66 (m, 1H), 7.65-7.57 (m, 1H), 7.34-7.27 (m, 2H), 7.26-7.16 (m, 2H), 7.12 (d, J=6.9 Hz, 1H), 5.21 (s, 1H), 4.83 (d, J=13.1 Hz, 2H), 4.78-4.64 (m, 1H), 4.04-3.87 (m, 1H), 3.61-3.23 (m, 3H), 3.04-2.85 (m, 2H), 2.77-2.60 (m, 2H), 2.15 (s, 1H), 1.97 (d, J=14.4 Hz, 1H), 1.81 (d, J=6.5 Hz, 2H), 1.50 (d, J=13.1 Hz, 2H) ppm.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[CH3:6][O:7][C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10](Cl)=[O:11]>C1(C)C=CC=CC=1>[CH3:6][O:7][C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[O:11]
Reactant: CCNCC
Reactant: COc1ccccc1C(=O)Cl
Solvent: Cc1ccccc1
Product: CCN(CC)C(=O)c1ccccc1OC
Yield: 94 %

Procedure:
A solution of diethylamine (25.8 g, 0.352 mol) in toluene (toluene 30.8 g) was placed in a 200-mL four-neck flask. Under cooling with ice, a solution of 2-methoxybenzoic chloride (20 g, 0.117 mol) in toluene (toluene 10.0 g) was added dropwise gradually in order to prevent sudden surge of heat. After completion of addition of the entire amount of the solution, the formed amine hydrochloride was removed through extraction with water. The thus-obtained toluene layer was dried over MgSO4, and the solvent was vaporized out, to thereby yield 22.8 g of 2-methoxy-N,N-diethylbenzamide (yield: 94%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C@:11]([CH3:18])([CH:13]([O:16][CH3:17])[O:14][CH3:15])[C@@H:10]3[O:19][C@@H:9]3[C:8]=2[CH:20]=1)([O-:3])=[O:2].[CH3:21][C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[C:24]([CH3:29])[C:23]=1[NH:30][CH2:31][C:32]1[N:33]=[N:34][N:35]([CH3:37])[N:36]=1>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C@:11]([CH3:18])([CH:13]([O:16][CH3:17])[O:14][CH3:15])[C@H:10]([OH:19])[C@@H:9]([N:30]([C:23]3[C:24]([CH3:29])=[CH:25][C:26]([CH3:28])=[CH:27][C:22]=3[CH3:21])[CH2:31][C:32]3[N:33]=[N:34][N:35]([CH3:37])[N:36]=3)[C:8]=2[CH:20]=1)([O-:3])=[O:2]
Reactant: Cc1cc(C)c(NCc2nnn(C)n2)c(C)c1
Reactant: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H]2O[C@H]21
Product: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H](N(Cc2nnn(C)n2)c2c(C)cc(C)cc2C)[C@H]1O
Yield: 35 %

Procedure:
The same procedure as step 3 of example 1 was accomplished, except for using the epoxide compound (400 mg, 1.43 mmol) obtained in step 1 of example 2 and N-(2,4,6-trimethylphenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine. The crude product was purified by silica gel column chromatography (developing solvent-n-hexane:ethyl acetate=1:2), to give desired compound (260 mg, yield: 35%).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[NH2:11][C:12]1([C:38]2[C:39]([O:44][CH2:45][CH3:46])=[N:40][CH:41]=[CH:42][CH:43]=2)[C:20]2[C:15](=[CH:16][C:17]([F:23])=[C:18]([C:21]#[N:22])[CH:19]=2)[N:14]([S:24]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:28]=2[O:35][CH3:36])(=[O:26])=[O:25])[C:13]1=[O:37]>N1C=CC=CC=1>[C:21]([C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][C:17]=1[F:23])[N:14]([S:24]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:28]=1[O:35][CH3:36])(=[O:25])=[O:26])[C:13](=[O:37])[C:12]2([NH:11][C:2](=[O:3])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:38]1[C:39]([O:44][CH2:45][CH3:46])=[N:40][CH:41]=[CH:42][CH:43]=1)#[N:22]
Reactant: CCOc1ncccc1C1(N)C(=O)N(S(=O)(=O)c2ccc(OC)cc2OC)c2cc(F)c(C#N)cc21
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Product: CCOc1ncccc1C1(NC(=O)Oc2ccccc2)C(=O)N(S(=O)(=O)c2ccc(OC)cc2OC)c2cc(F)c(C#N)cc21
Reaction time: 0.08 h
Yield: 71.9 %

Procedure:
61 μl (0.49 mmol) of phenyl chloroformate were slowly added dropwise to a solution, cooled to 0° C., of 226 mg (0.44 mmol) of 3-amino-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile in 4 ml of pyridine. After 5 minutes, the solvent was evaporated. The residue was mixed with 20 ml of water and extracted with diethyl ether (2×). The organic phase was washed with water and saturated sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (Redisep cartridge, mobile phase gradient from 0 to 5% methanol in ethyl acetate). 200 mg of the title compound were obtained.