Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=2[OH:17])[C:12]#[N:13])[C:4]1=[O:18].[Cl:19][C:20]1[C:28]2[CH:27]=[C:26]([S:29](Cl)(=[O:31])=[O:30])[S:25][C:24]=2[CH:23]=[C:22]([Cl:33])[CH:21]=1>N1C=CC=CC=1>[OH:17][C:16]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][C:9]=1[CH2:8][N:5]1[CH2:6][CH2:7][CH:3]([NH:2][S:29]([C:26]2[S:25][C:24]3[CH:23]=[C:22]([Cl:33])[CH:21]=[C:20]([Cl:19])[C:28]=3[CH:27]=2)(=[O:31])=[O:30])[C:4]1=[O:18]
Reactant: N#Cc1ccc(O)c(CN2CCC(N)C2=O)c1
Reactant: O=S(=O)(Cl)c1cc2c(Cl)cc(Cl)cc2s1
Agent: Cl
Solvent: c1ccncc1
Product: N#Cc1ccc(O)c(CN2CCC(NS(=O)(=O)c3cc4c(Cl)cc(Cl)cc4s3)C2=O)c1
Reaction time: 6 h

Procedure:
To a solution of 3-[(3-amino-2-oxo-pyrrolidin-1-yl)-methyl]-4-hydroxy-benzonitrile hydrochloride (0.20 g, 0.75 mmol) in 3 mL of pyridine at 0° C. is added 4,6-dichlorobenzo[b]thiophene-2-sulfonyl chloride. The solution is allowed to warm to ambient temperatures and is stirred for 6 h. After this time, the solution is concentrated. The residue is dissolved in CH2 Cl2. The organic solution is washed with 1N HCl and saturated NaCl. The crude product is triturated with Et2O to give the title compound (0.22 g, 0.44 mmol) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH:9]2[CH2:11][CH2:10]2)=[N:6][CH:7]=1.[Li]CCCC.C[O:18]B(OC)OC.C(OO)(=O)C.OS([O-])=O.[Na+]>C1COCC1>[CH:9]1([O:8][C:5]2[N:6]=[CH:7][C:2]([OH:18])=[CH:3][CH:4]=2)[CH2:11][CH2:10]1
Reactant: COB(OC)OC
Reactant: Brc1ccc(OC2CC2)nc1
Agent: CC(=O)OO
Agent: O=S([O-])O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Oc1ccc(OC2CC2)nc1
Reaction time: 0.17 h

Procedure:
A mixture of 5-bromo-2-cyclopropoxypyridine (Milestone Pharmtech, 500 mg) in THF (10 mL) was cooled (−78° C.) and n-BuLi (2.5 M in toluene, 1.49 mL) was added dropwise within 10 minutes. After 20 minutes trimethylborate (429 μL) was added. After 2 hours peracetic acid (32% in AcOH, 786 μL) was added dropwise. After 10 minutes the reaction temperature was changed to 0° C. After 1 hour the mixture was poured into aqueous NaHSO3-solution (5%, 5 mL). The mixture was extracted with EA. The organic phase was dried (Na2SO4), filtered and concentrated. The residue was purified by chromatography (silica gel, heptane to EA/heptane 2:3) to provide the subtitle compound. MS ESI+: m/z=152 [M+H]+.
Reaction SMILES: [BrH:1].[CH:2]1([NH:6][CH:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([OH:18])[C:13]=3[OH:17])[C:8]2=[O:19])[CH2:5][CH2:4][CH2:3]1>[Pd].O>[BrH:1].[CH:2]1([NH:6][CH:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([OH:18])[C:13]=3[OH:17])[CH:8]2[OH:19])[CH2:3][CH2:4][CH2:5]1
Reactant: O=C1c2ccc(O)c(O)c2CCC1NC1CCC1
Agent: [Pd]
Agent: Br
Solvent: O
Product: Oc1ccc2c(c1O)CCC(NC1CCC1)C2O

Procedure:
In the presence of 1.53 parts of 5 % palladium-on-carbon, 1.5 parts of 2-cyclobutylamino-5,6-dihydroxy-3,4-dihydro-1(2H)-naphthalenone hydrobromide in 200 volume parts of water is subjected to catalytic reduction at ordinary temperature and pressure. When a stoichiometric amount of hydrogen has been absorbed, the reaction mixture is filtered to remove the catalyst and filtrate is freeze-dried. The residue is recrystallized from a mixture of water, ethanol and ethyl ether, whereby 2-cyclobutylamino-1,5,6-trihydroxy-1,2,3,4-tetrahydronaphthalene hydrobromide is obtained as colorless crystals. Yield 0.65 part; melting point: 190°-200° C (decomposition).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11]O)[CH:6]=[CH:7][CH:8]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:37]I>C(#N)C.C(OCC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11][I:37])[CH:6]=[CH:7][CH:8]=1
Reactant: II
Reactant: COc1cccc(CCCO)c1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCOCC
Product: COc1cccc(CCCI)c1
Reaction time: 0.75 h
Yield: 84.9 %

Procedure:
A magnetically stirred solution of 3-(3-methoxyphenyl)propan-1-ol (62.48 g, 375.9 mmol), triphenylphosphine (128.6 g, 490.4 mmol), and imidazole (35.53 g, 516.7 mmol) in anhydrous acetonitrile (300 mL) / anhydrous diethyl ether (600 mL) at 5° C. was treated portion wise with iodine (136.20 g, 536.6 mmol). The yellow suspension turned orange with the last addition. The suspension was stirred 45 min, filtered, the cake washed with fresh diethyl ether (300 mL), the combined filtrate was concentrated in vacuo to 300 mL and diluted with diethyl ether (200 mL). The resultant organic solution was washed with saturated sodium thiosulfate (2×500 mL), saturated cupric sulfate (2×500 mL), brine (2×500 mL), filtered and concentrated in vacuo. The residue was digested with hexanes (300 mL), filtered and concentrated in vacuo. Kugelrohr distillation (0.1 torr, 120° C.) provided the desired product as a yellow liquid (88.10 g, 85%): 1H NMR (CDCl3) δ 7.20 (t, J=8 Hz, 1H), 6.81-6.73 (m, 3H), 3.81 (s, 3H), 3.17 (t, J=8 Hz, 2H), 2.70 (t, J=8 Hz, 2H), 2.14 (quint, J=8 Hz, 2 H).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]([CH:25]=[O:26])=[C:12]([CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([C:21]([F:24])([F:23])[F:22])[CH2:17][CH2:16]3)[N:13]=2)=[CH:5][CH:4]=1.[CH2:29]([Mg]Br)[CH3:30].OP([O-])(O)=O.[K+]>O1CCCC1.COC(C)(C)C>[F:28][C:2]([F:1])([F:27])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]([CH:25]([OH:26])[CH2:29][CH3:30])=[C:12]([CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([C:21]([F:22])([F:24])[F:23])[CH2:17][CH2:16]3)[N:13]=2)=[CH:5][CH:4]=1
Reactant: CC[Mg]Br
Reactant: O=Cc1sc(-c2ccc(C(F)(F)F)cc2)nc1CN1CCC(C(F)(F)F)CC1
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: CCC(O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1CN1CCC(C(F)(F)F)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 530 mg of 2-(4-trifluoromethyl-phenyl)-4-(4-trifluoromethyl-piperidin-1-ylmethyl)-thiazole-5-carbaldehyde in 43 ml tetrahydrofuran at 0° C. was slowly added 2.2 ml of a molar solution of ethylmagnesium bromide in tert-butyl methyl ether. The reaction mixture was stirred at 0° C. for one hour then poured onto an aqueous solution of KH2PO4 and extracted with dichloromethane. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give 545 mg 1-[2-(4-trifluoromethyl-phenyl)-4-(4-trifluoromethyl-piperidin-1-ylmethyl)-thiazol-5-yl]-propan-1-ol which was used without further purification.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[C:9]([C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10]>C(O)(C(F)(F)F)=O.OS(O)(=O)=O>[Br:8][C:18]1[CH:17]=[C:16]([N+:19]([O-:21])=[O:20])[CH:15]=[CH:14][C:13]=1[C:9]([CH3:12])([CH3:10])[CH3:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)c1ccc([N+](=O)[O-])cc1
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1ccc([N+](=O)[O-])cc1Br
Temperature: 0 °C
Reaction time: 24 h

Procedure:
NBS (125.0 g, 697.5 mmol, 1.5 eq) was slowly added to a solution of TFA:H2SO4 (5:1, 750 mL) and tert-butyl-4-nitrobenzene (100.0 g, 558.0 mmol) at RT. The solution was stirred for 24 h and poured over 5 kg of ice. The resulting suspension was filtered and washed with a 1:1 MeOH:H2O solution (200 mL) and dried in a vacuum oven. MS (ES+): 258.1, 260.1 (M+H)+. Calc'd for C10H12BrNO2: 257.0.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[CH:4][CH:3]=1.[C:21]1([C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[NH:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[C:21]1([C:27](=[N:28][C:2]2[CH:7]=[CH:6][C:5]([C@H:8]3[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]3)=[CH:4][CH:3]=2)[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](c2ccc(Br)cc2)C1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCO[C@H](c2ccc(N=C(c3ccccc3)c3ccccc3)cc2)C1
Temperature: 90 °C
Reaction time: 18 h
Yield: 88 %

Procedure:
(R)-tert-butyl 2-(4-bromophenyl)morpholine-4-carboxylate (5.4 g, 15.8 mmol), diphenylmethanimine (3.43 g, 3.17 ml, 18.9 mmol), BINAP (737 mg, 1.18 mmol) and Pd2(dba)3 (361 mg, 0.39 mmol) were dissolved under Argon in dry and de-aerated toluene (108 ml) and treated with sodium tert-butoxide (2.12 g, 22.1 mmol). The dark brown mixture was stirred at 90° C. for 18 h. The yellow/brown reaction mixture was diluted with toluene (100 ml), cooled to rt and extracted twice with water. The organic layer was separated, dried over magnesium sulfate and concentrated in vacuo. The crude product was diluted with 50 ml hexane, stirred for 1 h and filtered off, leading to a yellow solid (7.4 g) which was purified by column chromatography (50 g silicagel, 5% to 15% ethylacetate/heptane). The combined and concentrated fractions were suspended in hexane, stirred for 17 h, filtered off andf dried in high vacuo, to yield 6.15 g (86%) yellow solid. MS (ISP): 443.4 ([M+H]+).
Reaction SMILES: [BH4-].[Na+].[CH:3]([C:5]1[CH:6]=[C:7](/[CH:16]=[CH:17]/[C:18]([NH:20][CH:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:23][CH2:22]2)=[O:19])[CH:8]=[CH:9][C:10]=1[N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1)=[O:4]>C(O)C>[OH:4][CH2:3][C:5]1[CH:6]=[C:7](/[CH:16]=[CH:17]/[C:18]([NH:20][CH:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:23][CH2:22]2)=[O:19])[CH:8]=[CH:9][C:10]=1[N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: O=Cc1cc(/C=C/C(=O)NC2CCc3ccccc32)ccc1-n1ccnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=C(/C=C/c1ccc(-n2ccnc2)c(CO)c1)NC1CCc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 10.5 %

Procedure:
Sodium borohydride (2 mg) is added to an ethanol (1 mL) solution of (E)-3-(3-formyl-4-(1H-imidazol-1-yl)phenyl)-N-indan-1-ylacrylamide (17 mg) obtained in Example 437 and the reaction mixture was agitated for 30 minutes at room temperature. After the reaction solution was concentrated under reduced pressure, water and ethyl acetate were added to the residue, and the organic layer was partitioned. The organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Carrier: Chromatorex™ NH, elution solvent:methanol-ethyl acetate system), and 1.8 mg of the title compound was obtained.
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:36])[C:16]([C:18]2[C:26]3[C:21](=[C:22]([C:29]4[N:30]=[CH:31][C:32]([OH:35])=[N:33][CH:34]=4)[N:23]=[CH:24][C:25]=3[O:27][CH3:28])[NH:20][CH:19]=2)=[O:17])[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CI.[C:39]([O-])([O-])=O.[K+].[K+]>CC(C)=O>[C:1]([N:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:36])[C:16]([C:18]2[C:26]3[C:21](=[C:22]([C:29]4[N:30]=[CH:31][C:32](=[O:35])[N:33]([CH3:39])[CH:34]=4)[N:23]=[CH:24][C:25]=3[O:27][CH3:28])[NH:20][CH:19]=2)=[O:17])[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: COc1cnc(-c2cnc(O)cn2)c2[nH]cc(C(=O)C(=O)N3CCN(C(=O)c4ccccc4)CC3)c12
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1cnc(-c2cn(C)c(=O)cn2)c2[nH]cc(C(=O)C(=O)N3CCN(C(=O)c4ccccc4)CC3)c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 48.6 %

Procedure:
1-(benzoyl)-4-[(4-methoxy-7-(2-hydroxyl-pyrazin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine (6 mg), MeI (5 mg) and K2CO3 (4 mg) were dissolved in acetone (5 ml). The reaction was stirred for four hours at room temperature. After solid was filtered away, the mother liquid was concentrated to give a residue which was purified using a Shimadzu automated preparative HPLC System to provide 3.0 mg of the desired compound, 1-(benzoyl)-4-[(4-methoxy-7-(1-methylpyrazin-2-on-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine. MS m/z: (M+H)+ Calc'd for C26H25N6O5: 501.19; found 501.14. HPLC retention time: 1.08 minutes (column G).
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]2[NH:6][N:7]=[N:8][C:4]=2[CH:3]=1.[OH-].[Na+].[Cl:14][CH2:15][CH2:16][CH2:17][CH2:18]Br>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:14][CH2:15][CH2:16][CH2:17][CH2:18][N:8]1[C:4]2[CH:3]=[C:2]([CH3:1])[C:10]([CH3:11])=[CH:9][C:5]=2[N:6]=[N:7]1
Reactant: ClCCCCBr
Reactant: Cc1cc2nn[nH]c2cc1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Product: Cc1cc2nnn(CCCCCl)c2cc1C
Temperature: 60 °C
Reaction time: 2 h
Yield: 73.2 %

Procedure:
5,6-dimethyl-1H-benzotriazole (14.7 g, 0.10 mol) is dissolved into 100 ml of 30% wt. sodium hydroxide, 4-chlorobromobutane (34.3 g, 0.20 mol), tetrabutyl ammonium bromide (0.8 g) are added, and mixed for 5 min. The reaction solution is gradually heated to 60° C., stirred for reaction for 2 hours. Post treatment was performed based on common method one for synthesis. The solution was separated and purified by HPLC to produce 17.4 g of 1-(4-chlorobutyl)-5,6-dimethyl-1H-benzotriazole, with a yield of 73.2%.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.O.O.[Sn](Cl)Cl.C(OCC)(=O)C.[BH4-].[Na+]>CC(O)(C)C>[Cl:11][C:4]1[N:3]=[C:2]([NH2:1])[C:7]([NH2:8])=[CH:6][CH:5]=1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(C)(C)O
Product: Nc1ccc(Cl)nc1N
Temperature: 60 °C
Reaction time: 1 h
Yield: 65.5 %

Procedure:
A mixture of 12.0 g of 2-amino-6-chloro-3-nitropyridine, 78.0 g of tin(II) chloride dihydrate and 360 ml of a 9:1 by volume mixture of ethyl acetate and 2-methyl-2-propanol was stirred at 60° C. for 1 hour, after which 1.32 g of sodium borohydride were added at 60° C., and the mixture was stirred for 3 hours at the same temperature. At the end of this time, the reaction mixture was freed from the solvent by distillation under reduced pressure. The resulting residue was diluted with water and neutralized by adding an aqueous solution of potassium carbonate, after which it was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure. The residue thus obtained was crystallized by trituration with a mixture of ethyl acetate and hexane, to give 6.50 g of title compound, melting at 120°-122° C.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([CH:13]=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].C1C(=O)N([I:24])C(=O)C1>C(#N)C>[CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([I:24])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)c1cc(C)nn2cc(C)nc12
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Product: CCC(CC)c1cc(C)nn2c(I)c(C)nc12
Temperature: 0 °C
Reaction time: 8 h

Procedure:
8-(1-Ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (5.1 g, 0.023 moles) and 50 mL of dry acetonitrile are added to a nitrogen purged flask and are cooled to 0° C. NIS (5.54 g, 0.025 moles) in 90 mL of dry acetonitrile is added. The bath is allowed to come to room temperature, and the reaction to stir overnight. The solvents are evaporated. The residue is taken up in ethyl acetate, washed two times with 50% aqueous solution of sodium thiosulfate and with brine. The organic layer is dried over sodium sulfate, filtered, and evaporated to a residue again. The crude product is triturated in a small amount of acetonitrile, and a solid is filter off. The trituration is repeated several times to obtain the title compound as a light tan solid weighing 7.29 g (0.021 moles, 91%). 1H-NMR (DMSO-d6), δ 6.96 (s, 1H); 3.0-3.3 (m, 1H); 2.51 (s, 3H); 2.35 (s, 3H); 1.71-1.80 (m, 4H); 0.71 (t, J=7.48 hz, 6H) ppm. MS/ES+=344 (100%, M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]3[N:15]([C:16]=2[C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[CH2:14][CH2:13][S:12]3)=[CH:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:31])C=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]=[C:11]3[N:15]([C:16]=2[C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[CH2:14][CH2:13][S:12]3=[O:31])=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2nc3n(c2-c2ccncc2)CCS3)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1ccc(-c2nc3n(c2-c2ccncc2)CCS3=O)cc1
Yield: 63.4 %

Procedure:
To 2.4 g of 6-(4-methoxyphenyl)-5-(4-pyridyl)-2,3-dihydroimidazo[2,1-b]thiazole in 200 ml methylene chloride was added 1.34 g of m-chloroperbenzoic acid in 150 ml of methylene chloride at ice-bath temperature. After 10 minutes the reaction mixture was diluted with methylene chloride and washed twice with 100 ml of 5 N sodium carbonate. Evaporation of the dried extracts left a solid which when recrystallized from chloroform-ether gave 1.6 g of the title product, m.p. 165°-170°.
Reaction SMILES: [C:1]([C:3]1[CH:48]=[CH:47][C:6]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([C@@H:15]([NH:21][C:22]([C@@H:24]3[CH2:29][CH2:28][CH2:27][N:26]([C:30](=[O:46])[CH2:31][CH2:32][CH:33]4[CH2:38][CH2:37][N:36](C(OC(C)(C)C)=O)[CH2:35][CH2:34]4)[CH2:25]3)=[O:23])[CH2:16][C:17]([O:19]C)=[O:18])[CH:12]=[N:13][CH:14]=2)=[CH:5][C:4]=1[F:49])#[N:2].CO.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-]>C(O)(C)(C)C>[C:1]([C:3]1[CH:48]=[CH:47][C:6]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([C@H:15]([NH:21][C:22]([C@H:24]3[CH2:29][CH2:28][CH2:27][N:26]([C:30](=[O:46])[CH2:31][CH2:32][CH:33]4[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]4)[CH2:25]3)=[O:23])[CH2:16][C:17]([OH:19])=[O:18])[CH:12]=[N:13][CH:14]=2)=[CH:5][C:4]=1[F:49])#[N:2]
Reactant: COC(=O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(OCc2ccc(C#N)c(F)c2)c1
Agent: [Ba+2]
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: CO
Solvent: O
Product: N#Cc1ccc(COc2cncc([C@@H](CC(=O)O)NC(=O)[C@H]3CCCN(C(=O)CCC4CCNCC4)C3)c2)cc1F
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 47.1 %

Procedure:
Tert-butyl 4-{3-[(3R)-3-{[(1S)-1-(5-(4-cyano-3-fluorobenzyloxy)pyridin-3-yl)-3-methoxy-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate (10 mg, 15 μmol) as solved in tert.-butanol (0.6 mL) and methanol (0.6 mL) and barium hydroxide octahydrate (23 mg, 74 μmol) was added. After stirring for 45 minutes room temperature the solvent was distilled off at 0° C. by high vacuum. The residue was acidified with formic acid (1 mL). After 18 hours at 5° C. the solvent was distilled off at 0° C. by high vacuum and the residue was purified by preparative HPLC to yield 4 mg of (3R)-3-{5-[(4-cyano-3-fluorobenzyl)oxy]pyridin-3-yl}-3-[({(3S)-1-[3-(piperidin-4-yl)propanoyl]piperidin-3-yl}carbonyl)amino]propanoic acid.
Reaction SMILES: [CH3:1][C:2]1[N:10]([C:11]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)=[O:12])[C:9]2[CH:8]=[CH:7][C:6]([O:20][CH3:21])=[CH:5][C:4]=2[C:3]=1[CH2:22][C:23](O)=[O:24].[OH:26][CH2:27][CH2:28][CH2:29][CH2:30][NH2:31].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[OH:26][CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:23](=[O:24])[CH2:22][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([O:20][CH3:21])[CH:5]=2)[N:10]([C:11](=[O:12])[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:2]=1[CH3:1]
Reactant: NCCCCO
Reactant: COc1ccc2c(c1)c(CC(=O)O)c(C)n2C(=O)c1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(CC(=O)NCCCCO)c(C)n2C(=O)c1ccc(Cl)cc1
Reaction time: 0.5 h
Yield: 58.3 %

Procedure:
To a stirred solution of indomethacin (3.57 g, 10 mmol) in DMF was added 4-hydroxybutylamine (4.64 g), HOBt (2.02 g, 15 mmol), DIPEA (3.88 g, 30 mmol), EDCl (2.10 g, 11 mmol) at 25° C. The resultant solution was stirred for 16 h at 25° C. Removal of solvent in vacuo afforded a residue, where 100 mL water was added and extracted with EtOAc (3×75 mL). Combined organic layers were dried over Na2SO4. Solvent was evaporated completely and the obtained mass was dissolved in CH2Cl2 (40 mL), then HCl (gas) was bubbled for 2 h at 25° C. Removal of solvent in vacuo afforded a yellow residue, where n-hexane was added (20 mL) and stirred for 30 min to a make good slurry, which was filtered to afford the desired N-(4-hydroxybutyl)-2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]acetamide as yellow solid (2.5 g, 70%). 1H NMR (500 MHz, DMSO-d6) δ 1.44-1.52 (m, 2H, CCH2CC), 1.53-1.59 (m, 2H, CCCH2C), 2.23 (s, 3H, CH3), 3.03-3.08 (m, 2H, CH2CCC), 3.52 (s, 2H, CH2CO), 3.75 (s, 3H, OCH3), 3.77-3.78 (m, 2H, CCCCH2), 4.53 (br s, 1H, OH), 6.684 (dd, J=9, 2.4 Hz, 1H, indolyl H-6), 6.916 (d, J=9 Hz, 1H, indolyl H-7), 7.144 (d, J=2.4 Hz, 1H, indolyl H-4), 7.64 (d, J=8.7 Hz, 2H, p-chlorobenzoyl H-3, H-5), 7.67 (d, J=8.7 Hz, 2H, p-chlorobenzoyl H-2, H-6), 8.24 (br s, 1H, NHCO). Mass (ESI) (M+Na) calcd for C23H25ClN2O4Na 451.15; found 451.04.
Reaction SMILES: [CH2:1]([CH:5]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:6][C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4].[Li]CCCC.[CH3:23][Sn:24](Cl)([CH3:26])[CH3:25]>C1COCC1.CCCCCC>[CH2:1]([CH:5]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:6][C:7]1[S:8][C:9]([Sn:24]([CH3:26])([CH3:25])[CH3:23])=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCC(CCCC)Cc1cccs1
Reactant: C[Sn](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCCC(CCCC)Cc1ccc([Sn](C)(C)C)s1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A solution of 2-(2-butyloctyl)thiophene (1.52 g, 6.02 mmol) in dry THF (30 mL) was cooled to −78° C., and a solution of n-BuLi (2.5 M, 3.6 mL, 9.0 mmol) was then added slowly. This mixture was stirred at −78° C. for additional 10 minutes, and allowed to warm to room temperature and stirred at room temperature for 30 minutes, before it was cooled back to −78° C. again. A solution of trimethylstannyl chloride (1.0 M, 9 mL, 9.0 mmol) was added slowly. This mixture was stirred at −78° C. for 1 hour, and then allowed to warm to room temperature, and stirred at room temperature overnight. The reaction was quenched by water. The resulting reaction mixture was diluted with hexane, washed with water, dried over Na2SO4, and concentrated on a rotary evaporator, leading to a slightly yellow oil (2.48 g, 99.2%), which was directly used in the next step without further purification.
Reaction SMILES: [N:1]1[S:2](=[O:15])(=[O:14])[CH2:3][CH2:4][N:5]2[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([OH:13])=O)[C:6]=12.[CH:16]1([C:19]2[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=2)[CH2:18][CH2:17]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[CH:16]1([C:19]2[CH:25]=[CH:24][C:22]([NH:23][C:11]([C:7]3[C:6]4=[N:1][S:2](=[O:15])(=[O:14])[CH2:3][CH2:4][N:5]4[CH:10]=[CH:9][CH:8]=3)=[O:13])=[CH:21][CH:20]=2)[CH2:18][CH2:17]1
Reactant: Nc1ccc(C2CC2)cc1
Reactant: O=C(O)C1=CC=CN2CCS(=O)(=O)N=C12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(C2CC2)cc1)C1=CC=CN2CCS(=O)(=O)N=C12
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.4 %

Procedure:
3,4-Dihydropyrido[2,1-c][1,2,4]thiadiazine-9-carboxylic acid 2,2-dioxide (150 mg) was dissolved in DMF (5 ml), 4-cyclopropylaniline (131 mg), HOBt (151 mg), EDCI HCl (189 mg) and DIEA (0.23 mL) were added and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was suspended in ethyl acetate, and insoluble crystals were collected by filtration to give the title compound (168 mg) as pale-yellow crystals.