Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N+:15]([O-])=[CH:14][CH:13]=[CH:12]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(OC(=O)C)(=O)C.[N+:27]([CH:30]([CH3:36])[C:31]([O:33][CH2:34][CH3:35])=[O:32])([O-:29])=[O:28]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([C:30]([N+:27]([O-:29])=[O:28])([CH3:36])[C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:13]=[CH:12]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCOC(=O)C(C)[N+](=O)[O-]
Reactant: CCCCCCCOc1ccc2c(ccc[n+]2[O-])c1
Solvent: CN(C)C=O
Solvent: CC(=O)OC(C)=O
Product: CCCCCCCOc1ccc2nc(C(C)(C(=O)OCC)[N+](=O)[O-])ccc2c1
Temperature: 23 °C
Reaction time: 12 h
Yield: 69.8 %

Procedure:
A solution of 6-Heptyloxy-quinoline 1-oxide (500 mg, 0.002 mol) and acetic anhydride (0.255 mL, 0.00270 mol) in N,N-dimethylformamide (5 mL, 0.06 mol) was added to a solution of ethyl 2-nitropropionate (284 mg, 0.00193 mol) in DMF (2 mL) at at 23° C. dropwise. The reaction mixture was then stirred at 23° C. for 12 hours. The reaction mixture was then heated at 50° C. for 6 hours. Solvent was removed under vacuum, and the residue was treated with Na2CO3 (sat), and DCM. Organic layer was collected, and dried over Na2SO4. The mixture was then purified via chromatography (SiO2, 24 g, ethyl acetate/hexanes 0-35%) to give a pure product 523 mg (70%). 1H NMR (CHLOROFORM-d) δ: 8.09 (d, J=8.5 Hz, 1H), 7.95 (d, J=9.0 Hz, 1H), 7.52 (d, J=8.8 Hz, 1H), 7.39 (dd, J=9.3, 2.5 Hz, 1H), 7.08 (d, J=2.5 Hz, 1H), 4.40 (q, J=7.0 Hz, 2H), 4.09 (t, J=6.5 Hz, 2H), 2.40 (s, 3H), 1.82-1.93 (m, 2H), 1.45-1.56 (m, 2H), 1.26-1.44 (m, 9H), 0.92 (t, J=6.7 Hz, 3H). MS (M+1): 389.30.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.O[CH2:14][C:15]1[S:19][C:18]2=[CH:20][N:21]=[CH:22][N:17]2[C:16]=1[CH3:23].[C:24]1(=[O:34])[NH:28][C:27](=[O:29])[C:26]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:25]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:24]1(=[O:34])[N:28]([CH2:14][C:15]2[S:19][C:18]3=[CH:20][N:21]=[CH:22][N:17]3[C:16]=2[CH3:23])[C:27](=[O:29])[C:26]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:25]12
Reactant: Cc1c(CO)sc2cncn12
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1c(CN2C(=O)c3ccccc3C2=O)sc2cncn12
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 43.6 %

Procedure:
Under an argon atmosphere at room temperature, 0.705 ml of diethyl azodicarboxylate was added dropwise to 10 ml of an anhydrous tetrahydrofuran solution containing 505 mg of 2-hydroxymethyl-3-methylimidazo[5,1-b]thiazole, 662 mg of phthalimide and 1180 mg of triphenylphosphine, and the mixture was then stirred at room temperature for 4.5 hours. The solvent was evaporated under reduced pressure to obtain an oil, and this oil was then purified by a silica gel column chromatograph and successively Cephadex LH-20 to obtain 389.3 mg of 2-phthalimidomethyl-3-methylimidazo[5,1-b]thiazole as a lemon crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]([OH:14])=O)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:15][CH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:26]=[C:27]([NH:31][C:32](=[O:34])[CH3:33])[CH:28]=[CH:29][CH:30]=2)[CH2:21][CH2:20]1>>[C:32]([NH:31][C:27]1[CH:26]=[C:25]([CH:22]2[CH2:23][CH2:24][N:19]([CH2:18][CH2:17][CH2:16][NH:15][C:12]([C:8]3([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[CH2:9][CH2:10][CH2:11]3)=[O:14])[CH2:20][CH2:21]2)[CH:30]=[CH:29][CH:28]=1)(=[O:34])[CH3:33]
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CCC1
Reactant: CC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Product: CC(=O)Nc1cccc(C2CCN(CCCNC(=O)C3(c4ccc(Cl)cc4)CCC3)CC2)c1

Procedure:
Example 74 was prepared from 1-(4-chlorophenyl)cyclo butanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}acetamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.55 (s, 1H), 7.36–7.26 (m, 7H), 6.97 (d, 1H, J=7.2 Hz), 6.50 (brs, 1H), 3.30 (dd, 2H, J=6.0, 12.0 Hz), 2.98–2.95 (m, 2H), 2.87–2.80 (m, 2H), 2.53–2.42 (m, 3H), 2.34 (t, 2H, J=6.4 Hz), 2.20 (s, 3H), 2.15–1.82 (m, 6H), 1.74–0.161 (m, 4H); ESMS m/e: 468.2 (M+H)+.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[CH3:14][C:15]1[N:16]([CH3:28])[N:17]=[C:18]2[C:23]=1[C:22]1[C:24](=O)[CH2:25][CH2:26][C:21]=1[CH:20]=[CH:19]2>O1CCCC1.C(=O)([O-])O.[Na+]>[CH3:14][C:15]1[N:16]([CH3:28])[N:17]=[C:18]2[C:23]=1[C:22]1[C:24](=[CH:5][C:3]#[N:4])[CH2:25][CH2:26][C:21]=1[CH:20]=[CH:19]2
Reactant: Cc1c2c3c(ccc2nn1C)CCC3=O
Reactant: CCOP(=O)(CC#N)OCC
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c2c3c(ccc2nn1C)CCC3=CC#N
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 45.2 %

Procedure:
To a suspension of 60% sodium hydride (58.1 mg, 1.45 mmol) in tetrahydrofuran (4 mL) was added diethyl cyanomethylphosphonate (255 μL, 1.58 mmol), and the mixture was stirred at room temperature for 15 min. A solution of 1,2-dimethyl-6,7-dihydrocyclopenta[e]indazol-8(2H)-one (243 mg, 1.21 mmol) in tetrahydrofuran (8 mL) was added thereto, and the mixture was stirred at 60° C. for 24 hr. The reaction solution was diluted with saturated aqueous sodium hydrogen carbonate solution, extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=30/70→80/20) to give the title compound (122 mg) as a mixture with 1,2-dimethyl-6,7-dihydrocyclopenta[e]indazol-8(2H)-one. The obtained title compound was used for the reaction of Reference Example 28 without purification.
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][N:4]([CH3:9])[C:3]=1[CH3:10].[C:11]1([S:17](Cl)(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>N1C=CC=CC=1>[C:11]1([S:17]([O:1][C:2]2[C:7](=[O:8])[CH:6]=[CH:5][N:4]([CH3:9])[C:3]=2[CH3:10])(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1c(O)c(=O)ccn1C
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Product: Cc1c(OS(=O)(=O)c2ccccc2)c(=O)ccn1C
Yield: 43 %

Procedure:
3-Hydroxy-1,2-dimethylpyridin-4(1H)-one (0.5 g, 3.6 mmol) was reacted with benzenesulfonyl chloride (0.51 mL, 4.0 mmol) in 40 mL of pyridine to afford PZBG-3a in 43% yield (0.43 g, 1.5 mmol). 1H NMR (500 MHz, CDCl3) δ=8.19 (d, J=6.9 Hz, 2H), 7.66 (t, J=7.5 Hz, 1H), 7.57 (t, J=7.5 Hz, 2H), 7.23 (d, J=8 Hz, 1H), 6.34 (d, J=8.1 Hz, 1H), 3.63 (s, 3H, NCH3), 2.49 (s, 3H, CH3). 13C NMR (100 MHz, CDCl3) δ=171.3, 144.8, 140.7, 139.9, 137.3, 134.3, 129.0, 128.9, 118.3, 41.8, 14.7. ESI-MS(+): m/z 280.09 [M+H]+.
Reaction SMILES: C(OC(=O)NC1CC(=O)OC1OC1CCCC1)C=C.NC1C=CC(C(NC(C)C(N2CCCC2C(O)=O)=O)=O)=CC=1Cl.[O:43]=[C:44]1[O:48][CH:47]([O:49][CH2:50][CH2:51][C:52]2C=CC=[CH:54][CH:53]=2)[CH:46]([NH:58][C:59]([CH:61]2[CH2:65][CH2:64][CH2:63][N:62]2[C:66](=[O:80])[CH:67]([NH:69][C:70](=[O:79])[C:71]2[CH:76]=[CH:75][C:74]([NH2:77])=[C:73]([Cl:78])[CH:72]=2)[CH3:68])=[O:60])[CH2:45]1>>[CH:50]1([O:49][CH:47]2[CH:46]([NH:58][C:59]([CH:61]3[CH2:65][CH2:64][CH2:63][N:62]3[C:66](=[O:80])[CH:67]([NH:69][C:70](=[O:79])[C:71]3[CH:76]=[CH:75][C:74]([NH2:77])=[C:73]([Cl:78])[CH:72]=3)[CH3:68])=[O:60])[CH2:45][C:44](=[O:43])[O:48]2)[CH2:51][CH2:52][CH2:53][CH2:54]1
Reactant: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCCc1ccccc1
Agent: C=CCOC(=O)NC1CC(=O)OC1OC1CCCC1
Agent: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)O
Product: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OC1CCCC1
Yield: 51 %

Procedure:
Prepared from (2-cyclopentyloxy-5-oxo-tetrahydro-furan-3-yl)-carbamic acid allyl ester and 97a following the method used for 98a to give the title compound (280 mg, 51% yield). 1H-NMR (500 MHz, CD3OD) δ 1.38 (d, 0.5H), 1.44 (d, 2.5H), 1.49-2.35 (m, 12H), 2.47 (dd, 0.7H), 2.56 (dd, 0.3H), 2.75 (dd, 0.3H), 2.81-2.88 (m, 0.1H), 2.97 (dd, 0.6H), 3.47-3.76 (m, 0.2H), 3.82-3.96 (m, 1H), 4.10-4.40 (m, 2H), 4.40-4.46 (m, 1H), 5.44 (d, 0.5H), 5.50 (d, 0.2H), 5.65 (d, 0.3H), 6.79 (d, 1H), 7.54-7.64 (m, 1H), 7.78 (d, 1H), 8.21-8.31 (m, 1H). Analytical HPLC 15.02, 15.34 min. LC-MS (ES+) m/e=507.3 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:29])[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:17]1=[O:30])(=[O:14])=[O:13])[CH:6]=[CH:5]2.[CH3:31][Si]([N-][Si](C)(C)C)(C)C.[Li+].S(C1C=CC(C)=CC=1)(OC)(=O)=O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]([CH3:31])[C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:29])[C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[C:17]1=[O:30])(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: C[C@@H](C(=O)OC(C)(C)C)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: COS(=O)(=O)c1ccc(C)cc1
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@H](C(=O)OC(C)(C)C)N1CC[C@H](N(C)S(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Reaction time: 16 h

Procedure:
A solution of tert-butyl (2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoate (0.1 g) in THF (5 ml) was cooled to −78° C. under nitrogen, and treated with lithium bis(trimethylsilyl) amide (1.0M solution in THF; 0.23 ml), followed by methyl tosylate (0.206 g). The resultant solution was allowed to reach room temperature and stirred for a further 16 h. The mixture was quenched with sodium acetate (0.074 g), stirred for 1 h and partitioned between water and ethyl acetate. The separated organic layer was washed with water, dried (over magnesium sulphate), and concentrated under reduced pressure. The residue was purified using SPE (silica, eluting with cyclohexane:ethyl acetate 10:1, 8:1, 5:1, 3:1, 2:1,1:1) to give the title compound (0.101 g) as a colourless gum.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[Br:13]Br>Cl>[Br:13][C:5]1[CH:6]=[N:1][C:2]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[N:3][CH:4]=1
Reactant: BrBr
Reactant: c1cnc(N2CCNCC2)nc1
Agent: Cl
Product: Brc1cnc(N2CCNCC2)nc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 59.6 %

Procedure:
To an ice-cooled solution of 1-(2-pyrimidinyl) piperazine (16.4 g, 0.1 mole) in 1N HCl (100 mL) was added dropwise bromine (15.98 g, 0.1 mole). After stirring at 0° for 0.5 h. the mixture was heated to 100° C. until dissipation of the red color had occurred. The mixture was filtered, cooled, made alkaline with 50% NaOH and extracted with Et2O. The dried extract (MgSO4) was concentrated in vacuo to provide 14.5 g (62%) of product, m.p. 73°-75° C.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH:8]([N+:12]([O-:14])=[O:13])[N+:9]([O-:11])=[O:10])(=[O:3])[CH3:2].[N-:15]=[N+:16]=[N-:17].[Na+].[OH-].[Na+]>>[C:1]([O:4][CH2:5][CH2:6][CH2:7][C:8]([N:15]=[N+:16]=[N-:17])([N+:12]([O-:14])=[O:13])[N+:9]([O-:11])=[O:10])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCCC([N+](=O)[O-])[N+](=O)[O-]
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)OCCCC(N=[N+]=[N-])([N+](=O)[O-])[N+](=O)[O-]
Reaction time: 5.25 h

Procedure:
A divided electrochemical H-cell was charged with 4,4-dinitro-1-butyl acetate (10.2 g), 30% aqueous NaN3 (25 ml) and 12N NaOH (4 ml) in the anode compartment and 30% NaN3 (35 ml) in the cathode compartment. This solution was electrolyzed at 650 mA using a platimum foil anode (6.5 cm2) and a stainless steel cathode. After 5.25 h the reaction was stopped, and the anolyte was extracted with CH2Cl2 (3×25 ml). Brine-washing, drying, and concentrating the extracts yielded a product which displayed a weak hydroxyl absorption in the infrared spectrum. The product was reacetylated by stirring with acetyl chloride (1 ml) in CH2Cl2 (30 ml) for 2 h. This reaction was quenched in ice water, dried, and concentrated. The crude yellow oil was purified by column chromatography on silica gel eluting with 10% ethyl acetate in hexanes. The purified product was a clear light yellow oil which was greater than 95 % pure by HPLC: nD =1.4649 (25C); IR: 2165, 1735, and 1590 cm-1 ; NMR (CDCl3): 4.07 (q, 2H), 2.58 (m, 2H), 2.07 (s, 3H), 1.73 (m, 2H). Elemental analyses calcluated for C6H9N5O6 : C, 29.15; H, 3.64; N, 28.34. Found: C, 29.59; H, 3.90; N, 27.89.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)=[CH:3][CH:2]=1.[N:17]1([C:23]2[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>>[N:17]1([C:23]2[CH:30]=[CH:29][C:26]([CH:27]=[C:9]3[C:8]4[C:12](=[CH:13][CH:14]=[CH:15][C:7]=4[C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)[NH:11][C:10]3=[O:16])=[CH:25][CH:24]=2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: O=C1Cc2c(cccc2-c2ccncc2)N1
Reactant: O=Cc1ccc(N2CCOCC2)cc1
Product: O=C1Nc2cccc(-c3ccncc3)c2C1=Cc1ccc(N2CCOCC2)cc1

Procedure:
4-Pyridin-4-yl-1,3-dihydroindol-2-one was condensed with 4-morpholin-4-yl-benzaldehyde to give the title compound.
Reaction SMILES: C[CH2:2][N:3]=[C:4]=NCCCN(C)C.Cl.CNC.C1COCC1.[I:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](O)=[O:26]>O>[I:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25]([N:3]([CH3:4])[CH3:2])=[O:26]
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1cccc(I)c1
Agent: CNC
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(=O)c1cccc(I)c1
Reaction time: 18 h

Procedure:
EDCl (1.3 g, 6.6 mmol) was added to a solution of dimethylamine in THF (2 M, 6 mL, 10 mmol) and 3-iodobenzoic acid (1.5 g, 6 mmol). After 18 h stirring the reaction was transferred into water, and then extracted with ethyl acetate. The organic phase was dried over sodium sulfate. The solvent was evaporated to afford the product as a viscous, clear oil. The product was used in the next reaction step without further purification. MS m/z: 276 [M+H].
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:18][C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=1)[C:22]([O:24][CH3:25])=[O:23]>CN(C)C=O.O>[Cl:1][C:2]1[C:3]2[N:10]([CH2:18][C:19]3[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=3)[C:22]([O:24][CH3:25])=[O:23])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: Clc1ncnc2cc[nH]c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc(Cn2ccc3ncnc(Cl)c32)c1
Temperature: 25 °C
Yield: 54.1 %

Procedure:
To a suspension of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (300 mg) in N,N-dimethylformamide (2.0 mL) was added cesium carbonate (955 mg) under ice-cooling, and the mixture was stirred while warming to room temperature for 15 min. To the reaction mixture was added methyl 3-(bromomethyl)benzoate (671 mg), and the mixture was stirred at room temperature for 4 hrs. The reaction mixture was diluted with water (40 mL), and extracted with a mixed solvent (40 mL×3) of ethyl acetate/tetrahydrofuran (1/1). The organic layer washed with saturated brine (120 mL×3) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (silica gel, eluent:hexane/ethyl acetate=80/20→10/90). The object fraction was concentrated under reduced pressure. Chloroform/diisopropyl ether (4/1) was added to the residue, and the resultant precipitate was collected by filtration, washed and dried under reduced pressure to give the title compound (319 mg) as a pale-brown powder.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([OH:10])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.N1C=CN=C1.[C:16]([Si:20](Cl)([CH3:22])[CH3:21])([CH3:19])([CH3:18])[CH3:17]>ClCCl>[Si:20]([O:10][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][N:2]=[CH:3]2)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:22])[CH3:21]
Reactant: Oc1ccc2[nH]ncc2c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 0.1 %

Procedure:
To a stirred solution of 1H-indazol-5-ol (5.0 g, 37.3 mol) and imidazole (12.7 g, 186.5 mmol) in dichloromethane (200 mL) was added tert-butylchlorodimethylsilane (16.8 g, 112 mol) and the mixture stirred at room temperature overnight. Then the reaction mixture was washed with brine (3×50 mL) and dried over Na2SO4. The crude mixture was purified by column chromatography (silica gel, 200-300 mesh, EtOAc:petroleum ether=1:10, v/v) to give 5-(tert-Butyldimethylsilyloxy)-1H-indazole (9.5 g, yield 100%) as yellow oil. MS: (M+H)+=249.2; 1H NMR (300 MHz, CDCl3): δ 7.95 (d, 1H, J=1.2 Hz), 7.34 (dt, 1H, J=8.7, 0.75 Hz), 7.12 (s, 1H), 6.97 (dd, 1H, J=8.7, 2.1 Hz), 1.01 (s, 9H), 0.23 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:32]([NH:34][CH:35]2[CH2:40][CH2:39][CH2:38][NH:37][CH2:36]2)=[O:33])=[CH:4][N:3]=1.[CH3:41][S:42](Cl)(=[O:44])=[O:43].C(N(CC)C(C)C)(C)C.C(=O)(O)[O-].[Na+]>ClCCl>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:32]([NH:34][CH:35]2[CH2:40][CH2:39][CH2:38][N:37]([S:42]([CH3:41])(=[O:44])=[O:43])[CH2:36]2)=[O:33])=[CH:4][N:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(-c2csc3c(C(=O)NC4CCCNC4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(-c2csc3c(C(=O)NC4CCCN(S(C)(=O)=O)C4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-amino-3-(3-methoxy-4-{[(1-methyl-1H-indol-2-yl)carbonyl]amino}phenyl)-N-piperidin-3-ylthieno[3,2-c]pyridine-7-carboxamide (150 mg, 0.270 mmol), methanesulfonyl chloride (26 μL, 0.32 mmol) and N,N-diisopropylethyl amine (0.15 mL, 0.81 mmol) in dichloromethane (5 mL) was stirred at room temperature for 2 hours. Saturated sodium bicarbonate (2 mL) was added. The layers were separated and the organic solvent was removed. The residue was purified by flash column chromatography on silica using dichloromethane/methanol/ammonium hydroxide (28–30% solution) (90:10:0.05) mixture as the mobile phase to give the title compound. 1H NMR (DMSO, d6) δ 1.58 (m, 2H), 1.91 (m, 2H), 2.58 (m, 1H), 2.71 (m, 1H), 3.50(m, 1H), 3.73 (m, 1H), 3.91 (s, 3H), 3.99 (m 1H), 4.04 (m, 3H), 7.07 (d, 1H), 7.15 (t, 1H), 7.19 (s, 1H), 7.33 (t, 1H), 7.35 (s, 1H), 7.58 (m, 2H), 7.71 (d, 1H), 7.99 (d, 1H), 8.34 (d, 1H), 8.61 (s, 1H), 9.50 (s, 1H). LCMS (Conditions a) Rt=3.22 min., 633.0 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].[NH2:12][C:13]1[CH:14]=[C:15]([CH:19]2[CH2:28][C:27]([CH3:30])([CH3:29])[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:31]#[N:32])[CH:25]=3)[NH:20]2)[CH:16]=[CH:17][CH:18]=1.N1C=CC=CC=1>ClCCl>[C:31]([C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]([C:15]1[CH:14]=[C:13]([NH:12][S:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])(=[O:10])=[O:9])[CH:18]=[CH:17][CH:16]=1)[CH2:28][C:27]2([CH3:30])[CH3:29])#[N:32]
Reactant: O=S(=O)(Cl)c1ccccc1F
Reactant: CC1(C)CC(c2cccc(N)c2)Nc2ccc(C#N)cc21
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C)CC(c2cccc(NS(=O)(=O)c3ccccc3F)c2)Nc2ccc(C#N)cc21
Reaction time: 8 h
Yield: 42.5 %

Procedure:
To a round bottom flask, 2-fluoro-benzenesulfonyl chloride (116 mg, 0.59 mmol) was added dropwise a mixture of 2-(3-amino-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonitrile (150 mg, 0.54 mmol) and pyridine (65 mg, 0.81 mmol) in dichloromethane (5 mL). The resultant mixture was allowed to stir overnight. The reaction mixture was washed by water, dried over magnesium sulfate. It was filtered and concentrated to provide the crude product. It was purified by column chromatography (silica gel, petroleum ether:ethyl acetate=5:1) to afford N-[3-(6-cyano-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-2-fluoro-benzenesulfonamide as off-white solid (100 mg, yield: 42.4%). MS (ESI+APCI) M+1=436.1.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].Br.Br[CH:7]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)=O.C(N(CC)CC)C>C(#N)C>[NH2:1][C:2]1[S:3][C:7]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)[N:4]=1
Reactant: COc1ccc(C(=O)C(Br)c2cccnc2)cc1
Reactant: NC(N)=S
Agent: Br
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(-c2nc(N)sc2-c2cccnc2)cc1
Yield: 82 %

Procedure:
In 40 ml of acetonitrile was dissolved 516 mg of thiourea. In the solution was suspended 2.5 g of 2-bromo-1-(4-methoxyphenyl)-2-(3-pyridyl)-ethanone hydrobromide. To the suspension was added dropwise slowly 0.95 ml of triethylamine while stirring. The mixture was stirred for 3 hours at a refluxing temperature, which was then left standing for cooling. Precipitating crystals were collected by filtration. The crystals were washed with an aqueous solution of saturated hydrogen carbonate, water, ethanol and ethylether in that order, followed by drying. The crystals were recrystallised from tetrahydrofuran to yield 1.5 g (90%) of 2-amino-4-(4-methoxyphenyl)-5-(3-pyridyl)-1,3-thiazol, m.p. 265°-266° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:19](O)=[O:20])[C:5](=[O:18])[NH:6][C:7]=1[C:8]([F:17])([F:16])[C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:34]([NH:36][CH2:37][CH3:38])[CH3:35]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:19]([N:36]([CH2:37][CH3:38])[CH2:34][CH3:35])=[O:20])[C:5](=[O:18])[NH:6][C:7]=1[C:8]([F:16])([F:17])[C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11]
Reactant: O=C(O)c1cc(Cl)c(C(F)(F)C(F)(F)C(F)(F)F)[nH]c1=O
Reactant: CCNCC
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1cc(Cl)c(C(F)(F)C(F)(F)C(F)(F)F)[nH]c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
After dissolution of 355 mg (1.04 mmol) of 5-chloro-6-(heptafluoropropyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid in 30 ml tetrahydrofuran and addition of 337 mg (2.08 mmol) of N,N-carbonyldiimidazole, the mixture was stirred initially at room temperature for 30 min and then under reflux for 30 min. 152 mg (0.22 ml, 2.08 mmol) of diethylamine were then added, and the mixture was heated under reflux for a further 2 h. The solution was evaporated to dryness and then taken up in dichloromethane, washed with 1N hydrochloric acid and water, dried and concentrated. This gave 300 mg (72% of theory) of the product.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.[C:25]([C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)#[N:26]>C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+].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>[NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:29]4[CH:28]=[C:27]([CH:32]=[CH:31][CH:30]=4)[C:25]#[N:26])[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1
Reactant: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(Br)cc32)N=C1N
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(-c4cccc(C#N)c4)cc32)N=C1N
Yield: 29.2 %

Procedure:
Pd(PPh3)4 (60 mg, 0.052 mmol) in a 100 mL flask under Ar was treated sequentially with 2′-amino-6-bromo-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (100 mg, 0.26 mmol) in toluene (15.6 mL), Na2CO3 (2 N, 7.8 mL), and 4-cyanophenylboronic acid (76.5 mg, 0.52 mmol). The mixture was refluxed under Ar for 3-5 h. The reaction mixture was concentrated in vacuo to give a residue, which was purified by preparative TLC followed by preparative HPLC to give pure 3-(2′-amino-1′-methyl-5′-oxo-2-phenyl-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)benzonitrile (31 mg, 29%) as a racemic product. 1H-NMR (CDCl3): 2.18 (m, 1H), 2.29 (t, 1H), 3.13 (s, 3H), 5.90 (d, 1H), 7.05 (d, 1H), 7.25 (m, 1H), 7.34 (m, 1H), 7.38 (m, 2H), 7.45 (m, 2H), 7.50-7.64 (m, 3H), 7.82-7.87 (m, 2H).