Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][CH:10]([NH:13][CH2:14][CH2:15][CH3:16])[CH2:9][CH2:8]2.I[CH2:18][CH2:19][CH2:20][N:21]1[C:25](=[O:26])[C:24]2[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=2[S:22]1(=[O:32])=[O:31].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][CH:10]([N:13]([CH2:14][CH2:15][CH3:16])[CH2:18][CH2:19][CH2:20][N:21]1[C:25](=[O:26])[C:24]3[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=3[S:22]1(=[O:32])=[O:31])[CH2:9][CH2:8]2
Reactant: O=C1c2ccccc2S(=O)(=O)N1CCCI
Reactant: CCCNC1CCc2cccc(OC)c2C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCCN(CCCN1C(=O)c2ccccc2S1(=O)=O)C1CCc2cccc(OC)c2C1

Procedure:
8-Methoxy-N-propyl-2-aminotetralin (Arvidsson L.-E. et al., J. Med. Chem., 27, 45 (1984) (2 g, 10 mmol), N-(3-iodopropyl)-2,3-dihydro-1,1-dioxo-3-benzisothiazolone (7.5 g), sodium carbonate (2.5 g), and acetonitrile (25 ml) were heated to reflux for 24 hours. After cooling, the solvent was removed in vacuo and the residue placed on a flash silica gel column (3 cm×35 cm) and eluted with ethyl acetate/hexane (5:95, 10:90, 15:85, 20:80, successively). Solvent removal in vacuo afforded the title compound as a white powder (m.p. 131° C.).
Reaction SMILES: C[Si](C)(C)CCOC[N:7]1[C:11]([C:12]2[CH:13]=[CH:14][C:15]([O:18][C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[N:25]=[C:24]([CH:29]=O)[CH:23]=[CH:22]4)=[N:16][CH:17]=2)=[CH:10][CH:9]=[N:8]1.[CH2:33]1[NH:38][CH2:37][CH2:36][N:35]2[C:39](=[O:42])[CH2:40][CH2:41][CH:34]12.N1NC(C2C=CC(OC3C=C4C(=CC=3)N=C(CN3CCC(N5CCOC5=O)CC3)C=C4)=NC=2)=CC=1>>[N:8]1[NH:7][C:11]([C:12]2[CH:13]=[CH:14][C:15]([O:18][C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[N:25]=[C:24]([CH2:29][N:38]3[CH2:37][CH2:36][N:35]5[C:39](=[O:42])[CH2:40][CH2:41][CH:34]5[CH2:33]3)[CH:23]=[CH:22]4)=[N:16][CH:17]=2)=[CH:10][CH:9]=1
Reactant: O=C1CCC2CNCCN12
Reactant: C[Si](C)(C)CCOCn1nccc1-c1ccc(Oc2ccc3nc(C=O)ccc3c2)nc1
Agent: O=C1OCCN1C1CCN(Cc2ccc3cc(Oc4ccc(-c5ccn[nH]5)cn4)ccc3n2)CC1
Product: O=C1CCC2CN(Cc3ccc4cc(Oc5ccc(-c6ccn[nH]6)cn5)ccc4n3)CCN12

Procedure:
The title compound 18 is synthesized from intermediate D (0.100 g, 0.224 mmol) and hexahydro-pyrrolo[1,2-a]pyrazin-6-one (78.5 mg, 0.560 mmol) according to the procedure described for the synthesis of compound 11.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]3[CH:18]=[CH:19][CH:20]=[C:10]3[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:30][C:31]1[C:39]([Cl:40])=[CH:38][CH:37]=[CH:36][C:32]=1[C:33](Cl)=[O:34]>ClCCl>[CH:18]1[N:11]2[C:12]3[C:17]([N:8]([C:6]([C:5]4[CH:4]=[CH:3][C:2]([NH:1][C:33](=[O:34])[C:32]5[CH:36]=[CH:37][CH:38]=[C:39]([Cl:40])[C:31]=5[Cl:30])=[CH:22][CH:21]=4)=[O:7])[CH2:9][C:10]2=[CH:20][CH:19]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3
Reactant: O=C(Cl)c1cccc(Cl)c1Cl
Reactant: Nc1ccc(C(=O)N2Cc3cccn3-c3ccccc32)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(C(=O)N2Cc3cccn3-c3ccccc32)cc1)c1cccc(Cl)c1Cl
Reaction time: 8 h
Yield: 13.3 %

Procedure:
As described for Example 157, 0.47 g of 4,5-dihydro-5-(4-aminobenzoyl)pyrrolo[1,2-a]quinoxaline, 346 μl of triethylamine and 5 ml of dichloromethane are chilled (ice bath) and 0.415 g of 2,3-dichlorobenzoyl chloride in 2 ml of dichloromethane added. After stirring overnight, an additional 346 μl of triethylamine is added and an additional 0.415 g of 2,3-dichlorobenzoyl chloride added. The mixture is stirred for 2 hours, diluted with 50 ml of dichloromethane and the solution washed with 20 ml each of H2O, 2N citric acid, 1M NaHCO3 and brine. The organic layer is dried (Na2SO4) and filtered through a thin pad of hydrous magnesium silicate and the filtrate concentrated to dryness. The residue is chromatographed on thick layer silica gel plates with ethyl acetate-hexane (1:1) as solvent to give 0.100 g of white solid, m.p. 230°-240° C.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]([OH:7])=[O:6])[OH:4].[ClH:8].[CH3:9]O>>[ClH:8].[NH2:1][CH2:2][CH:3]([OH:4])[C:5]([O:7][CH3:9])=[O:6]
Reactant: CO
Reactant: NCC(O)C(=O)O
Agent: Cl
Product: COC(=O)C(O)CN
Yield: 92 %

Procedure:
A suspension of isoserine (18) (20.0 g, 0.19 mol) in anhydrous methanol (100 mL) was saturated with HCl gas at 0° C. while being stirred with exclusion of moisture. The solid material slowly dissolved to yield a pale yellow liquid after a few minutes. The HCl saturated solution was stirred overnight (20 h) at room temperature. Excess HCl gas was removed by bubbling nitrogen into the reaction mixture and the solvent was removed under reduced pressure to yield the product as a syrup (27.1 g; yield 92%) Mass Spectrum M+H 120. The product was immediately taken to the next step without further purification.
Reaction SMILES: [Si]([O:8][C@@H:9]1[CH2:13][C:12](=[O:14])[N:11]([C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([Cl:23])[C:16]=2[CH3:24])[C@H:10]1[CH2:25][CH3:26])(C(C)(C)C)(C)C.CO.Cl.C(=O)([O-])O.[Na+]>O1CCCC1>[Cl:23][C:17]1[C:16]([CH3:24])=[C:15]([N:11]2[C:12](=[O:14])[CH2:13][C@@H:9]([OH:8])[C@@H:10]2[CH2:25][CH3:26])[CH:22]=[CH:21][C:18]=1[C:19]#[N:20]
Reactant: CC[C@H]1[C@H](O[Si](C)(C)C(C)(C)C)CC(=O)N1c1ccc(C#N)c(Cl)c1C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC[C@H]1[C@H](O)CC(=O)N1c1ccc(C#N)c(Cl)c1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 49.3 %

Procedure:
To a solution of 4-[(2S,3R)-3-(tert-butyldimethylsilyloxy)-2-ethyl-5-oxopyrrolidin-1-yl]-2-chloro-3-methylbenzonitrile (650 mg) in tetrahydrofuran (20 mL)-methanol (10 mL) was added 6 mol/L hydrochloric acid (10 mL), and the mixture was stirred at room temperature for 18 hr. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane/ethyl acetate=10/1→1/9) to give the title compound as a colorless solid (yield: 227.1 mg, 49%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]=[O:11])=[O:9])=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH:10]([C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=2)[OH:11])=[O:9])=[CH:6][CH:7]=1
Reactant: O=CC(=O)c1ccc(Br)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: Cc1ccc(C(O)C(=O)c2ccc(Br)cc2)cc1
Reaction time: 5 h

Procedure:
A solution of 67 g. (0.314 mole) of p-bromophenylglyoxal in 300 ml. of dry toluene is added dropwise over 1 1/2 hours to a stirrred suspension of 84 g. (0.6 mole) of anhydrous aluminum chloride in 1.25 1. of dry toluene cooled in an ice-bath. Stirring in the cold is continued for 5 hours and the mixture then is held at 5°-10° C. overnight. The mixture is poured into about 2 1. of ice and 6N hydrochloric acid. The aqueous phase is separated and re-extracted with three portions of benzene. The combined, washed and dried organic extracts are concentrated under reduced pressure to a volume of about 200 ml. Dilution with 150 ml. of petroleum ether precipitates the white crystalline product, m.p. 80°-82° C. Repeated recrystallization from 60% ethanol affords the analytical sample, m.p. 82°-83.5° C.
Reaction SMILES: Cl.[CH:2]1[C:12]2[CH:11]=[CH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[C:7](=[C:17]3[CH2:22][CH2:21][N:20]([C:23](=[O:26])[CH2:24][NH2:25])[CH2:19][CH2:18]3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:27]([O:31][C:32]([N:34]1[CH2:38][CH2:37][CH2:36][C@@H:35]1[C:39](O)=[O:40])=[O:33])([CH3:30])([CH3:29])[CH3:28].Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C.CN(C1C=CC=CN=1)C>ClCCl>[CH:13]1[C:9]2[CH:10]=[CH:11][C:12]3[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=3[C:7](=[C:17]3[CH2:18][CH2:19][N:20]([C:23](=[O:26])[CH2:24][NH:25][C:39]([CH:35]4[CH2:36][CH2:37][CH2:38][N:34]4[C:32]([O:31][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:33])=[O:40])[CH2:21][CH2:22]3)[C:8]=2[CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)O
Reactant: NCC(=O)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCC1C(=O)NCC(=O)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
700 mg (1.91 mmol) of the compound of Example 2, 493 mg (2.29 mmol) of (R)-1-(t-butoxycarbonyl)-2-pyrrolidinecarboxylic acid and 512 mg (2.67 mmol) of 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride were dissolved in 20 ml of dichloromethane. 0.77 ml (5.59 mmol) of triethylamine and 24 mg (0.2 mmol) of dimethylaminopyridine were added to the obtained solution under cooling with ice, and they were stirred at room temperature overnight. The solvent was evaporated under reduced pressure. Ethyl acetate was added to the residue, and they were washed with water. The organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by the silica gel chromatography (hexane:ethyl acetate=9:1 to 1:4) to obtain the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([NH2:13])=[CH:10]2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Na+].[Na+].[I:20]I>O1CCCC1.O>[I:20][C:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2)[CH:7]=[CH:8][C:9]=1[NH2:13]
Reactant: II
Reactant: COc1ccc2ccc(N)cc2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2ccc(N)c(I)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.8 %

Procedure:
To a mixture of 7-methoxynaphthalen-2-amine (5 g, 29 mmol) and sodium carbonate (6.1 g, 57.6 mmol) in tetrahydrofuran (200 ml) and water (20 ml) was added iodine (7.0 g, 27.67 mmol) in portions at 0° C. The resulting solution was stirred overnight at room temperature and then diluted with water (250 ml), extracted with ethyl acetate (3×200 ml). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to give a residue, which was purified by silica gel column chromatography using 5% ethyl acetate in petroleum ether to afford 1-iodo-7-methoxynaphthalen-2-amine as a yellow solid (5.2 g, 60%). (ES, m/z): [M+H]+ 300.1; 1H NMR (300 MHz, CDCl3): δ 7.54 (dd, J=8.7, 5.4 Hz, 2H), 7.30 (d, J=2.4 Hz, 1H), 6.91 (dd, J=8.7, 2.4 Hz, 1H), 6.84 (d, J=8.4 Hz, 1H), 4.04 (br s, 2H), 3.96 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][C:10]1[C:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])=[CH:14][CH:13]=[CH:12][C:11]=1[CH:25](O)[C:26]([OH:28])=[O:27].[S:30](Cl)(Cl)=O.CN(C=O)C.S1C=CC=C1CC(O)=O.CC(C)([O-])C.[K+]>C(Cl)Cl.CCO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][C:10]1[C:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])=[CH:14][CH:13]=[CH:12][C:11]=1[CH:25]([SH:30])[C:26]([OH:28])=[O:27]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C(O)c1cccc(OCc2ccccc2Cl)c1OCc1ccccc1Cl
Agent: CC(C)(C)[O-]
Agent: O=C(O)Cc1cccs1
Agent: [K+]
Solvent: CCO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(O)C(S)c1cccc(OCc2ccccc2Cl)c1OCc1ccccc1Cl
Reaction time: 1 h
Yield: 64 %

Procedure:
To a stirred solution of Example 1 Part B compound (462 mg, 1.00 mmol) in CH2Cl2 (5 mL) under argon at room temperature was added thionyl chloride (80 μL, 1.1 mmol) and then DMF (80 μL, 1.0 mmol) over 2 min. The reaction mixture was stirred for 1 h, then quenched with saturated sodium bicarbonate solution and extracted twice with CH2Cl2. The extracts were combined, dried (MgSO4) and evaporated. The residuum was immediately dissolved in EtOH (5 mL) and added to a solution prepared from thiolacetic acid (0.35 mL, 4.9 mmol) and potassium t-butoxide (539 mg, 4.8 mmol) in EtOH (5 mL). After 16 h, the reaction mixture was quenched with water and extracted three times with EtOAc. The organic extracts were combined, dried (MgSO4) and evaporated. Purification by flash chromatography on silica gel provided the title compound as a colorless oil, 330 mg (64% yield). LC/MS gave the correct molecular ion [(M+H)+=519] for the desired compound.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[N:8]=[C:9]([CH2:11][CH3:12])[NH:10][C:5]2=[C:4]([CH3:13])[CH:3]=1.[H-].[Na+].[Cl:16][C:17]1[CH:35]=[C:34]([CH2:36]O)[CH:33]=[C:32]([CH2:38][CH2:39][CH3:40])[C:18]=1[O:19][CH:20]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=1)[C:21]([O:23][CH3:24])=[O:22]>CN(C=O)C>[C:21]([CH:20]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=1)[O:19][C:18]1[C:32]([CH2:38][CH2:39][CH3:40])=[CH:33][C:34]([CH2:36][N:8]2[C:6]3=[N:7][C:2]([CH3:1])=[CH:3][C:4]([CH3:13])=[C:5]3[N:10]=[C:9]2[CH2:11][CH3:12])=[CH:35][C:17]=1[Cl:16])([O:23][CH3:24])=[O:22]
Reactant: CCc1nc2nc(C)cc(C)c2[nH]1
Reactant: CCCc1cc(CO)cc(Cl)c1OC(C(=O)OC)c1cccc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1cc(Cn2c(CC)nc3c(C)cc(C)nc32)cc(Cl)c1OC(C(=O)OC)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.6 %

Procedure:
To a solution of 0.085 g (0.49 mmol) of 5,7-dimethyl-2-ethylimidazo[4,5-b]pyridine in 1.0 mL anhydrous DMF was added 21.0 mg (0.54 mmol) of a 60% oil dispersion of sodium hydride and the reaction mixture was stirred under a nitrogen atmosphere at room temperature for 1 hour. A solution of 0.250 g (0.56 mmol) of the product of Step C in 0.5 mL of DMF was added and the reaction was stirred an additional 2 hours at room temperature. The reaction mixture was partitioned between EtOAc and water, separated, dried (MgSO4), filtered and evaporated. The residue was purified on a silica gel flash chromatography column eluted with 50% EtOAc-hexane. Evaporation of the purified fractions and drying in vacuo afforded 0.150 g (58%) of the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([S:11]([NH:14][C:15]2[C:16]([Br:22])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)(=[O:13])=[O:12])[CH:7]=[CH:8][C:9]=1[Cl:10])(=[O:3])[CH3:2].[CH3:23][Mg]Br>C1COCC1.C(OCC)C>[Br:22][C:16]1[C:15]([NH:14][S:11]([C:6]2[CH:7]=[CH:8][C:9]([Cl:10])=[C:4]([C:1]([OH:3])([CH3:23])[CH3:2])[CH:5]=2)(=[O:12])=[O:13])=[CH:20][C:19]([Cl:21])=[CH:18][N:17]=1
Reactant: CC(=O)c1cc(S(=O)(=O)Nc2cc(Cl)cnc2Br)ccc1Cl
Reactant: C[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(O)c1cc(S(=O)(=O)Nc2cc(Cl)cnc2Br)ccc1Cl
Temperature: -78 °C

Procedure:
365 mg (0.86 mmol) of 3-acetyl-N-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-benzenesulfonamide was dissolved in 3 mL of anhydrous THF and cooled down under nitrogen atmosphere to −78° C. To that solution 0.86 mL of 3M methylmagnesium bromide solution in diethyl ether was added dropwise. The solution was allowed to warm up to 0° C. and was then quenched with aqueous ammonium chloride and extracted with DCM. The organic layer was evaporated under reduced pressure and purified on silica using 5-40% ethyl acetate in hexanes to yield 288 mg of a white solid. LC-MSD, m/z for C14H13BrCl2N2O3S [M+H]+=438.9, 440.9, 442.9.
Reaction SMILES: [Br:1]Br.[Br-].[K+].[CH2:5]([C:12]1[CH:17]=[CH:16][N:15]=[C:14]([O:18][CH3:19])[CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH-].[K+].S([O-])([O-])=O.[Na+].[Na+]>[Cl-].C([N+](CC)(CC)CC)C.O>[CH2:5]([C:12]1[C:17]([Br:1])=[CH:16][N:15]=[C:14]([O:18][CH3:19])[CH:13]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: COc1cc(Cc2ccccc2)ccn1
Reactant: BrBr
Agent: CC[N+](CC)(CC)CC
Agent: O=S([O-])[O-]
Agent: [Br-]
Solvent: O
Product: COc1cc(Cc2ccccc2)c(Br)cn1

Procedure:
A mixed solution of 22 ml of bromine, 90 g of potassium bromide and 500 ml of water was added dropwise into a mixture of 73 g of 4-benzyl-2-methoxypyridine, 28 g of potassium hydroxide, 1.7 g of tetraethylammonium chloride, 90 g of potassium bromide and 500 ml of water under stirring in an ice bath. After stirring overnight, sodium sulfite was added thereto and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and the solvent was removed. The residue was subjected to silica gel column chromatography using 5-10% ethyl acetate/hexane, to give 62 g of the target compound.
Reaction SMILES: [C:1]1([C:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:8]2[CH:12]=[C:11]([CH2:13][OH:14])[N:10]=[CH:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:27](OC(=O)C)(=[O:29])[CH3:28].CCOC(C)=O>N1C=CC=CC=1>[C:21]1([C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:8]2[CH:12]=[C:11]([CH2:13][O:14][C:27](=[O:29])[CH3:28])[N:10]=[CH:9]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: OCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)OCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reaction time: 48 h

Procedure:
1-Triphenylmethyl-4-(hydroxymethyl)-imidazole (260 mmol) was suspended in 500 mL of pyridine. Acetic anhydride (74 mL, 780 mmol) was added dropwise, and the reaction was stirred for 48 hours during which it became homogeneous. The solution was poured into 2 L of EtOAc, washed with water (3×1 L), 5% aq. HCl soln. (2×1 L), sat. aq. NaHCO3, and brine, then dried (Na2SO4), filtered, and concentrated in vacuo to provide the title product as a white powder which was sufficiently pure for use in the next reaction.
Reaction SMILES: CC(C)=[O:3].[OH:5][N:6]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=[O:16].[CH2:17]=[CH:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>C(N(CC)CC)C>[OH:5][N:6]1[C:7](=[O:16])[C:8]2=[CH:15][CH:14]=[CH:13][CH:12]=[C:9]2[C:10]1=[O:11].[CH2:17]=[CH:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([O-:27])(=[O:3])=[O:26])=[CH:21][CH:20]=1
Reactant: CC(C)=O
Reactant: C=Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C1c2ccccc2C(=O)N1O
Solvent: CCN(CC)CC
Product: C=Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 20 °C

Procedure:
50 ml of acetone was added to 3.3 g of N-hydroxyphthalimide and 4.1 g of p-styrenesulfonyl chloride. 2.0 g of triethylamine was dropwise added to the mixture under stirring at room temperature (about 20° C.). The mixture was stirred at room temperature for additional 1 hr. and poured into 200 g of ice/water. The precipitate thus formed was recrystallized from a solvent mixture of benzene/ethanol to obtain 4.6 g of N-hydroxyphthalimide-p-styrenesulfonate.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C@@H:6]([NH2:8])[CH3:7].[CH:9]1([N:15]2[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.C(N(CC)CC)C.C([BH3-])#N.[Na+]>ClCCl.[Ti](Cl)(Cl)(Cl)Cl.CO>[CH:9]1([N:15]2[CH2:20][CH2:19][CH:18]([NH:8][C@H:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)[CH3:7])[CH2:17][CH2:16]2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: C[C@H](N)c1ccco1
Reactant: O=C1CCN(C2CCCCC2)CC1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](NC1CCN(C2CCCCC2)CC1)c1ccco1
Reaction time: 16 h
Yield: 52.1 %

Procedure:
(1S)-1-(Furan-2-yl)ethanamine (0.55 gr, 5 mmol) and 1-cyclohexylpiperidin-4-one (0.91 gr, 5 mmol) were dissolved in dry dichloromethane (20 mL) in the presence of triethylamine (2 mL, 15 mmol) and titanium(IV) chloride (1M in dichloromethane, 2.5 mmol, 2.5 mL). Reaction mixture was stirred under nitrogen atmosphere for 16 hours. After dilution with methanol (10 mL), sodium cyanoborohydride was added (0.95 gr, 25 mmol) and the resulting reaction mixture was stirred for 4 hours. After dilution with ethyl acetate, the organic phase was washed with 15% ammonium hydroxide and evaporated to dryness. Title compound (0.72 gr, Y=52%) was isolated by column chromatography (dichloromethane/methanol/7N ammonia in methanol 96:2:2)
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][N:21]3[C:24](=[O:40])[N:25]([CH2:27][C:28]4[C:29]([CH2:38][OH:39])=[N:30][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:32][CH:33]=4)[N:26]=[C:20]3[C:19]=2[C:41]2[CH:46]=[CH:45][N:44]=[CH:43][CH:42]=2)=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:23]=[CH:22][N:21]3[C:24](=[O:40])[N:25]([CH2:27][C:28]4[C:29]([CH:38]=[O:39])=[N:30][C:31]([C:34]([F:36])([F:37])[F:35])=[CH:32][CH:33]=4)[N:26]=[C:20]3[C:19]=2[C:41]2[CH:42]=[CH:43][N:44]=[CH:45][CH:46]=2)=[CH:16][CH:17]=1
Reactant: O=c1n(Cc2ccc(C(F)(F)F)nc2CO)nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)ccn12
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=Cc1nc(C(F)(F)F)ccc1Cn1nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)ccn2c1=O
Temperature: -30 °C
Reaction time: 0.25 h
Yield: 70 %

Procedure:
To a stirring solution of oxalyl chloride (12 μL, 0.134 mmol) in CH2Cl2 (0.5 mL) cooled at −30° C. under argon was added anhydrous DMSO (19 μL, 0.268 mmol) over 5 min. After stirring at −30° C. for 15 min, the reaction mixture was cooled at −60° C., then a solution of 7-(4-chlorophenyl)-2-((2-(hydroxymethyl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (36 mg, 0.07 mmol) in CH2Cl2 (1.0 mL) was added over 5 min. After stirring at −60° C. for 30 min, triethylamine (72 μL, 0.54 mmol) was added, the reaction mixture was stirred at −60° C. for 30 min before warming up to room temperature. The mixture was partitioned between water and CH2Cl2. The aqueous layer was extracted with CH2Cl2 (10 mL×2), and the combined CH2Cl2 layers were washed with saturated aqueous NaCl, dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified using a silica gel cartridge (4 g) eluted with a gradient of ethyl acetate (50-100%) in hexanes to afford 25 mg of the title compound as a yellow foam. The product was further purified using preparative reverse phase HPLC (Phenomenex Luna 5 μm C-18 21.2×100 mm column eluted with a linear gradient of 50% to 80% B over 8 min (A=90% water, 10% methanol and B=90% methanol, 10% water) with flow rate at 20 mL/min and UV detection at 220 nm). The desired fractions were concentrated under reduced pressure. The residue was dissolved in acetonitrile, frozen and lyophilized to afford 15 mg of the title compound as a yellow powder. HPLC/MS: retention time=2.76 min, [M+H]+=510.6.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[CH3:16][N:17]1[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=2)[C:18]1=[O:32].C(N(C(C)C)CC)(C)C>>[C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][CH:9]1[CH2:10][CH2:11][N:12]([S:28]([C:25]2[CH:26]=[CH:27][C:22]([N:19]3[CH2:20][CH2:21][N:17]([CH3:16])[C:18]3=[O:32])=[CH:23][CH:24]=2)(=[O:30])=[O:29])[CH2:13][CH2:14]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1CCN(c2ccc(S(=O)(=O)Cl)cc2)C1=O
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2ccc(S(=O)(=O)N3CCC(CNC(=O)OC(C)(C)C)CC3)cc2)C1=O
Yield: 65 %

Procedure:
Prepared according to the procedure used for example 46 (Step A, part 1) from piperidin-4-ylmethyl-carbamic acid t-butyl ester (1.09 g, 5.1 mmol), 4-(3-methyl-2-oxo-imidazolidin-1-yl)-benzenesulfonyl chloride (1.4 g, 5.1 mmol) and 0.89 mL of diisopropylethyl amine to give 1.5 g of the title compound
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[C:13]([CH3:18])[CH:14]=[CH:15][CH:16]=3)[NH:11][N:10]=2)=[CH:5][CH:4]=1.[H-].[Na+].I[CH:22]([CH3:24])[CH3:23]>>[CH:22]([N:10]1[C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[C:17]2[C:12]([C:13]([CH3:18])=[CH:14][CH:15]=[CH:16]2)=[N:11]1)([CH3:24])[CH3:23]
Reactant: CC(C)I
Reactant: COc1ccc(-c2n[nH]c3c(C)cccc23)cc1
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(-c2c3cccc(C)c3nn2C(C)C)cc1
Yield: 7.1 %

Procedure:
Prepared according to Method D step B from 3-(4-methoxyphenyl)-7-methyl-1H-indazole (0.115 g, 0.5 mmol), sodium hydride (60% in oil, 0.024 g, 0.6 mmol) and 2-iodopropane (0.10 mL, 1.0 mmol) to give the title compound (0.01 g) as a white solid.