Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)=[CH:7][CH:6]=[CH:5][C:4]=1[N+:16]([O-])=O.O.NN>[Ni].C(O)C>[CH3:1][O:2][C:3]1[C:8]([N:9]2[CH2:10][CH2:11][N:12]([CH3:15])[CH2:13][CH2:14]2)=[CH:7][CH:6]=[CH:5][C:4]=1[NH2:16]
Reactant: COc1c(N2CCN(C)CC2)cccc1[N+](=O)[O-]
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: O
Product: COc1c(N)cccc1N1CCN(C)CC1
Yield: 67 %

Procedure:
Compound 54A is prepared according to the procedure described for compound 33C, using the following reactants: 2-methoxy-3-(4-methylpiperazin-1-yl)-1-nitrobenzene (3.6 g); hydrazine hydrate (4 ml); ethanol (50 ml); Raney nickel (one spatula-ful). The crude product is purified by flash chromatography with a mixture (90/9/1) of dichloromethane/methanol/aqueous ammonia).
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[N:15][C:14]2[C:9]1=[N:10][C:11]([Cl:18])=[N:12][C:13]=2N)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:19].C(N1C=NC2C1=NC(OCCC)=NC=2N)C1C=CC=CC=1>C(O)CC>[CH2:1]([N:8]1[CH:16]=[N:15][C:14]2[C:9]1=[N:10][C:11]([Cl:18])=[N:12][C:13]=2[Cl:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1ccccc1
Reactant: Cl
Agent: CCCOc1nc(N)c2ncn(Cc3ccccc3)c2n1
Solvent: CCCO
Product: Clc1nc(Cl)c2ncn(Cc3ccccc3)c2n1

Procedure:
A mixture of 9-benzyl-2-chloro-9H-adenine (130 mg., 0.5 mmole) and 1.25 ml. of 1 N sodium n-propoxide in n-propanol in 13 ml. of n-propanol is refluxed overnight, neutralized with hydrochloric acid and evaporated in vacuo. Trituration of residual material with water provides 118 mg. of crude product which crystallized from aqueous ethanol affords 90 mg. (64%) of analytically pure 9-benzyl-2-n-propoxy-9H-adenine, m.p. 178°-180° C. (dec.). IR(KBr): 3280, 3130, 2970, 1660, 1595, 1405, 1350, 1330, 1275 cm-1. UV:λmaxEtOH 254 nm(ε8,800), 269.5 nm(ε12,800). NMR(CDCl3):δ1.02(3H,t,J=7 Hz), 1.6-2.1(2H,m), 4.25(2H,t,J=7 Hz), 5.20(2H,s), 6.00(2H,br.s), 7.23(5H,m), 7.50(1H,s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[S:15][C:16]1[S:20][C:19]([NH2:21])=[CH:18][CH:17]=1.N1C=CC=CC=1.Cl[C:29]([O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:30].C(OCC)(=O)C>O1CCCC1.CN(C)C=O.O>[C:32]1([O:31][C:29](=[O:30])[NH:21][C:19]2[S:20][C:16]([S:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:17][CH:18]=2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: COc1cc2nccc(Sc3ccc(N)s3)c2cc1OC
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc2nccc(Sc3ccc(NC(=O)Oc4ccccc4)s3)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
After dissolving 5-(6,7-dimethoxyquinolin-4-ylsulfanyl)thiophen-2-ylamine (696 mg, 2.00 mmol) and pyridine (174 mg, 2.20 mmol) in a tetrahydrofuran (10 ml)-dimethylformamide (5 ml) mixed solvent, phenyl chloroformate (329 mg, 2.10 mmol) was added while cooling on ice, and the mixture was stirred at room temperature for 1 hour. The reaction solution was distributed between ethyl acetate and water, the organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate, the drying agent was filtered off and the filtrate was distilled off under reduced pressure. After adding ethyl acetate and then hexane to the obtained crude product, the precipitated crystals were filtered out and blow-dried to obtain the title compound (720 mg, 1.64 mmol, 82%) as yellowish-brown crystals.
Reaction SMILES: [CH2:1]([C:4]1[C:13]([O:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[C:25]([O:27][CH3:28])=[O:26])[CH:2]=[CH2:3]>C(Cl)Cl.C(#N)C.[Pd](Cl)Cl>[CH3:24][S:21]([C:18]1[CH:17]=[CH:16][C:15]([O:14][C:13]2[C:4]([CH:1]=[CH:2][CH3:3])=[C:5]([C:25]([O:27][CH3:28])=[O:26])[CH:6]=[C:7]([CH:12]=2)[C:8]([O:10][CH3:11])=[O:9])=[CH:20][CH:19]=1)(=[O:22])=[O:23]
Reactant: C=CCc1c(Oc2ccc(S(C)(=O)=O)cc2)cc(C(=O)OC)cc1C(=O)OC
Agent: Cl[Pd]Cl
Solvent: ClCCl
Solvent: CC#N
Product: CC=Cc1c(Oc2ccc(S(C)(=O)=O)cc2)cc(C(=O)OC)cc1C(=O)OC
Yield: 74.3 %

Procedure:
To a solution of dimethyl 4-allyl-5-(4-(methylsulfonyl)phenoxy)isophthalate (3.0 g, 8.814 mmol) in CH2Cl2 (25 mL) was added bis(acetonitrile-palladium(II) chloride (229 mg, 0.881 mmol). The mixture was refluxed under N2 for 14 hours. After removal of the solvent, the crude material was introduced into a silica gel column and eluted with EtOAc in hexanes (10/90 to 30/70) to afford the title compound (2.65 g, 88%) as a white solid. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.82 (dd, J=6.69, 1.79 Hz, 3 H) 3.04-3.18 (m, 3 H) 3.93 (d, 6 H) 6.00 (none, 1 H) 6.22 (dd, J=16.01, 6.78 Hz, 1 H) 6.62 (dd, J=16.01, 1.70 Hz, 1 H) 6.94-7.09 (m, 2 H) 7.77 (d, J=1.70 Hz, 1 H) 7.85-8.00 (m, 2 H) 8.28 (d, J=1.70 Hz, 1 H); LC-MS (ESI)+m/z 405.00 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)=[CH:10][C:3]=12.Br[C:30]1[C:31]([C:37]2[CH:42]=[CH:41][C:40]([NH:43][C:44](=[O:48])[N:45]([CH3:47])[CH3:46])=[CH:39][CH:38]=2)=[N:32][N:33]([CH2:35][CH3:36])[CH:34]=1>>[CH3:18][N:17]([CH3:19])[C:14]1[CH:13]=[CH:12][C:11]([C:9]2[N:8]([S:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)(=[O:21])=[O:22])[C:4]3=[N:5][CH:6]=[CH:7][C:2]([C:30]4[C:31]([C:37]5[CH:42]=[CH:41][C:40]([NH:43][C:44](=[O:48])[N:45]([CH3:47])[CH3:46])=[CH:39][CH:38]=5)=[N:32][N:33]([CH2:35][CH3:36])[CH:34]=4)=[C:3]3[CH:10]=2)=[CH:16][CH:15]=1
Reactant: CCn1cc(Br)c(-c2ccc(NC(=O)N(C)C)cc2)n1
Reactant: CN(C)c1ccc(-c2cc3c(Br)ccnc3n2S(=O)(=O)c2ccccc2)cc1
Product: CCn1cc(-c2ccnc3c2cc(-c2ccc(N(C)C)cc2)n3S(=O)(=O)c2ccccc2)c(-c2ccc(NC(=O)N(C)C)cc2)n1

Procedure:
Following the procedure described for Intermediate 32 with {4-[4-bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]phenyl}dimethylamine. Using this product crude and following the procedure described in Intermediate 100 using N′-[4-(4-bromo-1-ethyl-1H-pyrazol-3-yl)phenyl]-N,N-dimethylurea provided the title product. ESMS [M+H]+: 634.6
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.Cl[C:12]1[N:17]=[CH:16][C:15]([CH2:18][CH3:19])=[CH:14][N:13]=1.CN(C)C=O.O1CCOCC1>C(N(CC)CC)C>[CH2:18]([C:15]1[CH:14]=[N:13][C:12]([N:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)=[N:17][CH:16]=1)[CH3:19]
Reactant: C1CC2(CCN1)OCCO2
Reactant: CCc1cnc(Cl)nc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CCc1cnc(N2CCC3(CC2)OCCO3)nc1
Reaction time: 22 h

Procedure:
1,4-Dioxa-8-azaspiro[4.5]decane (1.76 g), 2-chloro-5-ethylpyrimidine (1.7 g), N,N-dimethylformamide (50 mL), 1,4-dioxane (75 mL) and triethylamine (5.07 ml) are heated in a sealed vessel at 120° C. with stirring for 22 h. After cooling the mixture is concentrated and partitioned between ethyl acetate (100 mL) and water (100 mL). The water layer is extracted with ethyl acetate (100 mL) and the combined ethyl acetate layers are dried over Na2SO4, filtered and concentrated to give the title compound. LC (method 20): tR=1.73 min; Mass spectrum (APCI): m/z=250 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[C:13]([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[C:24](=[O:28])[O:23][CH2:22]3)[C:4]=1[O:5][CH2:6][C:7]([CH3:12])([CH3:11])[C:8]([OH:10])=O.Cl.C[N:31](C)[CH2:32][CH2:33][CH2:34]N=C=NCC.C(N(CC)CC)C.O.ON1C2C=CC=CC=2N=N1.C(N)CC>ClCCl.O>[CH3:1][O:2][C:3]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[C:13]([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[C:24](=[O:28])[O:23][CH2:22]3)[C:4]=1[O:5][CH2:6][C:7]([CH3:11])([CH3:12])[C:8]([NH:31][CH2:32][CH2:33][CH3:34])=[O:10]
Reactant: COc1ccc(-c2ccc3c(c2)COC3=O)c(OCC(C)(C)C(=O)O)c1OC
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCNC(=O)C(C)(C)COc1c(-c2ccc3c(c2)COC3=O)ccc(OC)c1OC
Reaction time: 0.17 h
Yield: 37.4 %

Procedure:
To a stirring solution of 3-(2,3-dimethoxy-6-(1-oxo-1,3-dihydroisobenzofuran-5-yl)phenoxy)-2,2-dimethylpropanoic acid (100 mg, 0.25 mmol) in dichloromethane (10 mL) was added 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC.HCl) (71.6 mg, 0.375 mmol), triethylamine (0.1 mL, 0.75 mmol) and 1-hydroxybenzotriazole hydrate (HOBT) (76.5 mg, 0.50 mmol) and stirred for 10 min. To this propylamine (59 mg, 1.0 mmol) was added and the resultant reaction mixture was stirred at RT for 16 h. The reaction mixture was diluted with water and extracted with dichloromethane (3×). The combined dichloromethane layers were washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. Purification of the residue by column chromatography (silica gel, 0-40% ethyl acetate in pet ether) afforded the title compound as a solid (40 mg, 36%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[H-].[Na+].Cl[C:12]1[C:21]2[C:16](=[CH:17][C:18]([F:23])=[CH:19][C:20]=2[F:22])[N:15]=[C:14]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[C:13]=1[CH3:30].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[Br:8][C:6]1[CH:7]=[C:2]([NH:1][C:12]2[C:21]3[C:16](=[CH:17][C:18]([F:23])=[CH:19][C:20]=3[F:22])[N:15]=[C:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[C:13]=2[CH3:30])[CH:3]=[N:4][CH:5]=1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Cl
Reactant: Nc1cncc(Br)c1
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Nc1cncc(Br)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A dry flask containing 3-amino-5-bromopyridine (0.13 g, 0.78 mmol) in dry DMF (5.0 mL) was cooled to 0° C., then sodium hydride, 60% dispersion in mineral oil (63.6 mg, 1.59 mmol) was added carefully in portions. The mixture was stirred at 0° C. for 15 min, then 4-chloro-5,7-difluoro-3-methyl-2-(2-pyridinyl)quinoline (0.25 g, 0.86 mmol) was added in portions. Upon complete addition, the mixture was warmed to 60° C. After 18 h, the reaction was cooled to rt then was carefully treated with 10% sodium carbonate solution. The black mixture was subsequently extracted five times with DCM:MeOH (90:10). The organic extraction was then washed one time with brine and dried over anhydrous magnesium sulfate. After filtration and concentration, the black residue was treated with MeOH and warmed to 45° C. After 30 min, the solid was filtered and rinsed twice with MeOH to afford a tan solid as mostly N-(5-bromo-3-pyridinyl)-5,7-difluoro-3-methyl-2-(2-pyridinyl)-4-quinolinamine.
Reaction SMILES: [F:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[S:7][CH2:8][C:9](=[O:11])[N:10]=1.[CH3:12][S:13](Cl)(=[O:15])=[O:14].C(N(CC)CC)C.O>C(Cl)Cl>[F:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[S:7][CH:8]=[C:9]([O:11][S:13]([CH3:12])(=[O:15])=[O:14])[N:10]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C1CSC(SCCCF)=N1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Oc1csc(SCCCF)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.9 %

Procedure:
6.2 g of 2-(3-fluoropropylthio)-1,3-thiazoline-4-one was dissolved in 80 ml of methylene chloride and cooled below 10° C. 5.5 g of methanesulfonyl chloride and 8.9 ml of triethylamine were added dropwise to the solution keeping the temperature below 15° C., followed by stirring at room temperature for 2 hours. After addition of water, the reaction mixture was extracted by methylene chloride, then organic layer is washed with water and dried over anhydrous sodium sulfate, followed by concentration to an oil, which is purified by silica-gel column chromatography to obtain 6.0 g of the objective compound as a pale brown oil (yield: 69.1%).
Reaction SMILES: Cl.[C:2]([N:6]1[CH:14]=[C:13]2[C:8]([C:9](=[O:20])[NH:10][C:11]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:12]2)=[N:7]1)([CH3:5])([CH3:4])[CH3:3].[Cl:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][C:26]([C:32](O)=[O:33])=[CH:27][CH:28]=2)[N:23]=1>>[C:2]([N:6]1[CH:14]=[C:13]2[C:8]([C:9](=[O:20])[NH:10][C:11]3([CH2:19][CH2:18][N:17]([C:32]([C:26]4[CH:25]=[C:24]5[C:29]([CH:30]=[CH:31][C:22]([Cl:21])=[N:23]5)=[CH:28][CH:27]=4)=[O:33])[CH2:16][CH2:15]3)[CH2:12]2)=[N:7]1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)n1cc2c(n1)C(=O)NC1(CCNCC1)C2
Reactant: O=C(O)c1ccc2ccc(Cl)nc2c1
Agent: Cl
Product: CC(C)(C)n1cc2c(n1)C(=O)NC1(CCN(C(=O)c3ccc4ccc(Cl)nc4c3)CC1)C2

Procedure:
The title compound was prepared by a method analogous to that described for Example 3 using 2′-tert-butyl-4′,6′-dihydrospiro[piperidine-4,5′-pyrazolo[3,4-c]pyridin]-7′(2′H)-one hydrochloride salt (Intermediate 4) and 2-chloroquinoline-7-carboxylic acid (Intermediate 44). +ESI (M+H) 452.3; 1H NMR (400 MHz, CDCl3, δ): 8.12 (d, J=8.2 Hz, 1H), 7.98 (br. s., 1H), 7.88 (dd, J=8.4 Hz, 1H), 7.61 (dd, J=8.4, 1.6 Hz, 1H), 7.44 (d, J=8.6 Hz, 1H), 7.39 (s, 1H), 5.91 (br. s., 1H), 4.06-4.22 (m, 1H), 3.38-3.64 (m, 3H), 2.85 (br. s., 2H), 1.67-1.97 (m, 4H), 1.61 (s, 9H).
Reaction SMILES: [F:1][C:2]1[C:7]([CH2:8][OH:9])=[C:6]([I:10])[CH:5]=[CH:4][N:3]=1.N1C=CN=C1.[CH3:16][C:17]([Si:20](Cl)([CH3:22])[CH3:21])([CH3:19])[CH3:18].C(OCC)C>C(Cl)Cl>[Si:20]([O:9][CH2:8][C:7]1[C:2]([F:1])=[N:3][CH:4]=[CH:5][C:6]=1[I:10])([C:17]([CH3:19])([CH3:18])[CH3:16])([CH3:22])[CH3:21]
Reactant: OCc1c(I)ccnc1F
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1c(I)ccnc1F
Yield: 88.1 %

Procedure:
To a solution of (2-fluoro-4-iodopyridin-3-yl)methanol (3.52 g, 13.91 mmol) in CH2Cl2 (80 mL) at room temperature was sequentially added imidazole (1.894 g, 27.8 mmol) and TBDMS-Cl (2.52 g, 16.69 mmol). The reaction was stirred at room temperature for 1 h before diethylether was added and the insoluble salts were filtered. Silica gel was added to the filtrate prior to the solvent removal under vacuum. The dry silica gel was packed, and the adsorbed product was purified by flash chromatography (hexane/EtOAc 10:0 to 7:3) to give 3-(((tert-butyldimethylsilyl)oxy)methyl)-2-fluoro-4-iodopyridine as a white solid (4.5 g). LC/MS m/z 368 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.O=[C:22]([CH2:26][CH3:27])[C:23]([OH:25])=[O:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:22]([C:23]([OH:25])=[O:24])[CH2:26][CH3:27])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1
Reactant: CCC(=O)C(=O)O
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Product: CCC(=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1)C(=O)O

Procedure:
In the manner given in Example 3, 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine was stirred with α-oxobutyric acid at room temperature to give 7-chloro-2-[(1-carboxypropylidene)hydrazino]-5-phenyl-3H-1,4-benzodiazepine.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([NH2:18])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].C(=O)([O-])O.[Na+].C(OC(N1[C:33](=[O:34])[C:32]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:31]2[C:30]1=[O:39])=O)C.Cl>C(#N)C.O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:18]2[C:33](=[O:34])[C:32]3[C:31](=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:30]2=[O:39])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: CCOc1cc(C(N)CS(C)(=O)=O)ccc1OC
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCOc1cc(C(CS(C)(=O)=O)N2C(=O)c3ccccc3C2=O)ccc1OC
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 69.9 %

Procedure:
A mixture of 1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethylamine (200 mg, 0.73 mmol) and sodium hydrogen carbonate (80 mg, 0.95 mmol) in acetonitrile and water (2 mL each) was stirred under nitrogen at room temperature for 2 minutes. To the resulting solution was added N-ethoxycarbonylphthalimide (170 mg, 0.78 mmol). After 17 hours, the resulting solution was stirred with hydrochloric acid (2 mL, 4 N), and water (30 mL) at room temperature for 30 minutes. The resulting suspension was filtered and the solid was washed with water (2×25 mL), and then dried in a vacuum oven overnight (60° C.,<1 torr) to yield 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]isoindoline-1,3dione as a solid (206 mg, 70% yield): mp, 151.0-152.0° C.; 1H NMR (CDCl3); δ 1.46 (t, J=6.9 Hz, 3H, CH3), 2.84 (s, 3H, CH3), 3.78 (dd, J=4.8, 14.4 Hz, I H, CHH), 3.84 (s, 3H, CH3), 4.10 (q, J=7 Hz, 2H, CH2), 4.54 (dd, J=10.1, 14.4 Hz, 1H, CHH), 5.90 (dd, J=4.8, 1 0.1 Hz, 1H, NCH), 6.83 (d, J=8.5 Hz, 1H, Ar), 7.11-7.15 (m, 2H, Ar), 7.67-7.73 (m, 2H, Ar), 7.80-7.84 (m, 2H, Ar); 13C NMR (CDCl3) δ 14.63, 41.49, 48.84, 54.82, 55.89, 64.45, 111.43, 112.50, 120.43, 123.51, 129.56, 131.58, 134.17, 148.57, 149.63, 167.80; Anal Calcd for C20H21NO6S: C, 59.54; H, 5.25; N, 3.47. Found: C, 59.66; H, 5.28; N, 3.29.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][N:9]=1>>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[N:9][CH:10]=1
Reactant: C1CNCCN1
Reactant: COc1ccc(Br)nc1
Product: COc1ccc(N2CCNCC2)nc1
Yield: 25 %

Procedure:
This compound was synthesized from piperazine and 2-bromo-5-methoxypyridine as described for example 39 step 1 (130 mg, yield 25%) as pale yellow liquid. 1H NMR (300 MHz, DMSO-d6) δ 7.87-7.86 (d, J=2.9 Hz, 1H), 7.27-7.23 (dd, J=9.1 Hz, 3.2 Hz, 1H), 6.80-6.77 (d, J=9.2 Hz, 1H), 3.71 (s, 3H), 3.32-3.28 (m, 4H), 2.86-2.83 (m, 4H). MS (ESI) m/z: Calculated for C10H15N3O: 193.12. found: 193.9 (M+H)+
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C@@H:10]([CH2:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[O:22][CH3:23])[C:11](O)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)([N:26]1C=CN=C1)=O.O.N>O1CCCC1>[NH2:26][C:11](=[O:12])[C@H:10]([CH2:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[O:22][CH3:23])[CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc(Cl)cc1C[C@H](CNC(=O)OC(C)(C)C)C(=O)O
Agent: N
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(Cl)cc1C[C@H](CNC(=O)OC(C)(C)C)C(N)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
(Step 3) To (2R)-3-[(tert-butoxycarbonyl)amino]-2-(5-chloro-2-methoxybenzyl)propanoic acid (15 g) in tetrahydrofuran (75 ml) solution, 1,1′-carbonyldiimidazole (7.8 g) was added under ice cooling and the mixture was stirred at room temperature for 1 hour. The reaction solution was cooled to 0° C., 28% ammonia water (15 ml) was added, and the mixture was stirred at room temperature for 30 minutes. To the reaction solution, distilled water, ethyl acetate, and tetrahydrofuran were added, the aqueous layer and the organic layer were separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layer was successively washed with saturated potassium hydrogensulfate aqueous solution and saturated saline, dried over with anhydrous sodium sulfate, and concentrated until a small amount of ethyl acetate remained. Hexane was added to the concentrated solution, and the precipitated solid was collected by filtration to obtain the title compound (13.5 g).
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([O:11][CH3:12])[C:4]=1[CH3:13])=[CH2:2].C1C=C(Cl)C=C(C(OO)=[O:22])C=1>C(Cl)Cl>[CH3:13][C:4]1[C:5]([O:11][CH3:12])=[C:6]([CH:9]=[CH:10][C:3]=1[CH:1]1[CH2:2][O:22]1)[C:7]#[N:8]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=Cc1ccc(C#N)c(OC)c1C
Solvent: ClCCl
Product: COc1c(C#N)ccc(C2CO2)c1C
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A mixture of 4-ethenyl-3-methyl-2-(methyloxy)benzonitrile (3.90 g, 22.5 mmol) and m-CPBA (85%, 11.7 g, 67.6 mmol) in 300 mL of DCM was stirred at room temperature for 120 hours. The reaction mixture was cooled to 0° C. and was washed subsequently with saturated NaHCO3 (50 mL), saturated Na2SO3 (50 mL), 5% NaOH (50 mL×2) and brine (50 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography (PE:EtOAc=20:1) to afford 3-methyl-2-(methyloxy)-4-oxiran-2-ylbenzonitrile.
Reaction SMILES: C[O:2][C:3](=[O:40])[CH2:4][CH2:5][NH:6][C:7](=[O:39])[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]([C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)[C:16]2[S:17][CH:18]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=3)[N:20]=2)=[CH:10][CH:9]=1.[OH-].[Na+]>C(O)C>[Cl:38][C:35]1[CH:34]=[CH:33][C:32]([N:15]([CH2:14][C:11]2[CH:10]=[CH:9][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:40])=[O:2])=[O:39])=[CH:13][CH:12]=2)[C:16]2[S:17][CH:18]=[C:19]([C:21]3[CH:22]=[CH:23][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:25][CH:26]=3)[N:20]=2)=[CH:37][CH:36]=1
Reactant: COC(=O)CCNC(=O)c1ccc(CN(c2ccc(Cl)cc2)c2nc(-c3ccc(OC(F)(F)F)cc3)cs2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCNC(=O)c1ccc(CN(c2ccc(Cl)cc2)c2nc(-c3ccc(OC(F)(F)F)cc3)cs2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 43.8 %

Procedure:
3-[4-({(4-Chlorophenyl)-[4-(4-trifluoromethoxyphenyl)thiazol-2-yl]amino}methyl)benzoylamino]propionic acid methyl ester (18.7 g, 31.7 mmol) was dissolved in ethanol (500 mL) and 1 N sodium hydroxide (63 mL, 63 mmol) was added. The resulting mixture was stirred at room temperature for 16 hours. The mixture was filtered, washed with ethanol and dried in vacuo at 40° C. for 16 hours to afford 8.0 g (42%) of the title compound as the sodium salt.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-])=O)[CH:15]=1)=[O:13])(=[O:10])=[O:9]>[Pd].O.C(O)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[CH:15]=1)=[O:13])(=[O:10])=[O:9]
Reactant: Cc1ccccc1S(=O)(=O)NC(=O)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: Cc1ccccc1S(=O)(=O)NC(=O)c1cccc(N)c1

Procedure:
In the same way as that described in Example 11, Step 2, using 1-(2-methylphenylsulphonylaminocarbonyl)-3-nitrobenzene (3 g, 9.4 mmol), 10% palladium on carbon (0.3 g, 10% (w/w)) in water (2 ml) and ethanol (60 ml), the title compound was afforded as a yellow solid. This was recrystallised from ethanol to give a pale yellow crystalline solid (2.21 g, 8.1%). mp 150°-152° C. 1H NMR (360 MHz, D6-DMSO) δ 2.61(3H, s), 6.78 (1H, d, J=7.8 Hz), 6.97-7.03 (2H, m), 7.12 (1H, t, J=7.8 Hz), 7.39-7.47 (2H, m), 7.58 (1H, t, J=7.5 Hz), 8.02 (1H, d, J =7.9 Hz).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[C:8]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)=[N:9][N:10]([CH:11]3[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]3)[C:6]=2[CH:5]=[CH:4][NH:3]1.Cl>C1COCC1>[OH:17][C:14]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:13][CH2:12][CH:11]([N:10]2[C:6]3[CH:5]=[CH:4][NH:3][C:2](=[O:1])[C:7]=3[C:8]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)=[N:9]2)[CH2:16][CH2:15]1
Reactant: NS(=O)(=O)c1ccc(-c2nn(C3CCC(=O)CC3)c3cc[nH]c(=O)c23)cc1
Agent: Cl
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc(-c2nn(C3CCC(O)(c4ccccc4)CC3)c3cc[nH]c(=O)c23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.7 %

Procedure:
To a solution of 4-(4-oxo-1-(4-oxocyclohexyl)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)benzenesulfonamide (30.0 mg) obtained in Example 173 in THF was added 1.6M phenyllithium butyl ether solution (0.194 mL) at −78° C., and the mixture was stirred overnight at room temperature under nitrogen atmosphere. To the reaction mixture was added 1N hydrochloric acid at 0° C., and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/methanol) to give the title compound (15.1 mg).