Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([CH2:15][Cl:16])[CH2:7][N:8]2[S:11]([CH3:14])(=[O:13])=[O:12])=[CH:4][CH:3]=1.[N+:17]([C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1)([O-:19])=[O:18].O.C1(C)C(S(O)(=O)=O)=CC=CC=1.C([BH3-])#N.Cl>C1C=CC=CC=1>[Cl:16][CH2:15][CH:6]1[C:5]2[C:9](=[CH:10][C:2]([NH:1][CH2:24][C:23]3[CH:26]=[CH:27][C:20]([N+:17]([O-:19])=[O:18])=[CH:21][CH:22]=3)=[CH:3][CH:4]=2)[N:8]([S:11]([CH3:14])(=[O:12])=[O:13])[CH2:7]1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: CS(=O)(=O)N1CC(CCl)c2ccc(N)cc21
Agent: Cc1ccccc1S(=O)(=O)O
Agent: Cl
Agent: [BH3-]C#N
Solvent: O
Solvent: c1ccccc1
Product: CS(=O)(=O)N1CC(CCl)c2ccc(NCc3ccc([N+](=O)[O-])cc3)cc21
Reaction time: 0.67 h
Yield: 87 %

Procedure:
A mixture of 6-amino-3-(chloromethyl)-1-(methanesulfonyl)indoline (29) [Tercel, M., Denny, W. A. and Wilson, W. R., Bioorg. Med. Chem. Lett., 1996, in press] (73 mg, 0.28 mmol), 4-nitrobenzaldehyde (51 mg, 0.34 mmol) and toluenesulfonic acid monohydrate (5 mg, 0.3 mmol) in benzene (30 mL) was heated to reflux and most of the benzene slowly distilled off over 40 min. The remaining orange-brown solution was cyanoborohydride (35 mg, 0.56 mmol) then 2N HCl (0.5 mL) were added and the mixture was stirred at 20 C for 40 min, then evaporated. The residue was diluted with water, extracted with EtOAc (×2), and the extracts dried (Na2SO4) and evaporated. Dry column chromatography, eluting with EtOAc/petroleum ether (1:2), gave 3-(chloromethyl)-1-(methanesulfonyl)-6-[(4-nitrobenzyl)amino]indoline (30) as a yellow oil (96 mg, 87%). 1H NMR (CDCl3) a 8.19 (d, J=8.8 Hz, 2 H, ArH o to NO2), 7.52 (d, J=8.8 Hz, 2 H, ArH m to NO2), 7.00 (d, J=8.2 Hz, 1 H, H-4), 6.73 (d, J=2.2 Hz, 1 H, H-7), 6.22 (dd, J=8.2, 2.2 Hz, 1 H, H-5), 4.47 (s, 2 H, NCH2Ar), 4.03 (dd, J=10.8, 8.8 Hz, 1 H, CHHN), 3.92 (dd, J=10.8, 4.6 Hz, 1 H, CHHN), 3.69 (dd, J=10.4, 4.1 Hz, 1 H, CHHCl), 3.67-3.60 (m, 1 H, H-3), 3.53 (dd, J=10.4, 7.9 Hz, 1 H, CHHCl), 2.83 (s, 3 H, NSO2CH3). 13C NMR a 148.7, 147.2, 146.8, 143.4, 119.9 (C-6,8,9,1,4), 127.8, 123.9 (C-2 and 6, 3 and 5), 125.7, 107.9, 98.6 (C-4,5,7), 54.6 (C-2), 47.5, 46.8 (CH2Cl, NCH2Ar), 41.9 (C-3), 34.5 (SO2CH3). MS (DEI, 35Cl) m/z 395 (35%, M+), 346 (100%, M-CH2Cl); HRMS calcd. for C17H18ClN3O4S 395.07066, found 395.06880.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[CH2:6]([O:8][C:9]([C@@H:11]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:12][C@H:13]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:14](Cl)=[O:15])=[O:10])[CH3:7]>C(Cl)Cl>[CH2:6]([O:8][C:9]([C@@H:11]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:12][C@H:13]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:14]([NH:1][CH2:2][CH2:3][CH2:4][OH:5])=[O:15])=[O:10])[CH3:7]
Reactant: CCOC(=O)[C@@H](Cc1ccccc1)C[C@H](Cc1ccccc1)C(=O)Cl
Reactant: NCCCO
Solvent: ClCCl
Product: CCOC(=O)[C@@H](Cc1ccccc1)C[C@H](Cc1ccccc1)C(=O)NCCCO
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To the solution of 0.52 g of 3-amino-1-propanol in 10 ml of methylene chloride is added 0.5 g of 4-ethoxycarbonyl-2,4-(R*,R*)-dibenzylbutyryl chloride in 10 ml of methylene chloride. The mixture is stirred 10 minutes at room temperature. The reaction mixture is concentrated and diluted with ethyl acetate. The organic portions are washed with 1N hydrochloric acid, saturated sodium bicarbonate and saturated sodium chloride. The organic layer is dried over magnesium sulfate, filtered and concentrated to give N-[4-ethoxycarbonyl-2,4-(R*,R*)-dibenzylbutyryl]-3-amino-1-propanol as a colorless oil; NMR (CDCl3) δ7.31 and 7.28 (s, 10H, Ar--H), 5.82 (t, 1H, J=7 Hz, NH), 4.02 (q, 2H, J=8 Hz, OCH2), 3.3-1.25 (m, 15H), 1.10 (t, 3H, J=8 Hz, CH3).
Reaction SMILES: [Na].[C:2]([CH2:7][C:8]1[N:12]=[C:11]([SH:13])[NH:10][N:9]=1)([O:4][CH2:5][CH3:6])=[O:3].CC(O[CH2:18][C:19]1[CH2:28][S:27][C@@H:22]2[C@H:23]([NH2:26])[C:24](=[O:25])[N:21]2[C:20]=1[C:29]([OH:31])=[O:30])=O>>[NH2:26][CH:23]1[C:24](=[O:25])[N:21]2[C:20]([C:29]([OH:31])=[O:30])=[C:19]([CH2:18][S:13][C:11]3[N:12]=[C:8]([CH2:7][C:2]([O:4][CH2:5][CH3:6])=[O:3])[NH:9][N:10]=3)[CH2:28][S:27][C@H:22]12
Reactant: CCOC(=O)Cc1n[nH]c(S)n1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: [Na]
Product: CCOC(=O)Cc1nc(SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)n[nH]1

Procedure:
Reaction of 3-carbethoxymethyl-1,2,4-triazole-5-thiol sodium salt, prepared as described in Example 8, and 7-aminocephalosporanic acid according to the procedure described in Example 8 gives the title compound.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][O:21][C:22](=[O:32])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([OH:31])[CH:24]=1.CCOC(/N=N/C(OCC)=O)=O.[Cl:45][C:46]1[CH:51]=[C:50]([Cl:52])[CH:49]=[CH:48][C:47]=1[CH2:53][CH2:54]O>C1COCC1>[CH3:20][O:21][C:22](=[O:32])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH2:54][CH2:53][C:47]2[CH:48]=[CH:49][C:50]([Cl:52])=[CH:51][C:46]=2[Cl:45])[CH:24]=1
Reactant: OCCc1ccc(Cl)cc1Cl
Reactant: COC(=O)c1ccc(OC)c(O)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC)c(OCCc2ccc(Cl)cc2Cl)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
20 g of triphenylphosphine and 10 g of 3-Hydroxy-4-methoxy-benzoic acid methyl ester were dissolved in 200 ml of anhydrous THF. The solution was cooled to 0° C. to 10° C. and a solution of 11.4 ml DEAD in 30 ml anhydrous THF was added dropwise over 20 min. The reaction was warmed to RT and stirred for 45 min. A solution of 11.3 ml 2-(2,4-Dichlorophenyl)-ethanol in 10 ml anhydrous THF was added with cooling. The reaction was stirred at RT for 16 h, and then the solvents were removed under reduced pressure. The residue was treated with n-heptane:ethyl acetate/1:1. The filtrate was dried under reduced pressure. The product was purified by silica gel chromatography, eluting with n-heptane:ethyl acetate/4:1, then n-heptane:ethyl acetate/3:1.
Reaction SMILES: I[C:2]1[N:6]2[CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>C(OCC)(=O)C.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>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[N:6]3[CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=[CH:10][C:5]3=[N:4][CH:3]=2)=[CH:19][CH:18]=1
Reactant: COC(=O)c1ccc2ncc(I)n2c1
Reactant: COc1ccc(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: COCCOC
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2ncc(-c3ccc(OC)cc3)n2c1
Yield: 55.9 %

Procedure:
A mixture of methyl 3-iodoimidazo[1,2-a]pyridine-6-carboxylate (1.40 g, 4.63 mmol), (4-methoxyphenyl)boronic acid (845 mg, 5.56 mmol), tetrakis(triphenylphosphine)palladium(0) (268 mg, 0.232 mmol), 2 M aqueous sodium carbonate solution (4.63 mL) and 1,2-dimethoxyethane (50 mL) was heated under reflux under an argon atmosphere overnight. After cooling, the reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1-0/1) to give the title compound (730 mg, yield 56%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]=[CH:15][CH:16]=[CH:17][C:12]=3[C:11](=[O:18])[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:19][O:20][C:21]1[N:26]=[CH:25][C:24]([CH2:27]O)=[CH:23][CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]=[CH:15][CH:16]=[CH:17][C:12]=3[C:11](=[O:18])[N:10]([CH2:27][C:24]3[CH:25]=[N:26][C:21]([O:20][CH3:19])=[CH:22][CH:23]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=c1[nH]nc(-c2cccc(Cl)c2)c2ncccc12
Reactant: COc1ccc(CO)cn1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(Cn2nc(-c3cccc(Cl)c3)c3ncccc3c2=O)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 0.1 %

Procedure:
To a suspension of 8-(3-chlorophenyl)pyrido-[2,3-d]pyridazin-5-one (0.515 g, 2.0 moles), 6-methoxy-3-hydroxymethyl pyridine (0,306g, 2.2 moles) and triphenylphosphine (0.792 g, 3.0 moles) in THF (50 mL) was added diisopropylazodicarboxylate (0.6mL, 3.0 moles). The reaction mixture was stirred for 18 hours at room temperature. The solvent was removed and the product was purified by chromatography (ethyl acetate/hexane 2:3) and crystallized from methanol to yield 0.588g of 8-(3-chlorophenyl)-6-(6-methoxy-3-pyridylmethyl)pyrido[2,3-d]-pyridazin-5-one, mp 145° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[F:15][C:16]([F:34])([CH:31]([F:33])[F:32])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:29](=[O:30])[NH:28][N:27]=[N:26]2)=[CH:21][CH:20]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([O:10][CH2:11]1)[C@H:12]([N:28]1[C:29](=[O:30])[N:25]([C:22]2[CH:21]=[CH:20][C:19]([O:18][CH2:17][C:16]([F:15])([F:34])[CH:31]([F:33])[F:32])=[CH:24][CH:23]=2)[N:26]=[N:27]1)[CH3:13]
Reactant: O=c1[nH]nnn1-c1ccc(OCC(F)(F)C(F)F)cc1
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Product: C[C@@H](n1nnn(-c2ccc(OCC(F)(F)C(F)F)cc2)c1=O)[C@@]1(c2ccc(F)cc2F)CO1

Procedure:
In the same manner as in Reference Example 5, starting from 1.39 g of (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 1.63-g of 1-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-5(1H,4H)-tetrazolone, 1.27 g of 1-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-5(1H,4H)-tetrazolone was obtained as a colorless oil.
Reaction SMILES: CO[C:3](=[O:15])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[CH:14]=[CH:13][CH:12]=[N:11]2)[CH:5]=1.[C:16]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:18])[CH3:17].[Li]>>[C:20]([O:19][C:16](=[O:18])[CH2:17][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[CH:14]=[CH:13][CH:12]=[N:11]2)[CH:5]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(=O)OC(C)(C)C
Reactant: COC(=O)c1cccc(-n2cccn2)c1
Agent: [Li]
Product: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2cccn2)c1

Procedure:
The title compound was prepared from 3-pyrazol-1-yl-benzoic acid methyl ester [CAS-No. 168618-35-7] by treatment with lithium tert.-butyl acetate according to general procedure K (method b). Obtained as a yellow oil (5.00 g).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:20][C:21]([F:35])([F:34])[C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:25]O.CCCCC.C(Cl)(Cl)(Cl)[Cl:42]>>[F:20][C:21]([F:35])([F:34])[C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:25][Cl:42]
Reactant: ClC(Cl)(Cl)Cl
Reactant: OCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCC
Product: FC(F)(F)c1cc(CCl)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 59 %

Procedure:
Triphenylphosphine (371 mg, 1.41 mmol) was added to a solution of 3,5-bistrifluoromethylbenzyl alcohol (257 mg, 1.05 mmol) in dry CCl4 (2 ml). The mixture was refluxed for 1 h, then cooled to room temp. Pentane (2 ml) was added, and the mixture stirred for a further 5 min., then filtered. The solid was washed with pentane (2 ml), and the filtrate concentrated in vacuo. The crude product was purified by column chromatography [SiO2: hexane-ethyl acetate 4:1] to give 3,5-bistrifluoromethylbenzyl chloride (162 mg, 59%); TLC (hexane-ethyl acetate 1:1) rf=0.73.
Reaction SMILES: [CH3:1][NH2:2].CO.[S:5]1[CH:9]=[C:8]([CH:10]=O)[C:7]2[CH:12]=[CH:13][CH:14]=[CH:15][C:6]1=2.CC(O)=O>>[CH3:1][NH:2][CH2:10][C:8]1[C:7]2[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=2[S:5][CH:9]=1
Reactant: O=Cc1csc2ccccc12
Reactant: CN
Solvent: CO
Solvent: CC(=O)O
Product: CNCc1csc2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
To a stirred solution of 2 M methylamine in methanol (75 mmole, 150 mmole) was added benzo[b]thiophen-3-carboxaldehyde (5.3 g, 33 mmole) and HOAc (4.3 mL, 75 mmole). The reaction was stirred at RT for 1 h, then NaB3CN (2.1 g, 33 mmole) was added portionwise over 5 minutes. The reaction was stirred for an additional 16 h then was concentrated under vacuum. The residue was taken up in Et2O (300 mL) and washed with 1.0 N NaOH (300 mL) then with brine, dried (Na2SO4), and concentrated. Purification by flash chromatography on silica gel (5% (5% NH4OH/MeOH)/CHCl3) gave the title compound (2.81 g, 48%) as a brownish oil: 1H NMR (400 MHz, CDCl3) δ•7.87 (2d, 2H), 7.40 (m, 2H), 7.32 (s, 1H), 4.02 (s, 2H), 2.56 (s, 3H), 1.5 (br s, 1H).
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27][C:28]2[CH:36]=[CH:35][C:31]([C:32]([OH:34])=O)=[CH:30][CH:29]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH:37]1([NH2:42])[CH2:41][CH2:40][CH2:39][CH2:38]1>>[CH:37]1([NH:42][C:32](=[O:34])[C:31]2[CH:35]=[CH:36][C:28]([S:27][CH2:26][C:16]3[C:17]4[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=4[CH:23]=[CH:24][C:15]=3[O:14][C@@H:7]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:6][N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)=[CH:29][CH:30]=2)[CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: O=C(O)c1ccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Reactant: NC1CCCC1
Product: O=C(NC1CCCC1)c1ccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Yield: 90.1 %

Procedure:
Using the method in Example 172, 4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoic acid (50 mg, 0.10 mmol, 0.20M in DMF) and cyclopentylamine (26 mg, 0.30 mmol, 0.6M in DMF) were combined to give 51 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 566 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=3)=[C:19]([O:30][CH2:31][CH2:32][O:33][C:34]3[CH:39]=[CH:38][N:37]=[C:36](SC)[N:35]=3)[N:18]=[CH:17][N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>[Ni].C(O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=3)=[C:19]([O:30][CH2:31][CH2:32][O:33][C:34]3[CH:39]=[CH:38][N:37]=[CH:36][N:35]=3)[N:18]=[CH:17][N:16]=2)(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cccc(Oc2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOc2ccnc(SC)n2)c1
Agent: [Ni]
Solvent: CCO
Product: COc1cccc(Oc2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOc2ccncn2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.9 %

Procedure:
A mixture of 4-tert-butyl-N-[5-(3-methoxyphenoxy)-6-{2-(2-methylthiopyrimidin-4-yloxy)ethoxy}pyrimidin-4-yl]benzenesulfonamide (250 mg), Raney-nickel (W-2) (2 g) and ethanol (5 ml) is stirred at room temperature overnight, and the mixture is refluxed for four hours. Raney-nickel is removed by filtration, and washed with ethanol and acetic acid. The filtrate is concentrated under reduced pressure, and the residue is extracted with ethyl acetate. The ethyl acetate layer is washed, dried, and evaporated to remove the solvent. The residue is purified by silica gel column chromatography (solvent; chloroform/methanol- 10:1), and recrystallized from ethyl acetate/n-hexane to give 4-tert-butyl-N-[5-(3-methoxyphenoxy)-6-{2-(pyrimidin-4-yloxy)ethoxy}pyrimidin-4-yl]benzenesulfonamide (76 mg) as crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[C:9]1[C:10]([C:22]2[O:26][C:25]([C:27]3[CH:32]=[CH:31][C:30]([CH2:33][N:34]([CH3:42])[C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:29][CH:28]=3)=[N:24][N:23]=2)=[N:11][C:12]([C:15]2[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH:16]=2)=[CH:13][N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO>[C:46]([O:45][C:43]([N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:9]1[C:10]([C:22]2[O:26][C:25]([C:27]3[CH:32]=[CH:31][C:30]([CH2:33][N:34]([CH3:42])[C:35](=[O:41])[O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[CH:29][CH:28]=3)=[N:24][N:23]=2)=[N:11][C:12]([C:15]2[CH2:20][CH2:19][CH:18]([OH:21])[CH2:17][CH:16]=2)=[CH:13][N:14]=1)=[O:44])([CH3:47])([CH3:48])[CH3:49]
Reactant: CN(Cc1ccc(-c2nnc(-c3nc(C4=CCC(=O)CC4)cnc3N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)o2)cc1)C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN(Cc1ccc(-c2nnc(-c3nc(C4=CCC(O)CC4)cnc3N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)o2)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 29 %

Procedure:
A solution of tert-butyl N-[[4-[5-[3-[bis(tert-butoxycarbonyl)amino]-6-(4-oxocyclohexen-1-yl)pyrazin-2-yl]-1,3,4-oxadiazol-2-yl]phenyl]methyl]-N-methyl-carbamate (431 mg, 0.64 mmol) in MeOH (2 mL) was cooled in an ice water bath. Sodium boranuide (27 mg, 0.70 mmol) was added and the reaction mixture was stirred for 40 minutes at 0° C. upon which the ice bath was removed. After stirring at room temperature for 8 h, the reaction mixture was quenched with water and aq. NaHCO3 and diluted with EtOAc. The layers were separated and the aqueous layer was extracted once more with EtOAc. The combined organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified by silica gel column chromatography using 0-40% EtOAc in DCM to yield tert-butyl N-[[4-[5-[3-[bis(tert-butoxycarbonyl)amino]-6-(4-hydroxycyclohexen-1-yl)pyrazin-2-yl]-1,3,4-oxadiazol-2-yl]phenyl]methyl]-N-methyl-carbamate (126 mg, 41%). 1H NMR (400 MHz, DMSO-d6) δ 9.04 (s, 1H), 8.11 (d, J=8.0 Hz, 2H), 7.49 (d, J=8.1 Hz, 2H), 7.01 (s, 1H), 4.81 (d, J=3.8 Hz, 1H), 4.49 (s, 2H), 3.93-3.86 (m, 1H), 2.83 (s, 5H), 2.64-2.53 (m, J=19.3 Hz, 2H), 1.97-1.90 (m, J=12.4 Hz, 1H), 1.71 (dd, J=14.0, 8.7 Hz, 1H), 1.45 (s, 3H), 1.36 (s, 6H), 1.26 (s, 18H); LC/MS m/z 579.9 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]2[C:10]([CH3:14])=[C:11]([CH3:13])[N:12]=[C:6]2[C:5]=1[NH:15]C(=O)C(C)(C)C)(=[O:3])[CH3:2].S(=O)(=O)(O)O.C(Cl)Cl.[OH-].[Na+]>CO>[C:1]([C:4]1[CH:9]=[CH:8][N:7]2[C:10]([CH3:14])=[C:11]([CH3:13])[N:12]=[C:6]2[C:5]=1[NH2:15])(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccn2c(C)c(C)nc2c1NC(=O)C(C)(C)C
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CC(=O)c1ccn2c(C)c(C)nc2c1N
Temperature: 0 °C
Yield: 39.6 %

Procedure:
A cooled solution of 80.4 g of 7-acetyl-2,3-dimethyl-8-pivaloylaminoimidazo[1,2-a]pyridine in 720 ml of methanol is treated with 496 ml of concentated sulfuric acid and heated at reflux for 2.5 hours. It is then poured onto 1 l of ice water, 400 ml of methylene chloride are added and the mixture is adjusted to pH 7 with 10 N sodium hydroxide solution with cooling. After phase separation, the aqueous phase is again extracted twice with 300 ml of methylene chloride each time, the organic phases are collectively washed with 1 l of water, dried over sodium sulfate and the solvent is stripped off in vacuo. The solid residue is purified on silica gel (eluent: ethyl acetate). 22.5 g of the title compound of m.p. 195–97° C. (diethyl ether) are obtained.
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([O:11]COCCOC)=[C:9]([C:18]([CH3:21])([CH3:20])[CH3:19])[N:8]=[C:7]([C:22]#[N:23])[N:6]=1)([CH3:4])[CH3:3].FC(F)(F)C(O)=O>>[CH3:4][C:2]([C:5]1[C:10]([OH:11])=[C:9]([C:18]([CH3:21])([CH3:20])[CH3:19])[N:8]=[C:7]([C:22]#[N:23])[N:6]=1)([CH3:1])[CH3:3]
Reactant: COCCOCOc1c(C(C)(C)C)nc(C#N)nc1C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1nc(C#N)nc(C(C)(C)C)c1O
Yield: 68.2 %

Procedure:
According to the procedure of Example 18, 4,6-bis (1,1-dimethylethyl)-5-[(2-methoxyethoxy)-methoxy]-2-pyrimidine carbonitrile (9.1 g, 28.3 mmol) is treated with trifluoroacetic acid to give 4,6-bis (1,1-dimethylethyl)-5-hydroxy-2-pyrimidine carbonitrile (4.5 g, 68%); mp 203°-205° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[C:19]([O:21][Si:22]([C:35]([CH3:38])([CH3:37])[CH3:36])([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:18]=[CH:17][C:16]=2[Br:39])[C:10](=[O:40])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Br:39][C:16]1[CH:17]=[CH:18][C:19]([O:21][Si:22]([C:35]([CH3:38])([CH3:37])[CH3:36])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:20][C:15]=1[CH2:14][N:11]1[CH2:12][CH2:13][NH:8][CH2:9][C:10]1=[O:40]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cc(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc2Br)C(=O)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)[Si](Oc1ccc(Br)c(CN2CCNCC2=O)c1)(c1ccccc1)c1ccccc1
Reaction time: 3 h

Procedure:
To a solution of product from Step D (2.30 g, 3.69 mmol) in methylene chloride (16 mL) was added trifluoroacetic acid (4 mL). The resulting solution was stirred for 3 hours, then poured onto saturated aqueous sodium bicarbonate, and extracted with methylene chloride (3×50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to provide the title product as a yellow oil which was sufficiently pure for use in the next step.
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:37])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([N:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22][CH:21]([NH:29]C(=O)OC(C)(C)C)[CH2:20]3)(=[O:18])=[O:17])=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:38].O>O1CCOCC1>[NH2:29][CH:21]1[CH2:22][C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:19]([S:16]([C:13]2[CH:14]=[CH:15][C:10]([NH:9][C:8]([NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:37])=[CH:11][CH:12]=2)(=[O:17])=[O:18])[CH2:20]1.[ClH:38]
Reactant: CC(C)(C)OC(=O)NC1Cc2ccccc2N(S(=O)(=O)c2ccc(NC(=O)Nc3ccccc3)cc2)C1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: NC1Cc2ccccc2N(S(=O)(=O)c2ccc(NC(=O)Nc3ccccc3)cc2)C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of tert-butyl 1-(4-(3-phenylureido)phenylsulfonyl)-1,2,3,4-tetrahydroquinolin-3-ylcarbamate in 1,4-dioxane (1 mL) was added 4 M hydrogen chloride in 1,4-dioxane (2 mL, 8.0 mmol). The reaction mixture was stirred at room temperature for 20 hours. Water (1.5 mL) was added and the mixture extracted with ethyl acetate (3×1.5 mL). The combined organics were dried over sodium sulfate and concentrated to give 1-(4-(3-amino-3,4-dihydroquinolin-1(2H)-ylsulfonyl)phenyl)-3-phenylurea as its HCl salt.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]=[C:13]=[O:14])(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2].[NH2:15][C:16]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:17]=1[C:18]([OH:20])=O>>[Cl:25][C:23]1[CH:24]=[C:16]2[C:17]([C:18](=[O:20])[N:12]([S:9]([C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)(=[O:11])=[O:10])[C:13](=[O:14])[NH:15]2)=[CH:21][CH:22]=1
Reactant: N#Cc1ccc(S(=O)(=O)N=C=O)cc1
Reactant: Nc1cc(Cl)ccc1C(=O)O
Product: N#Cc1ccc(S(=O)(=O)n2c(=O)[nH]c3cc(Cl)ccc3c2=O)cc1
Yield: 17.6 %

Procedure:
1.14 g (5.49 mmol) of 4-cyanobenzenesulfonylisocyanate and 943 mg (5.50 mmol) of 2-amino-4-chlorobenzoic acid were treated in the same way as in Example 1 to obtain 349 mg of the above-identified compound (yield 17.6%). Properties: colorless crystal, Melting point: >250° C. (decomposition), PMR (δppm, DMSO-d6):7.13 (1H,s), 7.24 (1H,d), 7.86 (1H,d), 8.16 (2H,d), 8.32 (2H,d), 11.9 (1H,br).