Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].[Cl:19][C:20]1[CH:21]=[C:22]([S:27](Cl)(=[O:29])=[O:28])[CH:23]=[C:24]([Cl:26])[CH:25]=1>CN(C)C1C=CN=CC=1>[Cl:26][C:24]1[CH:23]=[C:22]([S:27]([NH:1][C:2]2[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=2[O:17][CH3:18])[C:5]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:6])(=[O:28])=[O:29])[CH:21]=[C:20]([Cl:19])[CH:25]=1
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Agent: CN(C)c1ccncc1
Product: COc1ccc(C(=O)Nc2ccccc2)cc1NS(=O)(=O)c1cc(Cl)cc(Cl)c1
Yield: 74.6 %

Procedure:
Prepared according to the procedure described for Example 116 using 3-amino-4-methoxy-N-phenyl-benzamide (0.7296 g, 3.00 mmol), 3,5-dichlorobenzenesulfonyl chloride (0.7327 g, 3.00 mmol), and 4-dimethylaminopyridine to obtain the product (1.01 g); m.p. 222-228° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[Br:10].[CH3:11][S:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1>>[Br:10][C:3]1[CH:4]=[C:5]([F:9])[C:6]([F:8])=[CH:7][C:2]=1[C:16]1[CH:17]=[CH:18][C:13]([S:12][CH3:11])=[CH:14][CH:15]=1
Reactant: CSc1ccc(B(O)O)cc1
Reactant: Fc1cc(Br)c(Br)cc1F
Product: CSc1ccc(-c2cc(F)c(F)cc2Br)cc1
Yield: 175.2 %

Procedure:
Following the general procedure outlined in Synthetic Scheme IV, 40 g (147 mmol) of 1,2-dibromo-4,5-difluorobenzene was reacted with 12.3 g (73 mmol) of 4-methylthiophenylboronic acid (Example 1, Step 2). Purification by silica gel chromatography with hexane gave 40.3 g of 1-bromo-4,5-difluoro-2-[4-(methylthio)phenyl]benzene as a yellow oil which was used without further purification.
Reaction SMILES: [C:1]([N-:5][CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][N:10]=1)[OH:8])(C)(C)C.[H-].[Na+].[OH2:18]>O1CCCC1>[Br:15][C:12]1[CH:13]=[CH:14][C:9]([CH:7]2[O:8][C:1](=[O:18])[NH:5][CH2:6]2)=[N:10][CH:11]=1
Reactant: CC(C)(C)[N-]CC(O)c1ccc(Br)cn1
Reactant: O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1NCC(c2ccc(Br)cn2)O1
Temperature: 0 °C
Yield: 72 %

Procedure:
Compound 14a (70 mg, 0.85 mmol) was dissolved in dried tetrahydrofuran (5 mL), cooled to 0° C. NaH (51 mg, 1.28 mmol) was added, and after its completion, the reaction mixture was raised to room temperature, and then raised to 50° C. to react for 4 hrs. The reaction was monitored by TLC (petroleum ether/ethyl acetate=8/1). After the reaction completed, water was added, and the mixture was extracted with ethyl acetate. The organic phase was combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate. Column chromatography (petroleum ether/ethyl acetate=5/1) afforded 150 mg of white solid (compound 14b), yield 72%.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15](O)[C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1)C1C=CC=CC=1>C(O)C.[C].[Pd]>[OH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccc(C(O)c2ccccc2OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1ccc(Cc2ccccc2O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94 %

Procedure:
To a solution of methyl 4-[(2-benzyloxyphenyl)-hydroxymethyl]benzoate (2.6 g) in ethanol (15 mL) was added 10% palladium-carbon powder (0.50 g), and the mixture was stirred under a hydrogen atmosphere at room temperature for 18 hours. An insoluble material was removed by filtration, and the solvent of the filtrate was removed under reduced pressure to give methyl 4-(2-hydroxybenzyl)benzoate (1.7 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([I:11])=[N:9][NH:10][C:4]=2[CH:3]=1.[H-].[Na+].[C:14](Cl)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([I:11])=[N:9][N:10]([C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:4]=2[CH:3]=1
Reactant: Clc1cc2[nH]nc(I)c2cn1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1cc2c(cn1)c(I)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.83 h
Yield: 93.1 %

Procedure:
A solution of 6-chloro-3-iodo-1H-pyrazolo[4,3-c]pyridine (1.874 g, 6.71 mmol) in THF (20 mL) was treated with NaH (60% in mineral oil; 0.402 g, 10.06 mmol) at 0° C. and the mixture was stirred for 50 min. Trityl chloride (2.244 g, 8.05 mmol) was added at the same temperature and the mixture was stirred for 16 h at room temperature, quenched with saturated NH4Cl and extracted with EtOAc. The organic phase was washed with water, brine, dried (Na2SO4) and concentrated in vacuo to afford a residue, which was purified by chromatography on silica gel (SNAP 50 g, from 0 to 10% EtOAc in hexanes, 5 CV; 10% EtOAc in hexanes, 15 CV) to yield 6-chloro-3-iodo-1-trityl-1H-pyrazolo[4,3-c]pyridine (3.26 g, 6.25 mmol, 93%) as a light yellow solid. MS ESI calc'd. for C25H18ClIN3[M+1]+522, found 522.
Reaction SMILES: Cl.Cl.Cl.[CH3:4][O:5][C:6](=[O:53])[NH:7][C@H:8]([C:12]([N:14]1[CH2:18][CH2:17][CH2:16][C@H:15]1[C:19]1[NH:20][C:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][C:33]([NH:36][C:37]([C:39]4[CH:40]=[N:41][C:42]([N:45]5[CH2:50][CH2:49][NH:48][CH2:47][C@H:46]5[CH3:51])=[CH:43][CH:44]=4)=[O:38])=[CH:32][C:31]=3[CH3:52])=[CH:26][CH:25]=2)=[CH:22][N:23]=1)=[O:13])[CH:9]([CH3:11])[CH3:10].C(N(CC)C(C)C)(C)C.CC(N(C)C)=O.[C:69]([N:72]1[CH2:76][CH2:75][CH2:74][C@@:73]1([CH3:80])[C:77](O)=[O:78])(=[O:71])[CH3:70].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[CH3:4][O:5][C:6](=[O:53])[NH:7][C@H:8]([C:12]([N:14]1[CH2:18][CH2:17][CH2:16][C@H:15]1[C:19]1[NH:20][C:21]([C:24]2[CH:25]=[CH:26][C:27]([C:30]3[CH:35]=[CH:34][C:33]([NH:36][C:37]([C:39]4[CH:40]=[N:41][C:42]([N:45]5[CH2:50][CH2:49][N:48]([C:77]([C@:73]6([CH3:80])[CH2:74][CH2:75][CH2:76][N:72]6[C:69](=[O:71])[CH3:70])=[O:78])[CH2:47][C@H:46]5[CH3:51])=[CH:43][CH:44]=4)=[O:38])=[CH:32][C:31]=3[CH3:52])=[CH:28][CH:29]=2)=[CH:22][N:23]=1)=[O:13])[CH:9]([CH3:11])[CH3:10]
Reactant: CC(=O)N1CCC[C@@]1(C)C(=O)O
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3ccc(NC(=O)c4ccc(N5CCNC[C@H]5C)nc4)cc3C)cc2)[nH]1)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3ccc(NC(=O)c4ccc(N5CCN(C(=O)[C@]6(C)CCCN6C(C)=O)C[C@H]5C)nc4)cc3C)cc2)[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.6 %

Procedure:
To a solution of [(((S)-2-methyl-1-{(S)-2-[5-(2′-methyl-4′-{[6-((R)-2-methyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-propyl)-carbamic acid methyl ester tri-HCl (15 mg, 0.019 mmol; Preparation 18) and N,N-diisopropylethylamine (33.1 uL, 0.190 mmol) dissolved in DMA (0.6 mL, 7 mmol) was added (S)-1-acetyl-2-methyl-pyrrolidine-2-carboxylic acid (3.2 mg, 0.019 mmol, Preparation 19) and HATU (11 mg, 0.028 mmol). The reaction mixture was stirred at room temperature overnight, concentrated, dissolved in 1:1 acetic acid:water (4 mL) and purified by preparative HPLC to provide the di-TFA salt of the title compound (9.1 mg). (m/z): [M+H]+ calcd for C46H57N9O6 832.44 found 832.4.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:11]=[C:10]([Cl:12])[N:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.Cl.[CH3:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][C:21]=1[O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[NH2:18]>O1CCOCC1>[ClH:1].[Cl:12][C:10]1[N:9]=[CH:8][C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH:18][C:17]3[CH:19]=[CH:20][C:21]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[C:15]([CH3:14])[CH:16]=3)[C:3]=2[CH:11]=1
Reactant: Clc1cc2c(Cl)ncnc2cn1
Reactant: Cc1cc(N)ccc1Oc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(Nc2ncnc3cnc(Cl)cc23)ccc1Oc1ccccc1
Temperature: 75 °C
Yield: 100 %

Procedure:
The 4,6-dichloro-pyrido[3,4-d]pyrimidine obtained from the previous reaction was taken up in dioxane (50 ml), the 3-methyl 4-phenoxy aniline hydrochloride (2.8 g, 12 mmol) was added and the contents heated to an external bath temperature of -80 oC for 3 hours, whereupon yellow precipitation occurred. Further dioxane (20 ml) was added and the contents heated at ˜75° C. for 12 hours. The solution was then filtered and the yellow solid placed under vacuum to provide the desired (6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-(3-methyl-4-phenoxy-phenyl)-amine hydrochloride (3.6 g, ˜100%). 1H NMR (CD3OD; 400 MHz) δ 9.05 (s, 1H), 8.87 (s, 1H), 8.64 (s, 1H), 7.69 (d, J=2.5 Hz, 1H), 7.58 (dd, J=8.7, 2.5 Hz, 1H),7.35 (dd, J=8.7, 7.5 Hz, 2H), 7.10 (t, J=7.2 Hz, 1H), 6.94 (d, J=8.7 Hz, 3H), 2.29 (s, 3H). MS m/z (MH+): 363.2
Reaction SMILES: O[CH:2]1[O:6][C:5](=O)[CH:4]=[C:3]1[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.[CH3:16][NH:17][NH2:18]>C(O)C>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:3]2[CH:2]=[N:18][N:17]([CH3:16])[C:5](=[O:6])[CH:4]=2)=[CH:9][CH:10]=1
Reactant: CNN
Reactant: COc1ccc(C2=CC(=O)OC2O)cc1
Solvent: CCO
Product: COc1ccc(-c2cnn(C)c(=O)c2)cc1
Temperature: 85 °C
Yield: 46 %

Procedure:
A suspension of 5-hydroxy-4-(4-methoxyphenyl)-5H-furan-2-one (2.06 g, 10 mmol) in 30 mL of ethanol was stirred as methylhydrazine (0.78 mL, 1.5 eq) was added dropwise. The reaction was heated to reflux at 85° C. for 2 h, then the solvent was reduced at reduced pressure to give a solid, which was collected and washed with cold EtOH to give 1.0 g (46%) of 5-(4-methoxy-phenyl)-2-methyl-2H-pyridazin-3-one: MS m/z 217 (M+H).
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][C@H:10]([N:13]([CH:21]2[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH2:22]2)[C:14](=O)[C:15]([CH3:19])([CH3:18])[CH2:16][OH:17])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].B.CSC>C1COCC1>[C:1]([N:8]1[CH2:12][CH2:11][CH:10]([N:13]([CH:21]2[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH2:22]2)[CH2:14][C:15]([CH3:19])([CH3:18])[CH2:16][OH:17])[CH2:9]1)([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC1(C)CCC(N(C(=O)C(C)(C)CO)[C@H]2CCN(C(=O)OC(C)(C)C)C2)CC1
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: CC1(C)CCC(N(CC(C)(C)CO)C2CCN(C(=O)OC(C)(C)C)C2)CC1
Temperature: 80 °C
Reaction time: 3 h
Yield: 69 %

Procedure:
To a solution of (3S)-1-Boc-3-[(4,4-dimethylcyclohexyl)(3-hydroxy-2,2-dimethylpropanoyl)amino]pyrrolidine (210 mg, 0.53 mmol) prepared in Step B of Example A8 in THF was added dropwise borane-methylsulfide complex (in THF, 2.0M, 0.4 ml, 0.8 mmol), and stirred at 80° C. for 3 h. After the reaction finished, the solvent was concentrated in vacuo, water added, extracted with EtOAc. The organic layer was dried over MgSO4, concentrated in vacuo, and purified by column chromatography (eluent: DCM/MeOH=9/1) to give the title compound (140 mg, 75%).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15]([C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[O:21])=[CH:14]3)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH:1]([N:4]1[CH2:5][CH2:6][CH:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:15]([C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[O:21])=[CH:14]3)[CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCOCC4)cc3c2)CC1
Reactant: OB(O)c1ccccc1
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCOCC2)n3-c2ccccc2)CC1

Procedure:
In analogy to the procedure described for the synthesis of example 6, the title compound was synthesized from [5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-morpholin-4-yl-methanone (intermediate 2) and phenylboronic acid. The title compound was obtained in 77% yield as yellow foam. MS (m/e): 448.2 (MH+, 100%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22][CH2:21]2)=[CH:16][CH:15]=1.[CH2:27]([O:35][C:36]1[CH:44]=[CH:43][C:39]([C:40](Cl)=[O:41])=[CH:38][CH:37]=1)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[CH2:21][CH2:22][CH:23]([O:26][C:40](=[O:41])[C:39]3[CH:38]=[CH:37][C:36]([O:35][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:44][CH:43]=3)[CH2:24][CH2:25]2)=[CH:16][CH:15]=1
Reactant: OC1CCC(c2ccc(OCCCCCCCCCCCBr)cc2)CC1
Reactant: CCCCCCCCOc1ccc(C(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCOc1ccc(C(=O)OC2CCC(c3ccc(OCCCCCCCCCCCBr)cc3)CC2)cc1
Temperature: 25 °C
Yield: 81.9 %

Procedure:
3 g (7.05 mmol) of 4-[4-(11-Bromo-undecyloxy)-phenyl]-cyclohexanol obtained in Step 2 and 2.02 g (7.52 mmol) of 4-Octyloxy-benzoyl chloride are dissolved in 100 mL of dry CH2Cl2. 0.95 g (7.52 mmol) of DMAP are added. The mixture is stirred at room temperature over night. The solvent is distilled off and then the resulting product is purified by column chromatography on silica gel using CH2Cl2 as eluent to give a pure product as a white solid (3.8 g, 82% yield).
Reaction SMILES: [C:1]1([O:11][CH2:12][CH2:13][OH:14])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.CS(Cl)(=O)=O.[O:20]=[C:21]1[C:26]2[CH:27]=[CH:28][C:29](O)=[C:30]([CH2:31][CH2:32][CH3:33])[C:25]=2[O:24][C:23]([CH2:42][CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45])([CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:22]1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.C(N(CC)CC)C>[O:20]=[C:21]1[C:26]2[CH:27]=[CH:28][C:29]([O:14][CH2:13][CH2:12][O:11][C:1]3[C:10]4[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=4[CH:4]=[CH:3][CH:2]=3)=[C:30]([CH2:31][CH2:32][CH3:33])[C:25]=2[O:24][C:23]([CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])([CH2:42][CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH2:22]1
Reactant: OCCOc1cccc2c1CCCC2
Reactant: CCCc1c(O)ccc2c1OC(CCC(=O)OCC)(CCC(=O)OCC)CC2=O
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCc1c(OCCOc2cccc3c2CCCC3)ccc2c1OC(CCC(=O)OCC)(CCC(=O)OCC)CC2=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 26.2 %

Procedure:
A solution of 202 mg (1.05 mmol) of the title product of Example 59 in 10 ml of CH2Cl2 was cooled with stirring to 0° C. and treated sequentially with 370 mg (3.70 mmol) of triethylamine and 362 mg (3.15 mmol) of methanesulfonyl chloride. After one hour, the mixture was treated with another 370 mg of triethylamine and 362 mg of methanesulfonyl chloride. After one-half hour, the mixture was washed successively with water, aqueous sodium bicarbonate solution, dilute aqueous hydrochloric acid, and water. The organic phase was dried (MgSO4), filtered, and the solvent removed under reduced pressure. The residue was taken up in 10 ml of dimethylformamide. To the resulting solution was added 406 mg (1.00 mmol) of the title product of Example 1 and 290 mg (2.10 mmol) of anhydrous potassium carbonate. The mixture was stirred overnight at room temperature. Another 290 mg of potassium carbonate was then added, and stirring was continued at 60° C. for six hours. The mixture was allowed to cool, and the solvent was removed under reduced pressure. The residue was partitioned between ethyl acetate and water. The aqueous layer was further extracted with two portions of ethyl acetate. The combined organic extracts were washed successively with water and with brine, dried (Na2SO4), filtered, and the solvent removed under reduced pressure. The residue was chromatographed over silica gel. Elution with 15% ethyl acetate/toluene produced 152 mg of the title compound as a solid.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>C(Cl)Cl>[CH3:15][S:16]([O:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1)(=[O:18])=[O:17]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.7 %

Procedure:
To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (4.50 g, 22.4 mmol, 1.0 eq) and TEA (11.3 g, 5.0 eq) in DCM (30.0 mL) at 0° C. was added MsCl (5.10 g, 44.5 mmol, 2.0 eq) in DCM (10.0 mL) dropwise. The resulting mixture was stirred at 0° C. for 30 min and then warmed to room temperature with stirring for 3 hr. After being quenched with water and extracted with ethyl acetate, the organic layers were combined, washed with brine, dried over MgSO4, filtered, and evaporated to afford the crude product, which was purified via silica gel chromatography eluting with EtOAc/petroleum ether (1:5) to afford tert-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate (4.8 g, 77% yield) as pale yellow solid. LCMS (ESI) m/z: 224.1 [M-56+H+].
Reaction SMILES: [C:1]1([NH:7][C:8]([O:10][CH:11]2[CH2:16][C:15]([CH3:18])([CH3:17])[N:14]([CH2:19][CH:20]([OH:27])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:13]([CH3:29])([CH3:28])[CH2:12]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:30]1([N:36]=[C:37]=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.N12CCN(CC1)CC2>C1C=CC=CC=1>[C:1]1([NH:7][C:8]([O:10][CH:11]2[CH2:16][C:15]([CH3:18])([CH3:17])[N:14]([CH2:19][CH:20]([O:27][C:37](=[O:38])[NH:36][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:13]([CH3:29])([CH3:28])[CH2:12]2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC1(C)CC(OC(=O)Nc2ccccc2)CC(C)(C)N1CC(O)c1ccccc1
Reactant: O=C=Nc1ccccc1
Agent: C1CN2CCN1CC2
Solvent: c1ccccc1
Product: CC1(C)CC(OC(=O)Nc2ccccc2)CC(C)(C)N1CC(OC(=O)Nc1ccccc1)c1ccccc1

Procedure:
A mixture of 3.0 parts of the products from Example 81, 0.90 parts of phenyl isocyanate and 0.1 parts of 1,4-diazabicyclo[2,2,2]octane in 25 parts of dry benzene was heated under reflux conditions for 24 hours. The benzene solvent was removed by distillation under reduced pressure and the residue crystallised from petroleum ether (b.p. 60°-80° C.) to give 4-phenylcarbamoyloxy-1-[2'-(phenylcarbamoyloxy)-2'-phenylethyl]-2,2,6,6-tetramethylpiperidine having a melting point of 173° C. and the following elemental analysis by weight
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:16]#[C:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:8]([NH:10]C(=O)CCC)[CH:9]=1)([O-:3])=[O:2].CC(C)([O-])C.[K+].O>CN1CCCC1=O>[N+:1]([C:4]1[CH:9]=[C:8]2[C:7]([CH:16]=[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCCC(=O)Nc1cc([N+](=O)[O-])ccc1C#Cc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: O=[N+]([O-])c1ccc2cc(-c3ccccc3)[nH]c2c1
Temperature: 70 °C
Reaction time: 16 h
Yield: 39.1 %

Procedure:
To a solution of N-(5-nitro-2-(phenylethynyl)phenyl)butyramide (580 mg, 1.88 mmol) in 1-Methyl-2-pyrrolidinone (20 mL) under nitrogen was added potassium tert-butoxide (243 mg, 2.16 mmol). The resulting solution was heated at 70° C. for 6 h, and then left at room temperature for 16 h. Water was added and the aqueous layer was extracted several times with ethyl acetate. The combined organic layers were washed 10 times with water, 3 times with brine, dried over anhydrous MgSO4 and evaporated. The resulting material was purified by column chromatography eluting with ethyl acetate/hexanes 15:85 v/v to afford 175 mg (39%) of the title compound.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:13][CH3:14])[CH2:4]1.C([O-])(=O)C.[Na+].[Br:20]Br>C(O)(=O)C>[NH2:2][C@@H:3]1[CH2:12][CH2:11][C:10]2[C:5](=[C:6]([Br:20])[CH:7]=[CH:8][C:9]=2[O:13][CH3:14])[CH2:4]1
Reactant: COc1cccc2c1CC[C@@H](N)C2
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(Br)c2c1CC[C@@H](N)C2
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
(R)-2-Amino-5-methoxy-1,2,3,4tetrahydronaphthalene hydrochloride (5.0 g, 23 mmol) was dissolved in acetic acid (300 mL) under nitrogen atmosphere. Sodium acetate (5.5 g, 70 mmol) was added and bromine (3.5 g, 23 mmol) was then added in one portion. The mixture was stirred for 5 minutes at room temperature. The solvent was removed in vacuo to give a solid residue which was partitioned between ethyl acetate and NaOH (2 M). The layers were separated and the aqueous phase was extracted twice with ethyl acetate. The organic layers were combined and dried (Na2SO4). The solvent was removed in vacuo to give a brown oily residue. The HCl salt was precipitated from diethyl ether/methylene chloride by the addition of HCl in diethyl ether (3 M): yield 7.7 g (94%). Recrystallization from methanol gave the title compound as needle crystals: mp 264-265° C.; [α]21D +54° (c 1, MeOH); EIMS (70 eV) m/z (relative intensity) 257 (30, M+, 81Br), 255 (31, M+, 79Br).
Reaction SMILES: C[N:2]([CH3:15])[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1)=O.N[C:17]1[C:21]([C:22]#[N:23])=C[NH:19][N:18]=1>C(O)(=O)C>[CH3:14][O:13][C:9]1[CH:8]=[C:7]([C:5]2[N:19]3[N:18]=[CH:17][C:21]([C:22]#[N:23])=[C:15]3[N:2]=[CH:3][CH:4]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: N#Cc1c[nH]nc1N
Reactant: COc1cccc(C(=O)C=CN(C)C)c1
Solvent: CC(=O)O
Product: COc1cccc(-c2ccnc3c(C#N)cnn23)c1

Procedure:
A mixture of 6.15 g. of 3-dimethylamino-3'-methoxyacrylophenone and 3.16 g. of 3-aminopyrazole-4-carbonitrile in 50 ml. of glacial acetic acid is refluxed for 15 hours and then cooled. The precipitate is recovered by filtration giving the desired product, m.p. 165°-166° C.
Reaction SMILES: C(S[C:9]([CH2:11][C:12]1[O:16][C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:14][CH:13]=1)=[NH:10])C1C=CC=CC=1.[NH2:22][CH:23]([C:27]#[N:28])[C:24]([NH2:26])=[O:25].C(=O)([O-])O.[Na+]>CO>[NH2:28][C:27]1[NH:10][C:9]([CH2:11][C:12]2[O:16][C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:14][CH:13]=2)=[N:22][C:23]=1[C:24](=[O:25])[NH2:26]
Reactant: CCOC(=O)c1ccc(CC(=N)SCc2ccccc2)o1
Reactant: N#CC(N)C(N)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)c1ccc(Cc2nc(C(N)=O)c(N)[nH]2)o1
Reaction time: 5 h
Yield: 68 %

Procedure:
30.5 g (0.09 M) of ethyl 5-benzylsulfanylcarbonimidoylmethylfuran-2-carboxylate, 8.9 g (0.09 M) of aminocyanoacetamide and 7.5 g (0.09 M) of sodium hydrogen carbonate in 180 ml of methanol are refluxed with stirring for 5 hours. The crude product obtained is purified by chromatography on silica using a dichloromethane/methanol mixture (90/10) as eluent, to give 17 g of ethyl 5-(5-amino-4-carbamoyl-1H-imidazol-2-ylmethyl)furan-2-carboxylate in the form of a vitreous brown solid.