Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.CN1CCOCC1.[O:14](C(OC(C)(C)C)=O)[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=O>C(Cl)Cl>[C:15]([N:1]1[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:14]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: C1=CCNCC1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CC=CCC1
Temperature: 25 °C
Reaction time: 36 h

Procedure:
To 1.66 g of 1,2,5,6-tetrahydropyridine in 25 ml of CH2Cl2, 2.02 g of N-methylmorpholine are added, the mixture obtained is treated with a solution of 4.36 g (BOC)2O in 30 ml of CH2Cl2 and the mixture obtained is stirred for ca. 36 hours at RT. N-BOC-1,2,5,6-tetrahydropyridine is obtained. 1H-NMR: 5.82(m,1H,HIV), 5.64(m,1H,HIII), 3.86(b,2H,HII), 3.47(t,2H,HVI), 2.12(b,1H,HV), 1.46(m,9H,(CH3)3).
Reaction SMILES: [H-].[Na+].S(Cl)(=O)(=O)N.O.[S:9](=[O:13])(=[O:12])([OH:11])[NH2:10].O[CH2:15][C@:16]1([O:25][CH2:24][C@@H:22]([OH:23])[C@@H:20]([OH:21])[C@@H:18]1[OH:19])[OH:17]>CN(C=O)C>[CH3:15][C:16]1([CH3:18])[O:21][C@@H:20]2[C@@H:22]([CH2:24][O:25][C@@:16]3([CH2:15][O:12][S:9]([NH2:10])(=[O:11])=[O:13])[O:17][C:22]([CH3:24])([CH3:20])[O:19][C@H:18]32)[O:23]1
Reactant: OC[C@@]1(O)OC[C@@H](O)[C@@H](O)[C@@H]1O
Reactant: NS(=O)(=O)O
Agent: NS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)O[C@@H]2[C@@H](CO[C@@]3(COS(N)(=O)=O)OC(C)(C)O[C@@H]23)O1
Reaction time: 1.5 h

Procedure:
To a cold solution (-4° C.) of 2,3:4,5-di-O-isopropylidene-β-fructopyranose (75 g, 0.29 mol) in DMF (725 ml) was added 50% oily sodium hydride (16.34 g, 0.34 mol as NaH). After stirring for 90 min, sulfamoyl chloride (54.9 g, 0.48 mol) was added and the stirring continued for an additional 3.5 hr at that temperature. The reaction mixture was poured into cold water and extracted with toluene. The organic layer was dried (Na2SO4) and the solvents removed under vacuum to give a syrup which crystallized immediately. Recrystallization from ethylacetate/hexane gave pure 2,3:4,5-bis-O-methylethylidene)-β-D-fructopyranose sulfamate, mp 125°-126° C.
Reaction SMILES: [CH3:1][C:2]1([OH:39])[CH:25]=[C:24]2[C@:19]([CH3:37])([CH2:20][CH2:21][C@H:22]([O:26][Si:27]([CH:34]([CH3:36])[CH3:35])([CH:31]([CH3:33])[CH3:32])[CH:28]([CH3:30])[CH3:29])[CH2:23]2)[C@@H:18]2[C@@H:3]1[C@H:4]1[C@:15]([CH3:38])([CH2:16][CH2:17]2)[C@@H:7]([C@H:8]([CH3:14])[CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH2:6][CH2:5]1.[CH3:40][Si](C=[N+]=[N-])(C)C.N#N>C1(C)C=CC=CC=1.CO>[OH:39][C:2]1([CH3:1])[CH:25]=[C:24]2[C@:19]([CH3:37])([CH2:20][CH2:21][C@H:22]([O:26][Si:27]([CH:28]([CH3:30])[CH3:29])([CH:31]([CH3:32])[CH3:33])[CH:34]([CH3:36])[CH3:35])[CH2:23]2)[C@@H:18]2[C@@H:3]1[C@H:4]1[C@:15]([CH3:38])([CH2:16][CH2:17]2)[C@@H:7]([C@H:8]([CH3:14])[CH2:9][CH2:10][C:11]([O:13][CH3:40])=[O:12])[CH2:6][CH2:5]1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)[Si](O[C@H]1CC[C@@]2(C)C(=CC(C)(O)[C@H]3[C@@H]4CC[C@H]([C@H](C)CCC(=O)O)[C@@]4(C)CC[C@@H]32)C1)(C(C)C)C(C)C
Agent: N#N
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@H]3[C@H](CC[C@]12C)[C@@]1(C)CC[C@H](O[Si](C(C)C)(C(C)C)C(C)C)CC1=CC3(C)O

Procedure:
To a solution of 7-hydroxy-7-methyl-3β-triisopropylsilyl-oxychol-5-en-24-oic acid (5) (5.38 g, 9.68 mmoles) in toluene (70 ml) and methanol (20 ml) was added dropwise at room temperature trimethylsilyldiazomethane (2.0N in hexane, ~5 ml). After 30 minutes N2 evolution ceased, and the reaction mixture was a pale yellow. The solvent was removed in vacuo to give 4.67 g of crude 6 as a brown syrup. NMR (CDCl3) indicated a mixture of 7-isomers: δ0.69 (two peaks, 18-Me); 3.63 (s, CO2Me); 5.12 & 5.18 (6-H). The mixture was used directly in the next reaction (Example 6).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[C:12]([OH:14])=O.[CH3:20][CH:21]([NH2:23])[CH3:22]>>[OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[C:12]([NH:23][CH:21]([CH3:22])[CH3:20])=[O:14]
Reactant: COc1ccc(C(=O)O)cc1OC1CCCCC1O
Reactant: CC(C)N
Product: COc1ccc(C(=O)NC(C)C)cc1OC1CCCCC1O

Procedure:
Prepared as in Example 24a from (±)-3-((2-hydroxycyclohexyl)oxy)-4-methoxybenzoic acid (Example 129e) and propan-2-amine as a white solid (80%). 1H NR (400 MHz, DMSO-d6) δ 1.14 (d, J=8.0 Hz, 6H), 1.25-1.30 (m, 4H), 1.61 (m, 2H), 1.85 (m, 2H), 3.56 (m, 1H), 3.79 (s, 3H), 4.03-4.12 (m, 2H), 4.81 (d, J=4.0 Hz, 1H), 6.98 (d, J=8.0 Hz, 1H), 7.45-7.49 (m, 2H), 8.01 (d, J=8.0 Hz, 1H). MS 308 (MH+).
Reaction SMILES: Br[C:2]1[C:3]([Cl:32])=[CH:4][C:5]([O:30][CH3:31])=[C:6]([NH:8][C@@H:9]([CH3:29])[C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH:18]3[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:19]3)[CH2:14][CH2:13]2)=[O:11])[CH:7]=1.[CH:33]1(B(O)O)[CH2:35][CH2:34]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>CN(C=O)C.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:32][C:3]1[C:2]([CH:33]2[CH2:35][CH2:34]2)=[CH:7][C:6]([NH:8][C@@H:9]([CH3:29])[C:10]([N:12]2[CH2:13][CH2:14][N:15]([CH:18]3[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:19]3)[CH2:16][CH2:17]2)=[O:11])=[C:5]([O:30][CH3:31])[CH:4]=1
Reactant: OB(O)C1CC1
Reactant: COc1cc(Cl)c(Br)cc1N[C@@H](C)C(=O)N1CCN(C2CN(C(=O)OC(C)(C)C)C2)CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(Cl)c(C2CC2)cc1N[C@@H](C)C(=O)N1CCN(C2CN(C(=O)OC(C)(C)C)C2)CC1
Temperature: 80 °C
Reaction time: 16 h
Yield: 61.5 %

Procedure:
A mixture of (S)-tert-butyl 3-(4-(2-((5-bromo-4-chloro-2-methoxyphenyl)amino)propanoyl)piperazin-1-yl)azetidine-1-carboxylate (700 mg, 1.32 mmol), cyclopropylboronic acid (114 mg, 1.32 mmol), Pd(OAc)2 (15 mg, 0.066 mmol), tricyclohexylphosphine (37 mg, 0.132 mmol), K3PO4.3H2O (974 mg, 4.62 mmol) in DMF (10 mL) and H2O (0.5 mL) was stirred under argon at 80° C. for 16 h. The mixture was allowed to cool to RT, and then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (methanol/dichloroethane=1:100) to afford the desired product (400 mg, 62%). ESI-MS m/z: 493.2[M+H]+.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][O:9][C:10]1[CH:62]=[CH:61][C:13]([CH2:14][N:15]([CH2:52][C:53]2[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[CH:55][CH:54]=2)[C:16]2[N:21]=[C:20]([CH3:22])[N:19]=[C:18]([C:23]3[CH:24]=[C:25]([CH2:38][CH:39]4[CH2:44][CH2:43][N:42](C(OC(C)(C)C)=O)[CH2:41][CH2:40]4)[CH:26]=[N:27][C:28]=3[NH:29][C:30]3[CH:31]=[N:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=3)[N:17]=2)=[CH:12][CH:11]=1.C(Cl)Cl.[CH3:66][S:67](Cl)(=[O:69])=[O:68]>>[CH3:8][O:9][C:10]1[CH:62]=[CH:61][C:13]([CH2:14][N:15]([CH2:52][C:53]2[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[CH:55][CH:54]=2)[C:16]2[N:17]=[C:18]([C:23]3[C:28]([NH:29][C:30]4[CH:31]=[N:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=4)=[N:27][CH:26]=[C:25]([CH2:38][CH:39]4[CH2:44][CH2:43][N:42]([S:67]([CH3:66])(=[O:69])=[O:68])[CH2:41][CH2:40]4)[CH:24]=3)[N:19]=[C:20]([CH3:22])[N:21]=2)=[CH:12][CH:11]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CC4CCN(C(=O)OC(C)(C)C)CC4)cnc3Nc3ccc(OC)nc3)n2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CC4CCN(S(C)(=O)=O)CC4)cnc3Nc3ccc(OC)nc3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.7 %

Procedure:
TFA (4.00 mL, 51.9 mmol) was slowly added to a slightly cooled stirred solution of tert-butyl 4-((5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)pyridin-3-yl)methyl)piperidine-1-carboxylate (0.2611 g, 0.350 mmol) in DCM (5.00 mL, 78 mmol) and the mixture was stirred at room temperature for 1 h. The mixture was concentrated (under vacuum to remove as much TFA as possible). The sticky residue was taken up in DCM (10.00 mL) and TEA (0.487 mL, 3.50 mmol) followed by methanesulfonyl chloride (0.082 mL, 1.049 mmol) were slowly added at 0° C. The mixture was stirred for 1 h and then concentrated. The crude product was partitioned between 1 N NaOH(aq) and DCM (20 mL each). The separated aqueous layer was extracted with DCM (2×20 mL) and the combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give the crude residue which was purified with flash column chromatography (ISCO Combiflash system, 10% to 50% ethyl acetate in hexanes) to give the desired product N,N-bis(4-methoxybenzyl)-4-(2-(6-methoxypyridin-3-ylamino)-5-((1-(methylsulfonyl)piperidin-4-yl)methyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (0.1923 g, 0.265 mmol, 76% yield) as a yellow film. m/z (ESI, +ve ion) 725.2 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[S:15]1[CH:19]=[C:18]([C:20]2[C:29]3[N:28]=[CH:27][CH:26]=[N:25][C:24]=3[C:23]([C:30](O)=[O:31])=[CH:22][CH:21]=2)[C:17]2[CH:33]=[CH:34][CH:35]=[CH:36][C:16]1=2>C(Cl)Cl.CO>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[CH:12][C:11]([NH:14][C:30]([C:23]3[C:24]4[N:25]=[CH:26][CH:27]=[N:28][C:29]=4[C:20]([C:18]4[C:17]5[CH:33]=[CH:34][CH:35]=[CH:36][C:16]=5[S:15][CH:19]=4)=[CH:21][CH:22]=3)=[O:31])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: O=C(O)c1ccc(-c2csc3ccccc23)c2nccnc12
Reactant: CN1CCN(c2ccc(N)cn2)CC1
Solvent: ClCCl
Solvent: CO
Product: CN1CCN(c2ccc(NC(=O)c3ccc(-c4csc5ccccc45)c4nccnc34)cn2)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but stirring the reaction mixture for 20 h at rt, using 6-(4-methylpiperazin-1-yl)-pyridin-3-ylamine (prepared as described in Example 33 but using N-methyl-piperazine in Step 33.2) and 8-benzo[b]thiophen-3-yl-quinoxaline-5-carboxylic acid (Example 59). Title compound: ESI-MS: 481.0 [M+H]+; tR=3.81 min (System 1); TLC: Rf=0.40 (DCM/MeOH, 9:1).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH3:20][O:21][CH2:22][CH2:23][NH2:24]>>[CH3:20][O:21][CH2:22][CH2:23][NH:24][C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1nc2cccc(Cl)n2n1)c1ccccc1
Reactant: COCCN
Product: COCCNc1cccc2nc(NC(=O)c3ccccc3)nn12

Procedure:
The title compound was prepared following procedure described for example 30 but starting from N-(5-chloro[1,2,4]triazolo[1,5-a]pyridin-2-yl)benzamide ((B3), 50 mg; 0.18 mmol; 1.0 eq.) and 2-methoxyethylamine (1.0 mL) as an off-white solid (52 mg, 91%). HPLC, Rt: 2.08 min. (purity 90.1%). LC/MS, M+(ESI): 312.1, M−(ESI): 310.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH:13][C:14](=[O:25])OC2C=CC([N+]([O-])=O)=CC=2)[CH2:7]1.[CH2:30]([NH2:33])[C:31]#[CH:32].ClCCl>C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH:13][C:14]([NH:33][CH2:30][C:31]#[CH:32])=[O:25])[CH2:7]1
Reactant: C#CCN
Reactant: O=C(NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CCNC(=O)NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Yield: 86.5 %

Procedure:
Example 56 was prepared in an analogous manner to Example 43 from Intermediate 10 (0.040 g) and propargylamine (0.006 g) using dichloromethane and triethylamine at a temperature of 22° C. to yield the title compound (0.028 g).
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].[C:5]1(=[O:11])[O:10][C:8](=[O:9])[CH:7]=[CH:6]1>C1COCC1>[CH2:1]([NH:4][C:5](=[O:11])/[CH:6]=[CH:7]\[C:8]([OH:10])=[O:9])[CH:2]=[CH2:3]
Reactant: C=CCN
Reactant: O=C1C=CC(=O)O1
Solvent: C1CCOC1
Product: C=CCNC(=O)/C=C\C(=O)O

Procedure:
Allylamine reacts readily with maleic anhydride in THF to give N-allylmaleamic acid (VIII) in quantitative yield. VIII reacts with bisulfite in water to form 3-carboxy-3-sulfo-N-allyl propionamide (IX). At 160° C., (IX) cyclolyzes slowly to form N-allyl-sulfo-succinimide (X).
Reaction SMILES: [CH3:1][O:2][C:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([CH3:16])[CH:10]=2)[N:4]=1.[C:17]([CH2:20][C:21](=O)[CH3:22])(=[O:19])[CH3:18]>C(O)(=O)C>[CH3:1][O:2][C:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:21](=[CH:20][C:17](=[O:19])[CH3:18])[CH3:22])=[C:11]([CH3:16])[CH:10]=2)[N:4]=1
Reactant: CC(=O)CC(C)=O
Reactant: COc1nn(-c2ccc(N)c(C)c2)c(=O)o1
Solvent: CC(=O)O
Product: COc1nn(-c2ccc(NC(C)=CC(C)=O)c(C)c2)c(=O)o1

Procedure:
The latter compound was obtained by reacting 5-methoxy-3-(4-amino-3-methylphenyl)-3H-(1,3,4)oxadiazol-2-one with equimolar amounts of acetylacetone in glacial acetic acid at 80° C. and was isolated by precipitation by adding water and filtration.
Reaction SMILES: [O:1]1[CH2:10][CH:2]1[CH2:3][C:4]1[N:8]=[C:7]([CH3:9])[O:6][N:5]=1.[N:11]1([C:22](=[O:23])[C:21]2[NH:20][CH:19]=[N:18][C:17]=2[N:15]([CH3:16])[C:13]1=[O:14])[CH3:12]>C(O)(C)C.N1C=CC=CC=1>[OH:1][CH:2]([CH2:3][C:4]1[N:8]=[C:7]([CH3:9])[O:6][N:5]=1)[CH2:10][N:20]1[C:21]2[C:22](=[O:23])[N:11]([CH3:12])[C:13](=[O:14])[N:15]([CH3:16])[C:17]=2[N:18]=[CH:19]1
Reactant: Cn1c(=O)c2[nH]cnc2n(C)c1=O
Reactant: Cc1nc(CC2CO2)no1
Solvent: CC(C)O
Solvent: c1ccncc1
Product: Cc1nc(CC(O)Cn2cnc3c2c(=O)n(C)c(=O)n3C)no1
Yield: 86 %

Procedure:
1.4 g. 3-(2,3-epoxy-propyl)-5-methyl-1,2,4-oxadiazole and 1.8 g. of theophylline are boiled under stirring in a mixture of 20 cm3 isopropyl alcohol and 0.1 cm3 of pyridine for 8 hours. 2.75 g. (86% yield) of 7-[2-hydroxy-3-(5-methyl-1,2,4-oxadiazol-3-yl)-propan-1-yl]-theophylline are obtained.
Reaction SMILES: [F:1][C@:2]1([CH3:18])[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:15]=[CH:14][C:13](=[O:16])[NH:12][C:11]1=[O:17].N1C=NN=N1.C(N([CH:31]([O:39][P:40]([O-])[O-:41])N(C(C)C)C(C)C)C(C)C)(C)C>N1C=CC=CC=1.C(#N)C>[F:1][C@:2]1([CH3:18])[C@@H:6]2[O:7][P@:40]([O:39][CH3:31])(=[O:41])[O:9][CH2:8][C@H:5]2[O:4][C@H:3]1[N:10]1[CH:15]=[CH:14][C:13](=[O:16])[NH:12][C:11]1=[O:17]
Reactant: C[C@@]1(F)[C@H](O)[C@@H](CO)O[C@H]1n1ccc(=O)[nH]c1=O
Reactant: CC(C)N(C(C)C)C(OP([O-])[O-])N(C(C)C)C(C)C
Agent: c1nnn[nH]1
Solvent: c1ccncc1
Solvent: CC#N
Product: CO[P@@]1(=O)OC[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@](C)(F)[C@@H]2O1
Reaction time: 2 h

Procedure:
To a stirred solution of 1-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyltetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione (730 mg, 2.8 mmol) in dry pyridine (15 mL) was added a 0.45M solution of tetrazole in acetonitrile (15 mL) followed by bis(N,N-diisopropylamino)methylphosphite (0.971 mL, 3.3 mmol) at room temperature. After 2 h, TLC indicated disappearance of the starting material and two non-polar products. The reaction mixture was concentrated under reduced pressure at room temperature and the residue was triturated with EtOAc (30 mL). Tetrazole salts precipitated were filtered off and the filtrate was concentrated under reduced pressure. The residue was chromatographed using 0-40% EtOAc/hexanes gradient to give pure product 2 (92 mg) and mixture of product 1&2 (102 mg). 1H NMR confirmed that the product 2 is a single isomer of the required compound. Stereochemistry is not determined.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH2:9].C(N(CC)CC)C.[CH2:17]([S:20](Cl)(=[O:22])=[O:21])[CH2:18][CH3:19].Cl>O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:20]([CH2:17][CH2:18][CH3:19])(=[O:22])=[O:21]
Reactant: Nc1ccc(F)cc1F
Reactant: CCCS(=O)(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCS(=O)(=O)Nc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2,4-difluoro-phenylamine (42, 3.0 mL, 29.8 mmol) in tetrahydrofuran (50 mL) were added triethylamine (9.13 mL, 65.5 mmol) and propane-1-sulfonyl chloride (2.90 mL, 25.8 mmol) under an atmosphere of nitrogen. The reaction was stirred at room temperature overnight. The reaction was poured into 1 M HCl and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give the compound (72, 2.0 g, 28%) that was used in the next step.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C=CC(O)=CC=1)O.[CH3:20][C:21]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH2:22].S(=O)(=O)(O)O.[CH3:33][C:34]([C:41]1[CH:47]=[C:46]([OH:48])[CH:45]=[CH:44][C:42]=1[OH:43])([CH3:40])[CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37]>O>[CH3:22][C:21]([C:45]1[CH:44]=[C:42]([OH:43])[C:41]([C:34]([CH3:40])([CH3:33])[CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:47][C:46]=1[OH:48])([CH3:20])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25]
Reactant: C=C(C)CC(C)(C)C
Reactant: CC(C)(C)CC(C)(C)c1cc(O)ccc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)(O)O
Agent: Oc1ccc(O)cc1
Solvent: O
Product: CC(C)(C)CC(C)(C)c1cc(O)c(C(C)(C)CC(C)(C)C)cc1O
Temperature: 58 °C

Procedure:
To a 500 mL, 3-neck, round-bottom flask equipped with a stirrer, thermocouple and nitrogen are added 67 weight percent p-toluenesulfonic acid (PTSA) in water (33.5 g), hydroquinone (20.0 g, 0.18 moles), diisobutylene (101.8 g, 0.91 moles) and 95% aqueous sulfuric acid (11.2 g, 0.112 moles). This mixture is heated to 58° C. under a nitrogen blanket with stirring. After 14 hours reaction time at 58° C., diisobutylene (50 g) is added and the lower aqueous phase (containing PTSA, sulfuric acid, hydroquinone, mono-(1,1,3,3-tetramethylbutyl)hydroquinone and small amounts of other polar side products) is transferred to another reactor. The diisobutylene phase is washed with 150 g water two times at 50° C. and once at 85°. The remaining clear organic phase at 85° C. is cooled to 70° C. and eventually to 0-10° C. and the 2,5-bis(1,1,3,3-tetramethylbutyl)hydroquinone product which crystallizes is collected by filtration. The product is washed with 60 g cold diisobutylene and dried at room temperature overnight. The 2,5-bis(1,1,3,3-tetramethylbutyl)hydroquinone product is obtained in a yield of 73% product and a purity greater than 98.5%.
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[O:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]=1[C:23](=[O:25])[CH3:24].[CH2:26](I)[CH2:27][CH2:28][CH3:29].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:26]([O:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[C:17]([C:23](=[O:25])[CH3:24])[CH:18]=1)[CH2:27][CH2:28][CH3:29]
Reactant: CCCCI
Reactant: COc1cc2nccc(Oc3ccc(O)cc3C(C)=O)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCOc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)c(C(C)=O)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.2 %

Procedure:
1-[2-(6,7-Dimethoxy-quinolin-4-yloxy)-5-hydroxy-phenyl]-ethanone (compound 176) (54 mg) was dissolved in N,N-dimethylformamide (2 ml) to prepare a solution. Butyl iodide (88 mg) and potassium carbonate (110 mg) were added to the solution, and the mixture was stirred at room temperature for 3 hr. The solvent was removed by distillation under the reduced pressure, water was then added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-hexane to give the title compound (41 mg, yield 65%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:14][S:15]([C:17]2[NH:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]=2)=[O:16])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[C:26]([CH2:29][NH:30][C:31](=[O:44])[CH2:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1)(=[O:28])[NH2:27]>ClCCl.C(N(CC)CC)C>[C:26]([CH2:29][NH:30][C:31](=[O:44])[CH2:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([S:40]([N:21]2[C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]=[C:17]2[S:15]([CH2:14][C:3]2[C:2]([CH3:1])=[C:7]([O:8][CH2:9][C:10]([F:13])([F:11])[F:12])[CH:6]=[CH:5][N:4]=2)=[O:16])(=[O:41])=[O:42])=[CH:36][CH:35]=1)(=[O:28])[NH2:27]
Reactant: NC(=O)CNC(=O)COc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2ccccc2[nH]1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2ccccc2n1S(=O)(=O)c1ccc(OCC(=O)NCC(N)=O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 74 %

Procedure:
2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole (185 mg) was dissolved in 20 ml of dichloromethane and 0.5 ml of triethylamine, and N-(carbamoylmethyl)-2-[4-(chlorosulfonyl)phenoxy]acetamide (158 mg) was added. The reaction mixture was stirred at room temperature for 24 hr. Dichloromethane (100 ml) was added to the reaction mixture. The reaction mixture was washed with saturated NaCl solution, and 0.1N sodium bicarbonate solution. Dichloromethane layer was separated and dried over anhydrous magnesium sulfate. Dichloromethane was evaporated under reduced pressure to give syrupy material, which was lyophilized in vacuo. 237 mg of the titled product was obtained.
Reaction SMILES: [CH:1]([N:14]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]([CH2:23]Cl)=[CH2:22])[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.O>C(O)C>[CH:1]([N:14]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]([CH2:23][N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH2:22])[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C(CCl)CN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: C1CCNCC1
Solvent: CCO
Solvent: O
Product: C=C(CN1CCCCC1)CN1CCN(C(c2ccccc2)c2ccccc2)CC1

Procedure:
A mixture of 7.0 g of 1-benzhydryl-4-(2-chloromethyl-2-propenyl)-piperazine (0.0205 mole) and 6.98 g of piperidine (0.082 mole) in 150 ml of absolute ethanol is heated until it has dissolved completely, and subjected to reflux for 3 hours. Then, it is conditioned to room temperature and the ethanol is removed by distillation. The resulting crude reaction product is treated with distilled water several times until a solid material is obtained which is then filtered and washed abundantly with water. By recrystallization from ethanol, 7.4 g crystals of 1-benzhydryl-4-(2-(1-piperidinylmethyl)-2-propenyl)-piperazine (I, R1 =benzhydryl, R2 =2-(1-piperidinylmethyl-2-propenyl) are obtained. Yield: 94%; m.p. 99°-102° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:28])[C:10]([C:16]1[CH:17]=[CH:18][C:19]2[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=2[CH:27]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[CH3:29][O:30][C:31]([C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)=[O:32]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.N1C=CC=CC=1>[CH3:29][O:30][C:31](=[O:32])[C:33]1[CH:38]=[CH:37][C:36]([O:8][C:6]2[CH:5]=[CH:4][C:3]([CH:9]([CH3:28])[C:10]([OH:15])([C:16]3[CH:17]=[CH:18][C:19]4[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=4[CH:27]=3)[C:11]([F:12])([F:13])[F:14])=[C:2]([Cl:1])[CH:7]=2)=[CH:35][CH:34]=1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Product: COC(=O)c1ccc(Oc2ccc(C(C)C(O)(c3ccc4c(c3)N(C)C(=O)CO4)C(F)(F)F)c(Cl)c2)cc1

Procedure:
In analogy to Example 5, 6-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (Example 56, step 4) was reacted with 4-methoxycarbonyl-phenylboronic acid, copper-(II)-acetate and pyridine to give the title compound as a white solid. MS (m/e, ISP neg. ion)=548.2 [M−H+]