Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OO.[N:3]1([CH2:9][CH2:10][CH2:11][NH:12][C:13]2[N:14]=[N+:15]([O-:26])[C:16]3[CH:22]=[C:21]4[O:23][CH2:24][CH2:25][C:20]4=[CH:19][C:17]=3[N:18]=2)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.C(O)(C(F)(F)F)=[O:28]>C(Cl)Cl.N>[N:3]1([CH2:9][CH2:10][CH2:11][NH:12][C:13]2[N:14]=[N+:15]([O-:26])[C:16]3[CH:22]=[C:21]4[O:23][CH2:24][CH2:25][C:20]4=[CH:19][C:17]=3[N+:18]=2[O-:28])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1
Reactant: [O-][n+]1nc(NCCCN2CCOCC2)nc2cc3c(cc21)OCC3
Reactant: O=C(O)C(F)(F)F
Agent: N
Agent: OO
Solvent: ClCCl
Product: [O-][n+]1nc(NCCCN2CCOCC2)[n+]([O-])c2cc3c(cc21)OCC3
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 13.5 %

Procedure:
H2O2 (70%, 1.6 mL, ca. 32 mmol) was added dropwise to a stirred solution of TFM (4.5 mL, 32 mmol) in DCM (40 mL) at 0° C. The solution was stirred at 20° C. for 10 min, then cooled to 0° C., added to a solution of 1-oxide 199 (1.06 g, 3.2 mmol) and TFA (1.25 mL, 16 mmol) in DCM (40 mL) at 0° C. The solution was stirred at 20° C. for 4.5 h, diluted with dilute aqueous NH3 solution (50 mL) and extracted with DCM (4×125 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM to give 1,4-dioxide 200 (150 mg, 14%) as a red solid: mp 145-148° C.; 1H NMR δ 8.26 (br s, 1H, NH), 8.14 (s, 1H, H-9), 7.53 (s, 1H, H-5), 4.74 (t, J=8.3 Hz, 2H, H-7), 3.83 (t, J=4.6 Hz, 4H, 2×CH2O), 3.65 (br q, J=5.9 Hz, 2H, CH2N), 3.43 (dt, J=8.3, 1.2 Hz, 2H, H-6), 2.58 (br t, J=6.1 Hz, 2H, CH2), 2.53 (br s, 4H, 2×CH2N), 1.88 (p, J=6.2 Hz, 2H, CH2); 13C NMR δ 159.8, 149.0, 141.5, 135.2, 130.8, 113.1, 97.4, 72.4, 66.8 (2), 57.7, 53.8 (2), 41.6, 29.7, 24.5; MS (APCI) m/z 348 (MH+, 100%); HRMS (FAB+) calcd for C16H22N5O4 (MH+) m/z 348.1672, found 348.1666. Anal. calcd for C16H21N5O4.0.4CH2Cl2: C, 51.7; H, 5.8; N, 18.4. Found: C, 51.7; H, 5.4; N, 18.1%.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[C:10]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=2)=[O:19])=[C:9]1[CH:30]([CH3:32])[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:39][O:40][CH2:41][CH2:42]Br>CN(C=O)C>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:42][CH2:41][O:40][CH3:39])[CH:15]=2)[C:10]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=2)=[O:19])=[C:9]1[CH:30]([CH3:32])[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(O)cc2n1Cc1ccccc1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1ccc2c(C(=O)NCc3ccc(F)c(F)c3)c(C(C)C)n(Cc3ccccc3)c2c1
Yield: 46.9 %

Procedure:
Following General Procedure A, 1-benzyl-N-(3,4-difluorobenzyl)-6-hydroxy-2-isopropyl-1H-indole-3-carboxamide (Compound 8, 17 mg, 0.039 mmol) in DMF (1.0 ml) was reacted with K2CO3 (28 mg, 0.20 mmol), 2-bromoethyl methyl ether (18 μl, 0.20 mmol) to yield the title compound (9 mg, 49%).
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([OH:12])(=[O:11])[C:8]([CH3:10])=[CH2:9].[C:13](=[O:21])([O:17][CH:18](Cl)[CH3:19])[O:14][CH2:15][CH3:16].C1OCCOCCOCCOCCOCCOC1>CN(C=O)C>[C:13](=[O:21])([O:17][CH:18]([O:11][C:7](=[O:12])[C:8]([CH3:10])=[CH2:9])[CH3:19])[O:14][CH2:15][CH3:16]
Reactant: C=C(C)C(=O)O
Reactant: CCOC(=O)OC(C)Cl
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(C)C(=O)OC(C)OC(=O)OCC
Temperature: 25 °C
Reaction time: 72 h
Yield: 37.5 %

Procedure:
Potassium tert. butoxide (3.70 g, 0.033 mol) was added to a solution of methacrylic acid (2.84 g, 0.033 mol) in DMF (100 ml). Ethyl 1-chloroethyl carbonate (5.08 g, 0.033 mol) from Example 9 above was added to the resulting suspension. 18-crown-6 (0.61 g, 2.3 mmol) was then added and the reaction mixture was left with stirring at room temperature for 3 days. The reaction mixture was filtered and the solvent was removed under reduced pressure. The residue was dissolved in chloroform (100 ml) and washed with saturated aqueous sodium hydrogen carbonate (50 ml) and water (50 ml). The organic phase was dried (MgSO4) and the solvent removed under reduced pressure. Flash chromatography gave 2.50 g (38%) of the title product. (Adjusted for recovered starting material the yield was 75%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=[O:10].[F:17][C:18]([F:30])([F:29])[C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:25]([C:22]2[CH:21]=[CH:20][C:19]([C:18]([F:17])([F:29])[F:30])=[CH:24][CH:23]=2)(=[O:27])=[O:26])=[C:3]([C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[O:10])[CH:4]=1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccncc1
Product: O=C(c1ccncc1)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(C(F)(F)F)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 116 mg of (2-amino-5-chloro-phenyl)-pyridin-4-yl-methanone and 122 mg of 4-Trifluoromethyl-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 7.31 (d, 1H, J=2.8 Hz), 7.36 (m, 2H), 7.54-7.59 (m, 2H), 7.73 (d,1H, J=8.0 Hz), 7.77 (d, 1H, J=9.2 Hz), 7.97 (d, 1H, J=8.0 Hz), 8.00 (s, 1H), 8.82 (dd, 2H, J=6.0 Hz, 1.2 Hz), 10.16 (s, 1H). MS: m/z 441.8 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][NH2:14])=[O:12])=[C:5]2[CH3:15].[C:16]1([CH3:24])[CH:21]=[CH:20][C:19]([CH:22]=O)=[CH:18][CH:17]=1>C(O)C>[CH3:24][C:16]1[CH:21]=[CH:20][C:19]([CH:22]=[N:14][NH:13][C:11]([C:6]2[NH:7][C:8]3[C:4]([C:5]=2[CH3:15])=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=3)=[O:12])=[CH:18][CH:17]=1
Reactant: Cc1c(C(=O)NN)[nH]c2ccc(Cl)cc12
Reactant: Cc1ccc(C=O)cc1
Solvent: CCO
Product: Cc1ccc(C=NNC(=O)c2[nH]c3ccc(Cl)cc3c2C)cc1
Yield: 44.3 %

Procedure:
A solution of 5-chloro-3-methyl-indole-2-carboxylic acid hydrazide (13 mg, 0.054 mmol),p-tolualdehyde (6.5 mg, 0.054 mmol) in ethanol (5 mL) was refluxed for 8 h. It was evaporated in vacuo and the residue was purified by column chromatography (silica gel, EtOAc/Hexane=4:1) to give 7.8 mg (42%) of the title compound. 1H NMR (CD3OD): 8.26 (s, 1H), 7.72 (d, J=8.1 Hz, 2H), 7.62 (bs, 1H), 7.39 (d, J=8.7 Hz, 1H), 7.28−7.21 (m, 3H), 2.58 (s, 3H), 2.39 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)#[CH:2].C([Li])CCC.[CH2:14]([Sn:18](Cl)([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:16][CH3:17]>C1COCC1.CCOCC>[CH2:23]([Sn:18]([CH2:14][CH2:15][CH2:16][CH3:17])([CH2:19][CH2:20][CH2:21][CH3:22])[C:2]#[C:1][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[CH2:24][CH2:25][CH3:26]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: C#Cc1ccccn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCC[Sn](C#Cc1ccccn1)(CCCC)CCCC
Reaction time: 0.25 h

Procedure:
Dissolve 2-ethynylpyridine (7.14 g, 69.23 mmol) in THF (350 mL) and cool the solution to −10° C. (ice/methanol) under nitrogen. Add n-butyllithium (1.6 M in hexanes, 47.6 mL, 76.16 mmol) dropwise and stir the mixture. After 15 minutes, add tributyltin chloride (20.7 mL, 76.2 mL) dropwise. Warn the mixture to room temperature overnight. Quench the reaction with water, dilute with ether, and wash with saturated ammonium chloride, then brine. Dry over sodium sulfate, filter and concentrate. No further purification necessary to give the title compound: 1H NMR (CDCl3) δ 8.50-8.54 (m, 1H), 7.51-7.59 (m, 1H), 7.35-7.43 (m, 1H), 7.11-7.18 (m, 1H), 1.59-1.64 (m, 6H), 1.32-1.42 (m, 6H), 1.05-1.10 (m, 6H), 0.88-0.94 (m, 9H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:10]3[CH:12]([CH3:16])[CH2:13][CH2:14][CH2:15][C:9]=3[C:8]([CH3:18])([CH3:17])[O:7][C:6]=2[CH:5]=[C:4]([CH:19]([CH:21]([CH3:27])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH3:20])[CH:3]=1.[ClH:28].[N:29]1([CH2:34][CH2:35][CH2:36][C:37](O)=[O:38])[CH2:33][CH2:32][CH2:31][CH2:30]1>>[ClH:28].[CH3:27][CH:21]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:19]([C:4]1[CH:3]=[C:2]([O:1][C:37](=[O:38])[CH2:36][CH2:35][CH2:34][N:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)[C:11]2[C:10]3[CH:12]([CH3:16])[CH2:13][CH2:14][CH2:15][C:9]=3[C:8]([CH3:17])([CH3:18])[O:7][C:6]=2[CH:5]=1)[CH3:20]
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2C(C)CCC1
Reactant: O=C(O)CCCN1CCCC1
Agent: Cl
Product: CCCCCC(C)C(C)c1cc(OC(=O)CCCN2CCCC2)c2c(c1)OC(C)(C)C1=C2C(C)CCC1

Procedure:
1-Hydroxy-3-(3-methyl-2-octyl)-7,8,9,10-tetrahydro-6,6,10-trimethyl-6H-dibenzo[ b,d] pyran from Example 32 is reacted with γ-pyrrolidinobutyric acid hydrochloride following the procedure of Example 9 to produce 3-(3-methyl-2-octyl)-1-[4-(pyrrolidino)-butyryloxy]-7,8,9,10-tetrahydro-6,6,10-trimethyl-6H-dibenzo[ b,d] pyran hydrochloride.
Reaction SMILES: [CH3:1][CH2:2][C:3](=O)[CH2:4][CH3:5].[Cl:7][C:8]1[C:13]([NH:14][NH2:15])=[CH:12][CH:11]=[CH:10][N:9]=1>C(O)C>[Cl:7][C:8]1[C:13]([NH:14][N:15]=[C:3]([CH2:4][CH3:5])[CH2:2][CH3:1])=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: NNc1cccnc1Cl
Reactant: CCC(=O)CC
Solvent: CCO
Product: CCC(CC)=NNc1cccnc1Cl
Yield: 88.2 %

Procedure:
3-Pentanone (1.1 ml, 10.4 mmol) was added to a solution of (2-chloropyridin-3-yl)-hydrazine (1 g, 6.96 mmol) prepared in Step 1 in ethanol (35 ml). The reaction mixture was refluxed overnight. The reaction mixture was concentrated under reduced pressure and then purified with silica gel column chromatography to give 1.3 g of the titled compound as pale yellow oil. (Yield: 88%).
Reaction SMILES: [CH2:1]([O:5][C@H:6]1[N:9]([CH:10](Cl)[C:11]([O:13][CH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[C:8](=[O:28])[C@@H:7]1[NH:29][C:30](=[O:38])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:2]([CH3:4])=[O:3].[C:39]1([P:45]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH2:1]([O:5][C@H:6]1[N:9]([C:10](=[P:45]([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:11]([O:13][CH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[C:8](=[O:28])[C@@H:7]1[NH:29][C:30](=[O:38])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:2]([CH3:4])=[O:3]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(=O)CO[C@@H]1[C@@H](NC(=O)Cc2ccccc2)C(=O)N1C(Cl)C(=O)OC(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)CO[C@@H]1[C@@H](NC(=O)Cc2ccccc2)C(=O)N1C(C(=O)OC(c1ccccc1)c1ccccc1)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C

Procedure:
To a solution of crude diphenylmethyl α-[4(R)-acetonyloxy-3(R)-phenylacetamido-2-oxo-azetidin-1-yl]-α-chloroacetate (2.251 g) in anhydrous methylene-chloride (20 ml) is added triphenylphosphine (1.50 g), and the mixture is refluxed for 4 hours under nitrogen atmosphere. The reaction mixture is poured into ice water, mixed with 5% aqueous solution of sodium hydrogen carbonate (20 ml), and extracted with methylene chloride. The organic layer is washed with water, dried over sodium sulfate, and evaporated under reduced pressure. Purification of the residue by chromatography over silica gel containing 10% water (100 g) using a mixture of benzene and ethyl acetate (1:2) as eluting solvent gives the product.
Reaction SMILES: C[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@@H](O[C@H]3[C@H](O)[C@@H](O)[C@H](O)O[C@@H]3CO)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1[NH:33][C@@H:34]1[C@H:39]([OH:40])[C@@H:38]([OH:41])[C@H:37]([OH:42])[C:36]([CH2:43][OH:44])=[CH:35]1.C(O)(C(F)(F)F)=O>>[CH:35]1[C@H:34]([NH2:33])[C@H:39]([OH:40])[C@@H:38]([OH:41])[C@H:37]([OH:42])[C:36]=1[CH2:43][OH:44]
Reactant: C[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@@H](O[C@H]3[C@H](O)[C@@H](O)[C@H](O)O[C@@H]3CO)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1N[C@H]1C=C(CO)[C@@H](O)[C@H](O)[C@H]1O
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1C=C(CO)[C@@H](O)[C@H](O)[C@H]1O
Yield: 114.2 %

Procedure:
1 g of a pure acarbose derivative (monosaccharide and trisaccharide) were place into 10% TFA solution at 5% final concentration. At reaction temperature of 100° C., it was reacted for 12 hours or more, followed by removal of TFA and water. Then, by using ion-exchange resins for purification, 0.45 g and 0.31 g of valienamine were obtained, respectively.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].Cl[C:12]1[C:13]2[CH:26]=[C:25]([Cl:27])[S:24][C:14]=2[N:15]=[C:16]([C:18]2[CH:23]=[N:22][CH:21]=[CH:20][N:19]=2)[N:17]=1>>[N:19]1[CH:20]=[CH:21][N:22]=[CH:23][C:18]=1[C:16]1[N:17]=[C:12]([NH:6][CH2:5][C:4]2[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=2)[C:13]2[CH:26]=[C:25]([Cl:27])[S:24][C:14]=2[N:15]=1
Reactant: Clc1cc2c(Cl)nc(-c3cnccn3)nc2s1
Reactant: NCc1ccc(Cl)c(Cl)c1
Product: Clc1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(-c3cnccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-dichlorobenzylamine with 4-chloro-2-(pyrazin-2-yl)-6-chloro-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-(3,4-dichlorobenzylamino)-6-chloro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: C(N(CC)CC)C.ClC(O[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O.[CH3:19][O:20][C:21](=[O:43])[CH2:22][NH:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][NH:32][C:33](=[O:42])[C:34]2[CH:39]=[CH:38][C:37]([C:40]#[N:41])=[CH:36][CH:35]=2)=[CH:26][CH:25]=1>C(Cl)(Cl)Cl>[CH3:19][O:20][C:21](=[O:43])[CH2:22][N:23]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:24]1[CH:25]=[CH:26][C:27]([CH2:30][CH2:31][NH:32][C:33](=[O:42])[C:34]2[CH:35]=[CH:36][C:37]([C:40]#[N:41])=[CH:38][CH:39]=2)=[CH:28][CH:29]=1
Reactant: COC(=O)CNc1ccc(CCNC(=O)c2ccc(C#N)cc2)cc1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)CN(Cc1ccccc1)c1ccc(CCNC(=O)c2ccc(C#N)cc2)cc1
Temperature: 50 °C

Procedure:
1.2 ml of triethylamine and 3 ml of benzyl chloroformate (50% in toluene) were added to a solution of 675 mg of N-[p-[2-(p-cyanobenzamido)ethyl]phenyl]glycine methyl ester in 15 ml of chloroform. The reaction mixture was maintained at 50° C. overnight. After working up and chromatography on silica gel with ether/petroleum ether 2:1, 500 mg of crystalline N-benzyl-N-[p-[2-(p-cyanobenzamido)ethyl]phenyl]glycine methyl ester, melting point 123°-124° C., were isolated.
Reaction SMILES: C(O[CH:4]=[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[N+:6]([O-:8])=[O:7])C.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][N:16]=1.C(O)C>C1(C)C=CC=CC=1>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][CH:4]=[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[N+:6]([O-:8])=[O:7])=[N:16][CH:17]=1
Reactant: CCOC=C(C(=O)OCC)[N+](=O)[O-]
Reactant: Nc1ccc(Br)cn1
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=CNc1ccc(Br)cn1)[N+](=O)[O-]
Yield: 63.2 %

Procedure:
A mixture of 2-ethoxy-1-ethoxycarbonyl-1-nitroethene (5.7 g) and 2-amino-5-bromopyridine (5.2 g) in toluene was heated at reflux with slow removal of the ethanol formed during 2 hours. The reaction mixture was cooled and concentrated in vacuo to give a yellow powder which was triturated with hot ethanol, to give 2-(5-bromopyrid-2-ylamino)-1-ethoxycarbonyl-1-nitroethene (6.0 g) in the form of a pale yellow powder, m.p. 141°-142° C.
Reaction SMILES: [NH2:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]1[OH:11].[CH3:12][C:13]1[N:14]=[C:15]2[C:20]([O:21][CH2:22][CH2:23][CH:24]([C:29]([F:32])([F:31])[F:30])[C:25]([F:28])([F:27])[F:26])=[CH:19][C:18]([CH3:33])=[CH:17][N:16]2[C:34]=1[C:35](O)=[O:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[OH:11][CH:3]1[CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:2]1[NH:1][C:35]([C:34]1[N:16]2[CH:17]=[C:18]([CH3:33])[CH:19]=[C:20]([O:21][CH2:22][CH2:23][CH:24]([C:25]([F:28])([F:27])[F:26])[C:29]([F:30])([F:31])[F:32])[C:15]2=[N:14][C:13]=1[CH3:12])=[O:36]
Reactant: NC1c2ccccc2CC1O
Reactant: Cc1cc(OCCC(C(F)(F)F)C(F)(F)F)c2nc(C)c(C(=O)O)n2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1cc(OCCC(C(F)(F)F)C(F)(F)F)c2nc(C)c(C(=O)NC3c4ccccc4CC3O)n2c1
Reaction time: 8 h

Procedure:
12 mg (0.08 mmol) of 1-aminoindan-2-ol were initially charged, 31 mg (0.08 mmol) of 2,6-dimethyl-8-[4,4,4-trifluoro-3-(trifluoromethyl)butoxy]imidazo[1,2-a]pyridine-3-carboxylic acid Example 91A, dissolved in 0.3 ml of DMF, 40 mg (0.104 mmol) of HATU, dissolved in 0.3 ml of DMF, and then 16 mg (0.16 mmol) of 4-methylmorpholine were added and the mixture was shaked at RT overnight. The target compound was isolated by preparative HPLC (Method 11). This gave 15 mg (36% of theory).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][C:11]2([O:13][CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][NH:25][CH:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:27][OH:28])=[CH:20][CH:19]=1>C(O)C>[OH:13][C:11]1([CH2:12][N:25]([CH:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:27][OH:28])[CH2:24][C:21]2[CH:20]=[CH:19][C:18]([O:17][CH3:16])=[CH:23][CH:22]=2)[CH2:14][CH2:15][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]1
Reactant: COc1ccc(CNC(CO)c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Solvent: CCO
Product: COc1ccc(CN(CC2(O)CCN(C(=O)OC(C)(C)C)CC2)C(CO)c2ccccc2)cc1
Yield: 82 %

Procedure:
A solution of tert-butyl-1-oxa-6-azaspiro[2.5]octane-6-carboxylate (0.7 g, 3.42 mmol) and 2-[(4-methoxyphenyl)methylamino]-2-phenyl-ethanol (800 mg, 3.109 mmol) in ethanol (5 mL) was stirred at 60° C. for 72 hours. The reaction mixture was concentrated in vacuo and purified by silica gel column chromatography using 0 to 10% MeOH in DCM as eluent to yield tert-butyl 4-hydroxy-4-[[(2-hydroxy-1-phenyl-ethyl)-[(4-methoxyphenyl)methyl]amino]methyl]piperidine-1-carboxylate (1.2 g, 82%). ESI-MS m/z calc. 470.6. found 471.5 (M+1)+; Retention time: 1.45 minutes (3 min run).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([O:8][CH2:9][CH2:10][O:11][C:12]2[N:17]=[CH:16][N:15]=[C:14]([NH:18][S:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[C:13]=2[C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)=[N:6][CH:7]=1.C([Li])CCC.[CH3:44][C:45]([CH3:47])=[O:46].[Cl-].[NH4+]>CCCCCC.O1CCCC1>[C:28]([C:25]1[CH:26]=[CH:27][C:22]([S:19]([NH:18][C:14]2[C:13]([C:32]3[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=3)=[C:12]([O:11][CH2:10][CH2:9][O:8][C:5]3[N:4]=[CH:3][C:2]([C:45]([OH:46])([CH3:47])[CH3:44])=[CH:7][N:6]=3)[N:17]=[CH:16][N:15]=2)(=[O:21])=[O:20])=[CH:23][CH:24]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)=O
Reactant: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOc2ncc(Br)cn2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOc2ncc(C(C)(C)O)cn2)cc1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 30.4 %

Procedure:
To a solution of N-[6-{2-(5-bromopyrimidin-2-yloxy)ethoxy}-5-(4-methylphenyl)pyrimidin-4-yl]-4-tert-butylbenzenesulfonamide (300 mg) in tetetrahydrofuran (10 ml) is added a 1.6M solution of n-butyl lithium in n-hexane (0.75 ml) at -78° C. The mixture is stirred at -78° C. for 5 minutes, and thereto is added a solution of acetone (58 mg) in tetrahydrofuran (1 ml), and the mixture is warmed to room temperature. The mixture is treated with aqueous ammonium chloride solution, and 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/ethyl acetate=2:1~1:1), and recrystallized from ethyl acetate/n-hexane to give 4-tert-butyl-N-[6-{2-(5-(1-hydroxy-1-methylethyl)primidin-2-yloxy)ethoxy}-5-(4-methylphenyl)pyrimidin-4-yl]benzenesulfonamide (88 mg) as crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH:22]2[C:27](=[O:35])[NH:28][CH2:29][C:30]([O:32]CC)=[O:31])[NH:12][C:11]([C:36]2[S:37][CH:38]=[CH:39][N:40]=2)=[N:10]1.[OH-].[Na+]>C(O)C.O>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([C:36]2[S:37][CH:38]=[CH:39][N:40]=2)[NH:12][C:13]([CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH:22]2[C:27]([NH:28][CH2:29][C:30]([OH:32])=[O:31])=[O:35])=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)CNC(=O)C1COCCN1CC1=C(C(=O)OCC)C(c2ccc(F)cc2Br)N=C(c2nccs2)N1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C1=C(CN2CCOCC2C(=O)NCC(=O)O)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 74 %

Procedure:
A mixture of ethyl 4-(2-bromo-4-fluorophenyl)-6-((3-((2-ethoxy-2-oxoethyl)carbamoyl)morpholino)methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.2 g, 0.31 mmol) and sodium hydroxide (0.13 g, 3.1 mmol) in ethanol (6 mL) and water (1 mL) was stirred at 25° C. for 20 minutes. The reaction solution was adjusted to pH 6-7 with con. HCl, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/MeOH (V/V)=25/1) to give the title compound as a yellow solid (0.14 g, 74%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [ClH:1].[CH:2]1([N:12]2[CH2:28][CH2:27][C:15]3([N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:18][NH:17][C:16]3=[O:26])[CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[C:29]1([CH:35]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:36][CH2:37]Br)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[ClH:1].[CH:2]1([N:12]2[CH2:28][CH2:27][C:15]3([N:19]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:18][N:17]([CH2:37][CH2:36][CH:35]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[C:16]3=[O:26])[CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: BrCCC(c1ccccc1)c1ccccc1
Reactant: O=C1NCN(c2ccccc2)C12CCN(C1CCCCCCCCC1)CC2
Agent: Cl
Product: O=C1N(CCC(c2ccccc2)c2ccccc2)CN(c2ccccc2)C12CCN(C1CCCCCCCCC1)CC2

Procedure:
The title compound, white solid, m.p. 219° C. and MS: m/e=564.5 (M+H+) was prepared in accordance with the general method of example 24 from 8-cyclodecyl-1-phenyl-1,3,8-triaza-spiro[4,5]decan-4-one hydrochloride and 3,3-diphenyl-1-propylbromide.
Reaction SMILES: [2H][C:2]1[C:7]([2H])=[C:6]([NH2:9])[C:5]([NH2:10])=[C:4]([2H])[C:3]=1[2H].C(N(CC)CC)C.[C:20](Cl)(=O)[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>C(Cl)Cl>[CH2:21]([C:20]1[NH:9][C:6]2[CH:7]=[CH:2][CH:3]=[CH:4][C:5]=2[N:10]=1)[CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: [2H]c1c([2H])c([2H])c(N)c(N)c1[2H]
Reactant: CCCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCc1nc2ccccc2[nH]1
Yield: 46.6 %

Procedure:
To a solution of O-phenylenediamine (2.2 g) and triethylamine (2.0 g) in methylene chloride (20 ml) was added dropwise caproyl chloride (2.3 g) with stirring under ice-cooling. The mixture was stirred for 3 hours at room temperature, washed with a saturated aqueous sodium bicarbonate and water, then dried. The solvent was evaporated. To the residue was added 3N-HCl, and the mixture was heated for 1.5 hour under reflux. The reaction mixture was made basic with 6N NaOH. Then precipitating crystals were recrystallized from ethyl acetate-hexane to give colorless needles (1.5 g, 47%), m.p. 161-162° C.