Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH2:19][C:18](=[O:22])[CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C1C=CC(N([S:37]([C:40]([F:43])([F:42])[F:41])(=[O:39])=[O:38])[S:30]([C:33]([F:36])([F:35])[F:34])(=[O:32])=[O:31])=CC=1>O1CCCC1>[C:9]([O:13][C:14]([N:16]1[CH2:17][C:18]([O:22][S:30]([C:33]([F:36])([F:35])[F:34])(=[O:32])=[O:31])=[CH:19][CH2:20][CH2:21]1)=[O:15])([CH3:12])([CH3:10])[CH3:11].[C:9]([O:13][C:14]([N:16]1[CH:17]=[C:18]([O:22][S:37]([C:40]([F:41])([F:42])[F:43])(=[O:38])=[O:39])[CH2:19][CH2:20][CH2:21]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1
Reactant: O=S(=O)(N(c1ccccc1)S(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C=C(OS(=O)(=O)C(F)(F)F)CCC1
Product: CC(C)(C)OC(=O)N1CCC=C(OS(=O)(=O)C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of lithium diisopropylamide (0.0144 mol, 2M in heptane/THF/EtPh, 7.2 mL) in tetrahydrofuran (25 mL) at −78° C. was added a solution of 3-Oxo-piperidine-1-carboxylic acid tert-butyl ester (2.00 g, 0.0100 mol) in tetrahydrofuran (5 mL) dropwise. After 15 minutes, N-phenylbis(trifluoromethanesulphonimide) (4.303 g, 0.01204 mol) in tetrahydrofuran (10 mL) was added. The reaction was slowly warmed to room temperature and stirred overnight. The reaction was cooled to 0° C. and quenched with saturated NH4Cl, diluted with water, and extracted 3 times with dichloromethane. The organic layers were combined, dried with MgSO4, and concentrated. The mixture was purified by flash chromatography (EtOAc/hexanes) to give 0.933 g of 5-Trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester and 1.1234 g of 5-Trifluoromethanesulfonyloxy-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[CH:9]=[N:10][NH:11][CH:12]=1)=[O:7])[CH3:4].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C)C=O>[CH2:13]([N:10]1[CH:9]=[C:8]([C:6]([O:5][CH2:3][CH3:4])=[O:7])[CH:12]=[N:11]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1cn[nH]c1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn(Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (containing 63%, 652 mg) in dimethylformamide (abbreviated as DMF hereinafter) was added a solution of 4-ethoxycarbonylpyrazole (2.00 g) in DMF (15 ml) at room temperature. After stirred for 30 min at room temperature, to the mixture was added benzylbromide (2.04 ml). After stirred for 30 min, the mixture was quenched by addition of water. The mixture was extracted with ethyl acetate-n-hexane. The extract was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1) to give the title compound (2.98 g) having the following physical data.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10]([C:12]1([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11])[CH2:2]2.[Cl:25][CH2:26][C:27]([NH:29][C:30]1[S:34][N:33]=[CH:32][N:31]=1)=[O:28]>CC#N>[Cl-:25].[C:19]1([C:12]2([C:10]([O:9][C@@H:3]3[CH:4]4[CH2:7][CH2:8][N+:1]([CH2:26][C:27](=[O:28])[NH:29][C:30]5[S:34][N:33]=[CH:32][N:31]=5)([CH2:6][CH2:5]4)[CH2:2]3)=[O:11])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(CCl)Nc1ncns1
Reactant: O=C(O[C@H]1CN2CCC1CC2)C1(c2ccccc2)CCCCCC1
Solvent: CC#N
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)C1(c3ccccc3)CCCCCC1)C2)Nc1ncns1
Product: [Cl-]
Yield: 19.8 %

Procedure:
1-phenyl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl) ester (Example 14e) (0.30 mmol) and 2-chloro-N-[1,2,4]thiadiazol-5-yl-acetamide (0.36 mmol) (Example 56a) in MeCN (1.5 mL) were stirred at room temperature overnight. The reaction mixture was filtered and the solid obtained was washed with cold MeCN to give the title compound (30 mg) as a solid.
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[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:40](Cl)([O:42]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:51][C:52]1[CH:60]=[CH:59][C:55]([CH:56]([OH:58])[CH3:57])=[CH:54][CH:53]=1>C(Cl)Cl>[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[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:40](=[O:42])[O:58][CH:56]([C:55]2[CH:59]=[CH:60][C:52]([CH3:51])=[CH:53][CH:54]=2)[CH3:57])=[C:18]([CH3:24])[CH:17]=1
Reactant: Cc1ccc(C(C)O)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc2nccc(Oc3cc(C)c(NC(=O)OC(C)c4ccc(C)cc4)cc3C)c2cc1OC
Temperature: 25 °C
Yield: 73.3 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (80 mg) was added to toluene/triethylamine=10/1 (8 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (111 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 4-methyl-α-methylbenzyl alcohol (50 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (88mg, yield 68%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[C:6]([OH:12])[CH:5]=1.[C:14]1([CH2:20][CH2:21][CH2:22][CH2:23]Cl)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[C:6]([O:12][CH2:23][CH2:22][CH2:21][CH2:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:5]=1
Reactant: ClCCCCc1ccccc1
Reactant: COC(=O)c1ccc(C#N)c(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C#N)c(OCCCCc2ccccc2)c1
Reaction time: 18 h

Procedure:
4-Cyano-3-hydroxybenzoic acid methyl ester, Example 34 Step 3 (300 mg, 1.7 mmol) was dissolved in DMF (85 ml) and treated with phenylbutylchloride (287 mg, 1.7 mmol). Cs2CO3 (610 mg, 1.87 mmol) was then added and the reaction mixture stirred at room temp. for 18 hours. The mixture was filtered and washed with DMF (3×10 mL). The solvent was removed in vacuo and the residue was purified by flash chromatography (10% EtOAc/Hexane) to yield desired product.
Reaction SMILES: [CH:1]([N:4]([CH:23]([CH3:25])[CH3:24])[CH2:5][CH2:6][C@@H:7]([C:14]1[CH:19]=[C:18]([CH:20]=O)[CH:17]=[CH:16][C:15]=1[OH:22])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:3])[CH3:2].[CH2:26]([NH2:28])[CH3:27].C([BH3-])#N.[Na+]>CO>[CH:23]([N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6][CH:7]([C:14]1[CH:19]=[C:18]([CH2:20][NH:28][CH2:26][CH3:27])[CH:17]=[CH:16][C:15]=1[OH:22])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([CH3:25])[CH3:24]
Reactant: CC(C)N(CC[C@H](c1ccccc1)c1cc(C=O)ccc1O)C(C)C
Reactant: CCN
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCNCc1ccc(O)c(C(CCN(C(C)C)C(C)C)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(R)-N,N-Diisopropyl-3-(5-formyl-2-hydroxyphenyl)-3-phenylpropanamine (prepared in Example 7.1) (1.23 g, 3.62 mmol) was dissolved in methanol (20 mL). Ethylamine [3.62 mL, 21.7 mmol (6M hydrochloric acid in methanol)] and sodium cyanoborohydride (0.14 g, 2.17 mmol) were added. The mixture was stirred overnight at room temperature. The solvent was evaporated and the residue was chromatographed on silica (toluene-ethyl acetate-triethylamine 7:3:1). The product was dissolved in diethyl ether and hydrogen chloride in diethyl ether was added. The resulting oil was stirred in diethyl ether over night to give crystals. Yield 0.70 g (44%); mp. 140-142° C.; [α]D−5.0° (c=0.5, methanol); 1H NMR (CD3OD) δ1.30 (m, 15H), 2.59 (m, 2H), 3.05 (m, 4H), 3.70 (m, 2H), 4.07 (s, 2H), 4.42 (t, 1H), 6.85 (d, 1H), 7.20 (m, 2H), 7.30 (t, 2H), 7.41 (d, 2H), 7.50 (s, 1H) Anal. (C24H36N2O*2.0 HCl*0.5H2O) C,H,N.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5][CH2:6][CH2:7][NH:8][S:9]([C:12]1[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=1[CH3:20])(=[O:11])=[O:10])#[N:4].Br[CH2:22][CH2:23][CH2:24][CH2:25][C:26]#[N:27].CCCCCC.CCOC(C)=O>CN(C=O)C>[C:26]([CH2:25][CH2:24][CH2:23][CH2:22][N:8]([CH2:7][CH2:6][CH2:5][C:3]#[N:4])[S:9]([C:12]1[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=1[CH3:20])(=[O:10])=[O:11])#[N:27]
Reactant: N#CCCCCBr
Reactant: Cc1cc(C)c(S(=O)(=O)NCCCC#N)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: Cc1cc(C)c(S(=O)(=O)N(CCCC#N)CCCCC#N)c(C)c1
Yield: 79.4 %

Procedure:
NaH (60%, 0.90 g, 23 mmol), 36 (5.02 g, 18.85 mmol), and 5-bromovaleronitrile (2.4 mL, 21 mmol) in DMF were combined and worked up by the method of 43. Column chromatography (1:1 hexane/EtOAc) provided 5.20 g (79%) of 38 as an oil: NMR δ 1.49-1.66 (m, 4 H), 1.82 (m, 2 H), 2.22 (t, 2 H, J=7), 2.25 (t, 2 H, J=7), 2.29 (s, 3 H), 2.57 (s, 6 H), 3.19 (t, 2 H, J=7), 3.29 (t, 2 H, J=7), 6.95 (s, 2 H). Anal. (C18H25N3O2S) C, H, N.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C@@H:5]([NH2:20])[C:6]1[CH:11]=[CH:10][C:9]([NH:12]C(OC(C)(C)C)=O)=[CH:8][CH:7]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23].C(N(C(C)C)CC)(C)C.O>CN(C)C=O>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C@@H:5]([NH:20][C:22](=[O:24])[CH3:23])[C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[CH:10][CH:11]=1
Reactant: COC(=O)C[C@@H](N)c1ccc(NC(=O)OC(C)(C)C)cc1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C[C@@H](NC(C)=O)c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of (R)-3-amino-3-[4-(tert-butoxycarbonylamino)phenyl]-propanoic acid methyl ester [7.2 g, Reference Example 7(c)] in dimethylformamide (30 ml), was treated with acetic anhydride (2.4 ml) and diisopropylethylamine (4.6 ml). After stirring at ambient temperature for 10 minutes the mixture was poured into water (500 ml) and then extracted twice with ethyl acetate (200 ml). The combined organic extracts were washed with brine (200 ml) then dried over magnesium sulphate and then evaporated. The resulting white foam (8.5 g) was dissolved in dichloromethane (75 ml) and the solution was treated with trifluoracetic acid (17 ml). After stirring at ambient temperature for 3 hours the reaction mixture was evaporated. The residue was treated with toluene (70 ml), concentrated to dryness and the resultant material treated with dichloromethane (200 ml). The resultant suspension was treated with saturated aqueous potassium carbonate solution (20 ml) with stirring at ambient temperature for 5 minutes. The organic layer was separated, dried over magnesium sulphate, and then evaporated to give the title compound (4.1 g) as a white foam.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=O)[CH3:2].[C:10]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])#[N:11].C([O-])(=O)C.[NH4+].C(O)(=O)C>O.C1(C)C=CC=CC=1>[CH2:16]([O:15][C:13](=[O:14])[C:12]([C:10]#[N:11])=[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2])[CH3:17]
Reactant: CCOC(=O)CC#N
Reactant: CC(=O)c1ccccc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C(C#N)=C(C)c1ccccc1
Temperature: 25 °C

Procedure:
A stirred mixture of acetophenone (180 g, 1.5 mol), ethyl cyanoacetate (170 g, 1.3 mol), ammonium acetate (23.1 g), acetic acid (72 g) and toluene (300 ml) was heated under reflux for 18 hours while water was removed from the reaction by azeotropic distillation. The mixture was allowed to cool to ambient temperature, toluene (100 ml) was added, then the mixture was washed with water (3×100 ml). The combined aqueous washings were shaken with toluene (50 ml), then the combined toluene solutions were dried (MgSO4) and the solvent was removed in vacuo. The residual oil was distilled under reduced pressure to give 2-cyano-3-phenyl-but-2-enoic acid ethyl ester as an oil which was used without further purification.
Reaction SMILES: CN1CCOCC1.[CH3:8][O:9][C:10](=[O:54])[NH:11][C@@H:12]([C:16]([N:18]1[CH2:22][CH2:21][CH2:20][CH:19]1[C:23]1[NH:24][C:25]([C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][C:37]([C:40]4[NH:41][C:42]([CH2:45][N:46]5[CH2:51][CH2:50][CH2:49][CH:48]([NH2:52])[C:47]5=[O:53])=[N:43][CH:44]=4)=[CH:36][CH:35]=3)=[CH:30][CH:29]=2)=[CH:26][N:27]=1)=[O:17])[CH:13]([CH3:15])[CH3:14].Cl[C:56]([O:58][CH3:59])=[O:57]>ClCCl>[CH3:59][O:58][C:56](=[O:57])[NH:52][C@@H:48]1[CH2:49][CH2:50][CH2:51][N:46]([CH2:45][C:42]2[NH:41][C:40]([C:37]3[CH:38]=[CH:39][C:34]([C:31]4[CH:30]=[CH:29][C:28]([C:25]5[NH:24][C:23]([CH:19]6[CH2:20][CH2:21][CH2:22][N:18]6[C:16](=[O:17])[CH:12]([NH:11][C:10]([O:9][CH3:8])=[O:54])[CH:13]([CH3:15])[CH3:14])=[N:27][CH:26]=5)=[CH:33][CH:32]=4)=[CH:35][CH:36]=3)=[CH:44][N:43]=2)[C:47]1=[O:53]
Reactant: COC(=O)N[C@@H](C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(CN5CCCC(N)C5=O)[nH]4)cc3)cc2)[nH]1)C(C)C
Reactant: COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(CN5CCC[C@@H](NC(=O)OC)C5=O)[nH]4)cc3)cc2)[nH]1)C(C)C
Yield: 319 %

Procedure:
4-Methylmorpholine (71 μL, 0.64 mmol) was added to a suspension of (R)-{1-[2-(5-{4′-[2-(3-amino-2-oxo-piperidin-1-yl methyl)-3H-imidazol-4-yl]-biphenyl-4-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (137 mg, 0.21 mmol) in dichloromethane (5 mL). Methyl chloroformate (16.5 μL, 0.21 mmol) was added to the resulting solution. After 20 minutes the solvent was removed under reduced pressure. The residue was taken up in tetrahydrofuran (4 mL) and methanol (2 mL) and an aqueous solution of sodium hydroxide (2 N, 1 mL) was added. After 2 hours the organic solvents were removed under reduced pressure and the aqueous phase was decanted. The residue was taken up in dimethylformamide (2 mL) and subjected to reverse phase chromatography with an eluent of 0.1% TFA in water and 0.1% TFA in acetonitrile. The product-containing fractions were combined and the solvent was removed by lyophilization to provide (R)-{1-[5-(4′-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-ylmethyl]-2-oxo-piperidin-3-yl}-carbamic acid methyl ester (46.7 mg, 0.67 mmol, 32%). C37H44N8O6 calculated 696.3 observed [M+1]+ 697.4; rt=1.58 min. 1H (DMSO-d6): δ=8.05 (s, 1H), 7.87 (m, 8H) 7.30 (m, 1H), 5.10 (t, J=7.2 Hz, 1H), 4.85 (d, J=15.6 Hz, 1H), 4.53 (d, J=16.0 Hz, 1H), 4.08 (m, 2H), 3.81 (m, 2H), 3.51 (s, 3H), 3.50 (s, 3H), 2.14 (m, 1H), 2.05-1.78 (series m, 8H), 0.78 (m, 6H).
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:8]=1[C:14]1[N:18]=[C:17]([C:19]2[S:20][C:21](Br)=[C:22]([Br:25])[C:23]=2[CH3:24])[N:16]([CH3:27])[N:15]=1.O>C1COCC1>[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:8]=1[C:14]1[N:18]=[C:17]([C:19]2[S:20][CH:21]=[C:22]([Br:25])[C:23]=2[CH3:24])[N:16]([CH3:27])[N:15]=1
Reactant: Cc1c(-c2nc(-c3c(F)cccc3Cl)nn2C)sc(Br)c1Br
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(Br)csc1-c1nc(-c2c(F)cccc2Cl)nn1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
n-Butyl lithium (6.04 mL, 2.5 mmol) was slowly added over a 15 min period to 3-(2-chloro-6-fluorophenyl)-5-(3-methyl-4,5-dibromothien-2-yl) 1-methyl [1,2,4] triazole (7.0 g) in THF (100 mL) at −70° C. under a nitrogen atmosphere and stirred for 1.0 h. After the addition of the distilled water, the reaction was allowed to warm to 25° C. The reaction mixture was extracted with diethyl ether (3×100 mL). The combined ether extracts was washed with water, dried over anhydrous sodium sulfate, filtered and concentrated to crude solid. This was chromatographed on silica gel (EtOAc/Hexane, 1:1) to give 5.0 g (86% yield) 3-(2-chloro-6-fluorophenyl)-5-(3-methyl-4-bromothien-2-yl) 1-methyl [1,2,4] triazole as white solid. MP 111-112° C. ; Anal. Calcd. For C14H10BrClFN3S: C, 43.49; H, 2.61; N, 10.87; S, 8.29. Found; C, 43.79; H, 2.66; N, 10.95; S, 8.28.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][NH2:17])=N[CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)[CH:21]=[C:22]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)[C:23]([O:25][CH3:26])=[O:24].[C:34](O)(C(F)(F)F)=O>C(O)C.CCOC(C)=O>[CH2:1]([NH:8][C:9]([C:10]1[CH:15]=[CH:14][C:13]([NH:16][NH:17][CH:21]=[C:22]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)[C:23]([O:25][CH3:26])=[O:24])=[CH:34][CH:11]=1)=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NNc1ccc(C(=O)NCc2ccccc2)cn1
Reactant: O=C(O)C(F)(F)F
Reactant: COC(=O)C(=CN(C)C)c1ccccn1
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)C(=CNNc1ccc(C(=O)NCc2ccccc2)cc1)c1ccccn1
Yield: 73.4 %

Procedure:
Combined N-benzyl-6-hydrazinylnicotinamide (200 mg, 0.826 mmol), methyl 3-(dimethylamino)-2-(pyridin-2-yl)acrylate (170 mg, 0.826 mmol) and TFA (0.127 mL, 1.651 mmol) in ethanol (3 mL) and stirred overnight at room temperature. The reaction mixture was diluted in EtOAc (50 mL), washed with saturated aqueous sodium bicarbonate (20 ml), brine (20 ml), dried with Na2SO4 and concentrated to give the title compound (244 mg) as an orange solid, was used without further purification. MS m/z [M+H]+ 404.4.
Reaction SMILES: [CH3:1][S:2]([N:5]([CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH3:23])[CH:21]=2)[O:16][C:15]([CH3:25])([CH3:24])[CH2:14]1)[CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])(=[O:4])=[O:3].[CH2:26](N(CCO)C)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C1CC[CH:41]([N:44]=[C:45]=NC2CCCCC2)[CH2:40]C1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:1][S:2]([N:5]([CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH3:23])[CH:21]=2)[O:16][C:15]([CH3:25])([CH3:24])[CH2:14]1)[CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:40][CH2:41][NH:44][CH2:45][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:11])(=[O:3])=[O:4]
Reactant: CN(CCO)Cc1ccccc1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: Cc1ccc2c(c1)C(N(CCCCC(=O)O)S(C)(=O)=O)CC(C)(C)O2
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc2c(c1)C(N(CCCCC(=O)OCCNCCc1ccccc1)S(C)(=O)=O)CC(C)(C)O2
Yield: 64.5 %

Procedure:
A solution of 0.5 g (1.35 mmol) of 5-[methylsulfonyl-(2,2,6-trimethylchroman-4-yl)amino]pentanoic acid, 0.25 g (1.5 mmol) of 2-(N-benzyl-N-methylamino)ethanol, 0.31 g (1.5 mmol) of DCC and a spatula tipful of DMAP in 10 ml of methylene chloride is stirred overnight at RT. After filtering off the precipitate, the solution is concentrated and the crude product is purified by chromatography on silica gel using methylene chloride/methanol 97:3, and 0.45 g of 2-(benzylmethylamino)ethyl 5-[methanesulfonyl-(2,2,6-trimethylchroman-4-yl)amino]pentanoate is obtained.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([CH2:15][CH2:16][C:17](=[O:19])[CH3:18])=[CH:10][C:11]=3[CH2:12]2)=[CH:4][CH:3]=1.[C:20](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH3:20][O:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([CH2:15][CH2:16][C:17](=[O:19])[CH3:18])=[CH:10][C:11]=3[CH2:12]2)=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CC(=O)CCc1ccc2c(c1)Cc1cc(O)ccc1-2
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1ccc2c(c1)Cc1cc(CCC(C)=O)ccc1-2
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.2 %

Procedure:
In 50 ml of acetone was dissolved 2.17 grams of 4-(7-hydroxy-2-fluorenyl)-butan-2-one, then 1.43 grams of potassium carbonate (anhydrous) was added, and heated to reflux for 2 hours after addition of an excess of methyl iodide. The mixture was stirred at room temperature for overnight and acetone was removed by evaporation in vacuo. The residue was dissolved in ethyl acetate, washed with water, dried with magnesium sulfate, and ethyl acetate was removed therefrom by evaporation in vacuo. The residue was subjected to a silica gel column chromatography, eluted with a 4:1 mixture of n-hexane and ethyl acetate, and the resulting crystals were recrystallized from methanol to give 1.15 grams of 4-(7-methoxy-2-flourenyl)-butan-2-one, white crystals, m.p. 100°-101° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9]([CH2:12][O:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[CH:16]=[C:17]([C:23](O)=[O:24])[NH:18]4)=[CH:10][O:11][C:7]=2[CH:6]=[C:5]([O:26][CH3:27])[CH:4]=1.Cl.Cl.Cl.[NH2:31][CH:32]1[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][N:40]2[CH2:45][CH2:44][CH:43]([OH:46])[CH2:42][CH2:41]2)[CH2:34][CH2:33]1>>[OH:46][CH:43]1[CH2:42][CH2:41][N:40]([CH2:39][CH2:38][N:35]2[CH2:34][CH2:33][CH:32]([NH:31][C:23]([C:17]3[NH:18][C:19]4[C:15]([CH:16]=3)=[C:14]([O:13][CH2:12][C:9]3[C:8]5[C:3]([O:2][CH3:1])=[CH:4][C:5]([O:26][CH3:27])=[CH:6][C:7]=5[O:11][CH:10]=3)[CH:22]=[CH:21][CH:20]=4)=[O:24])[CH2:37][CH2:36]2)[CH2:45][CH2:44]1
Reactant: COc1cc(OC)c2c(COc3cccc4[nH]c(C(=O)O)cc34)coc2c1
Reactant: NC1CCN(CCN2CCC(O)CC2)CC1
Agent: Cl
Product: COc1cc(OC)c2c(COc3cccc4[nH]c(C(=O)NC5CCN(CCN6CCC(O)CC6)CC5)cc34)coc2c1

Procedure:
This compound is synthesized analogously to example 1 from 4-(4,6-dimethoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid, 126 (see example 99) and amine 21.
Reaction SMILES: [CH3:1][C:2]1[N:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:12][CH2:13][CH2:14][OH:15])[N:3]=1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl>[CH3:23][S:24]([O:15][CH2:14][CH2:13][O:12][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[CH:10]=[N:11][C:2]([CH3:1])=[N:3]2)(=[O:26])=[O:25]
Reactant: Cc1ncc2c(OCCO)cccc2n1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ncc2c(OCCOS(C)(=O)=O)cccc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.8 %

Procedure:
To a solution of 2-(2-methylquinazolin-5-yloxy)ethanol (0.330 g, 1.62 mmol) in dichloromethane (20 mL) and triethylamine (0.34 mL, 2.43 mmol) was added methane sulfonyl chloride (0.14 mL, 1.78 mmol) dropwise. The reaction mixture was allowed to stir at room temperature for 2 h. The reaction mixture was diluted with further dichloromethane and partitioned with saturated NaHCO3 aq. The organic phase was washed with brine, dried (MgSO4) and evaporated in vacuo to give the title compound as a cream solid (0.452 g, 99%).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]3[CH:21]=[CH:20][C:19]4[C:14](=[CH:15][CH:16]=[CH:17][C:18]=4[N+:22]([O-])=O)[C:13]3=[O:25])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.O.O.[Sn](Cl)Cl.O1CCCC1>>[NH2:22][C:18]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:19]=1[CH:20]=[CH:21][N:12]([CH2:11][C:9]1[CH:8]=[CH:7][C:6]3[O:1][CH2:2][CH2:3][O:4][C:5]=3[CH:10]=1)[C:13]2=[O:25]
Reactant: O=c1c2cccc([N+](=O)[O-])c2ccn1Cc1ccc2c(c1)OCCO2
Agent: Cl[Sn]Cl
Solvent: O
Solvent: C1CCOC1
Product: Nc1cccc2c(=O)n(Cc3ccc4c(c3)OCCO4)ccc12

Procedure:
2-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-5-nitro-2H-isoquinolin-1-one (0.9 g, 0.002 mol), tin dichloride dihydrate (2 g, 0.009 mol) were stirred in tetrahydrofuran (10 mL, 0.1 mol) at room temperature for 20 hours. The volatiles were removed and the residue was purified via flash column chromatography (40 g of silica gel, 50% EtOAc/Hexanes) to give a red oil. MS m/z (M+H) 309.4.