Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:12]=[C:11]([CH3:13])[NH:10][N:9]=1.Cl[C:15]1[C:20]([Cl:21])=[CH:19][C:18]([C:22]([F:25])([F:24])[F:23])=[CH:17][N:16]=1.Cl>CN(C=O)C>[Cl:21][C:20]1[C:15]([O:7][C:8]2[CH:12]=[C:11]([CH3:13])[NH:10][N:9]=2)=[N:16][CH:17]=[C:18]([C:22]([F:24])([F:23])[F:25])[CH:19]=1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: Cc1cc(O)n[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(Oc2ncc(C(F)(F)F)cc2Cl)n[nH]1
Temperature: 60 °C
Yield: 75.6 %

Procedure:
Potassium carbonate (7.60 g, 55.0 mmol) was added to a solution of 3-hydroxy-5-methylpyrazole (4.90 g, 50.0 mmol) and 2,3-dichloro-5-trifluoromethylpyridine (10.8 g, 50.0 mmol) in DMF (50 ml) at room temperature, and the mixture was stirred under heating at 60° C. for 4 hours. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid (100 ml) and extracted with ethyl acetate (30 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/2), to give a white solid of 3-(3-chloro-5-trifluoromethylpyridin-2-yloxy)-5-methylpyrazole (10.5 g, yield: 76.0%). mp: 93-95° C.; 1H-NMR (CDCl3, TMS, ppm): δ 2.32 (s, 3H), 5.90 (s, 1H), 7.98 (d, J=2.0 Hz, 1H), 8.33 (m, 1H), 10.80-11.60 (br s, 1H).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[C:10]1([S:16]([NH:19][C:20]([C:22]2[N:27]=[C:26]3[N:28]([CH2:32][C:33]4[CH:38]=[CH:37][C:36]([CH2:39]OS(C)(=O)=O)=[CH:35][C:34]=4[Cl:45])[C:29]([CH3:31])=[N:30][C:25]3=[CH:24][CH:23]=2)=[O:21])(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl>CN(C)C=O.O>[C:10]1([S:16]([NH:19][C:20]([C:22]2[N:27]=[C:26]3[N:28]([CH2:32][C:33]4[CH:38]=[CH:37][C:36]([CH2:39][O:7][C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)=[CH:35][C:34]=4[Cl:45])[C:29]([CH3:31])=[N:30][C:25]3=[CH:24][CH:23]=2)=[O:21])(=[O:17])=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cc1nc2ccc(C(=O)NS(=O)(=O)c3ccccc3)nc2n1Cc1ccc(COS(C)(=O)=O)cc1Cl
Reactant: Oc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc2ccc(C(=O)NS(=O)(=O)c3ccccc3)nc2n1Cc1ccc(COc2ccccc2)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.7 %

Procedure:
To a solution of phenol (12 mg, 0.13 mmol) in N,N-dimethylformamide (0.5 ml) was added sodium hydride (60% in mineral oil, 5.2 mg) under ice-cooling. Thirty minutes later, a solution of 5-(benzenesulfonylcarbamoyl)-3-(2-chloro-4-((methanesulfonyloxy)methyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine (68 mg, 0.12 mmol) in N,N-dimethylformamide (1 ml) was dropwise added, which was followed by stirring at room temperature for 3 hr. The reaction mixture was cooled with ice and water was added. Its pH was adjusted to 4 by dropwise addition of 1N hydrochloric acid. The resulting product was extracted with ethyl acetate, washed three times with water, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel thin layer chromatography (eluent: chloroform/methanol=20/1) and crystallized from ethyl acetate to give 5-(benzenesulfonylcarbamoyl)-3-(2-chloro-4-((phenyloxy)methyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine (30 mg) as colorless crystals.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:7]=[C:8]([C@H:12]([NH:14]C(=O)COC)[CH3:13])[CH:9]=[CH:10][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].N(CCO)(CCO)CCO.[OH-].[Na+]>O>[C:1]([O:5][C:6]1[CH:7]=[C:8]([C@H:12]([NH2:14])[CH3:13])[CH:9]=[CH:10][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COCC(=O)N[C@H](C)c1cccc(OC(C)(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: OCCN(CCO)CCO
Product: C[C@@H](N)c1cccc(OC(C)(C)C)c1
Yield: 92 %

Procedure:
(R)—N-1-(3-tert-Butoxyphenyl)ethylmethoxyacetamide from example 2.3 (63.5 g with a purity of 93%; corresponds to 0.22 mol of pure substance) was mixed with triethanolamine (6 ml) with stirring and then admixed with 50% NaOH (23.2 g, 0.29 mol). The mixture was then stirred at a bath temperature of 140° C. for another 16 hours, after which all of the amide had reacted according to GC analysis. The mixture was diluted with water (100 ml), cooled and extracted with tert-butyl methyl ether (3×100 ml). The combined extracts were washed with saturated sodium chloride solution (50 ml) and dried over Na2SO4. After the solvent had been removed on a rotary evaporator, 41 g (92%) of (R)-1-(3-tert-butoxyphenyl)ethylamine were obtained in the form of a colorless oil. The chemical purity was 99.4%, the optical purity 98.9% ee.
Reaction SMILES: [CH3:1][N:2]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]2[CH:22]=[N:23][C:24]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[N:25][CH:26]=2)[CH:16]=1)[C:3](=[O:13])[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[C:33](Cl)(=[O:38])[O:34][CH:35]([CH3:37])[CH3:36].O>ClCCl>[C:8]([O:7][C:6]([NH:5][CH2:4][C:3]([N:2]([CH2:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:22]=[N:23][C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:33]([O:34][CH:35]([CH3:37])[CH3:36])=[O:38])[CH2:29][CH2:28]3)=[N:25][CH:26]=2)[CH:18]=[CH:19][CH:20]=1)[CH3:1])=[O:13])=[O:12])([CH3:11])([CH3:9])[CH3:10]
Reactant: CN(Cc1cccc(-c2cnc(N3CCNCC3)nc2)c1)C(=O)CNC(=O)OC(C)(C)C
Reactant: CC(C)OC(=O)Cl
Solvent: ClCCl
Solvent: O
Product: CC(C)OC(=O)N1CCN(c2ncc(-c3cccc(CN(C)C(=O)CNC(=O)OC(C)(C)C)c3)cn2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 64.8 %

Procedure:
tert-Butyl (2-{methyl[3-(2-piperazin-1-ylpyrimidin-5-yl)benzyl]amino}-2-oxoethyl)carbamate (200 mg) and TEA (92 mg) were dissolved in dichloromethane, followed by ice-cooling. Isopropyl chlorocarbonate (83 mg) was added thereto, followed by stirring at room temperature for 4 hours. Water was added thereto, followed by extraction with chloroform. The organic layer was dried over MgSO4, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain isopropyl 4-{5-[3-({[N-(tert-butoxycarbonyl)glycyl](methyl)amino}methyl)phenyl]pyrimidin-2-yl}piperazine-1-carboxylate (155 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:25])([CH2:19][N:20]1[CH:24]=[N:23][CH:22]=[N:21]1)[CH:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[OH:11].[C:26](N1C=CN=C1)(N1C=CN=C1)=[O:27].C(Cl)(Cl)Cl>O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH2:19][N:20]2[CH:24]=[N:23][CH:22]=[N:21]2)[CH:10]([C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)[O:11][C:26](=[O:27])[O:25]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: OC(c1ccc(F)cc1)C(O)(Cn1cncn1)c1ccc(Cl)cc1Cl
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C1OC(c2ccc(F)cc2)C(Cn2cncn2)(c2ccc(Cl)cc2Cl)O1
Yield: 78.7 %

Procedure:
A mixture of 500 mg of 2-(2,4-dichlorophenyl)-1-(4-fluorophenyl)-3-(1H-1,2,4-triazol-1-yl)-1,2-propanediol, 530 mg of 1,1'-carbonyldiimidazole and 10 ml of dry chloroform is heated under reflux for 1 hour. Water is added to the reaction mixture, and the chloroform layer is separated, dried over anhydrous sodium sulfate, and concentrated. The residue is chromatographed on a column of silica-gel and eluted with a mixture of methylene chloride and methanol (100:0-98:2 v/v). The eluate is concentrated, and the residue is crystallized from ethyl acetate-isopropyl ether to give 420 mg of 4-(2,4-dichlorophenyl)-5-(4-fluorophenyl)-2-oxo-4-(1H-1,2,4-triazol-1-yl)methyl-1,3-dioxolane as crystals. m.p. 191°-192° C. Yield: 78.7%
Reaction SMILES: [CH2:1]([N:8]1[C:21](=[O:22])[C@H:20]([CH2:23][C:24]([OH:26])=O)[CH2:19][C:18]2[CH:17]=[CH:16][C:15]3[NH:14][N:13]=[CH:12][C:11]=3[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:27]1([CH:33]2[CH2:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[NH:35][C:34]2=[O:43])[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.ClC1C2NN=CC=2C2CN(CC(C)(C)C)C(=O)[C@H](CC(=O)N3CCC(N4CC5C(=CC=CC=5)NC4=O)CC3)CC=2C=1>>[CH2:1]([N:8]1[C:21](=[O:22])[C@H:20]([CH2:23][C:24](=[O:26])[N:30]2[CH2:31][CH2:32][N:27]([CH:33]3[CH2:42][C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[NH:35][C:34]3=[O:43])[CH2:28][CH2:29]2)[CH2:19][C:18]2[CH:17]=[CH:16][C:15]3[NH:14][N:13]=[CH:12][C:11]=3[C:10]=2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1Nc2ccccc2CC1N1CCNCC1
Reactant: O=C(O)C[C@@H]1Cc2ccc3[nH]ncc3c2CN(Cc2ccccc2)C1=O
Agent: CC(C)(C)CN1Cc2c(cc(Cl)c3[nH]ncc23)C[C@@H](CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C1=O
Product: O=C1Nc2ccccc2CC1N1CCN(C(=O)C[C@@H]2Cc3ccc4[nH]ncc4c3CN(Cc3ccccc3)C2=O)CC1
Yield: 21 %

Procedure:
(S)-2-(9-Benzyl-8-oxo-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetic acid (80 mg, 0.24 mmol) and 3-(piperazin-1-yl)-3,4-dihydroquinolin-2(1H)-one (75 mg, 0.32 mmol) were reacted in a manner analogous to the preparation of 4-chloro-9-(2,2-dimethyl-propyl)-7-(S)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e] inden-8-one. Material was obtained as white solid in 21% yield. MS m/e (M+H)+=543.3. 1H NMR (500 MHz, DMSO-D6): δ=13.01 (s, 1H), 10.13 (s, 1H), 8.21 (s, 1H), 7.36 (d, J=8.54, 1H), 7.19 (d, J=7.02, 1H), 7.11 (m, 2H), 6.90 (t, J=7.32, 1H), 6.82 (d, J=7.93, 1H), 5.36 (d, J=17.40, 1H), 4.61 (d, J=17.09, 1H), 3.84 (m, 1H), 3.57 (d, J=13.12, 1H), 3.47 (m, 2H), 3.38 (m, 1H), 3.32 (M, 1H), 3.09 (m, 1H), 3.02 (d, J=14.04, 1H), 2.985 (m, 2H), 2.85 (m, 1H), 2.75 (m, 1H), 2.65 (m, 3H), 2.50 (m, 2H), 2.31 (d, J=16.48, 1H), 0.71 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1)[C:6]([CH:24]([OH:29])[CH2:25][CH2:26][CH2:27][CH3:28])=[C:5]2[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CO.C(OC(C)C)(C)C>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([S:20]([CH3:23])(=[O:21])=[O:22])=[CH:18][CH:19]=1)[C:6]([C:24](=[O:29])[CH2:25][CH2:26][CH2:27][CH3:28])=[C:5]2[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CCCCC(O)c1c(-c2ccccc2)c2cc(Cl)ccc2c(=O)n1Cc1ccc(S(C)(=O)=O)cc1
Solvent: CO
Solvent: CC(C)OC(C)C
Product: CCCCC(=O)c1c(-c2ccccc2)c2cc(Cl)ccc2c(=O)n1Cc1ccc(S(C)(=O)=O)cc1

Procedure:
In the same manner as in Example 311, the title compound was synthesized using 6-chloro-3-(1-hydroxypentyl)-2-(4-methanesulfonylbenzyl)-4-phenyl-2H-isoquinolin-1-one. Crystals (methanol-diisopropyl ether).
Reaction SMILES: [N:1]([CH:4]1[CH:8]([O:9][CH2:10][CH3:11])[O:7][C:6](=[O:12])[CH2:5]1)=[N+]=[N-].[C:13]1([P:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[C:26]1([P:19](=[N:1][CH:4]2[CH:8]([O:9][CH2:10][CH3:11])[O:7][C:6](=[O:12])[CH2:5]2)([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCOC1OC(=O)CC1N=[N+]=[N-]
Solvent: Cc1ccccc1
Product: CCOC1OC(=O)CC1N=P(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 102.1 %

Procedure:
A solution of 4-azido-5-ethoxy-dihydrofuran-2-one (0.05 g, 0.29 mmol) and triphenylphosphine (0.078 g, 0.29 mmol) in toluene (5 mL) was stirred at room temperature under nitrogen for 5 h. The solvent was evaporated to afford 4-[(triphenylphosphoranylidene)amino]-5-ethoxy-dihydrofuran -2-one (0.12 g, 100% yield) as an off-white, waxy solid. 1H-NMR (500 MHz, CDCl3) δ 7.50 (m, 6H), 7.40 (m, 3H), 7.33 (m, 6H), 5.08 (d, J=3.1 Hz, 1H), 3.63 (m, 1H), 3.23 (m, 1H), 2.50 (dd, J=17.1, 5.9 Hz, 1H), 2.27 (dd, J=17.1, 5.9 Hz, 1H), 0.91 (t, J=7.0 Hz, 3H) ppm.
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:19]1([CH3:29])[C:20]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:22]=[CH:23][CH:24]=1>>[C:19]1([CH3:29])[C:20]([S:25]([N:4]2[CH2:5][CH2:6][N:1]([C:7]3[CH:16]=[CH:15][CH:14]=[C:13]4[C:8]=3[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]4)[CH2:2][CH2:3]2)(=[O:27])=[O:26])=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Nc1nc(N)c2c(N3CCNCC3)cccc2n1
Reactant: Cc1ccccc1S(=O)(=O)Cl
Product: Cc1ccccc1S(=O)(=O)N1CCN(c2cccc3nc(N)nc(N)c23)CC1
Yield: 37 %

Procedure:
Title compound was prepared via Resin Method using 5-piperazin-1-yl-quinazoline-2,4-diamine (50 mg; 0.2 mmol) and o-toluenesulfonyl chloride (78.2 mg; 0.41 mmol) to obtain 29.3 mg. (37% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.49 (br s, 1H), 7.86 (d, J=8.0 Hz, 1H), 7.61 (m, 1H), 7.73 (m, 3H), 7.47 (m, 2H), 7.38 (t, J=8.0 Hz, 1H), 6.99 (m, 2H), 6.82 (d, J=7.2 Hz, 1H), 5.93 (br s, 2H), 3.67 (d, J=12 Hz, 2H), 3.12 (d, J=12.0 Hz, 2H), 2.94 (t, J=11.5 Hz, 1H), 2.78 (t, J=11.5 Hz, 2H), 2.62 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]([NH:17][CH:18]([C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=2)[CH3:19])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[C:11]1([CH:10]([NH:17][CH:18]([C:20]2[CH:21]=[C:22]([F:27])[CH:23]=[C:24]([F:26])[CH:25]=2)[CH3:19])[C:6]2[CH:5]=[C:4]([NH2:1])[CH:9]=[CH:8][CH:7]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(NC(c1ccccc1)c1cccc([N+](=O)[O-])c1)c1cc(F)cc(F)c1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(NC(c1ccccc1)c1cccc(N)c1)c1cc(F)cc(F)c1
Yield: 89.4 %

Procedure:
In a similar manner to that described in Example (1b), a solution of isomer A of [(3-nitrophenyl)phenylmethyl]-[1-(3,5-difluorophenyl)ethyl]amine (900 mg) [prepared as described in step (a) above] in methanol (20 ml), nickel chloride hexahydrate (1.14 g) and sodium borohydride (363 mg) were reacted, to afford isomer A of the title compound (739 mg) as a pale yellow oil.
Reaction SMILES: [CH2:1]([N:4]1[CH2:15][CH:14]2[CH2:16][CH:6]([C:7](=O)[C:8]3[C:9]([O:17]C)=[CH:10][CH:11]=[CH:12][C:13]=32)[CH2:5]1)[CH:2]=[CH2:3].Cl.[NH2:21][OH:22].C(=O)([O-])[O-].[Ba+2]>CO>[CH2:1]([N:4]1[CH2:15][CH:14]2[CH2:16][CH:6]([C:7](=[N:21][OH:22])[C:8]3[C:13]2=[CH:12][CH:11]=[CH:10][C:9]=3[OH:17])[CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCN1CC2CC(C1)c1cccc(OC)c1C2=O
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Ba+2]
Solvent: CO
Product: C=CCN1CC2CC(C1)c1cccc(O)c1C2=NO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
11-Allyl-6-methoxy-11-aza-tricyclo[7.3.1.02,7]trideca-2(7),3,5-trien-8-one (243 mg, 1.0 mmol), hydroxylamine hydrochloride (80 mg, 1.15 mmol) an barium carbonate (227 mg, 1.15 mmol) were stirred and warmed to reflux in methanol (10 mL) for 18 h. Additional hydroxylamine hydrochloride (30 mg, 0.43 mmol) an barium carbonate (70 mg, 0.35 mmol) were introduced and heating continued for 2 h. The mixture was cooled to ambient temperature and filtered through Celite™, rinsed with methanol, concentrated and the residue dissolved in dichloromethane (30 mL), H2O (30 mL) and saturated aqueous NaHCO3 solution (˜30 mL) to achieve pH 8.5. The layers were separated and the aqueous layer was extracted with dichloromethane (2×30 mL), dried through a cotton plug and concentrated to an oily solid (275 mg). This material was triturated with stirring for in dichloromethane (20 mL) for 60 h and the resulting orange solid filtered (100 mg, 39%). (TLC 20% EtOAc/Hex Rf 0.28); 1H NMR (400 MHz, CDCl3) δ 8.10 (br s, OH),), 7.11 (dd, J=8.3, 7.5 Hz, 1H), 6.76 (dd, J=8.3, 0.8 Hz, 1H), 6.64 (dd, J=7.5, 0.8 Hz, 1H), 5.63 (m, 1H), 5.02 (m, 2H), 3.61 (br s, 3H), 3.24 (d, J=10.8 Hz, 1H), 2.97 (br s, 3H), 2.94–2.85 (m, 2H), 2.35 (dd, J=10.8, 2.4 Hz, 1H), 2.24 (dd, J=10.8, 2.4 Hz, 1H), 1.96 (dd, J=12.5, 1.5 Hz, 1H), 1.74 (ddd, J=12.5, 5.6, 2.7 Hz, 1H).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH:11]=[O:12])=[CH:4][C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+].C>C(Cl)Cl.CCCCCC>[CH2:13]([O:1][C:2]1[C:3]([CH:11]=[O:12])=[CH:4][C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: O=Cc1cc2c(cc1O)CCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCCCCC
Product: O=Cc1cc2c(cc1OCc1ccccc1)CCO2
Temperature: 25 °C
Yield: 78.7 %

Procedure:
A 2-liter, 3-neck flask equipped with a nitrogen inlet, internal thermometer, mechanical stirrer, and reflux condenser was charged with 5-hydroxy-2,3-dihydrobenzofuran-6-carboxaldehyde (50.00 g; 0.30 moles), benzylbromide (38.6 ml, 0.34 moles), and crushed anhydrous K2CO3 (165.84 g, 1.20 moles). The reaction mixture was refluxed for 16 hours, cooled to room temperature and suction filtered. The filtrate was concentrated in vacuo to afford a yellow solid. The solid was dissolved in methylene chloride (600 ml) and washed sequentially with 0.5N sodium hydroxide solution (3×250 ml) and brine (2×250 ml). The organic phase was dried over MgSO4, suction filtered, and the filtrate concentrated in vacuo to yield a crude solid (85 g). The solid was dissolved in methylene chloride (300 ml)/n-hexane (200 ml), treated with charcoal and suction filtered through a bed of celite. The filtrate was evaporated in vacuo to approximately 300 ml and slowly cooled to 0° C. to produce yellowish flat needles (60 g, 78%).
Reaction SMILES: [Cl-:1].[NH2:2][N+:3]1[CH:7]=[CH:6][N:5]([NH2:8])[C:4]=1[CH3:9].[CH3:10][N:11]([CH3:24])[C:12]1[C:19]([O:20][CH3:21])=[CH:18][C:15]([CH:16]=O)=[CH:14][C:13]=1[O:22][CH3:23]>C(O)(=O)C>[Cl-:1].[CH3:10][N:11]([CH3:24])[C:12]1[C:19]([O:20][CH3:21])=[CH:18][C:15]([CH:16]=[N:2][N+:3]2[CH:7]=[CH:6][N:5]([N:8]=[CH:16][C:15]3[CH:18]=[C:19]([O:20][CH3:21])[C:12]([N:11]([CH3:10])[CH3:24])=[C:13]([O:22][CH3:23])[CH:14]=3)[C:4]=2[CH3:9])=[CH:14][C:13]=1[O:22][CH3:23]
Reactant: Cc1n(N)cc[n+]1N
Reactant: COc1cc(C=O)cc(OC)c1N(C)C
Agent: [Cl-]
Solvent: CC(=O)O
Product: COc1cc(C=Nn2cc[n+](N=Cc3cc(OC)c(N(C)C)c(OC)c3)c2C)cc(OC)c1N(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2.2 g of 1,3-diamino-2-methylimidazolium chloride and 6.9 g of 4-dimethylamino-3,5-dimethoxy-benzaldehyde are dissolved in 100 ml of glacial acetic acid, whereupon the solution is stirred at room temperature for 48 hours. The glacial acetic acid is distilled off in vacuo and the residue is dissolved in 100 ml of ethyl acetate. After crystallization sets in a further 300 ml of ethyl acetate are added thereto, whereupon the mixture is cooled to 10°. The crystallized-out material is filtered off under suction, washed with 100 ml of ethyl acetate and dried over potassium hydroxide in vacuo at 80°. There is obtained 1,3-bis[[4-(dimethylamino)-3,5-dimethoxybenzylidene]amino]-2-methylimidazolium chloride of decomposition point 226°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13](Cl)=[N:12][CH:11]=1.[CH2:18]([NH2:21])[CH2:19][NH2:20]>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([NH:20][CH2:19][CH2:18][NH2:21])=[N:12][CH:11]=1
Reactant: NCCN
Reactant: Nc1ccccc1NC(=O)c1ccc(Cl)nc1
Product: NCCNc1ccc(C(=O)Nc2ccccc2N)cn1
Yield: 55 %

Procedure:
N-(2-Aminophenyl)-6-chloronicotinamide (248 mg, 1 mmol) and 5 ml of ethylenediamine were heated to 80° C. for 3 hours. The excess ethylenediamine was removed under vacuum. To the residue was added 5 ml of 0.20 M NaOH. The mixture was extracted with 100 ml of ethyl acetate. The ethyl acetate was removed under vacuum to give the title compound (150 mg, 55% yield) as a brown solid. LC-MS (m/z) 272 (M+1).
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:13]([Br:14])=[CH:12][C:8]([C:9]([OH:11])=O)=[C:7]([Cl:15])[CH:6]=1)[CH:2]=[CH2:3].Cl.[CH3:17][NH:18][O:19][CH3:20].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>C(Cl)Cl>[CH2:1]([O:4][C:5]1[C:13]([Br:14])=[CH:12][C:8]([C:9]([N:18]([O:19][CH3:20])[CH3:17])=[O:11])=[C:7]([Cl:15])[CH:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1cc(Cl)c(C(=O)O)cc1Br
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C=CCOc1cc(Cl)c(C(=O)N(C)OC)cc1Br
Temperature: 25 °C
Reaction time: 15 h
Yield: 95.6 %

Procedure:
To a suspension of 4-(allyloxy)-5-bromo-2-chlorobenzoic acid 21 (5.0 g, 17.2 mmol) in CH2Cl2 (50 mL) were added N,O-dimethylhydroxylamine HCl (2.1 g, 20.6 mmol), EDCI (4.9 g, 25.8 mmol), HOBT (4.7 g, 34.4 mmol) and NMM (9.5 mL, 86.0 mmol). The reaction mixture was stirred at rt for 15 hours and evaporated in vacuo to remove volatiles. The mixture was extracted with EtOAc/H2O (100 mL/100 mL). The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The residue was triturated with hexane (100 mL) and stirred at r.t. for 30 min. The solid was precipitated, filtered, washed with hexane (50 mL) and dried under high vacuum to obtain the desired product (5.5 g, 95%).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C@H:7]2[CH2:12][CH2:11][C@@H:10]([O:13][CH3:14])[CH2:9][C@H:8]2[CH2:15][NH:16][C:17](=[O:19])[CH3:18])[C:3]1=[O:20].C(N(CC)CC)C.Cl[C:29]1[C:38]2[C:33](=[CH:34][CH:35]=[C:36]([C:39]([F:42])([F:41])[F:40])[CH:37]=2)[N:32]=[CH:31][N:30]=1>CC(O)C>[CH3:14][O:13][C@H:10]1[CH2:9][C@@H:8]([CH2:15][NH:16][C:17](=[O:19])[CH3:18])[C@@H:7]([N:4]2[CH2:5][CH2:6][C@H:2]([NH:1][C:29]3[C:38]4[C:33](=[CH:34][CH:35]=[C:36]([C:39]([F:41])([F:42])[F:40])[CH:37]=4)[N:32]=[CH:31][N:30]=3)[C:3]2=[O:20])[CH2:12][CH2:11]1
Reactant: FC(F)(F)c1ccc2ncnc(Cl)c2c1
Reactant: CO[C@@H]1CC[C@H](N2CC[C@H](N)C2=O)[C@H](CNC(C)=O)C1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CO[C@@H]1CC[C@H](N2CC[C@H](Nc3ncnc4ccc(C(F)(F)F)cc34)C2=O)[C@H](CNC(C)=O)C1
Reaction time: 8 h
Yield: 80.7 %

Procedure:
A sample of the N-(((1S,2S,5R)-2-((S)-3-amino-2-oxopyrrolidin-1-yl)-5-methoxycyclohexyl)methyl)acetamide (220 mg, 0.776 mmol) was dissolved in 2-propanol (10 ml) at room temperature. To this solution was added triethylamine (0.433 ml, 3.11 mmol), followed by 4-chloro-6-(trifluoromethyl)quinazoline (235 mg, 1.009 mmol). The reaction mixture was stirred overnight. It was concentrated and chromatographed (120 g silica gel eluting with 5% followed by 10% MeOH in CH2Cl2) to afford the title compound (300 mg, 0.626 mmol, 81% yield) as a white solid. LC/MS found [M+H]+=480.4. 1H-NMR (400 MHz, CDCl3), δ ppm: 8.6 (s, 1H), 8.51 (s, 1H), 7.92 (br s, 1H), 7.87-7.82 (m, 2H), 6.28 (br s, 1H), 5.00 (dd, J=16.02, 8.65 Hz, 1H), 4.36-4.35 (m, 1H), 3.72-3.68 (m, 1H), 3.63-3.56 (m, 1H), 3.37-3.23 (m, 2H), 3.31 (s, 3H), 3.18-3.13 (m, 1H), 2.69-2.66 (m, 1H), 2.12-2.07 (m, 1H), 2.06-1.89 (m, 4H), 1.96 (s, 3H), 1.74-1.67 (m, 1H), 1.57-1.51 (m, 1H), 1.30-1.28 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2.[CH3:11][N:12]([CH3:26])[C:13]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][CH:16]3[CH2:15][CH2:14][C:13]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)([N:12]([CH3:26])[CH3:11])[CH2:18][CH2:17]3)=[CH:10][CH:9]=2)[CH2:5][CH2:6]1
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Reactant: Nc1ccc2c(c1)CCC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CN(C)C1(c2ccccc2)CCC(Nc2ccc3c(c2)CCC3)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
5-Aminoindane (266 mg) and 4-dimethylamino-4-phenylcyclohexanone (434 mg) were dissolved in dry 1,2-dichloroethane (10 ml) under argon. Glacial acetic acid (2 mmol) and sodium triacetoxyborohydride (600 mg) were added and the mixture was stirred for 24 hours at RT. For working up, the reaction mixture was concentrated and the residue was adjusted to pH 11 with five molar sodium hydroxide solution. The alkaline phase was diluted with water (10 ml) and extracted with ethyl acetate (4×20 ml). The combined extracts were dried over sodium sulfate and filtered and the filtrate was concentrated. The crude product obtained was chromatographed over silica gel with ethyl acetate/ethanol (1:1). 270 mg of the nonpolar diastereoisomer of N′-indan-5-yl-N,N-dimethyl-1-phenyl-cyclohexane-1,4-diamine were obtained as a white solid (m.p. 162-164° C.).