Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:21])=[C:6]([CH:20]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([C:17]([NH2:19])=[O:18])=[CH:13][CH:12]=1)[CH2:9][CH3:10].[CH:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C([BH3-])#N.[Na+]>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:6]([CH:20]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([C:17]([NH2:19])=[O:18])=[CH:13][CH:12]=1)[CH2:9][CH3:10]
Reactant: O=Cc1ccccc1
Reactant: CCN(Cc1cc(Br)ccc1N)c1ccc(C(N)=O)nn1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCN(Cc1cc(Br)ccc1NCc1ccccc1)c1ccc(C(N)=O)nn1
Temperature: 50 °C
Yield: 75.1 %

Procedure:
To a mixture of 6-[N-(5-bromo-2-aminobenzyl)-N-ethylamino]pyridazine-3-carboxamide (900 mg, 2.57 mmol), benzaldehyde (0.6 ml, 5.9 mmol) and methanol (50 ml) stirred at 50° C., was added portionwise sodium cyanoborohydride (400 mg, 6.36 mmol). The solution was stirred for 16 hours at 20° C., by which time the product crystallised. It was filtered off and washed with methanol (10 ml) to give 6-[N-(5-bromo-2-benzylaminobenzyl)-N-ethylamino]pyridazine-3-carboxamide (850 mg) m.p. 160-162° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[NH2:11][C:12]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][CH:15]=[CH:14][C:13]=1[OH:21].C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CC#N>[N+:18]([C:17]1[C:12]2[N:11]=[C:3]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:2][O:21][C:13]=2[CH:14]=[CH:15][CH:16]=1)([O-:20])=[O:19]
Reactant: O=C(CBr)c1ccccc1
Reactant: Nc1c(O)cccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cccc2c1N=C(c1ccccc1)CO2
Reaction time: 3 h
Yield: 100.8 %

Procedure:
The 2-bromoacetophenone (3.9 g, 19 mmol) [Aldrich, cat. #115835] was added portion wise to a stirred suspension of 2-amino-3-nitrophenol (2.5 g, 16 mmol) [Aldrich, cat. #297003] and K2CO3 (3.4 g, 24 mmol) in MeCN (100 mL) at room temperature. The reaction was monitored by LC/MS. After stirring for 3 h the reaction was complete and then EtOAc added and solution filtered to remove the solids and the organic layer was washed with water, 1 N HCl, brine, dried over MgSO4, filtered and concentrated to give 5-nitro-3-phenyl-2H-1,4-benzoxazine as a dark oil (4.1 g, 100%). LCMS calc. for C14H11N2O3 (M+H)+: m/z=255.3. found: 255.1.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:8][C:9]=1[N:10]([CH:20]1[CH2:25][CH2:24][N:23]([C:26](=[O:28])[CH3:27])[CH2:22][CH2:21]1)[C:11]([CH:13]1[CH2:18][CH2:17][CH:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].O.[Li+].[OH-]>O1CCOCC1>[C:26]([N:23]1[CH2:22][CH2:21][CH:20]([N:10]([C:11]([CH:13]2[CH2:14][CH2:15][CH:16]([CH3:19])[CH2:17][CH2:18]2)=[O:12])[C:9]2[CH:8]=[C:7]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[S:6][C:5]=2[C:3]([OH:4])=[O:2])[CH2:25][CH2:24]1)(=[O:28])[CH3:27]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)C1CCC(C)CC1)C1CCN(C(C)=O)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)N1CCC(N(C(=O)C2CCC(C)CC2)c2cc(-c3ccccc3)sc2C(=O)O)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 55.4 %

Procedure:
3-[(1-Acetyl-piperidin-4-yl)-(4-methyl-cyclohexanecarbonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (50 mg, 0.104 mmol) was dissolved in a 4:1 mixture of dioxane:H2O (1 ml) and then LiOH 1N (310 ul, 0.310 mmol) was added. After 5 hours of stirring at room temperature and 4 hours at reflux, solvents were removed and then partitioned between 5 ml of H2O acidified to pH 4 and 5 ml of EtOAc. The organic layer was separated and the aqueous phase was washed twice with ethyl acetate (2×5 mL). The combined ethyl acetate layer was dried (Na2SO4) and concentrated. The residue was purified by preparative chromatography (100/90/16/1 CH2Cl2/CHCl3/MeOH/Et3N) to obtain 27 mg (56%) of 3-[(1-Acetyl-piperidin-4-yl)-(4-methyl-cyclohexanecarbonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid (Compound 48).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:42])=[CH:4][C:5]([O:40][CH3:41])=[C:6]([CH:39]=1)[C:7]([NH:9][C@H:10]1[CH2:15][CH2:14][N:13]([CH:16]([CH3:36])[CH2:17][C:18]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:19]([N:21]([CH3:23])[CH3:22])=[O:20])[CH2:12][C@H:11]1[O:37][CH3:38])=[O:8].ClCCl.[C:46](Cl)(=[O:50])[CH2:47][CH2:48][CH3:49]>C(N(CC)CC)C>[Cl:42][C:3]1[C:2]([NH:1][C:46](=[O:50])[CH2:47][CH2:48][CH3:49])=[CH:39][C:6]([C:7]([NH:9][C@H:10]2[CH2:15][CH2:14][N:13]([CH:16]([CH3:36])[CH2:17][C:18]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:19]([N:21]([CH3:22])[CH3:23])=[O:20])[CH2:12][C@H:11]2[O:37][CH3:38])=[O:8])=[C:5]([O:40][CH3:41])[CH:4]=1
Reactant: COc1cc(Cl)c(N)cc1C(=O)N[C@H]1CCN(C(C)CC(C(=O)N(C)C)(c2ccccc2)c2ccccc2)C[C@H]1OC
Reactant: CCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(=O)Nc1cc(C(=O)N[C@H]2CCN(C(C)CC(C(=O)N(C)C)(c3ccccc3)c3ccccc3)C[C@H]2OC)c(OC)cc1Cl
Reaction time: 0.25 h
Yield: 46.5 %

Procedure:
To a stirred solution of 6.52 parts of cis-4-[(5-amino-4-chloro-2-methoxybenzoyI)amino]-3-methoxy-N,N,γ-trimethyl-α,α-diphenyl-1piperidinebutanamide in 195 parts of dichloromethane were added 2.6 parts of butanoyl chloride. After stirring for 15 minutes, 2.94 parts of N,N-diethylethanamine were added. The whole was stirred overnight at room temperature. The reaction mixture was washed successively with a sodium carbonate solution and water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was stirred in 2,2'-oxybispropane. The product was filtered off and dried, yielding 3.39 parts (46.5%) of cis-4-[[4-chloro-2-methoxy-5-[(1-oxobutyl)amino]benzoyl]amino]-3-methoxy-N,N,γ-trimethyl-α,α-diphenyl-1-piperidinebutanamide; mp. 130.7° C. (compound 65).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][NH2:16])[N:9]=[CH:8][CH:7]=[C:6]2[O:17][C:18]1[C:19]([CH3:28])=[N:20][C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2.[C:29]([NH:36][C:37]([NH:46][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])=NS(C(F)(F)F)(=O)=O)([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>ClCCl.CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][NH:16][C:37]([NH:36][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[N:46][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[N:9]=[CH:8][CH:7]=[C:6]2[O:17][C:18]1[C:19]([CH3:28])=[N:20][C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2
Reactant: CC(C)(C)OC(=O)NC(=NS(=O)(=O)C(F)(F)F)NC(=O)OC(C)(C)C
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCCN
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCCNC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 39.9 %

Procedure:
A solution of 2-[6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-yloxy]-ethylamine (compound 354) (340 mg) in dichloromethane (1 ml) and N,N-dimethylformamide (0.5 ml) were added to 1,3-diboc-2-(trifluoromethylsulfonyl)guanidine (355 mg), and the mixture was stirred at room temperature for 4 hr. The solvent was removed from the reaction solution under the reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give N-{2-[6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-yloxy]-ethyl}-N′,N″-diboc-guanidine (223 mg, yield 33%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]([OH:16])=[O:15])[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][C:18](=[CH2:20])[CH3:19].S(=O)(=O)(O)O>ClCCl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]([O:16][C:18]([CH3:20])([CH3:19])[CH3:17])=[O:15])[CH3:13])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: C=C(C)C
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of benzyloxycarbonyl-L-alanine (160 g., 0.72 mole), anhydrous dichloromethane (270 ml.), condensed isobutylene (700 ml.), and concentrated sulfuric acid (7.5 ml.) is shaken in a Parr apparatus at room temperature for 3 days. The isobutylene is allowed to evaporate at room temperature overnight and the residue is dissolved in 1 1. of ether. The resulting solution is washed with 1N sodium bicarbonate and brine. After drying over anhydrous MgSO4, the solvent is removed at reduced pressure to give 195 g. of benzyloxy-L-alanine, t-butyl ester as a yellow oil which is used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1)([O-])=O.C(#N)C.CN(C)C=[O:17]>>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[O:17])=[CH:6][CH:5]=1
Reactant: CN(C)C=O
Reactant: Cc1ccc([N+](=O)[O-])cc1
Solvent: CC#N
Product: Nc1ccc(C=O)cc1

Procedure:
The procedure of Example 1 was followed except that 2.3 g (3.4 wt.% of the p-nitrotoluene) of acetonitrile were substituted for the N, N-dimethylformamide, to obtain 37.7 g (0.312 mol) of p-aminobenzaldehyde and then obtain 38.5 g (0.315 mol) of p-hydroxybenzaldehyde.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[C:12]([O:16][C:17]([N:19]1[CH2:23][CH:22]=[CH:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].O>C(Cl)(Cl)Cl>[C:12]([O:16][C:17]([N:19]1[CH2:23][CH:22]2[O:9][CH:21]2[CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CC=CC1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CC2OC2C1
Yield: 58.8 %

Procedure:
2.96 g (0.012 mole) of 70% aqueous m-chloroperbenzoic acid were added to a solution of 1.69 g (0.01 mole) of 1-t-butoxycarbonyl-3-pyrroline [prepared as described in Step (a) above] in 10 ml of chloroform, whilst ice-cooling, and the mixture was stirred with ice-cooling for 8 hours and then with water-cooling for 15 hours. At the end of this time, the reaction mixture was extracted with toluene and the extract was washed, in turn, with an aqueous solution of sodium bicarbonate, a 0.1N aqueous solution of sodium thiosulfate and water. It was then dried over anhydrous sodium sulfate, and the solvent was removed by evaporation under reduced pressure. The residue was subjected to silica gel column chromatography eluted with a 1:5 by volume mixture of ethyl acetate and toluene, to afford 1.09 g of 1-t-butoxycarbonyl-3,4-epoxypyrrolidine as a colorless oily substance.
Reaction SMILES: C([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:47])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:46])[CH2:12][CH2:13][C@@:14]3([C:30](=[O:45])[NH:31][C@H:32]4[CH2:35][C@@H:34]([C:36]([N:38]5[CH2:42][CH2:41][CH2:40][CH2:39]5)=[O:37])[C:33]4([CH3:44])[CH3:43])[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:49])[CH3:48])(=O)C.[OH-].[Na+]>CO.C1COCC1>[CH3:43][C:33]1([CH3:44])[C@H:34]([C:36]([N:38]2[CH2:39][CH2:40][CH2:41][CH2:42]2)=[O:37])[CH2:35][C@@H:32]1[NH:31][C:30]([C@:14]12[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]1[C@@H:16]1[C@@:11]([CH3:46])([CH2:12][CH2:13]2)[C@@:10]2([CH3:47])[C@@H:19]([C@:20]3([CH3:23])[C@@H:7]([CH2:8][CH2:9]2)[C:6]([CH3:48])([CH3:49])[C@@H:5]([OH:4])[CH2:22][CH2:21]3)[CH2:18][CH2:17]1)=[O:45]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@H]3C[C@@H](C(=O)N4CCCC4)C3(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(C)=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@H]3C[C@@H](C(=O)N4CCCC4)C3(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.5 %

Procedure:
To a stirred solution of (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((1S,3R)-2,2-dimethyl-3-(pyrrolidine-1-carbonyl)cyclobutylcarbamoyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl acetate (Example 13, 0.230 g, 0.340 mmol) in MeOH:THF (2:1) (9 ml) NaOH (2N, 3 ml) was added at about 0° C. and allowed to stir at room temperature for about 16 hours. After completion of the reaction (monitored by TLC), the volatiles were evaporated and the aqueous layer was extracted with ethyl acetate and the organic layer was washed with water, brine and dried with Na2SO4. The solvent was evaporated and purified by silica gel column (100-200 mesh, elution 15% EtOAc in hexane) to afford the title compound as an off white solid. Wt: 0.150 g: Yield: 69.5%; 1H NMR (300 MHz, CDCl3): δ 6.39 (d, 1H, J=8.4 Hz), 4.73 (s, 1H), 4.57 (s, 1H), 4.13-4.03 (m, 1H), 3.58-3.28 (m, 4H), 3.21-3.07 (m, 2H), 2.79 (t, 1H, J=7.2 Hz), 2.57-2.33 (m, 2H), 2.27-2.18 (m, 1H), 2.04-1.72 (m, 8H), 1.70-1.10 (m, 23H), 0.95, 0.92, 0.88, 0.83, 0.80, 0.75 (s, 21H); Mass: [M+1]+ 635 (100%), [M+Na]+ 657 (90%); IR (KBr, cm−1): 3489, 2947, 2869, 1637, 1615, 1441, 1376, 1357, 1250, 1194, 1050, 881, 717; M.R: 172.4° C.-173.8° C.; HPLC: 96.79%.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([C:15]([F:18])([F:17])[F:16])[CH:9]=2)=[CH:6][CH:7]=1.[C:19]([NH:22][NH2:23])(=O)[CH3:20]>C(O)CCC>[CH3:20][C:19]1[N:3]2[N:4]=[C:5]([C:8]3[CH:13]=[CH:12][C:11]([F:14])=[C:10]([C:15]([F:18])([F:17])[F:16])[CH:9]=3)[CH:6]=[CH:7][C:2]2=[N:23][N:22]=1
Reactant: Fc1ccc(-c2ccc(Cl)nn2)cc1C(F)(F)F
Reactant: CC(=O)NN
Solvent: CCCCO
Product: Cc1nnc2ccc(-c3ccc(F)c(C(F)(F)F)c3)nn12

Procedure:
As described in Example 36, 3-chloro-6-[4-fluoro-3-(trifluoromethyl)phenyl]pyridazine is reacted with acetic acid hydrazide in n-butanol to give the product of the example.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]([N:16]1[CH2:21][CH2:20][CH:19]([CH2:22][CH2:23][C:24](O)=[O:25])[CH2:18][CH2:17]1)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(=S)=S>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:24](=[O:25])[CH2:23][CH2:22][CH:19]2[CH2:18][CH2:17][N:16]([C:8](=[O:15])[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:21][CH2:20]2)=[CH:4][CH:3]=1
Reactant: Clc1ccccc1
Reactant: O=C(O)CCC1CCN(C(=O)c2ccccc2)CC1
Solvent: S=C=S
Product: O=C(CCC1CCN(C(=O)c2ccccc2)CC1)c1ccc(Cl)cc1
Yield: 187.6 %

Procedure:
The procedure is as in Example 1, starting from 18 g of chlorobenzene instead of 9.9 g of anisol, 350 ml of carbon disulfide instead of 157 ml and 35 g instead of 15.7 g of 3-(1-benzoyl 4-piperidyl) propionic acid. 40.1 g of crude 1-(4-chlorophenyl) 3-(1-benzoyl 4-piperidyl) 1-propanone are obtained in the form of an oil which crystallizes.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([NH:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[O:21][CH3:22])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:23]I>>[Cl:1][C:2]1[N:11]=[C:10]([N:12]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[O:21][CH3:22])[CH3:23])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CI
Reactant: COc1ccc(OC)c(Nc2nc(Cl)nc3ccccc23)c1
Product: COc1ccc(OC)c(N(C)c2nc(Cl)nc3ccccc23)c1

Procedure:
The title compound was prepared from (2-chloro-quinazolin-4-yl)-(2,5-dimethoxy-phenyl)-amine and methyl iodide by a procedure similar to Example 36 (78% yield). 1H NMR (CDCl3): 7.72-7.75 (m, 1H), 7.56 (ddd, J=8.4, 5.7 and 2.1 Hz, 1H), 6.98-7.00 (m, 2H), 6.92-6.92 (m, 2H), 6.78-6.79 (m, 1H), 3.75 (s, 3H), 3,58 (s, 3H), 3.56 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[CH:3]=1.[CH2:11]([O:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([O:18][C:19]1[CH:20]=[C:21]([CH:22]2[C:3]3[C:4](=[O:10])[CH2:5][C:6]([CH3:9])([CH3:8])[CH2:7][C:2]=3[NH:1][C:2]3[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[C:3]2=3)[CH:24]=[CH:25][CH:26]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1cccc(OCc2ccccc2)c1
Reactant: CC1(C)CC(=O)C=C(N)C1
Product: CC1(C)CC(=O)C2=C(C1)NC1=C(C(=O)CC(C)(C)C1)C2c1cccc(OCc2ccccc2)c1

Procedure:
3-Amino-5,5-dimethyl-2-cyclohexen-1-one was reacted with 3-benzyloxybenzaldehyde in an analogous manner to that described in Example 1 to give 9-(3-benzyloxyphenyl)-3,4,6,7,9,10-hexahydro-3,3,6,6-tetramethyl-1,8(2H,5H)-acridinedione. Crystallization from ethanol gave a cream coloured crystalline solid of melting point >300° C. (decomposition).
Reaction SMILES: [NH:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[NH:3]1.[C:12]1([NH2:19])[CH:17]=[CH:16][CH:15]=[C:14]([NH2:18])[CH:13]=1.O.NN>CCO>[NH2:18][C:14]1[CH:13]=[C:12]([NH:19][C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4](=[O:11])[NH:3][N:1]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: Nc1cccc(N)c1
Reactant: N=C1NC(=O)c2ccccc21
Agent: NN
Solvent: O
Solvent: CCO
Product: Nc1cccc(Nc2n[nH]c(=O)c3ccccc23)c1
Temperature: 80 °C

Procedure:
3-Imino-2,3-dihydro-isoindol-1-one (50 mg, 0.34 mmol) and benzene-1,3-diamine (110 mg, 0.102 mmol) were heated at 200° C. for 16 hrs. The resulting mixture was dissolved in EtOH (600 μL) and hydrazine hydrate (200 μL) was added. After heating for 2 hours at 80° C. the mixture was concentrated in vacuo and dissolved in 1500 μL DMSO and directly applied to preparative HPLC to afford 4-(3-amino-phenylamino)-2H-phthalazin-1-one.
Reaction SMILES: [NH2:1][C:2]1[O:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH:17]1([C:20](Cl)=[O:21])[CH2:19][CH2:18]1.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH:17]1([C:20]([NH:1][C:2]2[O:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:3]=2)=[O:21])[CH2:19][CH2:18]1
Reactant: O=C(Cl)C1CC1
Reactant: COC(=O)c1ccc(N)o1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc(NC(=O)C2CC2)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
To a solution of methyl 5-aminofuran-2-carboxylate (1.0 g) and pyridine (1.2 mL) in methylene chloride (6.0 mL) is added dropwise cyclopropanecarbonyl chloride (0.78 mL) under ice-cooling and the mixture is stirred at room temperature for 2 hours. To the reaction mixture is added a saturated sodium hydrogencarbonate solution and the mixture is extracted with chloroform. The extract is dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is purified by column chromatography on silica gel (Solvent; n-hexane:ethyl acetate=3:1) to give methyl 5-[(cyclopropylcarbonyl)amino]furan-2-carboxylate (0.82 g, yield; 56%) as colorless crystals. MS (APCI) m/z: 210 [M+H]+
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[Br:12]Br.O>CO>[Br:12][C:10]1[C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=[C:3]([CH:11]=1)[CH:2]=[O:1]
Reactant: BrBr
Reactant: COc1cc(C=O)ccc1O
Solvent: CO
Solvent: O
Product: COc1cc(C=O)cc(Br)c1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 92.6 %

Procedure:
To a solution of vanillin (7.6 g, 50 mmol) in MeOH (60 mL) was added dropwise Br2 (2.8 mL, 50 mmol) over a 2 h period at 0° C. The mixture was warm to room temperature for another 1 h. Then cooling to 0° C., water (25 mL) was poured over a 20 min period and resulted in the precipitation of white solid. The mixture was stirred for further 15 min. The precipitate was filtered, washed with ice water and dried to give 10.7 g of white solid. Spectrum analysis verified the compound is 5-Br-vanillin.
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1C(N2C=CN=C2)=CN=C(CCN)N=1.Cl[C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[C:26]([NH2:33])[N:25]=1.[Cl:34][C:35]1[CH:40]=[C:39]([Cl:41])[CH:38]=[CH:37][C:36]=1[C:42]1[C:47]([C:48]2[NH:49][CH:50]=[CH:51][N:52]=2)=[CH:46][N:45]=[C:44]([NH:53][CH2:54][CH2:55][NH:56]C2C=CC([N+]([O-])=O)=C(OC)N=2)[N:43]=1>>[NH2:33][C:26]1[N:25]=[C:24]([NH:56][CH2:55][CH2:54][NH:53][C:44]2[N:43]=[C:42]([C:36]3[CH:37]=[CH:38][C:39]([Cl:41])=[CH:40][C:35]=3[Cl:34])[C:47]([C:48]3[NH:52][CH:51]=[CH:50][N:49]=3)=[CH:46][N:45]=2)[CH:29]=[CH:28][C:27]=1[N+:30]([O-:32])=[O:31]
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: COc1nc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]
Agent: NCCc1ncc(-n2ccnc2)c(-c2ccc(Cl)cc2Cl)n1
Product: Nc1nc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]

Procedure:
{2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}[4-(2,4-dichlorophenyl)-5-imidazolylpyrimidin-2-yl]amine was prepared from [4-(2,4-dichlorophenyl)-5-imidazol-1-ylpyrimidin-2-ylethylamine and 2-chloro-5-nitro-6-aminopyridine in accordance with the procedure described above for the preparation of [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(6-methoxy-5-nitro(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][CH2:15][CH3:16])=[C:6]([C:17]([OH:19])=O)[C:5]=1[C:20]([OH:22])=[O:21])[CH3:2].S(Cl)(Cl)=O>C(Cl)(Cl)Cl>[CH2:15]([O:14][C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]([O:3][CH2:1][CH3:2])=[C:5]2[C:20]([O:21][C:17](=[O:19])[C:6]=12)=[O:22])[CH3:16]
Reactant: CCOc1c(C(=O)O)c(C(=O)O)c(OCC)c2ccccc12
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCOc1c2c(c(OCC)c3ccccc13)C(=O)OC2=O
Yield: 99.3 %

Procedure:
1,4-Diethoxy-2,3-naphthalenedicarboxylic acid (25 g, 82 mmol) was added to a solution of thionyl chloride (23.3 g) in chloroform (150 ml) and stirred at reflux for 1 h. The resulting solution was cooled and evaporated to dryness. Further chloroform was added and evaporation repeated to give the title compound as a yellow solid (23.3 g, 99%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH2:13][CH2:12][CH2:11][N:10]([CH2:14][C:15](O)=[O:16])[C:9]2=[O:18])=[CH:4][CH:3]=1.[N:26]1([C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CN(C)C1C=CN=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)[CH2:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]([N:29]3[CH2:30][CH2:31][N:26]([C:32]([O:34][CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[O:33])[CH2:27][CH2:28]3)=[O:16])[C:9]2=[O:18])=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Reactant: O=C(O)CN1CCCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O)N1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(3,3-bis(4-fluorophenyl)-2-oxopiperidin-1-yl)acetic acid (0.34 g, 1.0 mmol, Example 23D) in CH2Cl2 (15 mL) was added benzyl piperazine-1-carboxylate (0.22 g, 1.0 mmol) under nitrogen. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.38 g, 2.0 mmol) and 4-(dimethylamino)pyridine (0.012 g, 0.1 mmol) were added to the reaction, and the mixture was stirred overnight at room temperature. The organic layer was washed with water and brine, dried over MgSO4, filtered, and concentrated. The crude product was purified by chromatography on silica gel (Analogix Intelliflash 280; CH3OH/CH2Cl2, 2:98 eluant) to afford the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.39-7.31 (m, 5H), 7.30-7.21 (m, 4H), 6.97 (dd, J=9.7, 7.7, 4H), 5.15 (s, 2H), 4.19 (s, 2H), 3.70-3.59 (m, 2H), 3.58-3.37 (m, 8H), 2.64-2.52 (m, 2H), 1.90-1.76 (m, 2H); MS (DCI +) m/z 565 (M+MH4)+.