Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:6]1[CH:22]=[C:21]([C:23]([CH2:26][CH3:27])([CH3:25])[CH3:24])[CH:20]=[CH:19][C:7]=1[O:8][C:9]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:10]=1[C:11](O)=[O:12])([CH2:4][CH3:5])([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[NH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.CCCCCCC>ClCCl.C(OCC)(=O)C>[C:1]([C:6]1[CH:22]=[C:21]([C:23]([CH2:26][CH3:27])([CH3:25])[CH3:24])[CH:20]=[CH:19][C:7]=1[O:8][C:9]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:10]=1[C:11]([NH:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:12])([CH2:4][CH3:5])([CH3:3])[CH3:2]
Reactant: Nc1ccccc1
Reactant: CCC(C)(C)c1ccc(Oc2ccc(O)cc2C(=O)O)c(C(C)(C)CC)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: ClCCl
Product: CCC(C)(C)c1ccc(Oc2ccc(O)cc2C(=O)Nc2ccccc2)c(C(C)(C)CC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-(2,4-di-tert-pentylphenoxy)-5-hydroxybenzoic acid (3.3 g, 8.9 mmol) and oxalyl chloride (1.25 g, 9.8 mmol) in dichloromethane (75 mL) was stirred at room temperature for 2 hours. The solvent was removed in vacuo and the residue triturated with toluene (25 mL) followed by distillation of the solvent. The crystalline residue was taken up in dichloromethane (80 mL) and aniline (1.66 g, 17.9 mmol) was added. The reaction mixture was allowed to stir at room temperature for 8 hours, then submitted to aqueous, acidic workup. Flash column chromatography on silica gel with 90:10 heptane:ethyl acetate yielded the addition product. Recrystallization from heptane/ethyl acetate yielded analytically pure product in 79% overall yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[C:6]([CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1.Cl[C:20]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:21].C([O:36]C(=O)NC1SC2C(C3C=CC=CC=3)=CC=C(OC)C=2N=1)C1C=CC=CC=1.C(N(C(C)C)C(C)C)C.[C@H]1(O)CC[C@H](O)CC1>CS(C)=O.ClCCl>[OH:36][C@H:26]1[CH2:27][CH2:28][C@H:23]([O:22][C:20](=[O:21])[NH:12][C:10]2[S:11][C:7]3[C:6]([CH:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=3[N:9]=2)[CH2:24][CH2:25]1
Reactant: COc1ccc(C2CCOCC2)c2sc(N)nc12
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COc1ccc(-c2ccccc2)c2sc(NC(=O)OCc3ccccc3)nc12
Agent: O[C@H]1CC[C@H](O)CC1
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C2CCOCC2)c2sc(NC(=O)O[C@H]3CC[C@H](O)CC3)nc12

Procedure:
4-Methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-ylamine (69 mg, 0.26 mmol) is first reacted with phenyl chloroformate as described for (4-methoxy-7-phenyl-benzothiazol-2-yl)-carbamic acid benzyl ester in WO01/97786 and then with N-ethyl-diisopropylamine (0.090 ml, 0.52 mmol) and (trans)-cyclohexane-1,4-diol (60 mg, 0.52 mmol) in dimethyl sulfoxide (10 ml) at 50° C. for 2 h. Then 100 ml dichoromethane are added, the mixture is extracted with saturated aqueous sodium carbonate and the organic phase is dried and evaporated. Flash-chromatographic purification (silica, eluting with dichloromethane/methanol) yielded the title compound as white solid (7% yield). MS: m/e=407(M+H+), mp 282-284° C. Following the general method of example 1 the compounds of examples 2 to 11 were prepared.
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])[C:6]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[CH:5][N:4]=1.[CH3:24][CH:25]([OH:33])[C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1>>[CH3:24][CH:25]([O:33][C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])[C:6]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[CH:5][N:4]=1)[C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1
Reactant: CC(O)c1ccc(F)cc1
Reactant: CSc1ncc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Product: CC(Oc1ncc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1)c1ccc(F)cc1

Procedure:
2-Methylthio-5-(4-chlorophenyl)-4-(2,4-dichlorophenyl)pyrimidine from Reference Example 3 was reacted with α-methyl-4-fluorobenzyl alcohol according to the procedure described in Example 59 to afford 2-(α-methyl-4-fluorobenzyloxy)-4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyrimidine (HRf): HPLC/MS: m/e=473 (M++1); Rt=4.80 min; 1H-NMR 400 MHz (CDCl3): δ 1.76 (d, J=9 Hz, 3H), 6.22-6.30 (dd, J=6 Hz, J=9 Hz, 1H), 6.90-7.05 (m, 4H), 7.15-7.18 (d, J=9 Hz, 2H), 7.21-7.23 (m, 3H), 7.38 (d, 1H), 7.45-7.52 (m, 2H), 8.58 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([O:16]CC)=[O:15])=[CH:9][C:8]=2[Cl:19])[N:5]=[C:4]([CH2:20][CH3:21])[C:3]=1[C:22]([NH2:24])=[O:23].[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34](OC)=O)=[CH:29][CH:28]=1.[Na].CC(O)=O>C(O)C>[Cl:13][C:12]1[CH:11]=[C:10]([C:14]([OH:16])=[O:15])[CH:9]=[C:8]([Cl:19])[C:7]=1[N:6]1[C:2]2=[N:1][C:34]([CH2:33][C:30]3[CH:31]=[CH:32][C:27]([O:26][CH3:25])=[CH:28][CH:29]=3)=[N:24][C:22](=[O:23])[C:3]2=[C:4]([CH2:20][CH3:21])[NH:5]1
Reactant: COC(=O)Cc1ccc(OC)cc1
Reactant: CCOC(=O)c1cc(Cl)c(-n2nc(CC)c(C(N)=O)c2N)c(Cl)c1
Agent: [Na]
Solvent: CC(=O)O
Solvent: CCO
Product: CCc1[nH]n(-c2c(Cl)cc(C(=O)O)cc2Cl)c2nc(Cc3ccc(OC)cc3)nc(=O)c1-2
Yield: 75.1 %

Procedure:
Part D: To a stirred solution of 500 mg (1.35 mmol) of 5-amino-3-ethyl-1-(2,6-dichloro-4-carboethoxyphenyl) pyrazole-4-carboxamide in 10 mL ethanol was added 1.45 g (8.1 mmol) of methyl 4-methoxyphenylacetate followed by 2.6 mL (8.1 mmol) of 2.66 M sodium ehtoxide in ethanol. The reaction was heated at relux for 18 h and then 10% aq. HOAc was added. After stirring an additional hour at relux, the heat was removed and the reaction solution was poured into ice water, stirred 10 min. and filtered. The solid was washed with water and diethyl ether and dried to give 480 mg (75%) of 1-(2,6-dichloro-4-carboxyphenyl)-3-ethyl-6-(4-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one, mp 277° C. Mass Spec.: (ES−) 471 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6](Cl)=[O:7].[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>ClCCl>[CH2:16]([NH:23][C:6](=[O:7])[C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: NCc1ccccc1
Solvent: ClCCl
Product: COc1cc(C(=O)NCc2ccccc2)cc(OC)c1OC

Procedure:
3,4,5-Trimethoxybenzoyl chloride (5.0 g, 21.7 mmol) was dissolved in dichloromethane (50 ml). The reaction mixture was cooled with an ice-bath and benzylamine (4.74 ml, 43.4 mmol) was added slowly. The solid material was removed by filteration. The filtrate was poured into 30 ml of water. The organic phase was washed several times with water. The crude product was recrystallized from i-propanol.
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:22])[CH:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:14][CH3:15])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[S:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[CH:25]=[C:24]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[S:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[CH:25]=[C:24]1[C:2]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:22])[CH:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:14][CH3:15])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: OB(O)c1cc2ccccc2s1
Reactant: CCC(C(=O)Nc1ccc(I)c(C(N)=O)c1)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CCC(C(=O)Nc1ccc(-c2cc3ccccc3s2)c(C(N)=O)c1)c1ccccc1
Temperature: 25 °C

Procedure:
A solution of 500 mg (1.23 mmol) of the compound of Example 5A, 262 mg (1.47 mmol) of 1-benzothien-2-ylboronic acid, 1.34 ml (2.70 mmol, 2M solution in water) of sodium carbonate and 42 mg (0.061 mmol) of bis(triphenylphosphine)palladium(II) chloride in 10 ml of dimethoxyethane are stirred under reflux for 3 hours. The solution is cooled to room temperature and then partitioned between 500 ml of ethyl acetate and water, and the aqueous phase is extracted twice with 200 ml of ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered with suction and concentrated. The residue is dissolved in dimethyl sulfoxide and purified by preparative RP-HPLC with acetonitrile and water. 146 mg (29% of theory) of the title compound are obtained.
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4]1[CH:9]=[C:8]([NH:10][C:11](=[O:19])[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[CH:7]=[CH:6][C:5]=1[O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CO.O.O.[OH-].[Li+]>O1CCCC1>[Cl:18][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[C:11]([NH:10][C:8]1[CH:7]=[CH:6][C:5]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:4]([CH:9]=1)[C:3]([OH:27])=[O:2])=[O:19]
Reactant: COC(=O)c1cc(NC(=O)c2cccc(Cl)c2)ccc1Oc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Oc2ccccc2)c(C(=O)O)c1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
5-(3-Chloro-benzoylamino)-2-phenoxy-benzoic acid methyl ester (1.56 g, 4.00 mmol) (see Example I1) was dissolved in a mixture of tetrahydrofuran (15 ml), methanol (1.5 ml), and water (1.5 ml). Lithium hydroxide monohydrate (336 mg, 8 mmol) was added and the reaction mixture stirred at ambient temperature for 3 days. The reaction mixture was concentrated and the residue extracted with water and tert-butyl-methyl-ether. The aqueous phase was acidified by the addition of a few drops of concentrated hydrochloric acid and extracted with ethyl acetate. The phases were separated, the organic phase was dried over sodium sulfate and concentrated. The residue was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:14][CH:13]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[CH2:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.[NH:47]1[C:51]([C:52]2[CH:57]=[CH:56][C:55]([C:58]3([NH2:61])[CH2:60][CH2:59]3)=[CH:54][CH:53]=2)=[N:50][N:49]=[N:48]1.C(N(CC)CC)C>CN(C)C=O>[NH:50]1[C:51]([C:52]2[CH:53]=[CH:54][C:55]([C:58]3([NH:61][C:7](=[O:9])[C:6]4[CH:10]=[C:2]([Cl:1])[CH:3]=[N:4][C:5]=4[N:11]4[CH2:14][CH:13]([O:15][C:16]5[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=5)[CH2:12]4)[CH2:59][CH2:60]3)=[CH:56][CH:57]=2)=[N:47][N:48]=[N:49]1
Reactant: NC1(c2ccc(-c3nnn[nH]3)cc2)CC1
Reactant: O=C(O)c1cc(Cl)cnc1N1CC(Oc2cccc(F)c2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NC1(c2ccc(-c3nnn[nH]3)cc2)CC1)c1cc(Cl)cnc1N1CC(Oc2cccc(F)c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.7 %

Procedure:
To mixture of 5-chloro-2-(3-(3-fluorophenoxy)azetidin-1-yl)nicotinic acid (D77) (60 mg, 0.186 mmol) in dry dimethylformamide (1 ml), 1-Hydroxybenzotriazole hydrate (28.5 mg, 0.189 mmol), 1-Ethyl-3-[3-dimethylaminopropyl]carbodiimide Hydrochloride (53.5 mg, 0.279 mmol) were added followed by the addition of a solution of 1-(4-(1H-tetrazol-5-yl)phenyl)cyclopropanamine hydrochloride (D17) (44.2 mg, 0.186 mmol) and triethylamine (26 μl, 0.189 mmol) in dry dimethylformamide. The mixture was stirred for 1 h at room temperature. The solvent was evaporated in vacuo and the resulting residue was taken in NH4Cl sat. sol (10 ml) and extracted with ethylacetate (2×10 ml). Collected organics after solvent evaporation afforded a residue that was washed with methanol (2 ml) to afford the title compound (E82) (30.8 mg)
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:7]=[C:8]([CH:13]=[C:14]([N:16]2[CH:20]=[CH:19][CH:18]=[CH:17]2)[CH:15]=1)[C:9]([O:11][CH3:12])=[O:10])(=[O:3])[CH3:2].ClS([N:25]=[C:26]=O)(=O)=O.CN(C)C=O.O>ClCCl>[C:1]([O:4][CH2:5][C:6]1[CH:7]=[C:8]([CH:13]=[C:14]([N:16]2[CH:17]=[CH:18][CH:19]=[C:20]2[C:26]#[N:25])[CH:15]=1)[C:9]([O:11][CH3:12])=[O:10])(=[O:3])[CH3:2]
Reactant: COC(=O)c1cc(COC(C)=O)cc(-n2cccc2)c1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1cc(COC(C)=O)cc(-n2cccc2C#N)c1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 3-acetoxymethyl-5-(pyrrol-1-yl)benzoate (4.68 g) in dichloromethane (94 ml) was added chlorosulfonyl isocyanate (2.1 ml) at -20° C. under nitrogen. After being stirred for 1 hour at -20° C., to the reaction mixture was added N,N-dimethylformamide (14.0 ml) at -20° C. After being stirred for 1 hour at -20° C. to -10° C., the reaction mixture was poured into water and the product was extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was purified by column chromatography on silica gel eluting with a mixture of hexane and ethyl acetate (5:1). The eluted fractions containing the desired product were collected and evaporated in vacuo to afford methyl 3-acetoxymethyl-5-(2-cyanopyrrol-1-yl)benzoate (4.26 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:12]=[CH:11][S:10][C:4]=2[N:5]=[C:6](SC)[N:7]=1.[CH2:13]1COCC1.O[O:19][S:20]([O-:22])=O.[K+]>O.CCOC(C)=O>[Cl:1][C:2]1[C:3]2[CH:12]=[CH:11][S:10][C:4]=2[N:5]=[C:6]([S:20]([CH3:13])(=[O:22])=[O:19])[N:7]=1
Reactant: CSc1nc(Cl)c2ccsc2n1
Reactant: O=S([O-])OO
Reactant: C1CCOC1
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1nc(Cl)c2ccsc2n1
Temperature: 0 °C

Procedure:
To 1 L round-bottom flask was added 4-chloro-2-(methylthio)thieno[2,3-d]pyrimidine (35.0 g, 162 mmol), THF (300 mL). The solution was stirred at 0° C. and treated dropwise with a solution of OXONE (209 g, 339 mmol) in water (350 mL). The resulting mixture was stirred at RT overnight. The reaction mixture was diluted with EtOAc (500 mL) and water (300 mL). Separated the layers, the aqueous layer was extracted with EtOAc (3×300 mL). Organic layers were combined, washed with brine (2×300 mL), dried over MgSO4, filtered and concentrated to give (33 g). MS (ES+): 249 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH2:21][NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH3:30])=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13]([CH3:19])([CH3:18])[CH:12]=[C:11]3[CH3:20])=[C:4]([O:31][CH3:32])[CH:3]=1.C(N(CC)CC)C.[C:40](Cl)(=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C(Cl)Cl>[C:40]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH2:21][NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH3:30])=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13]([CH3:19])([CH3:18])[CH:12]=[C:11]3[CH3:20])=[C:4]([O:31][CH3:32])[CH:3]=1)(=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: COc1ccccc1NCc1c(-c2ccc(O)cc2OC)ccc2c1C(C)=CC(C)(C)N2
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1NCc1c(-c2ccc(OC(=O)c3ccccc3)cc2OC)ccc2c1C(C)=CC(C)(C)N2
Reaction time: 0.5 h
Yield: 65 %

Procedure:
6-(4-Hydroxy-2-methoxyphenyl)-5-(2-methoxyphenylaminomethyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Reference Compound No. 4-1, 25.0 mg, 0.0581 mmol) was dissolved in methylene dichloride (0.5 mL), and then triethylamine (16.2 μL, 0.116 mmol) and benzoyl chloride (8.7 μL, 0.075 mmol) were added thereto successively under ice cooling. The reaction mixture was stirred under ice cooling for 30 minutes. The reaction mixture was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (13.0 mg) as a colorless amorphous product. (Yield 65%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]2[N:15]=[N:14][CH:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[C:10](=O)[CH2:9]1.[C:26]([NH:29][NH2:30])([NH2:28])=[NH:27].Cl.Cl.O>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]2[N:15]=[N:14][CH:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[C:10](=[N:30][NH:29][C:26]([NH2:28])=[NH:27])[CH2:9]1
Reactant: O=C1CC(c2ccccc2Cl)Cc2nncc(-c3ccc(Cl)cc3)c21
Reactant: N=C(N)NN
Agent: Cl
Solvent: O
Solvent: CCO
Product: N=C(N)NN=C1CC(c2ccccc2Cl)Cc2nncc(-c3ccc(Cl)cc3)c21
Yield: 115.5 %

Procedure:
To a solution of 7-(2-chlorophenyl)-4-(4-chlorophenyl)-5,6,7,8-tetrahydrocinnolin-5-one (0.18 g) and aminoguanidine hydrochloride (65 mg) in ethanol (10 ml) were added concentrated hydrochloric acid (0.12 ml) and water (0.12 ml), and the mixture was refluxed for 6 hours. Under reduced pressure, the solvent was evaporated, and to the residue was added sodium hydrogen carbonate solution to make the solution alkaline. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate-methanol). The resulting crystals were dissolved in 1N hydrochloric acid (1 ml), and the solution was concentrated. The residue was recrystallized from ethanol-ethyl acetate to give 7-(2-chlorophenyl)-4-(4-chlorophenyl)-5-guanidinoimino-5,6,7,8-tetrahydrocinnoline hydrochloride (Compound 145) (0.13 g) as colorless crystals.
Reaction SMILES: B1C2CCCC1CCC2.[Cl:10][C:11]1[CH:12]=[C:13]([CH:17]([CH2:30][CH:31]=[CH2:32])[CH2:18][N:19]([CH3:29])[S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH:14]=[CH:15][CH:16]=1.[OH-:33].[Na+].OO>C1COCC1>[Cl:10][C:11]1[CH:12]=[C:13]([CH:17]([CH2:30][CH2:31][CH2:32][OH:33])[CH2:18][N:19]([CH3:29])[S:20]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)(=[O:22])=[O:21])[CH:14]=[CH:15][CH:16]=1
Reactant: C=CCC(CN(C)S(=O)(=O)c1ccccc1)c1cccc(Cl)c1
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(CC(CCCO)c1cccc(Cl)c1)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 37.1 %

Procedure:
9-BBN (119 mg, 0.488 mmol) was added in one portion to an ice cold solution of N-(2-(3-chlorophenyl)pent-4-enyl)-N-methylbenzenesulfonamide (100 mg, 0.286 mmol) in 1.0 mL of THF, and the mixture was allowed to warm to room temperature. After 15 h, an additional portion of 9-BBN (26 mg, 0.11 mmol) was added and stirring was continued for another 1 h. Aqueous 2.5 N sodium hydroxide solution (0.29 mL, 0.73 mmol) and aqueous 30% hydrogen peroxide solution (0.176 mL) were added and the mixture was stirred 45 min at room temperature, 5 h at 50 ° C., and overnight at room temperature. The reaction was concentrated and the residue was partitioned between 25 mL of ethyl acetate and a mixture of 20 mL of water and 5 mL of brine. The aqueous layer was extracted with 2×25 mL of ethyl acetate. The combined organic layers were washed with 25 mL of brine, dried over sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel, eluting with 5-50% ethyl acetate in dichloromethane to give 39 mg the title compound. 1NMR (400 MHz, CD3OD): δ 7.72 (d, 2H, J=8 Hz), 7.63 (tt, 11H, J=8, 1 Hz), 7.56 (t, 2H, J=8 Hz), 7.29 (dd, 1H, J=9, 8 Hz), 7.24-7.20 (m, 2H), 7.16 (dt, 1H, J=8, 1 Hz), 3.49 (t, 2H, J=7 Hz), 3.24 (dd, 1H, J=13, 8 Hz), 3.13 (dd, 1H, J=13, 7 Hz), 2.97-2.88 (m, 1H), 2.59 (s, 3H), 1.87-1.77 (m, 1H), 1.65-1.54 (m, 1H), 1.45-1.27 (m, 2H). Mass spectrum (NH3 /CI): m/z=368 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][N:18]([CH:26]3[CH2:31][CH2:30][C:29]([CH3:33])([CH3:32])[CH2:28][CH2:27]3)[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[NH2:34]O.CC1C=CC(S(O)(=O)=O)=CC=1.O.C[CH2:49][OH:50]>>[CH3:32][C:29]1([CH3:33])[CH2:30][CH2:31][CH:26]([N:18]([CH2:17][CH2:16][O:15][C:12]2[CH:11]=[CH:10][C:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:1]4[N:34]=[CH:49][O:50][N:2]=4)[CH:4]=3)=[CH:14][CH:13]=2)[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:27][CH2:28]1
Reactant: CC1(C)CCC(N(CCOc2ccc(-c3cccc(C#N)c3)cc2)C(=O)OC(C)(C)C)CC1
Reactant: CCO
Reactant: NO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CC1(C)CCC(N(CCOc2ccc(-c3cccc(-c4ncon4)c3)cc2)C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 70 h

Procedure:
To a solution of 1,1-dimethylethyl {2-[(3′-cyano-4-biphenyl)oxy]ethyl}(4,4-dimethylcyclohexyl)carbamate (0.125 g; 0.279 mmol; step 1 above) in EtOH (2.5 mL) at room temperature was added a solution of hydroxylamine (0.25 mL of a 50 wt % aq solution). The mixture was stirred 70 h at room temperature and volatiles were removed in vacuo (1×PhMe chase). The residue was dissolved in trimethyl orthoformate (2 mL), TsOH.H2O (0.0025 g; 0.013 mmol) was added and the mixture was heated at 100° C. in a sealed vial for 1 h. Upon cooling, the mixture was adsorbed onto a small amount of silica gel and purified by flash chromatography (EtOAc/hexanes), affording the title compound as a colorless gum. LC/MS (method A) tR 3.34 min, m/z 492 (M+H, 5%), 514 (M+Na, 100%), 392 ([M-Boc]+H, 53%).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.Cl.[C:13]([C:15]([CH3:21])([CH2:18][CH2:19][CH3:20])[CH2:16][OH:17])#[N:14]>N1C=CC=CC=1>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O:17][CH2:16][C:15]([C:13]#[N:14])([CH3:21])[CH2:18][CH2:19][CH3:20])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: CCCC(C)(C#N)CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CCCC(C)(C#N)COS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
In a round-bottomed flask, 1.35 mg (10.6 mM) of (-)-2-cyano-2-methylpentanol was dissolved in 2.52 g of dry pyridine. The mixture was placed on an ice bath, and 2.22 g (11.7 mM) of p-toluenesulfonyl chloride was added, followed by 6 hours of stirring at room temperature. After the reaction, 10 ml of 6N-hydrochloric acid was added, followed by 3 times of extraction with 15 ml of diethyl ether. The extract was dried overnight on anhydrous sodium sulfate, followed by distilling-off of the solvent and purification by column chromatography by using 80 g of silica gel and a dichloromethane/benzene (2/1) solvent to obtain (-)-2-cyano-2-methylpentyl p-toluenesulfonate. Yield: 2.57 g (9.1 mM), 86%
Reaction SMILES: [C:1]1([C:7]2([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[NH:11][C:10](=[O:12])[N:9]([CH2:13][OH:14])[C:8]2=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:22][CH2:23][C:24](Cl)=[O:25].Cl>C(OCC)C>[Br:22][CH2:23][C:24]([O:14][CH2:13][N:9]1[C:8](=[O:15])[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:11][C:10]1=[O:12])=[O:25]
Reactant: O=C(Cl)CBr
Reactant: O=C1NC(c2ccccc2)(c2ccccc2)C(=O)N1CO
Agent: Cl
Solvent: CCOCC
Product: O=C(CBr)OCN1C(=O)NC(c2ccccc2)(c2ccccc2)C1=O
Temperature: 0 °C

Procedure:
5,5-Diphenyl-3-hydroxymethyl-2,4-imidazolidinedione (2 g, 0.0071 mol) was dissolved in bromoacetylchloride (15 g, 8 mL, 0.096 mol) by heating in an oil bath (70°-80° C. bath temperature) for about 15 minutes, until the formation of HCl ceased. The mixture was cooled and 30 mL of ethyl ether were added. White crystals formed. The mixture was cooled to 0° C., then the crystals were removed by filtration and dried over P2O5. Yield: 2.15 g (75%), m.p. 179°-183° C. Anal. calc. for C18H15N2O4Br: C, 53.61, H, 3.75; N, 6.95; Br, 19.82. Found: C, 53.6; H, 3.79; N, 6.92; Br, 19.9. The product had the formula: ##STR73##