Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](=[O:23])[N:6]([CH2:8][CH2:9][O:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=3)[N:14]=[CH:13][CH:12]=2)[CH:7]=1.C(N(CC)CC)C.[CH2:31]([NH:34][C:35](=[O:42])[CH2:36][N:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1)[C:32]#[CH:33]>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.[Cu]I>[CH3:22][O:21][C:17]1[CH:16]=[C:15]2[C:20]([C:11]([O:10][CH2:9][CH2:8][N:6]3[C:5](=[O:23])[CH:4]=[CH:3][C:2]([C:33]#[C:32][CH2:31][NH:34][C:35](=[O:42])[CH2:36][N:37]4[CH2:41][CH2:40][CH2:39][CH2:38]4)=[CH:7]3)=[CH:12][CH:13]=[N:14]2)=[CH:19][CH:18]=1
Reactant: COc1ccc2c(OCCn3cc(Br)ccc3=O)ccnc2c1
Reactant: C#CCNC(=O)CN1CCCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COc1ccc2c(OCCn3cc(C#CCNC(=O)CN4CCCC4)ccc3=O)ccnc2c1
Yield: 21.7 %

Procedure:
To a 50 mL round bottom flask was charged with the 5-bromo-1-(2-(7-methoxyquinolin-4-yloxy)ethyl)pyridin-2(1H)-one (0.136 g, 0.4 mmol), trans-dichlorobis(triphenyl-phosphine)palladium (II) (0.005 g, 0.007 mmol), and copper(I) iodide (0.0002 ml, 0.007 mmol) along with a magnetic stirring bar and degassed and back-filled three times with N2. Triethylamine (0.2 ml, 1 mmol) was introduced into the reaction flask using a syringe under the gaseous mixture atmosphere. Then N-(prop-2-ynyl)-2-(pyrrolidin-1-yl)acetamide (0.06 g, 0.4 mmol) was added to the reaction flask. After refluxing for 16 hours, the solvent was evaporated and the residue was shaken with 20 mL of saturated aqueous sodium bicarbonate solution and 50 mL of EtOAc. The organic layer was washed with 20 mL of brine and then dried over anhydrous sodium sulfate. The organic solution was concentrated in vacuo and the residue was purified by a Prep-HPLC to give a yellow solid (0.04 g, 24% yield). MS (ESI pos. ion) m/z (MH+): 461.1. Calc'd Exact Mass for C26H28N4O4: 460.21.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:14]1([CH2:20][C:21](Cl)=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)Cl>[C:2]1([NH:1][C:21](=[O:22])[CH2:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: O=C(Cl)Cc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Cc1ccccc1)Nc1ccccc1
Temperature: 25 °C
Yield: 95 %

Procedure:
To a stirred solution of 9.3 g (0.10 Mole) of aniline (IIIa) and 8.3 g (0.10 Mole) pyridine in 100 mL CH2Cl2 at 0° C. under an argon atmosphere was added a solution of 15.5 g (0.10 Mole) phenylacetyl chloride (IIa) in 25 mL CH2Cl2 over a 30 minute period. The solution was allowed to warm to 25° C. over 1 hour and was quenched into 200 mL H2O. The aqueous layer was washed with two 100 mL portions of CH2Cl2 and the combined organic layers were washed with two 100 mL portions of 10% HCl solution. The organic extract was dried over MgSO4, filtered, concentrated, and crystallized from CH2Cl2 /hexane to give 20.07 g (95%) of colorless needles. mp. 115°-116° C. δ1H-NMR (CDCl3) ppm 7.0-7.6 (m, 11 H); 3.67 (S, 2H).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[NH2:25][CH2:26][C@H:27]([NH:31][C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])[C:28]([OH:30])=[O:29].C[O-].[Na+]>COCCO>[CH2:35]([O:34][C:32]([NH:31][C@@H:27]([CH2:26][NH:25][C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH:9]=2)=[O:4])[C:28]([OH:30])=[O:29])=[O:33])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: NC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: COCCO
Product: N#Cc1nc(C(=O)NC[C@H](NC(=O)OCc2ccccc2)C(=O)O)c(O)c2ccc(Oc3ccccc3)cc12
Yield: 27 %

Procedure:
To mixture of 1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (200 mg, 0.63 mmol) and 3-amino-2-(S)-benzyloxycarbonylamino-propionic acid (745 mg, 3.12 mmol) (Bachem) in 2-methoxyethanol (10 mL) was added NaOMe solid (135 mg, 2.5 mmol). The resultant mixture was refluxed overnight. Reaction mixture was concentrated. Residue was dissolved in water (100 mL) and acidified by 1 N HCl to pH=3-4. Precipitate was collected, rinsed with water and dried. It was purified by silica gel chromatography, eluting with 10-100% EtOAc (with 0.075% acetic acid)/CH2Cl2 (with 0.01% acetic acid) to provide the title compound 91 mg (0.17 mmol) in 28% yield. LC-MS ESI−: 525.05 (M−1)−.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]([C:12]1[S:13][CH:14]=[CH:15][C:16]=1[CH3:17])[NH:10][CH3:11].[Cl:18]N1C(=O)CCC1=O>CN(C)C=O.C(OCC)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:18])=[CH:4][C:3]=1[CH2:8][CH:9]([C:12]1[S:13][CH:14]=[CH:15][C:16]=1[CH3:17])[NH:10][CH3:11]
Reactant: CNC(Cc1ccccc1N)c1sccc1C
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CNC(Cc1cc(Cl)ccc1N)c1sccc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.5 %

Procedure:
A stirred solution of 8 g of 2-amino-N-methyl-α-(3-methyl-2-thienyl)benzeneethanamine in 40 ml of N,N-dimethylformamide was treated with a solution of 6.41 g of N-chlorosuccinimide in 40 ml of N,N-dimethylformamide and then stirred at room temperature for 8 hours. Evaporation of the volatiles afforded an oil which was decanted into 100 ml of water, basified with 30 ml of 10% aqueous sodium hydroxide and extracted with dichloromethane (2×100 ml). The extract was washed with water (2×100 ml), dried over anhydrous sodium sulfate and concentrated. Thin layer chromatography of the resultant oil indicated a multicomponent mixture. Purification of the mixture was accomplished by successive HPLC separations (Water's Associates Prep LC/System 500, silica gel, elution with methanol). Concentration of the appropriate fractions afforded a residue which was dissolved in diethyl ether, filtered free of insolubles and concentrated. The resultant oil crystallized upon standing to yield 1.05 g of 2-amino-5-chloro-N-methyl-α-(3-methyl-2-thienyl)benzeneethanamine, mp 59°-61° C.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[CH:18]=[C:17]([CH2:19][CH:20]([O:22][CH3:23])[CH3:21])[CH:16]=[CH:15][C:10]=1[O:11][CH2:12][CH2:13][NH2:14].Cl[C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=[CH:27][N:26]=1>C1(C)C=CC=CC=1>[CH3:8][C:9]1[CH:18]=[C:17]([CH2:19][CH:20]([O:22][CH3:23])[CH3:21])[CH:16]=[CH:15][C:10]=1[O:11][CH2:12][CH2:13][NH:14][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=[CH:27][N:26]=1
Reactant: Clc1ncnc2ccccc12
Reactant: COC(C)Cc1ccc(OCCN)c(C)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(C)Cc1ccc(OCCNc2ncnc3ccccc23)c(C)c1
Reaction time: 3 h
Yield: 63.5 %

Procedure:
1.0 g of triethylamine and 2.2 g of 2-[2-methyl-4-(2-methoxypropyl)phenoxy]ethylamine were added to 1.7 g of 4-chloroquinazoline dissolved in 50 ml of toluene. The mixture was then heated under reflux, whilst stirring, for 3 hours. At the end of this time, the reaction product was washed with water and dried over anhydrous sodium sulfate. Toluene was removed by distillation under reduced pressure. The oily product thus obtained was subjected to column chromatography (Wakogel C-200, eluted with a 1:1 by volume mixture of toluene and ethyl acetate) to isolate the product, and the crystals obtained were recrystallized from hexane, to give 2.2 g of the title compound as a colorless crystalline powder, melting at 95°-97° C.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].[CH3:9][C:10]1[N:11]=[C:12]([NH:22][C:23](=[NH:27])SCC)[S:13][C:14]=1[C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=1>CC(O)C.C(OCC)(=O)C>[CH3:9][C:10]1[N:11]=[C:12]([NH:22][C:23]([NH:2][OH:3])=[NH:27])[S:13][C:14]=1[C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=1
Reactant: NO
Reactant: CCSC(=N)Nc1nc(C)c(-c2cc(C)ccn2)s1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: Cc1ccnc(-c2sc(NC(=N)NO)nc2C)c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 43.9 %

Procedure:
To a suspension of hydroxylamine hydrochloride (146 mg) and sodium acetate (172 mg) in 2-propanol (4 ml) was added N-(4-methyl-5-(4-methylpyridin-2-yl)thiazol-2-yl)-S-ethylisothiourea (205 mg), and the mixture was stirred at 90° C. for 1 hour. The mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel, 3 to 4% methanol in dichloromethane) to give N-(4-methyl-5-(4-methylpyridin-2-yl)thiazol-2-yl)-N′-hydroxyguanidine (81 mg).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[OH:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH:24]([CH2:30][CH2:31][O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:19][CH:18]=1>ClCCl>[CH3:8][S:9]([O:13][CH2:14][CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:23][CH:24]([CH2:30][CH2:31][O:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:21][CH:22]=1)(=[O:11])=[O:10]
Reactant: CCOC(=O)C(CCOc1ccccc1)Cc1ccc(OCCO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(CCOc1ccccc1)Cc1ccc(OCCOS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Triethylamine (0.29 ml) and methanesulfonyl chloride (0.12 ml) were added to a solution of ethyl 3-[4-(2-hydroxyethoxy)phenyl]-2-(2-phenoxyethyl)propionate (503 mg), which is the product of Reference example 3(f), in anhydrous dichloromethane (10 ml). The reaction mixture was stirred at ambient temperature for 2 hours. At the end of this time the reaction mixture was concentrated. The residue was partitioned between ethyl acetate and water. The ethyl acetate layer was separated and dried over anhydrous magnesium sulfate and then concentrated. The residue was purified via chromatography on silica gel column using hexane/ethyl acetate=2/1-3/2 as the eluant to afford the desired compound (632 mg) as a syrup.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].C1N2CN3CN(C2)CN1C3.[C:21](O)(=[O:23])C>>[CH3:8][C:7]1[C:2]([CH3:1])=[C:3]([OH:10])[C:4]([CH3:9])=[CH:5][C:6]=1[CH:21]=[O:23]
Reactant: CC(=O)O
Reactant: Cc1ccc(C)c(O)c1C
Agent: C1N2CN3CN1CN(C2)C3
Product: Cc1cc(C=O)c(C)c(C)c1O
Temperature: 125 °C
Reaction time: 0.38 h
Yield: 90 %

Procedure:
A 500 ml three neck round bottom flask equipped with mechanical stirrer and pot thermometer, was charged with 50 g (0.36 mol) of 2,3,6-trimethyl-phenol, 200 ml glacial acetic acid and 20.61 g (0.14 mol) of hexamethylenetetramine. The reaction mass was refluxed for 2 hrs at 120-130° C. The completion of reaction was confirmed by TLC. 100 ml of acetic acid were distilled out at reflux temperature. The reaction mass was allowed to cool at 100° C. and 50 ml 20% sulphuric acid were slowly added over a period of 5-10 min. The mixture was stirred at 100° C. for 15-30 min. Heating was stopped and the reaction mass cooled to 20° C. in an ice bath. 500 ml process water were added and stirred for 10 min at 20-25° C. The reaction mass was filtered and washed with 300 ml process water. The crude product was dried at 60-80° C. under vacuum to afford 54 g (90%) of crude 2,3,5-trimethyl-4-hydroxy-benzaldehyde. Subsequently, a 1% one equivalent solution of sodium hydroxide was prepared in process water. 54 g of crude 2,3,5-trimethyl-4-hydroxy-benzaldehyde were added to it under stirring at room temperature. The mixture was stirred for 15-20 min and filtered. The residue was to be scraped as impurity. The filtrate was collected, acidified with 19.75 g of glacial acetic acid and filtered. The product was suck-dried under vacuum, dried at 60-80° C. for 3-4 hrs to give 48 g (80%) of pure 2,3,5-trimethyl-4-hydroxy-benzaldehyde as off-white amorphous solid (Table 1, no. 13). Melting point: 135-137° C. 1H NMR (400 MHz, CDCl3) δ 10.15 (s, 1H), δ 7.49 (s, 1H), δ 5.32 (bs, 1H), δ 2.58 (s, 3H), δ 2.28 (s, 3H), δ 2.22 (s, 3H).
Reaction SMILES: CCN(C(C)C)C(C)C.Br[CH2:11][CH2:12][C:13]([F:16])([F:15])[F:14].[CH3:17][C:18]1([CH3:51])[O:23][C:22]([NH:24][C:25]23[CH2:32][CH:31]4[CH2:33][C:27]([C:34]([NH2:36])=[O:35])([CH2:28][CH:29]2[CH2:30]4)[CH2:26]3)=[N:21][S:20](=[O:38])(=[O:37])[C@@H:19]1[C:39]1[CH:44]=[CH:43][C:42]([CH:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)=[CH:41][CH:40]=1>CN(C=O)C>[CH3:17][C:18]1([CH3:51])[O:23][C:22]([NH:24][C:25]23[CH2:32][CH:31]4[CH2:33][C:27]([C:34]([NH2:36])=[O:35])([CH2:28][CH:29]2[CH2:30]4)[CH2:26]3)=[N:21][S:20](=[O:37])(=[O:38])[C@@H:19]1[C:39]1[CH:40]=[CH:41][C:42]([CH:45]2[CH2:50][CH2:49][N:48]([CH2:11][CH2:12][C:13]([F:16])([F:15])[F:14])[CH2:47][CH2:46]2)=[CH:43][CH:44]=1
Reactant: CC1(C)OC(NC23CC4CC2CC(C(N)=O)(C4)C3)=NS(=O)(=O)[C@@H]1c1ccc(C2CCNCC2)cc1
Reactant: FC(F)(F)CCBr
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)OC(NC23CC4CC2CC(C(N)=O)(C4)C3)=NS(=O)(=O)[C@@H]1c1ccc(C2CCN(CCC(F)(F)F)CC2)cc1
Reaction time: 8 h

Procedure:
DIPEA (75 mg) and 3-bromo-1,1,1-trifluoropropane (500 mg) were added to a solution of 3a-[(R)-6,6-dimethyl-4,4-dioxo-5-(4-piperidin-4-yl-phenyl)-5,6-dihydro-4H-4lambda*6*-[1,4,3]oxathiazin-2-ylamino]hexahydro-2,5-methanopentalene-2-carboxamide (73 mg) in DMF (1.5 mL), and the mixture was stirred overnight. The resulting mixture was purified in a purification laboratory by means of preparative HPLC. This gave the product with a molecular weight of 596.7 g/mol (C29H39F3N4O4S); MS (ESI): m/e=597 (M+H+).
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH:6]=[C:5]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:9])[CH:4]=[CH:3]1.[CH2:17]([NH:24][C:25]([C:27]1[S:31][C:30](Br)=[N:29][C:28]=1[CH3:33])=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([NH:24][C:25]([C:27]1[S:31][C:30]([N:7]2[CH:6]=[C:5]([C:8](=[O:9])[NH:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:4]=[CH:3][C:2]2=[O:1])=[N:29][C:28]=1[CH3:33])=[O:26])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(Nc1ccccc1)c1ccc(=O)[nH]c1
Reactant: Cc1nc(Br)sc1C(=O)NCc1ccccc1
Product: Cc1nc(-n2cc(C(=O)Nc3ccccc3)ccc2=O)sc1C(=O)NCc1ccccc1
Yield: 31 %

Procedure:
Following the procedure as described in Example 3, making variations only as required to use 6-oxo-N-phenyl-1,6-dihydropyridine-3-carboxamide in place of 4-aminopyridin-2(1H)-one to react with N-benzyl-2-bromo-4-methylthiazole-5-carboxamide, the title compound was obtained as a colorless solid in 31% yield: mp 223-225° C. (hexane/ethyl acetate); 1H-NMR (300 MHz, DMSO-d6) δ 10.39 (s, 1H), 9.40 (d, J=2.5 Hz, 1H), 8.89 (t, J=5.9 Hz, 1H), 8.14 (dd, J=9.6, 2.5 Hz, 1H), 7.70-7.68 (m, 2H), 7.36-7.28 (m, 6H), 7.26-7.18 (m, 1H), 7.11-7.07 (m, 1H), 6.86 (d, J=9.6 Hz, 1H), 4.41 (d, J=5.9 Hz, 2H), 2.61 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 162.4, 161.6, 160.1, 153.5, 150.5, 139.7, 139.3, 139.1, 134.0, 129.1, 128.7, 127.7, 127.3, 125.3, 124.4, 121.0, 120.2, 116.2, 43.2, 17.5; (ES+) m/z 445.1 (M+1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@@H:4]1[CH2:6][C@@H:5]1[CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:9][CH2:8]1.[H-].[Na+].Br[C:26]1[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][N:27]=1.O>CN(C)C=O>[CH3:35][S:32]([C:29]1[CH:30]=[CH:31][C:26]([O:1][CH2:2][CH2:3][C@@H:4]2[CH2:6][C@@H:5]2[CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[O:14])[CH2:9][CH2:8]2)=[N:27][CH:28]=1)(=[O:34])=[O:33]
Reactant: CS(=O)(=O)c1ccc(Br)nc1
Reactant: O=C(OCc1ccccc1)N1CCC([C@H]2C[C@H]2CCO)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(OCC[C@@H]2C[C@@H]2C2CCN(C(=O)OCc3ccccc3)CC2)nc1
Temperature: 50 °C
Reaction time: 0.33 h

Procedure:
To a solution of 860 mg (2.83 mmol) benzyl 4-[(1R,2S)-2-(2-hydroxyethyl)cyclopropyl]piperidine-1-carboxylate in 14.5 ml anhydrous N,N-dimethylformamide at ambient temperature was added 147 mg (3.68 mmol) sodium hydride. The solution was stirred for 20 minutes. 669 mg (2.83 mmol) 2-bromo-5-(methylsulfonyl)pyridine was added into the solution. It was heated to 50° C., and stirred for 3 hours. 100 ml water was added into the mixture, and it was extracted with 50 ml ethyl acetate three times. The crude product was dried and purified using a Biotage Horizon® system (0-50% ethyl acetate/hexanes mixture) to give the title compound as colorless oil. 1H NMR (CDCl3): δ 8.71 (d, J=2.4 Hz, 1H), δ 8.03 (dd, J=8.8 Hz, 2.5 Hz, 1H), δ 7.30-7.37 (m, 5H), δ 6.84 (d, J=8.7 Hz, 1H), δ 5.13 (s, 2H), δ 4.49 (t, J=7.1 Hz, 2H), δ 4.10-4.16 (m, 2H), δ 3.07 (s, 2H), δ 2.75-2.76 (m, 2H), δ 2.08-2.12 (m, 1H), δ 1.74-1.75 (m, 2H), δ 1.50-1.56 (m, 2H), δ 1.29-1.40 (m, 2H), δ 0.88-0.99 (m, 2H), δ 0.56-0.70 (m, 2H). LC/MS 459.2 (M+1).
Reaction SMILES: [N+:1]([C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:5]=1[OH:11])([O-:3])=[O:2].[Cl-].[Al+3].[Cl-].[Cl-].[C:16](OC(=O)C)(=[O:18])[CH3:17]>[N+](C1C=CC=CC=1)([O-])=O>[OH:10][C:9]1[C:4]([N+:1]([O-:3])=[O:2])=[C:5]([OH:11])[CH:6]=[CH:7][C:8]=1[C:16](=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: O=[N+]([O-])c1c(O)cccc1O
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: CC(=O)c1ccc(O)c([N+](=O)[O-])c1O
Temperature: 100 °C

Procedure:
2-Nitrobenzene-1,3-diol (24.5 g) was added portionwise over 15 minutes to a vigorously stirred solution of aluminum chloride (46.3 g) in nitrobenzene (325 mL). Acetic anhydride (15.7 mL) was then added dropwise to the mixture over a further 15 minutes and the mixture then heated at 100° C. for 5 h. The reaction was cooled to ambient temperature and carefully quenched with ice'cold 2M hydrochloric acid (300 mL). The mixture was extracted with diethyl ether (2×500 mL) and the combined diethyl ether extracts then extracted with 2M aqueous sodium hydroxide (2×400 mL). The combined basic extracts were washed with diethyl ether (4×500 mL) and then acidified to pH 1 with 2M hydrochloric acid (700 mL). The resulting precipitate was filtered off, washed with water, and dried under vacuum at 40° C. to afford the subtitled compound as a yellow-brown solid. Yield 29.5 g.
Reaction SMILES: [CH2:1]([N:8]1[C@H:12]2[CH2:13][S:14][C:15](=[O:16])[C@@H:11]2[N:10]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:9]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1>C(Cl)(Cl)Cl>[CH2:1]([N:8]1[C@H:12]2[CH2:13][S:14][C:15](=[O:16])[C@H:11]2[N:10]([CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:9]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1SC[C@H]2[C@H]1N(Cc1ccccc1)C(=O)N2Cc1ccccc1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: O=C1SC[C@H]2[C@@H]1N(Cc1ccccc1)C(=O)N2Cc1ccccc1
Temperature: 25 °C
Reaction time: 23 h
Yield: 75.1 %

Procedure:
In 1 ml of chloroform was dissolved 100 mg of (3aR,6aR)-1,3-dibenzyl-hexahydro-4H-thieno[3,4-d]imidazol-2,4-dione, 0.5 ml of pyridine was added to the solution, and the resulting mixture was stirred at room temperature for 23 hours. The reaction mixture was successively washed with 2M hydrochloric acid, water, a saturated sodium bicarbonate solution, and saturated brine. The organic layer was dried and then concentrated. By adding isopropyl ether, precipitated crystal was collected by filtration to give 75.1 mg of (3aS,6aR)-1,3-dibenzyl-hexahydro-4H-thieno[3,4-d]imidazol-2,4-dione.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([NH:8][CH2:9][C@H:10]2[C@@H:15]([CH3:16])[CH2:14][CH2:13][CH2:12][NH:11]2)=[N:6][CH:7]=1.C(NC(C)C)(C)C.[F:24][C:25]([F:37])([F:36])[O:26][C:27]1[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=1[C:29](Cl)=[O:30]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([NH:8][CH2:9][C@H:10]2[C@@H:15]([CH3:16])[CH2:14][CH2:13][CH2:12][N:11]2[C:29]([C:28]2[CH:32]=[CH:33][CH:34]=[CH:35][C:27]=2[O:26][C:25]([F:24])([F:36])[F:37])=[O:30])=[N:6][CH:7]=1
Reactant: C[C@H]1CCCN[C@H]1CNc1ncc(Cl)cn1
Reactant: O=C(Cl)c1ccccc1OC(F)(F)F
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: C[C@H]1CCCN(C(=O)c2ccccc2OC(F)(F)F)[C@H]1CNc1ncc(Cl)cn1

Procedure:
To a solution of the forementioned rac-cis-5-chloro-N-((3-methylpiperidin-2-yl)methyl)pyrimidin-2-amine and diisopropylamine (3 eq) in DCM was added 2-(trifluoromethoxy)benzoyl chloride (1.2 eq) dropwise. The reaction was stirred at reflux for 3 h and concentrated in vacuo. The crude reaction mixture was purified by reverse-phase preparative HPLC to afford the title compound. (ESI) 429.1 (M+H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][C:9]([NH:18][N:19]=[C:20]2[C:24]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[CH:26]=3)=[N:23][NH:22][C:21]2=[O:35])=[CH:8][CH:7]=1.[CH3:36][NH:37][CH3:38]>>[CH3:34][O:33][C:27]1[CH:26]=[C:25]([C:24]2[C:20](=[N:19][NH:18][C:9]3[CH:10]=[C:11]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:37]([CH3:38])[CH3:36])=[CH:7][CH:8]=3)[C:21](=[O:35])[NH:22][N:23]=2)[CH:30]=[CH:29][C:28]=1[O:31][CH3:32]
Reactant: COc1ccc(C2=NNC(=O)C2=NNc2ccc(OCCCBr)c(-c3ccccc3)c2)cc1OC
Reactant: CNC
Product: COc1ccc(C2=NNC(=O)C2=NNc2ccc(OCCCN(C)C)c(-c3ccccc3)c2)cc1OC
Temperature: 50 °C

Procedure:
5-(3,4-Dimethoxy-phenyl)-4-{[6-(3-dimethylamino-propoxy)-biphenyl-3-yl]-hydrazono}-2,4-dihydro-pyrazol-3-one (compound 121) was prepared by dissolving 4-{[6-(3-bromo-propoxy)-biphenyl-3-yl]-hydrazono}-5-(3,4-dimethoxy-phenyl)-2,4-dihydro-pyrazol-3-one (s) in 1 mL of a dimethylamine solution (2 M in THF) and heating to 50° C. for one hour. The solvent was then evaporated and the residue was purified by silica gel chromatography (eluent: 10% methanol/DCM) to afford 6 mg product (compound 121): HPLC (Rt): 5.490 minutes; m/e: 501.23, MS (ES+): 502.2.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][N:3]=1.[CH2:9]=O>FC(F)(F)C(O)=O>[I:8][C:5]1[CH:6]=[CH:7][C:2]([N:1]=[CH2:9])=[N:3][CH:4]=1
Reactant: C=O
Reactant: Nc1ccc(I)cn1
Solvent: O=C(O)C(F)(F)F
Product: C=Nc1ccc(I)cn1
Yield: 76.6 %

Procedure:
Add trifluoroacetic acid (3 drops) to a suspension of 2-amino-5-iodopyridine (1.0 g, 4.5 mmol) and paraformaldehyde (1.0 g). Heat the mixture at reflux for 15 h and concentrate. Purification by flash chromatography eluting with ethyl acetate gives 0.8 g (75%) of the title compound as a white solid. ES+ m/e 232.6 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.[NH2:10][CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13]>O1CCCC1>[Cl:9][C:4]1[CH:5]=[C:6]([Cl:8])[N:7]=[C:2]([NH:10][CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[N:3]=1
Reactant: CC(C)(C)CN
Reactant: Clc1cc(Cl)nc(Cl)n1
Solvent: C1CCOC1
Product: CC(C)(C)CNc1nc(Cl)cc(Cl)n1

Procedure:
After dropwise adding 25 g (136.3 mmoles) of 2,4,6-trichloropyrimidine to a solution of 23.84 g (273.5 mmoles) of 1-amino-2,2-dimethylpropane in 200 ml of tetrahydrofuran at a temperature between 10° and 15° C. while cooling under stirring, the reaction mixture is stirred at room temperature for 30 minutes, then evaporated. The residue is distributed between 300 ml of chloroform and 50 ml of 10% sodium hydroxide solution. After separation the organic phase is washed 4 times with 100 ml of water each, dried and evaporated. The residue is subjected to chromatography on a silica gel column by using mixtures of hexane/ethyl acetate elution. By eluting with a 19:1 mixture, 4,6-dichloro-2-(2,2-dimethylpropylamino) pyrimidine is obtained which is recrystallized from a mixture of ether and hexane to give a yield of 13.60 g (42.6%), m.p.:63°-66° C.