Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[CH3:59][C:60]1([CH2:64]O)[CH2:63][O:62][CH2:61]1>C(OCC)(=O)C.O1CCCC1>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:59][C:60]2([CH3:64])[CH2:63][O:62][CH2:61]2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC1(CO)COC1
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCc1nc(C)n(CC2(C)COC2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 63.1 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), 1,1′-(azodicarbonyl)dipiperidine (1.44 g), tributylphosphine (1.78 mL), (3-methyloxetan-3-yl)methanol (0.44 g) and tetrahydrofuran (50 mL) was stirred at room temperature for 4 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.78 g, 62%).
Reaction SMILES: Cl[C:2]1[C:11]([Cl:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Cl:12][C:11]1[C:2]([NH:23][S:20]([C:17]2[CH:18]=[CH:19][C:14]([CH3:13])=[CH:15][CH:16]=2)(=[O:21])=[O:22])=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: Clc1nc2ccccc2nc1Cl
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1ccc(S(=O)(=O)Nc2nc3ccccc3nc2Cl)cc1
Yield: 74 %

Procedure:
According to the step of Example 6-1, by use of 2,3-dichloroquinoxaline (1.00 g, 5.02 mmol) dissolved in dimethyl sulfoxide (30 mL), 4-methylbenzene-1-sulfonamide (860 mg, 5.02 mmol) and potassium carbonate (694 mg, 5.02 mmol), the mixture was stirred and reacted at 150° C. for 4.2 hours. Then, slurry purification was performed using diisopropyl ether, to give N-(3-chloroquinoxalin-2-yl)-4-methylbenzenesulfonamide (Compound AB) (1.24 g, yield: 74%).
Reaction SMILES: Cl.[OH:2][N:3]1[CH:7]=[CH:6][N:5]=[C:4]1[S:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[N:15]1([C:21](Cl)=[O:22])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>>[C:9]1([S:8][C:4]2[N:3]([O:2][C:21]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[O:22])[CH:7]=[CH:6][N:5]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: On1ccnc1Sc1ccccc1
Reactant: O=C(Cl)N1CCOCC1
Agent: Cl
Product: O=C(On1ccnc1Sc1ccccc1)N1CCOCC1

Procedure:
The title compound was prepared from 1-hydroxy-2-phenylsulfanylimidazole, hydrochloride and 4-morpholine carbonyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc) (98%, oil).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6]([O:12][CH2:13][C:14]2([CH3:19])[CH2:18][CH2:17][NH:16][CH2:15]2)[C:7]([C:10]#[N:11])=[N:8][CH:9]=1.[F:20][C:21]([F:32])([F:31])[C@H:22]1[CH2:27][CH2:26][C@H:25]([C:28](O)=[O:29])[CH2:24][CH2:23]1.N1C2C(=CC=CC=2)C=C1C(O)=O>>[Cl:3][C:4]1[CH:5]=[C:6]([O:12][CH2:13][C:14]2([CH3:19])[CH2:18][CH2:17][N:16]([C:28]([C@H:25]3[CH2:24][CH2:23][C@H:22]([C:21]([F:20])([F:31])[F:32])[CH2:27][CH2:26]3)=[O:29])[CH2:15]2)[C:7]([C:10]#[N:11])=[N:8][CH:9]=1
Reactant: O=C(O)[C@H]1CC[C@H](C(F)(F)F)CC1
Reactant: CC1(COc2cc(Cl)cnc2C#N)CCNC1
Agent: Cl
Agent: O=C(O)c1cc2ccccc2[nH]1
Product: CC1(COc2cc(Cl)cnc2C#N)CCN(C(=O)[C@H]2CC[C@H](C(F)(F)F)CC2)C1

Procedure:
The title compound was prepared according to the procedure described in Step 3 of EXAMPLE 1 using 5-chloro-3-((3-methylpyrrolidin-3-yl)methoxy)picolinonitrile dihydrochloride (EXAMPLE 84, Step 4) and trans-4-(trifluoromethyl)cyclohexanecarboxylic acid instead of (R)-3-(pyrrolidin-2-ylmethoxy)picolinamide dihydrochloride and indole-2-carboxylic acid.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][NH:11][C:10]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[C:9]=2[C:8]1=[O:30].[C:40]([NH:43][CH:44]1[CH2:48][CH2:47][NH:46][CH2:45]1)(=[O:42])[CH3:41]>>[C:40]([NH:43][CH:44]1[CH2:48][CH2:47][N:46]([C:16]2[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[C:9]3[C:8](=[O:30])[N:7]([CH2:6][C:5]4[CH:31]=[C:32]([C:34]([F:36])([F:37])[F:35])[CH:33]=[C:3]([C:2]([F:1])([F:38])[F:39])[CH:4]=4)[CH2:14][CH2:13][CH2:12][NH:11][C:10]=3[N:15]=2)[CH2:45]1)(=[O:42])[CH3:41]
Reactant: Cc1ccccc1-c1nc(S(C)(=O)=O)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCN2
Reactant: CC(=O)NC1CCNC1
Product: CC(=O)NC1CCN(c2nc3c(c(-c4ccccc4C)n2)C(=O)N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CCCN3)C1
Yield: 99.5 %

Procedure:
In a similar manner to Example 1, 6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-2-(methylsulfonyl)-5-oxopyrimido[4,5-b][1,5]diazocine (Compound of Reference Example 19; 85.9 mg) was reacted with 3-(acetylamino)pyrrolidine (23.1 mg) to obtain 2-[3-(acetylamino)pyrrolidine-1-yl]-6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-5-oxopyrimido[4,5-b][1,5]diazocine (92.6 mg, 99%).
Reaction SMILES: C(Cl)CCl.[Cl:5][C:6]1[CH:28]=[CH:27][C:9]([O:10][CH2:11][CH2:12][CH2:13][S:14]([CH2:17][C:18]2([C:24](O)=[O:25])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)(=[O:16])=[O:15])=[CH:8][CH:7]=1.[Si]([NH:36][OH:37])(C(C)(C)C)(C)C>ClCCl>[OH:37][NH:36][C:24]([C:18]1([CH2:17][S:14]([CH2:13][CH2:12][CH2:11][O:10][C:9]2[CH:27]=[CH:28][C:6]([Cl:5])=[CH:7][CH:8]=2)(=[O:16])=[O:15])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[O:25]
Reactant: O=C(O)C1(CS(=O)(=O)CCCOc2ccc(Cl)cc2)CCOCC1
Reactant: CC(C)(C)[Si](C)(C)NO
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(NO)C1(CS(=O)(=O)CCCOc2ccc(Cl)cc2)CCOCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 38.5 %

Procedure:
EDC (40 mg) was added to a solution of Example 13 (75 mg) in dichloromethane (20 ml), followed by tert-butyldimethylsilylhydroxylamine (32 mg) and N,N-dimethylaminopyridine (2 mg), and the resulting clear solution was stirred at room temperature for 3 h. The mixture was then washed with water, saturated bicarbonate and brine, dried over MgSO4 and evaporated. The residue was dissolved in a minimum amount of fresh dichloromethane and 1M aqueous hydrochloric acid in ether (2 ml) was added. The solution was stirred for 10 min, then evaporated and the residue purified by chromatography on silica, eluting with ethyl acetate, to give the title compound (30 mg) as a colourless glass.
Reaction SMILES: C(OCC)(=O)[CH2:2][C:3](OCC)=[O:4].[Na].[CH2:13]1[C:21]2[C:16](=[CH:17][C:18]([CH:22]=[CH:23][C:24](=[O:26])[CH3:25])=[CH:19][CH:20]=2)[CH2:15][CH2:14]1.[OH-].[Na+]>C(O)C.O>[OH:26][C:24]1[CH2:23][CH:22]([C:18]2[CH:17]=[C:16]3[C:21](=[CH:20][CH:19]=2)[CH2:13][CH2:14][CH2:15]3)[CH2:2][C:3](=[O:4])[CH:25]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(=O)C=Cc1ccc2c(c1)CCC2
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C1C=C(O)CC(c2ccc3c(c2)CCC3)C1

Procedure:
Diethyl malonate (17.5 g; 110 mmole) was added to a solution of sodium metal (1.91 g; 83 mmole) in anhydrous absolute ethanol (50 ml) and the mixture was heated to reflux temperature. A mixture of 1-(5-indanyl)but-1-en-3-one (19.25 g; 103 mmole) in anhydrous absolute ethanol (50 ml) was added over a period of two minutes and the mixture was heated under reflux for a period of 2 hours. An aqueous solution of sodium hydroxide (30% solution, 50 ml) was added and the mixture was heated under reflux for a further 11/2 hours. The solution was poured into water (200 ml) and the aqueous mixture was extracted twice with ethyl acetate (2×100 ml). The aqueous phase was acidified with concentrated hydrochloric acid and warmed gently until the evolution of carbon dioxide ceased. The aqueous mixture was extracted with ethyl acetate, dried over anhydrous sodium sulphate, and the solvent was removed by evaporation under reduced pressure using a rotary evaporator. The product, 3-hydroxy-5-(5-indanyl)cyclohex-2-en-1-one, was obtained as a white solid (18.70 g; 79.6%), mp 198° C.
Reaction SMILES: CC1[N:3]=[CH:4][NH:5]C=1CSCCN.[S:12]([OH:16])([OH:15])(=[O:14])=[O:13].CSC(=N)[NH2:20]>O>[S:12]([OH:16])([OH:15])(=[O:14])=[O:13].[NH2:3][C:4]([NH2:5])=[NH:20]
Reactant: Cc1nc[nH]c1CSCCN
Reactant: CSC(=N)N
Agent: O=S(=O)(O)O
Solvent: O
Product: N=C(N)N

Procedure:
A solution of 4-methyl-5-((2-aminoethyl)thiomethyl)imidazole (19.0 g.) and S-methylisothiourea sulphate (15.1 g.) in water (100 ml.) was heated under reflux for 3 hours. Concentration, acidification with sulphuric acid and dilution with ethanol afforded 2-[(4-methyl-5-imidazolyl)methylthio)ethyl]guanidine sulphate (13.0 g.) m.p. 230°-235° (from aqueous methanol).
Reaction SMILES: [F:1][C:2]1[CH:18]=[C:17]([C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21])[CH:16]=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([O:13]C)[CH:8]=1)=[O:5]>Br.C(O)(=O)C.O>[F:1][C:2]1[CH:18]=[C:17]([C:19]([F:25])([F:24])[C:20]([F:21])([F:23])[F:22])[CH:16]=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=1)=[O:5]
Reactant: COc1cc(NC(=O)c2ccc(C(F)(F)C(F)(F)F)cc2F)ccn1
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: O=C(Nc1cc[nH]c(=O)c1)c1ccc(C(F)(F)C(F)(F)F)cc1F
Temperature: 100 °C
Reaction time: 4 h
Yield: 71.6 %

Procedure:
2-fluoro-N-(2-methoxy-4-pyridyl)-4-(1,1,2,2,2-pentafluoroethyl)benzamide (200 mg, 0.55 mmol) in HBr in acetic acid (1.3 mL of 33% w/v, 5.49 mmol) was stirred at 100° C. for 2 hours, at this time 1 ml of HBr in acetic acid (33% w/v) was added and the mixture was stirred at 100° C. for 4 hours, then cooled to room temperature. The reaction mixture was diluted with water and a precipitate formed. The precipitate was filtered off, washed with water (2×), cold methyl-tert-butyl ether and dried under vacuum to give 2-fluoro-N-(2-oxo-1H-pyridin-4-yl)-4-(1,1,2,2,2-pentafluoroethyl)benzamide (138 mg, 72%) as a light grey solid. ESI-MS m/z calc. 350.05. found 351.3 (M+1)+; Retention time: 1.3 minutes (3 minutes run).
Reaction SMILES: [C:1]([C:4]1[CH:44]=[CH:43][C:7]([O:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([N:15]3[C:20](=[O:21])[C:19]([CH2:22][C:23]4[CH:28]=[CH:27][C:26]([C:29]5[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=5)=[CH:25][CH:24]=4)=[C:18]([CH2:37][CH2:38][CH3:39])[N:17]4[N:40]=[CH:41][N:42]=[C:16]34)[CH2:11][CH2:10]2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:45][Mg]Br.Cl>O1CCCC1>[OH:3][C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([N:15]3[C:20](=[O:21])[C:19]([CH2:22][C:23]4[CH:28]=[CH:27][C:26]([C:29]5[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=5)=[CH:25][CH:24]=4)=[C:18]([CH2:37][CH2:38][CH3:39])[N:17]4[N:40]=[CH:41][N:42]=[C:16]34)[CH2:11][CH2:10]2)=[CH:43][CH:44]=1)([CH3:45])[CH3:2]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](Oc3ccc(C(C)=O)cc3)CC2)c2ncnn12
Reactant: C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](Oc3ccc(C(C)(C)O)cc3)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4′-({4-[trans-4-(4-Acetylphenoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.27 g) was dissolved in tetrahydrofuran (1 mL), methylmagnesium bromide (1.4 mL, 1.0 M tetrahydrofuran solution) was added dropwise, and the mixture was stirred at room temperature for 16 hr. Methylmagnesium bromide (0.11 mL, 1.0 M tetrahydrofuran solution) was further added dropwise, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was added to 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.17 g, 60%).
Reaction SMILES: [CH:1]1([N:6]2[CH:10]=[C:9]([CH:11]([C:20]([O:22][CH3:23])=[O:21])[C:12]([O:14][CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)=[O:13])[N:8]=[CH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:27][C:28]1[CH:29]=[CH:30][C:31]([NH:34]C(=O)OC(C)(C)C)=[N:32][CH:33]=1>CN(C=O)C>[NH2:34][C:31]1[N:32]=[CH:33][C:28]([CH2:27][C:11]([C:9]2[N:8]=[CH:7][N:6]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[CH:10]=2)([C:20]([O:22][CH3:23])=[O:21])[C:12]([O:14][CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19]2)=[O:13])=[CH:29][CH:30]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CBr)cn1
Reactant: COC(=O)C(C(=O)OC1CCCC1)c1cn(C2CCCC2)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1ccc(N)nc1)(C(=O)OC1CCCC1)c1cn(C2CCCC2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Cyclopentyl methyl 2-(1-cyclopentyl-1H-imidazol-4-yl)malonate (0.46 g; 1.44 mmol) was dissolved in absolute DMF (5 ml). At 0° C., sodium hydride (50%; 0.07 g; 1.44 mmol) was added. The mixture was stirred at RT for 1 h and then cooled again to 0° C. Then tert-butyl (5-bromomethylpyridin-2-yl)carbamate (0.41 g; 1.44 mmol) was added, and the mixture was stirred at RT for 2 h. While cooling in ice, the mixture was quenched with H2O and then extracted twice with EA. The organic phase was separated off and dried over Na2SO4, and the solvent was removed under reduced pressure. Purification of the crude product through a cartridge (50 g of silica gel) resulted in 0.31 g of cyclopentyl methyl 2-(6-aminopyridin-3-ylmethyl)-2-(1-cyclopentyl-1H-imidazol-4-yl)malonate.
Reaction SMILES: [CH3:1][S-:2].[Na+].Br[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:16][C:17]([O:19][CH3:20])=[O:18])=[C:11]([O:26][CH3:27])[CH:10]=1.COCCCOC1C=CC(C(CCCCC)CC(O)=O)=C(OC)C=1>CO.C(OCC)(=O)C>[CH3:1][S:2][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:16][C:17]([O:19][CH3:20])=[O:18])=[C:11]([O:26][CH3:27])[CH:10]=1
Reactant: CCCCCC(CC(=O)OC)c1ccc(OCCCBr)cc1OC
Reactant: C[S-]
Agent: CCCCCC(CC(=O)O)c1ccc(OCCCOC)cc1OC
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCCC(CC(=O)OC)c1ccc(OCCCSC)cc1OC
Yield: 83 %

Procedure:
200 mg (2.85 mmol) of sodium thiomethoxide were added to a solution of 278 mg (0.69 mmol) of methyl 3-[4-(3-bromopropoxy)-2-methoxyphenyl]octanoate, which was a synthetic intermediate of the compound of Preparation 50A, in 6 ml of methanol, and the resulting mixture was stirred for 1 hour. The reaction mixture was then diluted with ethyl acetate, and the diluted solution was washed several times with water and once with a saturated aqueous solution of sodium chloride, after which it was dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through 50 g of silica gel, using a 1:3 by volume mixture of ethyl acetate and hexane as the eluent, to give methyl 3-[4-(3-methylthiopropoxy)-2-methoxyphenyl]octanoate containing a small amount of impurities. Oxidation of the product and subsequent treatment of the reaction mixture were conducted in a similar manner to that described in Example 21 to give 230 mg of the sulfone derivative as an oily substance in a 83% yield over the two steps. This product was hydrolyzed in a similar manner to that described in Preparation 7 to give the title compound as an oily substance.
Reaction SMILES: [O:1]=[C:2]([NH:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=1)[CH2:3][C:4]1[CH:21]=[CH:20][C:7]([O:8][CH2:9][C:10]2[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=2[C:12]([O:14]C)=[O:13])=[CH:6][CH:5]=1.[OH-].[Li+]>C1COCC1.O>[O:1]=[C:2]([NH:22][CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:28][CH:29]=1)[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]2[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=2[C:12]([OH:14])=[O:13])=[CH:20][CH:21]=1
Reactant: COC(=O)c1ccccc1COc1ccc(CC(=O)NCc2ccc(C(F)(F)F)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(Cc1ccc(OCc2ccccc2C(=O)O)cc1)NCc1ccc(C(F)(F)F)cc1
Reaction time: 8 h
Yield: 56.7 %

Procedure:
Methyl 2-{[4-(2-oxo-2-{[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]methyl}-benzoate (71 mg, 0.155 mmol) in THF (1.5 ml) was cooled in an ice-bath. Lithium hydroxide (7.5 mg, 0.310 mmol) in water (1.5 ml) was dropped in. The cooling-bath was then removed and the mixture was stirred overnight. HPLC showed that the reaction was not complete. More lithium hydroxide (0.2M, 0.5 ml) was added. The reaction mixture was stirred for 4 days more. It was then evaporated in vacuum to remove THF. The residue was acidified with 1% hydrochloric acid, pH=3-4, and then extracted with ethyl acetate. The organic phase was dried with magnesium sulphate and evaporated. Chromatography of the residue on a column (ISOLUTE® SI, 2 g/6 ml) using DCM, MeOH/DCM (0.5:99.5, then 1:99, and then 2:98) as eluant gave 39 mg white solid product, yield 57%.
Reaction SMILES: [CH3:1][S:2]([C:4]1[S:12][C:11]2[C:6](=[N:7][CH:8]=[CH:9][C:10]=2[O:13][C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][C:15]=2[F:21])[CH:5]=1)=[O:3].[C:22]1([CH2:28][C:29]([N:31]=[C:32]=[S:33])=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1>[CH3:1][S:2]([C:4]1[S:12][C:11]2[C:6](=[N:7][CH:8]=[CH:9][C:10]=2[O:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:32]([NH:31][C:29](=[O:30])[CH2:28][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[S:33])=[CH:16][C:15]=2[F:21])[CH:5]=1)=[O:3]
Reactant: CS(=O)c1cc2nccc(Oc3ccc(N)cc3F)c2s1
Reactant: O=C(Cc1ccccc1)N=C=S
Solvent: C1CCOC1
Product: CS(=O)c1cc2nccc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)c2s1
Reaction time: 3 h
Yield: 52.8 %

Procedure:
To a suspension of 234 (280 mg, 0.868 mmol) in THF (8 mL) was added 2-phenyl acetyl isothiocyanate (185 mg, 1.04 mmol). The reaction mixture was stirred for 3 hours, concentrated; the solid residue washed with Et2O and dried, to afford title compound 235 (229 mg, 53% yield) as a white-rose solid. 1HNMR: (DMSO-d6) δ (ppm):12.41(s,1H), 11.75(s,1H), 8.54(d, J=5.3 Hz, 1H), 7.98 (s, 1H), 7.96(d, J=13.5 Hz, 1H), 7.48(d, J=5.0 Hz, 2H), 7.30-7.26(m, 2H), 7.26-7.18(m, 3H), 6.69(d, J=5.5 Hz, 1H), 3.25(s, 2H), 2.98(s, 3H). MS (m/z): 500.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:20]([CH3:21])=[CH:19][C:18]([Cl:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([NH2:27])[CH2:25][CH3:26])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:35](OC(=O)C)(=[O:37])[CH3:36]>O1CCCC1.C(=O)(O)[O-].[Na+]>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:20]([CH3:21])=[CH:19][C:18]([Cl:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([NH:27][C:35](=[O:37])[CH3:36])[CH2:25][CH3:26])=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: CCC(N)c1ccc(Cl)c2nc3n(c12)CCCN3c1c(C)cc(Cl)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCC(NC(C)=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1c(C)cc(Cl)cc1Cl

Procedure:
Ethylmagnesium bromide (3 M solution in diethyl ether, 4.50 mL, 13.5 mmol) was added to a stirred suspension of 9-chloro-1-(2,4-dichloro-6-methylphenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carbonitrile (530 mg, 1.35 mmol) in tetrahydrofuran (14 mL) at room temperature. After the resultant mixture was refluxed for 3 hr, a suspension of sodium tetrahydroborate (1.02 g, 27.0 mmol) in 2-propanol (14 mL) was added at room temperature. The resultant mixture was stirred at 50° C. for 30 min, diluted with water, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give crude 1-[9-chloro-1-(2,4-dichloro-6-methylphenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-amine (609 mg), which was used for the next step without further purification. To a mixture of crude 1-[9-chloro-1-(2,4-dichloro-6-methylphenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-amine (120 mg) and triethylamine (0.0742 mL, 0.532 mmol) in tetrahydrofuran (2.7 mL) was added acetic anhydride (0.0302 mL, 0.319 mol) at 0° C. The resultant mixture was stirred at room temperature for 10 min, diluted with aqueous sodium bicarbonate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 20-100% ethyl acetate/n-hexane gradient mixture and preparative HPLC eluting with a 10-40% acetonitrile/water gradient mixture to give the two title compounds as colorless solids.
Reaction SMILES: [CH3:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][NH:4][N:3]=1.[H-].[Na+].Br[CH2:13][C:14]([N:16]([CH3:18])[CH3:17])=[O:15]>CN(C=O)C>[CH3:17][N:16]([CH3:18])[C:14](=[O:15])[CH2:13][N:4]1[CH:5]=[C:6]([N+:7]([O-:9])=[O:8])[C:2]([CH3:1])=[N:3]1
Reactant: CN(C)C(=O)CBr
Reactant: Cc1n[nH]cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nn(CC(=O)N(C)C)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-methyl-4-nitropyrazole (Apollo, Cheshire, UK, 500 mg, 3.93 mmol) in DMF (10 ml) was added 55% NaH in oil (198 mg, 4.54 mmol) and the reaction mixture was stirred for 30 min at rt. Then to the reaction mixture was added a solution of 2-bromo-N,N-dimethylacetamide (stage L.3, 720 mg, 4.34 mmol) in DMF (3 ml). The reaction mixture was stirred for 1 h at it then quenched with saturated aqueous NaHCO3 and extracted with EtOAc (2×). The combined organic layers were washed with water (2×), brine, dried over Na2SO4, filtered and evaporated. The crude product was purified by Prep. HPLC (H2O (0.1% TFA)/CH3CN 97:2 to 75:25; reverse phase silica gel). The fractions containing product were collected together, basified with NaHCO3 and concentrated before being extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated to give the title compound as a white solid (HPLC tR 2.06 min (Method A); M+H=213 MS-ES).
Reaction SMILES: I.[NH2:2][C:3]1[C:4]([C:11]([NH:13][C:14](=[NH:17])SC)=[O:12])=[N:5][C:6]([Cl:10])=[C:7]([NH2:9])[N:8]=1.[OH:18][C@@H:19]1[CH2:24][O:23][C@@H:22]([CH3:25])[O:21][C@H:20]1[CH2:26][N:27]([CH2:42][C@H:43]1[C@H:48]([OH:49])[CH2:47][O:46][C@@H:45]([CH3:50])[O:44]1)[CH2:28][CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][CH2:39][CH2:40][NH2:41])=[CH:33][CH:32]=1.C(N(C(C)C)CC)(C)C>C1COCC1>[OH:18][C@@H:19]1[CH2:24][O:23][C@@H:22]([CH3:25])[O:21][C@H:20]1[CH2:26][N:27]([CH2:42][C@H:43]1[C@H:48]([OH:49])[CH2:47][O:46][C@@H:45]([CH3:50])[O:44]1)[CH2:28][CH2:29][O:30][C:31]1[CH:32]=[CH:33][C:34]([CH2:37][CH2:38][CH2:39][CH2:40][NH:41][C:14]([NH:13][C:11]([C:4]2[C:3]([NH2:2])=[N:8][C:7]([NH2:9])=[C:6]([Cl:10])[N:5]=2)=[O:12])=[NH:17])=[CH:35][CH:36]=1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Reactant: C[C@@H]1OC[C@@H](O)[C@H](CN(CCOc2ccc(CCCCN)cc2)C[C@@H]2O[C@H](C)OC[C@H]2O)O1
Agent: I
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C[C@@H]1OC[C@@H](O)[C@H](CN(CCOc2ccc(CCCCNC(=N)NC(=O)c3nc(Cl)c(N)nc3N)cc2)C[C@@H]2O[C@H](C)OC[C@H]2O)O1
Temperature: 25 °C
Yield: 73.4 %

Procedure:
1-(3,5-Diamino-6-chloropyrazinoyl-2-methylisothiourea hydriodide (0.39 g, 1.0 mmol) was added to a solution of 13 (0.49 g, 1.07 mmol) in THF (8 mL) containing diisopropylethylamine (0.18 mL, 2 mmol). The reaction mixture was stirred at reflux for 2.5 h and at room temperature overnight. After this time, the solvent was removed under reduced pressure. The brown residue was washed with ether (2×30 mL) and methylene chloride (2×10 mL). The residue was dissolved in a minimal volume of methanol (approx. 2 mL) and poured into water. The precipitate was collected, washed with water and dried overnight to give crude 11 (0.5 g) as a yellow solid. The compound 11 (0.4 g, 54%) was purified by flash chromatography on silica gel (eluent: chloroform/methanol/ammonium hydroxide=10:1:0.1) as a yellow solid. [α]D25=−20.4° (c=1.0, MeOH).