Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])=[CH:12][C:11]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[CH:10][CH:9]=2)=[O:5])C.[OH-].[K+].CCOC(C)=O.Cl>C1COCC1.C(O)C.O>[C:28]1([C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6]([C:4]([OH:5])=[O:3])=[C:14]3[CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19])[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CCOC(=O)c1[nH]c2ccc(-c3ccccc3)cc2c1CCCC(=O)OCc1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(CCCc1c(C(=O)O)[nH]c2ccc(-c3ccccc3)cc12)OCc1ccccc1
Temperature: 50 °C
Reaction time: 6 h
Yield: 93.4 %

Procedure:
5-Phenyl-3-[3-benzyloxycarbonyl-propyl]-1H-indole-2-carboxylic acid ethyl ester (40 mg, 0.088 mmol, 1.0 equiv) was dissolved in 4 mL of a 1:1 mixture of THF and ethanol. To this homogenous solution, KOH in water was added and the reaction mixture was stirred at 50° C. for 6 h. At this point TLC (100% EtOAc) showed only baseline material. The reaction was poured into 20 mL of 1 M HCl and was extracted 2×25 mL of EtOAc. The pooled organic fractions were dried (Na2SO4), filtered, and evaporated to yield 5-phenyl-3-[3-benzyloxycarbonyl-propyl]-1H-indole-2-carboxylic acid (34 mg, 90%).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[NH2:7][C:8]1[C:16]2[C:15]([C:17](OCC)=[O:18])=[CH:14][C:13]([CH3:22])=[N:12][C:11]=2[S:10][C:9]=1[C:23](=[O:25])[NH2:24]>C1COCC1>[NH2:7][C:8]1[C:16]2[C:11](=[N:12][C:13]([CH3:22])=[CH:14][C:15]=2[CH2:17][OH:18])[S:10][C:9]=1[C:23]([NH2:24])=[O:25]
Reactant: CCOC(=O)c1cc(C)nc2sc(C(N)=O)c(N)c12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(CO)c2c(N)c(C(N)=O)sc2n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 73.7 %

Procedure:
To a suspension of LiAlH4 (22 g, 0.57 mol) in anhydrous THF (250 mL) was added a solution of ethyl 3-amino-2-carbamoyl-6-methyl-thieno[2,3-b]pyridine-4-carboxylate (40 g, 143 mmol) in anhydrous THF (250 mL) at −40° C. dropwise. The reaction was then allowed to warm to room temperature and the mixture was heated to reflux and stirred for 5 h. After cooling to room temperature, the reaction was quenched by aqueous NaOH (2N, 22 mL) at 0° C., filtered through Celite and washed with THF (50 mL×5). The filtrate was collected and evaporated under reduced pressure to give crude 3-amino-4-hydroxymethyl-6-methyl-thieno[2,3-b]pyridine-2-carboxamide (74%, 25 g).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1)[C:7]([O:9]C)=[O:8].Cl>C(O)C>[F:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1ccc(Cc2cccc(F)c2)c(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(Cc2cccc(F)c2)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.1 %

Procedure:
A solution of sodium hydroxide 2M (1 mL; 2 mmol) was added to a solution of methyl 3-fluoro-4-(3-fluorobenzyl)benzoate (0.143 g; 0.545 mmol) in ethanol (1 mL). The mixture was stirred at room temperature for 1 hour and the pH of the solution was adjusted to 1 by addition of a solution of 6N hydrochloric acid. The precipitate was collected by filtration and dried under reduced pressure to give 0.111 g (82%) of 3-fluoro-4-(3-fluorobenzyl)benzoic acid as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:34]=[CH:33][C:18]([NH:19][CH2:20][C:21]3[CH:30]=[C:29]4[C:24]([CH:25]=[CH:26][C:27]([C:31]#[N:32])=[CH:28]4)=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:35]([O:39][C:40](=[O:46])[NH:41][S:42](Cl)(=[O:44])=[O:43])([CH3:38])([CH3:37])[CH3:36]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([N:19]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]4[C:29](=[CH:28][C:27]([C:31]#[N:32])=[CH:26][CH:25]=4)[CH:30]=3)[S:42]([NH:41][C:40](=[O:46])[O:39][C:35]([CH3:37])([CH3:36])[CH3:38])(=[O:43])=[O:44])=[CH:33][CH:34]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NCc3ccc4ccc(C#N)cc4c3)cc2)CC1
Product: CC(C)(C)OC(=O)NS(=O)(=O)N(Cc1ccc2ccc(C#N)cc2c1)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1

Procedure:
Starting compound: 7-[[4-[(1-t-butoxycarbonyl-4-piperidyl)oxy]anilino]methyl]-2-naphthalenecarbonitrile, t-butyl(chlorosulfonyl)carbamate In this connection, the method for the synthesis of t-butyl(chlorosulfonyl)carbamate is described in Tetrahedron, 49(1), 65 (1993).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([CH2:14][CH3:15])[N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[C:6]=2[CH:23]=1.[Br:24]Br.C(=O)([O-])[O-].[Na+].[Na+]>Br>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([CH2:14][CH3:15])[N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[C:6]=2[C:23]=1[Br:24]
Reactant: BrBr
Reactant: CCC1N=C(c2ccccc2Cl)c2cc(N)ccc2N(C)C1=O
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCC1N=C(c2ccccc2Cl)c2c(ccc(N)c2Br)N(C)C1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
9.6 g (0.029 M) of rac-7-amino-3-ethyl-5-(o-chlorophenyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one dissolved in 50 ml of concentrated aqueous hydrobromic acid are treated slowly at between 0°-5° C. with 5.2 g (1.65 ml) of bromine and the mixture is stirred at 0° C. for 1 hour. The mixture is then poured on to a mixture of ice and sodium carbonate solution, extracted with methylene chloride and the extract is dried over sodium sulphate, filtered and concentrated. After crystallisation from methylene chloride/ether/petroleum ether, there is obtained rac-7-amino-3-ethyl-6-bromo-5-(o-chlorophenyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one which melts at 251° C. with decomposition.
Reaction SMILES: [CH3:1][C:2]1[CH:26]=[CH:25][C:5]2[S:6][C:7]([C:9]3[CH:14]=[CH:13][C:12]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[C:11]([C:21]([F:24])([F:23])[F:22])[CH:10]=3)=[CH:8][C:4]=2[CH:3]=1.C(Cl)(Cl)[Cl:28]>>[Cl:28][C:8]1[C:4]2[CH:3]=[C:2]([CH3:1])[CH:26]=[CH:25][C:5]=2[S:6][C:7]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[C:11]([C:21]([F:22])([F:23])[F:24])[CH:10]=1
Reactant: Cc1ccc2sc(-c3ccc(-c4ccccc4)c(C(F)(F)F)c3)cc2c1
Reactant: ClC(Cl)Cl
Product: Cc1ccc2sc(-c3ccc(-c4ccccc4)c(C(F)(F)F)c3)c(Cl)c2c1
Yield: 56 %

Procedure:
To a solution of 5-methyl-2-(2-trifluoromethyl-biphenyl-4-yl)-benzo[b]thiophene (184 mg, 0.5 mmol) in CHCl3 (2.5 mL) is added SO2Cl2 (44 μL, 1.1 eq.). The mixture is heated to reflux overnight (about 14 hours). All the solvent is removed under reduced pressure. The residue is extracted with CH2Cl2 (50 mL), washed with saturated aqueous NaHCO3, brine, dried over MgSO4, filtered, and concentrated to give an oil. The mixture is purified by column chromatography (EtOAc/Hexane, gradient) to give 112 mg of 3-chloro-5-methyl-2-(2-trifluoromethyl-biphenyl-4-yl)-benzo[b]thiophene in 56% yield.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:5](=[O:15])[CH2:4][N:3]1[C:16]([O:18][CH2:19][CH:20]=[CH2:21])=[O:17].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[OH:15][CH:5]1[CH2:4][N:3]([C:16]([O:18][CH2:19][CH:20]=[CH2:21])=[O:17])[C@H:2]([CH3:1])[CH2:7][CH:6]1[C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9]
Reactant: C=CCOC(=O)N1CC(=O)C(C(=O)OC(C)(C)C)C[C@H]1C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: C=CCOC(=O)N1CC(O)C(C(=O)OC(C)(C)C)C[C@H]1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 95.1 %

Procedure:
To a solution of 1-allyl 4-tert butyl (2R)-2-methyl-5-oxo-1,4-piperidinedicarboxylate (1.93 g, 6.5 mmol) in methanol (40 ml) were added acetic acid (0.45 ml, 7.9 mmol) and sodium cyanoborohydride (0.49 g, 7.8 mmol), and the mixture was stirred at room temperature for 20 minutes. The solvent was removed in vacuo and the residue was purified by silica gel chromatography to give 1-allyl 4-tert-butyl (2R)-5-hydroxy-2-methyl-1,4-piperidinedicarboxylate (1.85 g, 95%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]([Cl:12])([Cl:11])[Cl:10])[N:3]=1.C(N(CC)CC)C.[C:20]1([N:26]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:27](Cl)=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(#N)C>[C:20]1([N:26]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:27](=[O:28])[O:1][C:2]2[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]([Cl:12])([Cl:10])[Cl:11])[N:3]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(Cl)N(c1ccccc1)c1ccccc1
Reactant: Cc1cc(O)nc(C(Cl)(Cl)Cl)n1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(OC(=O)N(c2ccccc2)c2ccccc2)nc(C(Cl)(Cl)Cl)n1
Yield: 88 %

Procedure:
To a mixture of 5.7 g (0.025 mole) 4-hydroxy-6-methyl-2-trichloromethylpyrimidine, 2.6 g (0.025 mole) triethylamine, and 100 ml acetonitrile was added 5.8 g (0.025 mole) diphenylcarbamoyl chloride. The reaction mixture was refluxed 4 hours. A precipitate was filtered out and ether was added to the filtrate yielding more precipitate. Rotary evaporation gave 9.3 g residue which was recrystallized from ligroin to give 6.15 g (58% yield) of product. An analytical sample was recrystallized a second time from ligroin and had mp 132°-134° C. The structure was confirmed via infrared and elemental analysis.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.C(O)=O.C([O-])(=O)C.[Cu+2:20].C([O-])(=O)C>CO>[Cu:20].[C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1
Reactant: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C(O)c1ccc(C(=O)O)cc1
Solvent: CO
Solvent: O=CO
Product: [Cu]

Procedure:
0.41 g of terephthalic acid was dissolved under heating in a mixture solvent of 250 cm3 of methanol and 15 cm3 of formic acid. After this solution was cooled to the normal temperature, into this solution, a further solution in which 0.50 g of copper acetate was dissolved in 40 cm3 of methanol was dripped and then this was kept still for a few days. Thereafter, the precipitation product was suction-filtered and dried for 110° C./4 hours, whereby 0.38 g of terephthalic acid copper was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:28][CH3:29])=[C:6]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[CH3:25])=[C:15]([CH2:26][OH:27])[CH:14]=3)[O:10][N:9]=2)[CH:7]=1>C(Cl)Cl.[O-2].[Mn+4].[O-2]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:28][CH3:29])=[C:6]([C:8]2[N:12]=[C:11]([C:13]3[CH:14]=[C:15]([CH:26]=[O:27])[C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[CH3:25])=[CH:17][CH:18]=3)[O:10][N:9]=2)[CH:7]=1
Reactant: COc1ccc(F)cc1-c1noc(-c2ccc(-c3ccccc3C)c(CO)c2)n1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COc1ccc(F)cc1-c1noc(-c2ccc(-c3ccccc3C)c(C=O)c2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.1 %

Procedure:
Manganese(IV) oxide (111 mg; 1.28 mmol; 10 eq.) was added to a solution of Example 77 (50 mg; 0.13 mmol; 1 eq.) in DCM (5 mL) and the reaction mixture was stirred at room temperature for 4 hours. The suspension was filtered through a pad of Celite® and the solution concentrated in vacuo to afford title compound (46 mg; 93%) as a white solid.
Reaction SMILES: [CH3:1][S:2]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)=[O:3].[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][C:13]=1[O:20][CH3:21]>>[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[N:8][C:7]2[CH:9]=[CH:10][C:4]([S:2]([CH3:1])=[O:3])=[CH:5][CH:6]=2)=[CH:14][C:13]=1[O:20][CH3:21]
Reactant: COc1cc(C=O)ccc1F
Reactant: CS(=O)c1ccc(N)cc1
Product: COc1cc(C=Nc2ccc(S(C)=O)cc2)ccc1F

Procedure:
Following a similar procedure to that described in section a of example 1, but starting from 4-methylsulfinylaniline (obtained in reference example 2) instead of 4-methylsulfonylaniline and from 4-fluoro-3-methoxybenzaldehyde instead of 4-isopropoxybenzaldehyde, the desired compound was obtained, which was directly used in the next step.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([N:13]2[CH2:18][CH2:17][N:16]([CH:19]([CH3:21])[CH3:20])[CH2:15][CH2:14]2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)[CH3:2].[BH4-].[Na+]>O.O.O.O.O.O.[Ni](Cl)Cl.CO.C1COCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([N:13]2[CH2:14][CH2:15][N:16]([CH:19]([CH3:21])[CH3:20])[CH2:17][CH2:18]2)[CH:7]=[CH:8][C:9]=1[NH2:10])[CH3:2]
Reactant: CCOc1cc(N2CCN(C(C)C)CC2)ccc1[N+](=O)[O-]
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCOc1cc(N2CCN(C(C)C)CC2)ccc1N
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 92.8 %

Procedure:
A mixture of 1-[3-(ethyloxy)-4-nitrophenyl]-4-(1-methylethyl)piperazine (0.285 g, 0.97 mmol) and nickel(II) chloride hexahydrate (0.116 g, 0.48 mmol) was stirred in 2:1 MeOH/THF (10 mL) under N2 at rt. To this mixture was added NaBH4 (0.129 g, 3.4 mmol) in 2 equal portions over 5 min. The reaction was stirred at rt for about 45 min, then concentrated under vacuum. The residue was dissolved in DCM and poured through Celite, washing with DCM and EtOAc. The filtrate was concentrated and chromatographed on silica gel to give the title compound of step B (238 mg, 0.90 mmol, 93%) as a grey oil. MS (ESI): 264 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[O:29]1[CH:33]=[CH:32][N:31]=[C:30]1[C:34](Cl)=O>C1COCC1.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([C:8](=[O:11])[C:9]([CH3:10])=[C:34]([C:30]3[O:29][CH:33]=[CH:32][N:31]=3)[N:12]2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1ncco1
Reactant: CCC(=O)c1ccc(Cl)cc1Nc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1c(-c2ncco2)n(-c2ccccc2)c2cc(Cl)ccc2c1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 23.6 %

Procedure:
In a 25 mL round-bottomed flask, 1-(4-chloro-2-phenylamino-phenyl)-propan-1-one (522 mg, 2.01 mmol) was combined with THF (4 mL) to give a yellow solution. Sodium bis(trimethylsilyl)amide (1.0 M in THF) (5.02 mL, 5.02 mmol) was added slowly dropwise, resulting in a dark red solution. A mixture of oxazole-2-carbonyl chloride (344 mg, 2.61 mmol) in THF (8 mL) and 8 drops of DMF were added to the reaction mixture. The resulting mixture was stirred at room temperature for 5 hr. The reaction mixture was quenched by the addition of water and the aqueous layer was extracted with ethyl acetate. The organic phase was dried (MgSO4), filtered, then concentrated to afford a yellow oil. The crude material was purified by flash chromatography (silica gel, 80 g, 25-65% ethyl acetate in hexanes) to give 7-chloro-3-methyl-2-oxazol-2-yl-1-phenyl-1H-quinolin-4-one (160 mg, 23.6%) as a yellowish solid. MS calcd. for C19H13ClN2O2 [(M+H)+] 337, obsd. 337.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:16]2[CH2:20][C@H:19]([CH2:21][NH2:22])[O:18][C:17]2=[O:23])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:14][CH2:13][C:12](=[O:15])[NH:11][CH2:10][CH2:9]1.C(N(CC)CC)C.[C:31](SCC)(=[S:33])[CH3:32]>C(Cl)Cl.CO>[F:1][C:2]1[CH:3]=[C:4]([N:16]2[CH2:20][C@H:19]([CH2:21][NH:22][C:31](=[S:33])[CH3:32])[O:18][C:17]2=[O:23])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:14][CH2:13][C:12](=[O:15])[NH:11][CH2:10][CH2:9]1
Reactant: CCSC(C)=S
Reactant: NC[C@H]1CN(c2ccc(N3CCNC(=O)CC3)c(F)c2)C(=O)O1
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(=S)NC[C@H]1CN(c2ccc(N3CCNC(=O)CC3)c(F)c2)C(=O)O1
Reaction time: 145 h

Procedure:
A stirred solution of 0.12 g of the product of Example 2, Step 2 and 0.40 mL of triethylamine in a mixture of methylene chloride (10 mL) and methanol (10 mL), under nitrogen, is treated with ethyl dithioacetate (0.05 mL) and kept at ambient temperature for 145 hours. Additional 0.05 m]L portions of ethyl dithioacetate are added after 24, 31 and 49 hours; additional triethylamine (1.0 mL) is also added after 49 hours. The mixture is concentrated to a small volume, diluted with ethyl acetate, washed with water and brine, dried (Na2SO4) and concentrated. Chromatography of the residue on silica gel with 3.5% methanol-methylene chloride gave 0.061 g of the titled product.
Reaction SMILES: [F:1][CH:2]([F:23])[O:3][C:4]1[C:5]([OH:22])=[C:6]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[C:17](=[O:21])[O:16][CH2:15]3)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][C:32]1[CH:40]=[CH:39][C:35]([C:36]([NH2:38])=[O:37])=[CH:34][CH:33]=1>C(#N)C>[F:23][CH:2]([F:1])[O:3][C:4]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[C:6]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[C:17](=[O:21])[O:16][CH2:15]3)[C:5]=1[O:22][CH2:31][C:32]1[CH:40]=[CH:39][C:35]([C:36]([NH2:38])=[O:37])=[CH:34][CH:33]=1
Reactant: COc1ccc(-c2ccc3c(c2)COC3=O)c(O)c1OC(F)F
Reactant: NC(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(-c2ccc3c(c2)COC3=O)c(OCc2ccc(C(N)=O)cc2)c1OC(F)F
Temperature: 70 °C
Yield: 31.2 %

Procedure:
To a stirring solution of 5-(3-(difluoromethoxy)-2-hydroxy-4-methoxyphenyl)isobenzofuran-1(3H)-one (80 mg, 0.246 mmol) in acetonitrile (10 mL) was added potassium carbonate (102 mg, 0.738 mmol) and 4-(bromomethyl)benzamide (106 mg, 0.496 mmol) and the resultant reaction mixture was heated to 70° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, 0-70% ethyl acetate in pet ether) to afford the title compound as a solid (35 mg, 30.9%).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24]([CH:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)[OH:11]>C(Cl)(Cl)Cl.C1COCC1.[O-2].[O-2].[Mn+4]>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:13]=[CH:14][C:15]([O:18][C:19]2[C:24]([CH:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:16][CH:17]=1)=[O:11]
Reactant: OC(c1ccc(Oc2ncccc2C2CCOCC2)cc1)c1nc2ccccc2[nH]1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: O=C(c1ccc(Oc2ncccc2C2CCOCC2)cc1)c1nc2ccccc2[nH]1
Temperature: 50 °C
Reaction time: 0.67 h

Procedure:
A suspension of (1H-benzo[d]imidazol-2-yl)(4-(3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yloxy)phenyl)methanol (0.500 g, 1.245 mmol) in Chloroform (50 mL) and THF (50.0 mL) was treated with manganese dioxide (1.083 g, 12.45 mmol) at RT under nitrogen. The mixture was heated to 50° C. while stirring. After 40 mins, the reaction was filtered while warm through a small pad of celite. The filtrate was reduced and purified by column chromatography on silica gel using a gradient of 0 to 10% MeOH is DCM. The pure fractions were reduced and the residue was triturated in ethyl ether to give (1H-benzo[d]imidazol-2-yl)(4-(3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yloxy)phenyl)methanone as an off-white solid. MS (ESI, pos. ion) m/z: 399.9 (M+1). IC50 (uM) +++++.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[C:10]1([NH:16][NH2:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O.[Cl:19][C:20]1[N:29]=[C:28](Cl)[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=1>C1COCC1>[Cl:19][C:20]1[N:29]=[C:28]([NH:17][NH:16][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=1
Reactant: NNc1ccccc1
Reactant: Clc1nc(Cl)c2ccccc2n1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Clc1nc(NNc2ccccc2)c2ccccc2n1
Reaction time: 0.5 h

Procedure:
To a stirred solution of N,N-diisopropylethylamine (10 ml, 57 mmol) in THF (150 ml), 2,4-dichloroquinazoline [prepared according to the procedure described by Curd, F. H. S. et al., J. Chem. Soc., (1947), 775] (5 g, 25 mmol) and phenylhydrazine (2.7 g, 25 mmol) was added. After stirring for 30 minutes, the reaction was poured into water and extracted with dichloromethane (3×100 ml). The combined organic layers were dried over Na2SO4 and evaporated under reduced pressure. The resulting solid was triturated with ethanol and filtered to afford 2-chloro-4-phenylhydrazinoquinazoline (3.2 g) as a yellow solid, m.p. 178° C. (dec.).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[N:15]3[C:11]([S:12][C:13]([C:16]4[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([O:23][CH3:24])[CH:17]=4)=[N:14]3)=[N:10][C:9]=2[CH3:25])=[CH:4][C:3]=1[C:26]([F:29])([F:28])[F:27].Cl.Cl[CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.C(N(C(C)C)C(C)C)C.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[O:37]1[CH2:38][CH2:39][N:34]([CH2:33][CH2:32][O:22][C:19]2[CH:20]=[CH:21][C:16]([C:13]3[S:12][C:11]4=[N:10][C:9]([CH3:25])=[C:8]([C:5]5[CH:4]=[C:3]([C:26]([F:28])([F:27])[F:29])[C:2]([NH2:1])=[N:7][CH:6]=5)[N:15]4[N:14]=3)=[CH:17][C:18]=2[O:23][CH3:24])[CH2:35][CH2:36]1
Reactant: COc1cc(-c2nn3c(-c4cnc(N)c(C(F)(F)F)c4)c(C)nc3s2)ccc1O
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(-c2nn3c(-c4cnc(N)c(C(F)(F)F)c4)c(C)nc3s2)ccc1OCCN1CCOCC1
Temperature: 105 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(5-(6-amino-5-(trifluoromethyl)pyridin-3-yl) -6-methylimidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2-methoxyphenol (0.042 g, 0.1 mmol, 1 eq) in dry DMF (1 mL), 4-(2-chloroethyl)morpholine hydrochloride (0.024 g, 0.13 mmol, 1.25 eq), iPr2EtN (0.021 mL, 0.13 mmol, 1.3 eq) and K2CO3 (0.018 g, 0.13 mmol, 1.25 eq) were added. The mixture was stirred at 105° C. for 1 h and cooled to RT. The solvent was evaporated, and the dry residue was taken up in DCM, washed with water (2×1 mL), dried (MgSO4), filtered and concentrated to dryness. Purification by reversed-phase chromatography (RP-C18, ACN/water) using a pre-packed cartridge and, subsequently, preparative HPLC gave the desired product. HPLC-MS: (5-100% B in 8 min, 0.6 mL/min): tR=3.3 min, [M+H]+ m/z 534.1; 1H NMR (300 MHz, CDCl3) δ/ppm 8.44 (d, J=1.7, 1H), 7.98 (d, J=1.8, 1H), 7.49 (d, J=0.8, 1H), 7.41 (d, J=2.0, 1H), 7.31 (d, J=2.1, 1H), 5.07 (s, 2H), 4.01-3.89 (m, 6H), 3.69-3.59 (m, 4H), 3.47 (s, 3H), 2.62-2.51 (m, 3H), 2.38 (dd, J=9.0, 2.7, 7H).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C1C=CC2N(O)N=NC=2C=1.O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:55][C:56]1[N:61]=[CH:60][C:59]([C:62](O)=[O:63])=[CH:58][CH:57]=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[CH3:55][C:56]1[N:61]=[CH:60][C:59]([C:62]([N:15]2[CH2:16][CH2:17][N:12]([S:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:18])[F:19])=[CH:8][CH:7]=3)(=[O:10])=[O:11])[CH2:13][CH2:14]2)=[O:63])=[CH:58][CH:57]=1
Reactant: Cc1ccc(C(=O)O)cn1
Reactant: O=S(=O)(c1ccc(C(F)(F)F)cc1)N1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(C(=O)N2CCN(S(=O)(=O)c3ccc(C(F)(F)F)cc3)CC2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.1 %

Procedure:
To a solution of 1-{[4-(trifluoromethyl)phenyl]sulfonyl}piperazine (Description 1) (100 mg, 0.340 mmol) in DMF (5 ml) was added HOBT.H2O (52.0 mg, 0.340 mmol), HBTU (129 mg, 0.340 mmol), 6-methyl-3-pyridinecarboxylic acid (46.6 mg, 0.340 mmol) and DIPEA (0.18 ml, 1.02 mmol). The reaction mixture was stirred for 2 h at room temperature. Reaction mixture was transferred to a 100 ml round bottom flask and was reduced to dryness in vacuo. The residue was dissolved in DCM (50 ml) and was transferred to a separating funnel then washed with saturated NaHCO3 solution (5 ml), twice. The organic layer was collected and dried with dried magnesium sulphate. The solid was removed by filtration and the filtrate collected in a 250 ml round bottom flask and reduced to dryness in vacuo. The residue was then dissolved in 1.8 ml 1:1 MeCN/DMSO and purified by MDAP in 2 batches. The fractions containing desired product were combined in a 250 ml round bottom flask and reduced in vacuo to yield the title compound (69 mg).