Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[O:11][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1>>[CH3:13][C:10]1([CH3:12])[O:9][C:8](=[O:14])[C:7]2[C:2]([O:1][CH2:15][C:16]3[CH:23]=[CH:22][C:19]([CH3:20])=[CH:18][CH:17]=3)=[CH:3][CH:4]=[CH:5][C:6]=2[O:11]1
Reactant: Cc1ccc(CBr)cc1
Reactant: CC1(C)OC(=O)c2c(O)cccc2O1
Product: Cc1ccc(COc2cccc3c2C(=O)OC(C)(C)O3)cc1

Procedure:
2,2-Dimethyl-5-(4-methyl-benzyloxy)-benzo[1,3]dioxin-4-one was prepared from 5-hydroxy-2,2-dimethyl-benzo[1,3]dioxin-4-one and 4-methylbenzyl bromide under conditions analogous to example 47-a. MS ESI(+) m/e: 299.12 (M+1).
Reaction SMILES: [O-]CC.[Na+].[C:5](OCC)(=O)[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].CS[C:18]1[N:19]=[CH:20]C2C(=O)OC(=O)N(C(C)C)C=2[N:32]=1.Cl>O>[CH2:10]([O:9][C:7]([C:6]1[N:32]=[CH:18][N:19]=[CH:20][CH:5]=1)=[O:8])[CH3:11]
Reactant: CSc1ncc2c(=O)oc(=O)n(C(C)C)c2n1
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1ccncn1

Procedure:
To a solution of sodium ethoxide (0.9 g. .039 g. atom of sodium in 75 ml. of ethanol) was added 6.24 g. (0.03 mole) of diethyl malonate. The ethanol was removed in a rotary evaporator. To the residue was added 100 ml. of dimethyl formamide followed by 3.3 g. (0.013 mole) of 7-methylthio-1-isopropyl-2H-pyrimido[4,5-d][1,3]oxazine-2,4(1H)-dione. The reaction mixture was heated under reflux for 1 hour, cooled in ice and poured into 400 ml. of water. The solution was acidified with conc. hydrochloric acid and the resulting product was collected by suction filtration. Recrystallization from ethanol gave 2 g. of product--m.p. 138°-140° C.
Reaction SMILES: [O:1]=[C:2]([P:6](=[O:11])([O:9]C)[O:7][CH3:8])[CH2:3][CH2:4][CH3:5].[I-].[Na+:13]>CC(CC)=O>[O:1]=[C:2]([P:6](=[O:9])([O-:11])[O:7][CH3:8])[CH2:3][CH2:4][CH3:5].[Na+:13]
Reactant: CCCC(=O)P(=O)(OC)OC
Agent: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: CCCC(=O)P(=O)([O-])OC

Procedure:
Dimethyl (1-oxobutyl)phosphonate (10.8 g, 0.06 mol) and sodium iodide (9.0 g, 0.06 mol) were dissolved in ethyl methyl ketone (160 ml) and the solution stirred and refluxed for 16 hours.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[N:14]=[C:13](O)[C:12]2[CH2:11][C:10]([CH3:17])([CH3:16])[CH2:9][CH2:8][C:7]=2[N:6]=1)[CH3:3].O=P(Cl)(Cl)[Cl:20]>C(Cl)(Cl)Cl>[Cl:20][C:13]1[C:12]2[CH2:11][C:10]([CH3:17])([CH3:16])[CH2:9][CH2:8][C:7]=2[N:6]=[C:5]([CH2:4][N:2]([CH3:3])[CH3:1])[N:14]=1
Reactant: CN(C)Cc1nc(O)c2c(n1)CCC(C)(C)C2
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CN(C)Cc1nc(Cl)c2c(n1)CCC(C)(C)C2
Temperature: 90 °C
Yield: 48 %

Procedure:
To a solution of the final residue from step 2 in CHCl3 (10 mL) was added POCl3 (10 mL). The reaction mixture was heated (90° C.) for two hours and concentrated. This residue was partitioned between dichloromethane and aqueous sodium bicarbonate and the resulting organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by silica gel chromatography (5-10% concentrated aqueous ammonia in methanol) in chloroform provided 1-(4-chloro-6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-2-yl)-N,N-dimethylmethanamine (1.3 g, 48% yield). 1H NMR (400 MHz, CD3OD) δ 4.52 (s, 2H), 3.02 (s, 6H), 2.98 (t, 2H), 2.61 (s, 2H), 1.71 (t, 2H), 1.06 (s, 6H); MS (ES) for C13H20ClN3: 254 (MH+)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=O.C(Cl)(=O)C(Cl)=O.[CH3:19][N:20]1[CH:24]=[C:23]([CH2:25][NH2:26])[CH:22]=[N:21]1>CN(C=O)C.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([NH:26][CH2:25][C:23]1[CH:22]=[N:21][N:20]([CH3:19])[CH:24]=1)=[O:7]
Reactant: COc1ccc(C(=O)O)cc1Br
Reactant: Cn1cc(CN)cn1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)NCc2cnn(C)c2)cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.3 %

Procedure:
To a 100 mL round bottom flask containing 3-bromo-4-methoxybenzoic acid (500 mg, 2.16 mmol) and DCM (5 mL) was added oxalyl chloride (0.23 mL, 2.60 mmol) and DMF (0.1 mL, 0.13 mmol). The reaction mixture was stirred at RT for one hour and concentrated in vacuo. The resulting colorless oil was taken up in DCM (2.5 mL) and added to a mixture of (1-methyl-1H-pyrazol-4-yl)methanamine (241 mg, 2.16 mmol), TEA (0.60 mL, 4.33 mmol) and DCM (2.5 mL) at 0° C. The reaction mixture was stirred at RT for 0.5 hours then concentrated in vacuo. The crude material was purified by silica gel chromatography (0-10% MeOH in DCM) to afford 3-bromo-4-methoxy-N-((1-methyl-1H-pyrazol-4-yl)methyl)benzamide (702 mg) MS [M+H+]=325.9.
Reaction SMILES: [OH-].[NH4+:2].[N:3]([CH2:6][CH2:7][CH2:8][S:9](Cl)(=[O:11])=[O:10])=[N+:4]=[N-:5]>C(O)C>[N:3]([CH2:6][CH2:7][CH2:8][S:9]([NH2:2])(=[O:11])=[O:10])=[N+:4]=[N-:5]
Reactant: [N-]=[N+]=NCCCS(=O)(=O)Cl
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: [N-]=[N+]=NCCCS(N)(=O)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 86 %

Procedure:
Ammonium hydroxide (28%) (10 mL) was added to a solution of 3-azido-1-propanesulfonyl chloride (˜2.29 g, 12.53 mmol; obtained in step 2) in ethanol (10 mL). The reaction mixture was stirred at room temperature for 3 h then concentrated. The residual material was passed through a short silica gel column using hexanes:ethyl acetate as eluent to isolate 3-azido-1-propanesulfonamide (1.5 g, 86%).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11]([OH:13])=O)[N:4]=1.Cl.[CH3:20][CH:21]1[CH2:26][NH:25][CH2:24][CH2:23][N:22]1[C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][N:28]=1>>[CH3:20][CH:21]1[CH2:26][N:25]([C:11](=[O:13])[C:10]2[CH:14]=[CH:15][CH:16]=[C:8]([C:5]3[N:4]=[C:3]([C:2]([F:1])([F:18])[F:17])[O:7][N:6]=3)[CH:9]=2)[CH2:24][CH2:23][N:22]1[C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][N:28]=1
Reactant: CC1CNCCN1c1ccc(C#N)cn1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Agent: Cl
Product: CC1CN(C(=O)c2cccc(-c3noc(C(F)(F)F)n3)c2)CCN1c1ccc(C#N)cn1
Yield: 43 %

Procedure:
This compound was synthesized from 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid and 6-(2-methylpiperazin-1-yl)nicotinonitrile hydrochloride as described for example 37 step 3 (70 mg, yield 43%). 1H NMR (400 MHz, MeOD) δ 8.43 (d, J=2.0 Hz, 1H), 8.27 (m, 1H), 8.22 (s, 1H), 7.78-7.73 (m, 3H), 6.86 (d, J=9.0 Hz, 1H), 4.66-4.56 (m, 2H), 4.34-4.29 (m, 1H), 3.85-3.83 (m, 1H), 3.65 (m, 1H), 3.49-3.40 (m, 1H), 3.26 (m, 1H), 1.29 (m, 3H). MS (ESI) m/z: Calculated for C21H17F3N6O2: 442.14. found: 443.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N+:12]([O-])=O)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]>C(O)C.[Pd]>[F:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([NH2:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(F)cc1F
Agent: [Pd]
Solvent: CCO
Product: Nc1cc(C(=O)O)c(F)cc1F
Reaction time: 2 h
Yield: 97.6 %

Procedure:
To a solution of 2,4-difluoro-5-nitrobenzoic acid (0.998 g, 4.91 mmol) in ethanol (50 mL) was added 10% palladium on charcoal (107 mg) and the mixture was hydrogenated at 30 psi. After 2 h, the mixture was degassed, filtered and the filtrate was concentrated in vacuo to afford 2,4-difluoro-5-aminobenzoic acid (0.83 g, 97%) as tan solid. LC/MS (ESI); (M−H)−=172.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]2[C:13]([Cl:14])=[C:12]([C:15]([F:18])([F:17])[F:16])[N:11]([CH3:19])[N:10]=2)=[CH:4][C:3]=1[S:20](Cl)(=O)=O>C(O)(=O)C.[Zn]>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]2[C:13]([Cl:14])=[C:12]([C:15]([F:18])([F:17])[F:16])[N:11]([CH3:19])[N:10]=2)=[CH:4][C:3]=1[SH:20]
Reactant: Cn1nc(-c2cc(S(=O)(=O)Cl)c(Cl)cc2F)c(Cl)c1C(F)(F)F
Agent: [Zn]
Solvent: CC(=O)O
Product: Cn1nc(-c2cc(S)c(Cl)cc2F)c(Cl)c1C(F)(F)F
Temperature: 80 °C
Reaction time: 4 h
Yield: 95.3 %

Procedure:
To a solution of 12.8 g (0.031 mole) 2-chloro-5-[4-chloro-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]-4-fluorobenzenesulfonyl chloride in 100 mL acetic acid was added 40.7 g (0.62 mole) zinc powder. The slurry was stirred at 80° C. for 4 hours, allowed to cool and filtered through Celite®. The filtrate was poured into 1.0 L water, the solid filtered and dried. The solid was recrystallized from ethanol/water to give 10.2 g (95%) of 2-chloro-5-[4-chloro-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]-4-fluorobenzenethiol as a yellow solid; mp 56°-58° C.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[CH3:22][C:23]1[NH:24][CH:25]=[CH:26][N:27]=1>>[CH3:22][C:23]1[N:24]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][C:11]=2[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]3=[O:21])[CH:25]=[CH:26][N:27]=1
Reactant: Cc1ncc[nH]1
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Product: Cc1nccn1-c1cc2c(=O)n(NS(C)(=O)=O)c(=O)[nH]c2cc1[N+](=O)[O-]
Yield: 49 %

Procedure:
N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (25 mg, 0.0786 mmol) is reacted with 2-methyl-1H-imidazole according to the GPA affording 14.5 mg (49%) of a yellowish powder. Rt=1.98 min.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[O:15][N:14]=[C:13]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22]C)=[O:21])[N:12]=1>CO>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[O:15][N:14]=[C:13]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[N:12]=1
Reactant: COC(=O)CCCCc1noc(-c2ccccc2OC)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccccc1-c1nc(CCCCC(=O)O)no1
Reaction time: 3.5 h
Yield: 72.4 %

Procedure:
Add a solution of 2 N sodium hydroxide (20 mL) to a solution of methyl 5-[5-(2-methoxyphenyl)[1,2,4]oxadiazol-3-yl]pentanoate (3.4 g, 11 mmol) in methanol (50 mL) at room temperature under nitrogen and stir the mixture for 3.5 h. Remove the solvent under reduced pressure, dilute the residue with water (200 mL) and wash with diethyl ether (200 mL). Adjust the aqueous layer to pH 1 with 1 N HCl and collect the solids by vacuum filtration to afford 5-[5-(2-methoxyphenyl)[1,2,4]oxadiazol-3-yl]pentanoic acid (2.2 g, 72%): APCI MS m/z 275 [C14H16N2O4−H]−.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:14][CH:13]2[CH2:15][CH:9]([CH2:10][N:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12]2)[CH:8]=1)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[Li+].[N:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1B(O)O>C(COC)OC.CCOCC>[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:7]2[CH2:14][CH:13]3[CH2:15][CH:9]([CH2:10][N:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12]3)[CH:8]=2)[CH:32]=1
Reactant: CCOC(=O)N1CC2C=C(OS(=O)(=O)C(F)(F)F)CC(C2)C1
Reactant: OB(O)c1ccccn1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Li+]
Solvent: COCCOC
Solvent: CCOCC
Product: CCOC(=O)N1CC2C=C(c3cccnc3)CC(C2)C1
Temperature: 95 °C
Yield: 33 %

Procedure:
To a solution of ethyl 7-(trifluoromethylsulfonyloxy)-3-azabicyclo[3.3.1]non-6-ene-3-carboxylate (0.34 g, 1.0 mmol) in dimethoxyethane (8 ml) was added saturated sodium carbonate solution (2.5 ml), lithium chloride (127 mg, 3.0 mmol) and pyridinylboronic acid (123 mg, 1.00 mmol). The flask was alternately evacuated and filled with argon three times. Then palladium tetrakistriphenylphosphine (23 mg, 0.02 mmol) was added and the evacuate/fill procedure performed once again. The flask was then sealed under argon and the stirred reaction mixture was heated at 95° C. for 2 h. The mixture was cooled to room temperature and then diluted with ether (10 ml) and filtered through a Celite pad. The Celite was washed with 30% ammonium hydroxide (25 ml) and ether (50 ml). The combined filtrates were separated into organic and aqueous phases, and the aqueous layer was extracted with ether (1×25 ml). Chloroform (20 ml) was added to the combined organic layers, and the mixture was dried over sodium sulfate and filtered. Concentrated of the filtrate by rotary evaporation, followed by purification of the residue (207 mg) by column chromatography, using a gradient of chloroform/methanol (0 to 2% methanol) as eluent, gave a light yellow oil (90 mg, 33%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH2:9][CH2:10][CH3:11])=[CH:6][CH:5]=[C:4]([N+:12]([O-])=O)[C:3]=1[CH3:15].[CH2:16](OC(OCC)N(C)C)C.N1CCCC1.O.NN>CN(C=O)C.[Ni].C1COCC1.CO>[Cl:1][C:2]1[C:7]([O:8][CH2:9][CH2:10][CH3:11])=[CH:6][CH:5]=[C:4]2[C:3]=1[CH:15]=[CH:16][NH:12]2
Reactant: CCCOc1ccc([N+](=O)[O-])c(C)c1Cl
Reactant: CCOC(OCC)N(C)C
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: CN(C)C=O
Solvent: C1CCNC1
Product: CCCOc1ccc2[nH]ccc2c1Cl
Yield: 17.7 %

Procedure:
Reaction of 2-chloro-3-n-propyloxy-6-nitrotoluene (8.50 g, 37.0 mmol) with dimethylformamide diethyl acetal (6.43 g, 43.7 mmol) and pyrrolidine (3.11 g, 43.7 mmol) in DMF and subsequent workup, as described in 1 (b), followed by treatment with hydrazine hydrate (2×2.7 ml) and Raney nickel (3.9 ml) in THF (70 ml) and methanol (70 ml), gave 4- chloro-5-n-propyloxyindole as an oil (1.37 g).
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][C:3]=1[C:4]([NH:6][CH2:7][C:8]([NH:10][C@@H:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]1[NH:17][C:18](=[O:27])[C:19]1[CH:24]=[CH:23][C:22]([S:25][CH3:26])=[CH:21][CH:20]=1)=[O:9])=[O:5].C(N(CC)CC)C.[CH2:43]([N:45]=[C:46]=[O:47])[CH3:44].Cl>C1COCC1.CCOC(C)=O>[CH2:43]([NH:45][C:46]([NH:1][C:2]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:28][C:3]=1[C:4]([NH:6][CH2:7][C:8]([NH:10][C@@H:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]1[NH:17][C:18](=[O:27])[C:19]1[CH:24]=[CH:23][C:22]([S:25][CH3:26])=[CH:21][CH:20]=1)=[O:9])=[O:5])=[O:47])[CH3:44]
Reactant: CSc1ccc(C(=O)N[C@H]2CCCC[C@H]2NC(=O)CNC(=O)c2cc(C(F)(F)F)ccc2N)cc1
Reactant: CCN=C=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCNC(=O)Nc1ccc(C(F)(F)F)cc1C(=O)NCC(=O)N[C@@H]1CCCC[C@@H]1NC(=O)c1ccc(SC)cc1
Reaction time: 72 h
Yield: 17.5 %

Procedure:
2-(amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl benzamide (Example 114a) (50 mg) was dissolved in THF (2.5 mL) prior to the addition of triethylamine (30 mg) and ethyl isocyanate (21 mg). After stirring for 72 h, EtOAc was added along with 1 N HCl solution. The EtOAc layer was washed with 1 N HCl and brine. The EtOAc was dried (MgSO4), filtered, and concentrated. Reverse phase HPLC purification (gradient elution, water/acetonitrile/TFA) provided the title benzamide (10 mg). MS found: (M+Na)+=602.4.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[I-].[Na+].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.[OH-].[Na+]>O>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:2]2[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])=[CH:16][CH:15]=1
Reactant: O=C(O)c1ccccc1Cl
Reactant: Oc1ccc(Cl)cc1
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1ccccc1Oc1ccc(Cl)cc1

Procedure:
To a well stirred mixture of 15.7 g. (0.1 mole) of 2-chlorobenzoic acid and 15.0 g. (0.1 mole) of sodium iodide in 250 ml. of 4-chlorophenol was rapidly added a solution of 16 g. (0.4 mole) of sodium hydroxide dissolved in 16 ml. of water. The reaction mixture was heated and concentrated under reduced pressure to an internal temperature of about 145° C. to remove the water and excess 4-chlorophenol. The residue was then stirred at 170° C. for about 7 hours, cooled and diluted with 250 ml. of water. The aqueous solution was extracted with ethyl acetate after acidifying with dilute hydrochloric acid. The ethyl acetate extractions were washed with water, dried and concentrated under reduced pressure. The residue was recrystallized from a benzene-hexane mixture to give pure 2-(4'-chlorophenoxy)benzoic acid, m.p. 114°-115° C.
Reaction SMILES: C([O:3][C:4](=O)[NH:5][C:6]1[C:11]([CH:12]2[CH2:17][CH2:16][CH2:15][N:14](C(=O)C(F)(F)F)[CH2:13]2)=[CH:10][CH:9]=[CH:8][C:7]=1[NH2:24])C>CO.O.[OH-].[K+]>[NH:14]1[CH2:15][CH2:16][CH2:17][CH:12]([C:11]2[C:6]3[NH:5][C:4](=[O:3])[NH:24][C:7]=3[CH:8]=[CH:9][CH:10]=2)[CH2:13]1
Reactant: CCOC(=O)Nc1c(N)cccc1C1CCCN(C(=O)C(F)(F)F)C1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=c1[nH]c2cccc(C3CCCNC3)c2[nH]1
Yield: 50.9 %

Procedure:
4 g of the product of Step E in 80 ml of methanol, 16 ml of water and 16 ml of potassium hydroxide were taken to 80° C. for 4 hours with stirring under an inert atmosphere. After evaporating the methanol under reduced pressure, adding 30 ml of water, adjusting the pH to 6-8 by acetic acid and taking to dryness under reduced pressure, the residue was purified by chromatography on silica, (eluent: methylene chloride-methanol-triethylamine (6-3-1) to obtain 2.15 g of crude product. The latter was triturated in ethyl ether, separated, dried and crystallized from ethanol to obtain 1.23 g of 1,3-dihydro-4-(3-piperidinyl)-2H-benzimidazol-2-one melting at about 260° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][N:15]3[C:19]4=[N:20][C:21]([C:24]5[CH:25]=[CH:26][C:27]([F:32])=[C:28]([CH:31]=5)[C:29]#[N:30])=[CH:22][N:23]=[C:18]4[N:17]=[N:16]3)[CH2:9]2)=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1.[F:45][C:46]1[CH:58]=[C:57](B2OC(C)(C)C(C)(C)O2)[CH:56]=[CH:55][C:47]=1[CH2:48][N:49]1[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[F:32][C:27]1[CH:26]=[CH:25][C:24]([C:21]2[N:20]=[C:19]3[N:15]([CH2:14][C@H:10]4[O:11][CH2:12][CH2:13][N:8]([C:5]5[N:4]=[CH:3][C:2]([C:57]6[CH:56]=[CH:55][C:47]([CH2:48][N:49]7[CH2:54][CH2:53][O:52][CH2:51][CH2:50]7)=[C:46]([F:45])[CH:58]=6)=[CH:7][N:6]=5)[CH2:9]4)[N:16]=[N:17][C:18]3=[N:23][CH:22]=2)=[CH:31][C:28]=1[C:29]#[N:30]
Reactant: CC1(C)OB(c2ccc(CN3CCOCC3)c(F)c2)OC1(C)C
Reactant: N#Cc1cc(-c2cnc3nnn(C[C@@H]4CN(c5ncc(Br)cn5)CCO4)c3n2)ccc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1cc(-c2cnc3nnn(C[C@@H]4CN(c5ncc(-c6ccc(CN7CCOCC7)c(F)c6)cn5)CCO4)c3n2)ccc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 93.7 %

Procedure:
In a pressure tube reactor, ((S)-5-(1-((4-(5-bromopyrimidin-2-yl)morpholine-2-yl)methyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)-2-fluorobenzonitrile (40 mg, 0.08 mmol) was added, and then K2CO3 (33 mg, 0.24 mmol) was added. Pd(dppf)2Cl2 (3 mg, 0.004 mmol) was further added, and then 1,4-dioxane (2 mL) and water (0.5 mL) were added. 4-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)benzyl)morpholine (12 g, 0.13 mmol) was added, and then stirred at room temperature under nitrogen gas for 10 minutes, followed by stirring at 85° C. for 2 hours. When the reaction was completed, the organic layer was extracted with ethyl acetate and water, and the extra water was removed by sodium sulfate, followed by concentration under reduced pressure. Column chromatography using 5% dichloromethane/methanol gave (S)-2-fluoro-5-(1-((4-(5-(3-fluoro-4-(morpholinomethyl)phenyl)-pyrimidin-2-yl)morpholine-2-yl)methyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)benzonitrile (46 mg, 0.075 mmol) with a yield of 46%.
Reaction SMILES: [F:1][C:2]1([F:26])[CH2:7][CH2:6][CH:5]([C:8]2[N:12]3[C:13]4[C:18]([NH:19][C:20](=[O:21])[C:11]3=[N:10][N:9]=2)=[CH:17][C:16]([C:22](O)=[O:23])=[C:15]([CH3:25])[CH:14]=4)[CH2:4][CH2:3]1.[F:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][CH2:32][CH2:31]2.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>O.CN(C)C=O>[F:26][C:2]1([F:1])[CH2:3][CH2:4][CH:5]([C:8]2[N:12]3[C:13]4[C:18]([NH:19][C:20](=[O:21])[C:11]3=[N:10][N:9]=2)=[CH:17][C:16]([C:22]([N:33]2[C:34]3[C:30](=[CH:29][C:28]([F:27])=[CH:36][CH:35]=3)[CH2:31][CH2:32]2)=[O:23])=[C:15]([CH3:25])[CH:14]=4)[CH2:6][CH2:7]1
Reactant: Fc1ccc2c(c1)CCN2
Reactant: Cc1cc2c(cc1C(=O)O)[nH]c(=O)c1nnc(C3CCC(F)(F)CC3)n12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc2c(cc1C(=O)N1CCc3cc(F)ccc31)[nH]c(=O)c1nnc(C3CCC(F)(F)CC3)n12
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.2 %

Procedure:
To a mixture of 150 mg of 1-(4,4-difluorocyclohexyl)-8-methyl-4-oxo-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline-7-carboxylic acid, 62.5 mg of 5-fluoroindoline, 0.25 mL of diisopropylethylamine, and 3 mL of N,N-dimethylformamide was added 146 mg of TBTU, followed by stirring at room temperature overnight. To the reaction liquid were added water and a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with chloroform. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (chloroform/methanol=100/0 to 95/5). The obtained solid was washed with a mixed solution of hot diethyl ether and normal hexane to obtain 108 mg of 1-(4,4-difluorocyclohexyl)-7-[(5-fluoro-2,3-dihydro-1H-indol-1-yl)carbonyl]-8-methyl[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([N:11]2[C:15]3[CH:16]=[C:17]([CH2:20][N:21]4[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]4)[CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)=[N:8][C:7]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:5])C.O1CCCC1.[OH-].[Li+]>O>[CH3:27][N:24]1[CH2:25][CH2:26][N:21]([CH2:20][C:17]2[CH:18]=[CH:19][C:14]3[N:13]=[CH:12][N:11]([C:9]4[S:10][C:6]([C:4]([OH:5])=[O:3])=[C:7]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[N:8]=4)[C:15]=3[CH:16]=2)[CH2:22][CH2:23]1
Reactant: CCOC(=O)c1sc(-n2cnc3ccc(CN4CCN(C)CC4)cc32)nc1-c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN1CCN(Cc2ccc3ncn(-c4nc(-c5ccccc5)c(C(=O)O)s4)c3c2)CC1
Yield: 64.8 %

Procedure:
To a mixture of 0.041 g (0.089 mmole) of 2-[6-(4-methyl-piperazin-1-ylmethyl)-benzoimidazol-1-yl]-4-phenyl-thiazole-5-carboxylic acid ethyl ester (I.1a), 1 mL of tetrahydrofuran and 1 mL of water was added 0.011 g of lithium hydroxide. The reaction mixture was heated to 60 degrees for 30 minutes and then concentrated under reduced pressure. The mixture was diluted with 5 mL of water and then extracted with 5 mL of ethyl acetate. The pH of the aqueous layer was adjusted to ca 7 by addition of 1M hydrochloric acid and then extracted with 5 mL of ethyl acetate. A precipitate formed in aqueous layer after extraction. The solid was collected by filtration and air dried to give 0.025 g of 2-[6-(4-methyl-piperazin-1-ylmethyl)-benzoimidazol-1-yl]-4-phenyl-thiazole-5-carboxylic acid (I.1b) as an off-white solid.
Reaction SMILES: [CH3:1][Si:2]([O:5][C:6](=[O:17])[CH:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:8](O)=[O:9])([CH3:4])[CH3:3].CC(N([SiH3])[SiH3])=O.S(Cl)([Cl:26])=O>ClC1C=CC=CC=1>[Cl:26][C:8]([CH:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:6]([O:5][Si:2]([CH3:4])([CH3:3])[CH3:1])=[O:17])=[O:9]
Reactant: C[Si](C)(C)OC(=O)C(C(=O)O)c1ccccc1
Reactant: O=S(Cl)Cl
Agent: CC(=O)N([SiH3])[SiH3]
Solvent: Clc1ccccc1
Product: C[Si](C)(C)OC(=O)C(C(=O)Cl)c1ccccc1
Temperature: 25 °C

Procedure:
To a solution of phenylmalonic trimethylsilyl ester prepared with 0.1 mole of the acid (18.0) and bisilylacetamide in chlorobenzene (100 ml), there is added thionyl chloride (10 ml) with stirring being maintained at room temperature (20°) for 60 minutes. Thereafter the mixture is distilled at ordinary pressure to draw off trimethylchlorosilane (13.0 ml) and the resulting solution gives trimethylsilyl alpha-chlorocarbonyl-phenylacetate. Thereafter phenol (15.0 g) is added and stirring is continued at 45° C for 8 hours. The mixture is then washed with water and the pH is adjusted to 7.0 with sodium bicarbonate solution. The water phase is decanted off and the pH is adjusted to 5.0 with hydrochloric acid. The phenylmalonic acid phenyl monoester precipitates out, yield 95%, m.p. 105°-110°(d) and when recrystallised from benzene-n-hexane, has m.p. 116°-118° (d).