Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[N:5]2[CH:11]=[N:10][CH:9]=[C:6]2[S:7][CH:8]=1.OCC1N2C=NC=C2SC=1.Cl[C:23]([O:25][CH2:26][CH:27]=[CH2:28])=[O:24].C(=O)([O-])O.[Na+]>O.ClCCl>[CH2:26]([O:25][C:23]([N:2]([CH2:3][C:4]1[N:5]2[CH:11]=[N:10][CH:9]=[C:6]2[S:7][CH:8]=1)[CH3:1])=[O:24])[CH:27]=[CH2:28]
Reactant: C=CCOC(=O)Cl
Reactant: CNCc1csc2cncn12
Agent: O=C([O-])O
Agent: OCc1csc2cncn12
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: C=CCOC(=O)N(C)Cc1csc2cncn12
Reaction time: 0.5 h

Procedure:
To 207 mg of a mixture of 3-(N-methylamino)methylimidazo[5,1-b]thiazole and 3-hydroxymethylimidazo[5,1-b]thiazole in a ratio of about 1:1, 10 ml of dichloromethane and 3 ml of water were added, and then 0.092 ml of allyl chloroformate was added thereto under ice-cooling. The mixture was stirred for 30 minutes under ice-cooling, while the aqueous layer was adjusted to pH 8.5 by adding a sodium hydrogencarbonate solution. The organic layer was separated, and the aqueous layer was extracted with dichloromethane. The combined organic layer was dried over anhydrous magnesium sulfate and then filtered, and the solvent was evaporated under reduced pressure. The resulting residue was purified by a silica gel column chromatograph to obtain 73.6 mg of the title compound.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:9]([CH2:18][C:19](O)=[O:20])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[Cl:53][C:54]1[CH:55]=[N:56][C:57]([CH:60]2[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]2)=[N:58][CH:59]=1.N>CN(C=O)C.CO.O>[C:1]1([C:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:9]([CH2:18][C:19]([N:63]3[CH2:62][CH2:61][CH:60]([C:57]4[N:56]=[CH:55][C:54]([Cl:53])=[CH:59][N:58]=4)[CH2:65][CH2:64]3)=[O:20])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)Cn1nc(-c2ccccc2)cc1-c1ccccc1
Reactant: Clc1cnc(C2CCNCC2)nc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: N
Solvent: CO
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cn1nc(-c2ccccc2)cc1-c1ccccc1)N1CCC(c2ncc(Cl)cn2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 23.9 %

Procedure:
28 mg (3,5-diphenyl-pyrazol-1-yl)-acetic acid was dissolved in 2 mL DMF and 26 mg DIPEA and 32 mg TBTU were added to this solution and the reaction was stirred for 5 minutes at RT. The mixture was added to 20 mg 5-chloro-2-piperidin-4-ylpyrimidine and stirred for 2 h. The reaction was cleaned by RP-chromatographie (methanol/water, 0.1% NH3) to yield 11 mg of the desired compound. Rt: 2.38 (method A), (M+H)+: 458
Reaction SMILES: COC(=O)[C@H](CC1C=CC=CC=1)NC(=O)[C@H](CC(=O)O)N.[CH3:22][C:23]1([O:27][C:28](N[C@@H]2C(=O)OC(=O)C2)=[O:29])[CH2:26][CH2:25][CH2:24]1.Cl.COC(=O)[C@H](CC1C=CC=CC=1)N.N[C@H](C(O)=O)CC(O)=O.[CH3:61][O:62][C:63](=[O:71])[C@H:64]([CH2:66][C:67]([O:69][CH3:70])=[O:68])[NH2:65].ClC([O-])=O.ClC(OC1(C)CCC1)=O>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH3:61][O:62][C:63](=[O:71])[C@H:64]([CH2:66][C:67]([O:69][CH3:70])=[O:68])[NH:65][C:28]([O:27][C:23]1([CH3:22])[CH2:26][CH2:25][CH2:24]1)=[O:29]
Reactant: CC1(OC(=O)N[C@H]2CC(=O)OC2=O)CCC1
Reactant: COC(=O)C[C@H](N)C(=O)OC
Agent: CC1(OC(=O)Cl)CCC1
Agent: COC(=O)[C@@H](N)Cc1ccccc1
Agent: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)C[C@H](NC(=O)OC1(C)CCC1)C(=O)OC

Procedure:
An example of the use of the novel N-protected-α-amino acid compounds of this invention in peptide synthesis is the preparation of α-aspartyl-phenylalanine methyl ester, a known sweetening agent. The dipeptide is conveniently prepared by coupling N-(1-methylcyclobutyloxycarbonyl) aspartic anhydride with phenylalanine methyl ester hydrochloride. Introduction of the N-(1-methylcyclobutyloxycarbonyl blocking group into aspartic acid is accomplished by reacting 1-methylcyclobutylchloroformate with aspartic acid dimethyl ester in accordance with the process of this invention. Equimolar quantities of the chloroformate and aspartic acid dimethyl ester are reacted in chloroform at 0°C. at pH 8. Reaction is carried out by portion-wise addition of 1-methylcyclobutyl chloroformate to the aspartic acid suspended in chloroform. Triethylamine is added to the reaction during the addition to maintain pH 8. After allowing the reaction to run to completion at room temperature, the reaction mixture is treated according to the procedure outlined above to afford the N-(1-methylcyclobutyloxycarbonyl) aspartic acid dimethyl ester. The free acid is obtained by saponifying the ester in a basic aqueous methanol solution. After acidifying the reaction mixture with sulfuric acid, the N-(1-methylcyclobutyloxycarbonyl) aspartic acid is isolated by extraction.
Reaction SMILES: O=[C:2]1[CH2:16][O:15][CH2:14][C:13](=O)[NH:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][NH:3]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1>[O:6]1[CH2:7][CH2:8][O:9][CH2:10][CH2:11][NH:12][CH2:13][CH2:14][O:15][CH2:16][CH2:2][NH:3][CH2:4][CH2:5]1
Reactant: O=C1COCC(=O)NCCOCCOCCN1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C1COCCNCCOCCOCCN1
Temperature: 25 °C
Yield: 89 %

Procedure:
A solution of 15.7 g. of the diamide obtained in Example 40 in 300 ml. hot anhydrous tetrahydrofuran is slowly added to a mixture of 50 ml. anhydrous tetrahydrofuran and 15 g. LiAlH4 while stirring over a period of 1.5 hours. After the addition is completed, the mixture is stirred under reflux and under a nitrogen atmosphere for twenty hours. After cooling to room temperature the excess reagent is destroyed by adding a mixture (45 ml.) of water and THF (1:2), followed by 15 ml. NaOH 15% and 45 ml. of water. The mixture is filtered and the filtrate is evaporated to dryness. The residue is dissolved in benzene and the solution is passed through a column of Al2O3 with benzene as eluant. The solution is evaporated to dryness and a semicrystalline product is obtained (mixture of crystals and an oil) which proves to be the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-:17])=[O:16])=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[CH:7]=1.Cl[CH2:19][S:20]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)(=[O:22])=[O:21].CC([O-])(C)C.[K+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[C:5]([N+:15]([O-:17])=[O:16])=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[CH:7]=1
Reactant: CN1CCN(c2cc(Cl)ccc2[N+](=O)[O-])CC1
Reactant: O=S(=O)(CCl)c1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN1CCN(c2cc(Cl)cc(CS(=O)(=O)c3ccc(F)cc3)c2[N+](=O)[O-])CC1
Temperature: 25 °C

Procedure:
A stirred mixture of 1-(5-chloro-2-nitrophenyl)-4-methylpiperazine (1.0 mmol) and chloromethyl-(4-fluorophenyl)sulfone (1.0 mmol) in THF is treated with 2.2 mL of a 1M KOt-Bu (2.2 mmol) solution in THF at −78° C., warmed to room temperature over a 2 h period, quenched with acetic acid and concentrated in vacuo. The resultant residue is partitioned between EtOAc and aqueous Na2CO3. The phases are separated and the aqueous phase is extracted with EtOAc. The organic phase is combined with the extracts, dried over Na2SO4 and concentrated to dryness in vacuo to afford the title product.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[C:3]=1[CH:21]([CH2:26]OC)[C:22]([O:24]C)=[O:23].[OH-].[Na+].Cl>CO>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[C:3]=1[C:21](=[CH2:26])[C:22]([OH:24])=[O:23]
Reactant: COCC(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCC3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C=C(C(=O)O)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCC3
Temperature: 60 °C
Yield: 56.9 %

Procedure:
To a solution of methyl 2-[2-methyl-4-(4-methylphenyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]-3-methoxypropanoate (0.307 g; 0.88 mmol) in methanol (8.8 mL) was added a solution of sodium hydroxide 10 N (0.88 ml) and the mixture was heated to 60° C. for 18 h. After cooling, the reaction mixture was acidified with 1N HCl (pH˜2) and partially concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was crystallized from a mixture of ethyl acetate/heptane to afford 0.175 g (68%) of the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH:5]=[O:6].[C:11](#[N:13])[CH3:12]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]([OH:6])[CH2:12][C:11]#[N:13])[CH:7]=[C:8]([F:10])[CH:9]=1
Reactant: CC#N
Reactant: O=Cc1cc(F)cc(Br)c1
Product: N#CCC(O)c1cc(F)cc(Br)c1

Procedure:
Alkylation of 3-bromo-5-fluorobenzaldehyde with acetonitrile following the method used in Example 50 except KOBu-t was used instead of LDA gave 3-(3-bromo-5-fluorophenyl)-3-hydroxypropanenitrile as a light color oil. Yield (2.5 g, 86%): 1H NMR (400 MHz, CDCl3) δ 7.34 (bs, 1H), 7.21-7.24 (m, 1H), 7.08-7.11 (m, 1H), 5.02 (t, J=6.4 Hz, 1H), 2.75 (d, J=6.4 Hz, 2H).
Reaction SMILES: [OH-].[Na+].Cl.[CH2:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH:6]([C:14]([OH:16])=[O:15])[NH:5]1.[C:17](Cl)(=[O:19])[CH3:18]>CC(C)=O>[C:17]([N:5]1[CH:6]([C:14]([OH:16])=[O:15])[CH2:7][C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:4]1)(=[O:19])[CH3:18]
Reactant: CC(=O)Cl
Reactant: O=C(O)C1Cc2ccccc2CN1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CC(=O)N1Cc2ccccc2CC1C(=O)O
Reaction time: 0.17 h

Procedure:
To a mixture of acetone (75 mL) and 2N NaOH (100 mL) was added portionwise 1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid hydrochloride (10.00 g, 46.8 mmol). After stirring for 10 min, acetyl chloride (7.38 g, 94 mmol) in acetone (50 mL) was added slowly into the above solution, followed with 2N NaOH at room temperature. The reaction mixture was maintained at a pH>10 and stirred for 1 hour. The acetone was evaporated in vacuo and acidified the residue by adding 3N HCl. The separated solid was collected by filtration, washed several times with water, and dried to afford the known 2-acetyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid as an enantiomeric mixture, 7.90 g, (76.9%); mp 178-180° C. (170-171° C.):21 1H NMR (DMSO-d6) δ 2.15 (3H, s, Me), 3.02-3.24 (2H, m), 4.29-4.75 (2H, m), 4.98-5.17 (1H, m), 7.17-7.21 (4H, m, 4×ArH), 12.70 (1H, brs, exchangeable, OH); m/z219.0 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:9])[CH:3]([CH3:8])[CH2:4][C:5]([OH:7])=[O:6].O[N:11]1[C:15](=[O:16])[CH2:14][CH2:13][C:12]1=[O:17].C1(N=C=NC2CCCCC2)CCCCC1.O.[C:34]1([CH3:44])[CH:39]=[CH:38][C:37]([S:40]([OH:43])(=[O:42])=[O:41])=[CH:36][CH:35]=1>C(Cl)Cl.C(#N)C>[S:40]([C:37]1[CH:38]=[CH:39][C:34]([CH3:44])=[CH:35][CH:36]=1)([OH:43])(=[O:42])=[O:41].[O:17]=[C:12]1[CH2:13][CH2:14][C:15](=[O:16])[N:11]1[O:6][C:5](=[O:7])[CH2:4][CH:3]([N:2]([CH3:9])[CH3:1])[CH3:8]
Reactant: CC(CC(=O)O)N(C)C
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: CC(CC(=O)ON1C(=O)CCC1=O)N(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
6.55 g (50 mMol) 3-dimethylamino-butyric acid 20 was added to 5.75 g (50 mMol) N-hydroxysuccinimide and 11.05 g (55 mMol) dicyclohexyl carbodiimide in 100 ml CH2Cl2. The reaction mixture was stirred for 16 h at RT. The obtained urea was filtrated and the solution was evaporated. The residue, dissolved in 10 ml acetonitrile, was added under stirring to a solution of 9.51 g (50 mMol) 4-toluenesulfonic acid monohydrate in acetonitrile (30 ml). The solvent was evaporated under vacuum and the product was recrystallized from acetonitrile or acetone.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([CH3:11])=[CH:4][N+:3]=1[O-:12].[CH3:13][O:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=1[CH2:23][NH2:24].CCN(C(C)C)C(C)C>C(O)CCC>[CH3:13][O:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=1[CH2:23][NH:24][C:2]1[N+:3]([O-:12])=[CH:4][C:5]([CH3:11])=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: Cc1c[n+]([O-])c(Cl)cc1[N+](=O)[O-]
Reactant: COc1ccc(CN)c(OC)c1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNc2cc([N+](=O)[O-])c(C)c[n+]2[O-])c(OC)c1
Temperature: 25 °C
Yield: 64.8 %

Procedure:
A mixture of 2-chloro-5-methyl-4-nitropyridine 1-oxide (1.1 g, 5.8 mmol), 1-(2,4-dimethoxyphenyl)methanamine (1.1 mL, 7.0 mmol), DIEA (2.0 mL, 11.6 mmol), and 1-butanol (9 mL) was subjected to microwave irradiation at 120° C. for 8 h. The reaction mixture was allowed to cool to rt and was filtered. The resulting solid was washed with water (20 mL) and dried to give N-(2,4-dimethoxybenzyl)-5-methyl-4-nitropyridin-2-amine 1-oxide (1.2 g, 67%), which was used in the next step without further purification.
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[NH2:7][CH:8]1[C:13](=[O:14])[N:12]2[CH:15]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[C:16](=[O:22])[N:17]([CH:19]([CH3:21])[CH3:20])[CH2:18][CH:11]2[N:10]([S:31]([C:34]2[CH:39]=[C:38]([Cl:40])[CH:37]=[CH:36][C:35]=2[O:41][CH3:42])(=[O:33])=[O:32])[CH2:9]1.C(N(C(C)C)CC)(C)C>ClCCl>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][CH:15]2[N:12]3[C:13](=[O:14])[CH:8]([NH:7][C:4]([CH:1]4[CH2:3][CH2:2]4)=[O:5])[CH2:9][N:10]([S:31]([C:34]4[CH:39]=[C:38]([Cl:40])[CH:37]=[CH:36][C:35]=4[O:41][CH3:42])(=[O:33])=[O:32])[CH:11]3[CH2:18][N:17]([CH:19]([CH3:21])[CH3:20])[C:16]2=[O:22])=[CH:25][CH:26]=1
Reactant: COc1ccc(Cl)cc1S(=O)(=O)N1CC(N)C(=O)N2C(Cc3ccc(Cl)cc3)C(=O)N(C(C)C)CC21
Reactant: O=C(Cl)C1CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Cl)cc1S(=O)(=O)N1CC(NC(=O)C2CC2)C(=O)N2C(Cc3ccc(Cl)cc3)C(=O)N(C(C)C)CC21
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.4 %

Procedure:
11 mg (0.105 mmol) of cyclopropanecarbonyl chloride are added to a solution of 3-amino-6-(4-chlorobenzyl)-1-(5-chloro-2-methoxybenzenesulfonyl)-8-isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione (56 mg, 0.10 mmol) in 1 ml of dichloromethane and 26 mg (0.20 mmol) of diisopropylethylamine. After stirring at room temperature for two hours, the reaction mixture is purified by chromatography on 1 g of silica gel (eluent EtOAc/DCM; gradient 0-20%). 42 mg of the desired product are obtained.
Reaction SMILES: COC(=O)C([N:6]1[C@H:9]([S:10][C:11](=[O:13])[CH3:12])[CH2:8][C:7]1=[O:14])=O.C(OC)(=O)C.O>CO>[C:11]([S:10][C@H:9]1[NH:6][C:7](=[O:14])[CH2:8]1)(=[O:13])[CH3:12]
Reactant: COC(=O)C(=O)N1C(=O)C[C@H]1SC(C)=O
Solvent: CO
Solvent: COC(C)=O
Solvent: O
Product: CC(=O)S[C@@H]1CC(=O)N1
Reaction time: 20 h

Procedure:
A solution of 140 mg of 2-[(4R)-4acetylthio-2-oxoazetidin-1-yl]-2-oxoacetic acid methyl ester (crude product) in a mixture of 20 ml of methanol, 2 ml of methyl acetate and 0.4 ml of water is allowed to stand for 20 hours at room temperature, concentrated in vacuo and evaporated again with benzene. The residue is chromatographed over silica gel thick layer plates with toluene/ethyl acetate (2:1) and yields the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([NH2:28])[C:24]([F:27])([F:26])[F:25])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:35](Cl)(=[O:37])[CH3:36].C(=O)([O-])O.[Na+]>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([NH:28][C:35](=[O:37])[CH3:36])[C:24]([F:25])([F:26])[F:27])=[CH:4][CH:3]=1
Reactant: NC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)C(F)(F)F
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)NC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 44.4 %

Procedure:
A solution of 6-(1-Azido-2,2,2-trifluoroethyl)-9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole (68.2 mg, 0.143 mmol) and triphenylphosphine (56.3 mg, 0.215 mmol) in tetrahydrofuran (5.0 mL) and water (0.10 mL) was stirred at 60° C. for 20 hr. The reaction mixture was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel eluting with a 30-100% ethyl acetate/n-hexane gradient mixture to give 1-[9-Chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]-2,2,2-trifluoroethanamine as a white solid (67.2 mg). To a solution of 1-[9-Chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]-2,2,2-trifluoroethanamine (67.9 mg) and pyridine (0.12 mL, 1.48 mmol) in tetrahydrofuran (5.0 mL) was added acetyl chloride (0.051 mL, 0.717 mmol) at 0° C. The mixture was stirred at 0° C. for 1 hr. Aqueous sodium hydrogen carbonate was added to the reaction mixture at room temperature and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 25-80% ethyl acetate/n-hexane gradient mixture to give the title compound (33.1 mg, 0.067 mmol, 47%) as white crystals.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[C:10]2[C:15]([CH3:16])=[CH:14][S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=3)[C:10]3[C:15]([CH3:16])=[CH:14][S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: Cc1csc2nc(Cl)nc(NCc3ccc(Cl)c(Cl)c3)c12
Product: Cc1csc2nc(-n3cncn3)nc(NCc3ccc(Cl)c(Cl)c3)c12

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-5-methyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-5-methyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C([O:9][C:10](=O)[CH:11]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[C:12](OCC)=[O:13])C>C(OCC)C>[CH3:24][O:23][C:20]1[CH:19]=[CH:18][C:17]([CH:11]([CH2:12][OH:13])[CH2:10][OH:9])=[CH:22][CH:21]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc(OC)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: COc1ccc(C(CO)CO)cc1
Temperature: 40 °C
Reaction time: 40 h
Yield: 65.9 %

Procedure:
LiAlH4 (5.75 g, 0.15 mol) was suspended in ethyl ether (150 mL), and into this suspension solution compound 19 (16.85 g, 0.10 mol) dissolved in 50 ml ethyl ether was added dropwise. The resulting solution was stirred at 40° C. for 40 hr, and cooled in ice bath, and ethyl ether (15 ml) was introduced dropwise to destroy the excess LiAlH4 remaining in the solution. After the addition was completed, the resulting solution was added with 200 ml HCl aqueous solution (HCl/H2O, 1:2) and stirred for one hr. The organic phase was removed. The aqueous phase was extracted with ethyl ether (2×200 ml). The ether layer was combined with the collected organic phase, and then was washed with NaHCO3 aqueous solution (2%, 20 ml), water (20 ml), saturated sodium chloride solution (20 ml), dried, and filtered. The residual was recrystallized from benzene to yield 12 g (66%) product 20. 1 H-NMR (CDCl3, TMS, δ in ppm): 2.17 (s, 2H, --OH), 3.08 (m, 1H PhCH), 6.82 and 7.13 (q, 4 aromatic protons).
Reaction SMILES: [CH:1]1([C:4]2[O:8][C:7]([CH2:9][O:10][C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[C:13]([N+:20]([O-])=O)[CH:12]=3)=[N:6][N:5]=2)[CH2:3][CH2:2]1.[O:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:34]=[CH:33][C:32]([NH:35][C:36]([C:38]3[CH:45]=[CH:44][C:41]([CH:42]=O)=[CH:40][CH:39]=3)=[O:37])=[CH:31][CH:30]=2)[CH2:25][CH2:24]1>>[CH:1]1([C:4]2[O:8][C:7]([CH2:9][O:10][C:11]3[CH:16]=[CH:15][C:14]4[N:17]=[C:42]([C:41]5[CH:40]=[CH:39][C:38]([C:36]([NH:35][C:32]6[CH:31]=[CH:30][C:29]([N:26]7[CH2:25][CH2:24][O:23][CH2:28][CH2:27]7)=[CH:34][CH:33]=6)=[O:37])=[CH:45][CH:44]=5)[NH:20][C:13]=4[CH:12]=3)=[N:6][N:5]=2)[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(OCc2nnc(C3CC3)o2)cc1[N+](=O)[O-]
Reactant: O=Cc1ccc(C(=O)Nc2ccc(N3CCOCC3)cc2)cc1
Product: O=C(Nc1ccc(N2CCOCC2)cc1)c1ccc(-c2nc3ccc(OCc4nnc(C5CC5)o4)cc3[nH]2)cc1

Procedure:
Compound 630 was prepared according to the procedure similar to that described in Scheme III from 1-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)methoxy-3,4-dinitrobenzene and 4-(4-(4-morpholinophenyl)aminocarbonylbenzaldehyde. [M+H]+ calcd for C30H28N6O4: 537.22; found: 537.06.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH:12]=[N:11][C:10]([C:13]([F:16])([F:15])[F:14])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.O1CCCC1.C([N-]C(C)C)(C)C.[Li+].[C:30](=[O:32])=[O:31]>CCCCCCC.O1CCCC1.C(C1C=CC=CC=1)C>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:30]([OH:32])=[O:31])=[N:11][C:10]([C:13]([F:16])([F:14])[F:15])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1ncn(-c2ncccc2Cl)n1
Reactant: O=C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCc1ccccc1
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: O=C(O)c1nc(C(F)(F)F)nn1-c1ncccc1Cl
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a mixture of 0.25 g of 3-chloro-2-(3-trifluoromethyl-1H-1,2,4-triazol-1-yl)pyridine and 5 ml of tetrahydrofuran was added dropwise 0.50 ml of a 2.0M lithium diisopropylamide solution in heptane/tetrahydrofuran/ethylbenzene at −78° C. and the mixture was stirred at −78° C. for 15 minutes. Carbon dioxide was introduced into the mixture at such a rate that an inner temperature was maintained at −60° C. or lower and, after the mixture turned yellow, the mixture was further stirred at −78° C. for 10 minutes. The temperature of the reaction mixture was raised to room temperature, followed by concentration. A 2N aqueous sodium hydroxide solution was added to adjust the pH of the aqueous layer to 10 to 12, the layers were separated, and the organic layer was extracted with a 0.5N aqueous sodium hydroxide solution. The aqueous layers were combined, and washed with chloroform, and 2N hydrochloric acid was added so that the pH of the aqueous layer became about 3, followed by extraction with ethyl acetate three times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure to obtain 0.13 g of crude 1-(3-chloro-2-pyridinyl)-3-trifluoromethyl-1H-1,2,4-triazole 5-carboxylic acid of the formula:
Reaction SMILES: N([O-])=[O:2].[Na+].N[C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C:9](=[O:18])[NH:8][C:7]=1[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1.[N-]=[N+]=[N-].[Na+]>O.C(O)(=O)C.S(=O)(=O)(O)O>[OH:2][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C:9](=[O:18])[NH:8][C:7]=1[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1
Reactant: O=N[O-]
Reactant: COc1ccc(-c2[nH]c(=O)c3cc(OC)ccc3c2N)cc1
Agent: O=S(=O)(O)O
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(-c2[nH]c(=O)c3cc(OC)ccc3c2O)cc1
Reaction time: 0.5 h

Procedure:
At 0° C., a solution of sodium nitrite (24.8 mg, 0.36 mmol) in water (0.5 mL) is added slowly to a solution of 4-amino-7-methoxy-3-(4-methoxyphenyl)isoquinolin-1(2H)-one (100 mg, 0.33 mmol) dissolved in acetic acid (1 mL) and sulphuric acid (0.5 mL). The mixture is left under stirring under cold conditions for 30 minutes then sodium azide (25.7 mg, 0.39 mmol) dissolved in a minimum amount of water (0.2 mL) is introduced slowly. Stirring, still under cold conditions, is maintained for another 3 hours, then water (10 mL) is poured onto the reaction mixture and the solid residue formed is collected by filtration. Silica gel column chromatography using a gradient of ethanol (0 to 2%) in CH2Cl2 as eluent makes it possible to isolate the compound possessing the greatest mobility which corresponds to the expected compound 41 (31 mg, 31%) in the form of a white solid, 1H NMR (CDCl3) 7.91 (1H, d), 7.74 (1H, d), 7.41 (2H, d), 7.16 (1H, dd), 6.85 (2H, d), 6.75 (1H, br s), 4.60 (1H, br s), 3.98 (3H, s), 3.78 (3H, s); MS 295 (M−2H).