Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:32])[O:3][C:4]1[C:9]2[O:10][C:11]3[C:12](=[O:19])[N:13]([CH2:17][CH3:18])[N:14]=[CH:15][C:16]=3[C:8]=2[C:7]([C:20]([O:22]C2C=CC([N+]([O-])=O)=CC=2)=O)=[CH:6][CH:5]=1.[NH2:33][C:34]1[C:39]([Cl:40])=[CH:38][N:37]=[CH:36][C:35]=1[Cl:41].[H-].[Na+].Cl>CN(C)C=O.O>[Cl:41][C:35]1[CH:36]=[N:37][CH:38]=[C:39]([Cl:40])[C:34]=1[NH:33][C:20]([C:7]1[C:8]2[C:16]3[CH:15]=[N:14][N:13]([CH2:17][CH3:18])[C:12](=[O:19])[C:11]=3[O:10][C:9]=2[C:4]([O:3][CH:2]([F:32])[F:1])=[CH:5][CH:6]=1)=[O:22]
Reactant: CCn1ncc2c(oc3c(OC(F)F)ccc(C(=O)Oc4ccc([N+](=O)[O-])cc4)c32)c1=O
Reactant: Nc1c(Cl)cncc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1ncc2c(oc3c(OC(F)F)ccc(C(=O)Nc4c(Cl)cncc4Cl)c32)c1=O
Temperature: 5 °C
Yield: 210.7 %

Procedure:
A suspension of 4-nitrophenyl 6-difluoromethoxy-3-ethyl-4-oxo-3,4-dihydrobenzo[4,5]furo[2,3-d]pyridazine-9-carboxylate (from step III) (81 mg, 0.18 mmol) and 4-amino-3,5-dichloro pyridine (32 mg, 0.19 mmol) in dimethyl formamide (3 ml) was cooled to −30-40° C. under nitrogen. Then sodium hydride (15 mg, 0.36 mmol) was added lotwise at the same temp. under nitrogen. Progress of reaction was monitored by TLC. At the end, reaction mixture was cooled to 0-10° C. Water (100 ml) was added dropwise to the reaction mixture at 0-10° C. and acidified with dilute HCl. the precipitate obtained was filtered and dried in oven. The solid was purified by column chromatography using 20% acetone in chloroform. 178 mg pure product was obtained as off white solid.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:16])[C@@H:11]1[CH2:15][CH2:14][CH2:13][NH:12]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([N:19](CC)CC)C.[C:24](Cl)(=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=1>C(Cl)Cl>[CH2:2]([O:9][C:10]([C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[NH:19][C:24](=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=1)=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: CCN(CC)CC
Agent: Cl
Solvent: ClCCl
Product: COc1cccc(C(=O)NN2CCC[C@H]2C(=O)OCc2ccccc2)c1
Yield: 93.1 %

Procedure:
L-Proline benzyl ester hydrochloride (500 mg, 2.073 mmol) was dissolved in CH2Cl2 (10 ml). Triethylamine (600 mg, 6.0 mmol) and 3-anisoyl chloride (422 mg, 2.48 mmol) were added. After 18 h at room temperature the solvent was removed in vacuo and the residue was taken up in ethyl acetate (100 ml). This solution was washed with 0.3M KHSO4, sat. NaHCO3, water and brine, dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (eluant: 3% methanol, 97% chloroform) to give a colourless oil identified as the title compound (654 mg, 1.93 mmol, 93%).
Reaction SMILES: [F:1][C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[O:14])[N:8]=1)=[O:5].[CH:27](=O)[CH2:28][CH3:29].[Na].C(O)(=O)C>CO.ClCCl>[F:26][C:21]1[CH:22]=[C:23]([F:25])[CH:24]=[C:2]([F:1])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([CH:15]2[CH2:16][CH2:17][N:18]([CH2:27][CH2:28][CH3:29])[CH2:19][CH2:20]2)=[O:14])[N:8]=1)=[O:5]
Reactant: O=C(Nc1cccc(C(=O)C2CCNCC2)n1)c1c(F)cc(F)cc1F
Reactant: CCC=O
Agent: [Na]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: CCCN1CCC(C(=O)c2cccc(NC(=O)c3c(F)cc(F)cc3F)n2)CC1
Reaction time: 1.5 h

Procedure:
Mix 2,4,6-trifluoro-N-[6-(piperidin-4-ylcarbonyl)-pyridin-2-yl]-benzamide (50 mg), propionaldehyde (80 mg), sodium triacetoxyborobydride (38 mg) and acetic acid (21 mg) with dichloromethane (5 mL) and stir for 1.5 hrs. Dilute with methanol and load on a SCX column (10 g), wash with methanol, elute the product with 2M NH3-methanol. Purify the product on a silica gel column (10 g, dichloromethane/2M NH3 in methanol, gradient) to obtain the title compound as a free base (26 mg). Mass spectrum (electrospray) m/z=406 (M+1); 1H NMR (CDCl3): 8.52 (d, 1H), 8.38 (br, 1H), 7.92 (t, 1H), 7.82 (dd, 1H), 6.82 (m, 2H), 3.61 (br, 1H), 3.00 (m, 2H), 2.34 (m, 2H), 2.11 (m, 2H), 1.87 (m, 3H), 1.60 (m, 5H), 0.90 (t, J=7.3 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]([CH3:14])[C:7](=[O:13])[CH2:8][CH2:9][C:10]([CH3:12])([CH3:11])[C:4]=2[CH:3]=1.Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[CH:26]=[C:27]([CH:32]=[CH:33][CH:34]=2)[C:28]([NH:30][CH3:31])=[O:29])[C:21]([Cl:35])=[CH:20][N:19]=1>>[Cl:35][C:21]1[C:22]([NH:24][C:25]2[CH:26]=[C:27]([CH:32]=[CH:33][CH:34]=2)[C:28]([NH:30][CH3:31])=[O:29])=[N:23][C:18]([NH:1][C:2]2[CH:16]=[CH:15][C:5]3[N:6]([CH3:14])[C:7](=[O:13])[CH2:8][CH2:9][C:10]([CH3:12])([CH3:11])[C:4]=3[CH:3]=2)=[N:19][CH:20]=1
Reactant: CNC(=O)c1cccc(Nc2nc(Cl)ncc2Cl)c1
Reactant: CN1C(=O)CCC(C)(C)c2cc(N)ccc21
Product: CNC(=O)c1cccc(Nc2nc(Nc3ccc4c(c3)C(C)(C)CCC(=O)N4C)ncc2Cl)c1
Yield: 43 %

Procedure:
In an analogous procedure to Example 651, part c, 7-Amino-1,5,5-trimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and 3-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide were combined to yield 3-[5-Chloro-2-(1,5,5-trimethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide (55.06 mg, 43% yield) as a white solid. 1H-NMR (DMSO-d6) δ 9.39 (s, 1H), 9.02 (s, 1H), 8.37 (m, 1H), 8.17 (s, 1H), 8.01 (s, 1H), 7.77 (d, J=7.7 Hz, 1H), 7.71 (d, J=8.8 Hz, 1H), 7.42 (m, 2H), 7.00 (d, J=8.8 Hz, 1H), 3.12 (s, 3H), 2.75 (d, J=4.2 Hz, 3H), 2.09 (br s, 2H), 2.09 (br s, 2H), 1.87 (br s, 2H), 1.13 (m, 6H). LC/MS (ESI+)=479 (M+H). 263-263.5° C.
Reaction SMILES: [C:1]([N:5]1[C:29](=[O:30])[C:28]2[N:13]3[CH2:14][CH2:15][C:16]4[CH:17]=[C:18]([O:26][CH3:27])[C:19]([O:22][CH:23]([CH3:25])[CH3:24])=[CH:20][C:21]=4[C:12]3=[CH:11][C:10]=2[CH2:9][O:8][CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[Br:31]N1C(=O)CCC1=O.O>CN(C=O)C.[O-]S([O-])(=S)=O.[Na+].[Na+]>[C:1]([N:5]1[C:29](=[O:30])[C:28]2[N:13]3[CH2:14][CH2:15][C:16]4[CH:17]=[C:18]([O:26][CH3:27])[C:19]([O:22][CH:23]([CH3:24])[CH3:25])=[CH:20][C:21]=4[C:12]3=[C:11]([Br:31])[C:10]=2[CH2:9][O:8][CH2:7][CH2:6]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: COc1cc2c(cc1OC(C)C)-c1cc3c(n1CC2)C(=O)N(C(C)(C)C)CCOC3
Reactant: O=C1CCC(=O)N1Br
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OC(C)C)-c1c(Br)c3c(n1CC2)C(=O)N(C(C)(C)C)CCOC3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.6 %

Procedure:
To a solution of 180 mg of 18c in 2 ml of DMF was added 85 mg of N-bromosuccinimide. The mixture was stirred for ½ hr at RT. 3 ml of water was added and two drops of sat. aq. Na2S2O3 and the mixture was stirred for ½ hr. The precipitate was filtered and washed with water, dried and then triturated with diisopropyl ether, to provide 175 mg of 18d as white crystalline material. Mp 160-162° C.
Reaction SMILES: [N+:1]([C:4]1[CH:30]=[CH:29][C:7]([CH2:8][O:9][C:10]([C:12]2[N:17]3[C:18](=[O:27])[CH:19]([NH:20][C:21](=[S:26])[CH2:22][CH2:23][C:24]#[N:25])[C@H:16]3[S:15][CH2:14][C:13]=2[OH:28])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].CC(N(C)C)=O.C1OC1C.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([C:12]2[N:17]3[C:18](=[O:27])[CH:19]([NH:20][C:21](=[S:26])[CH2:22][CH2:23][C:24]#[N:25])[C@H:16]3[S:15][CH2:14][C:13]=2[O:28][S:42]([CH3:41])(=[O:44])=[O:43])=[O:11])=[CH:29][CH:30]=1)([O-:3])=[O:2]
Reactant: CS(=O)(=O)Cl
Reactant: N#CCCC(=S)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12
Agent: CC1CO1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CS(=O)(=O)OC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C(NC(=S)CCC#N)[C@H]2SC1
Reaction time: 4 h

Procedure:
To a solution of 2.5 g. of 7-cyanomethylthioacetamido-3-cephem-3ol-4-carboxylic acid p-nitrobenzyl ester in 25 ml. of dry dimethylacetamide is added 1 ml. of propylene oxide and one equivalent of methanesulfonyl chloride. After stirring for 4 hours, the mixture is taken up in ethyl acetate and washed with saturated sodium chloride solution. Solvent is removed from the ethyl acetate solution under reduced pressure and the residue is purified by thin layer chromatography yielding the product 7-cyanomethylthioacetamido-3-methylsulfonyloxy-3-cephem-4-carboxylic acid p-nitrobenzyl ester as an amorphous solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][C:3]=1[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Mg].C(O[CH2:21][C:22]([F:36])=[CH:23][C:24]1([C:27]2[CH:32]=[CH:31][C:30]3[O:33][CH2:34][O:35][C:29]=3[CH:28]=2)[CH2:26][CH2:25]1)(=O)C>O1CCCC1>[F:36][C:22]([CH2:21][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:4]=1)=[CH:23][C:24]1([C:27]2[CH:32]=[CH:31][C:30]3[O:33][CH2:34][O:35][C:29]=3[CH:28]=2)[CH2:26][CH2:25]1
Reactant: CC(=O)OCC(F)=CC1(c2ccc3c(c2)OCO3)CC1
Reactant: Fc1ccc(Br)cc1Oc1ccccc1
Agent: [Mg]
Solvent: C1CCOC1
Product: FC(=CC1(c2ccc3c(c2)OCO3)CC1)Cc1ccc(F)c(Oc2ccccc2)c1
Yield: 25.8 %

Procedure:
The method of Example 25 was repeated using a Grignard reagent, prepared from 4-fluoro-3-phenoxyphenyl bromide (0.313 g), tetrahydrofuran. (2 ml) and magnesium (24 mg) and 1-(3-acetoxy-2-fluoroprop-1-enyl)-1-(3,4-methylenedioxyphenyl) cyclopropane (Example 22) (0.138 g). The residue after evaporation was purified by preparative thin layer chromatography (solvent: diethyl ether/hexane; 1:9) to afford 1-(2-fluoro-3-(4-fluoro-3-phenoxyphenyl)prop-1-enyl)-1-(3,4-methylenedioxyphenyl)cyclopropane (52 mg, 26%).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C([Mg]Cl)(C)C.[C:12]([C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1)(=[O:14])[CH3:13]>C1COCC1>[OH:14][C:12]([C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1)([C:4]1[S:3][CH:2]=[N:6][CH:5]=1)[CH3:13]
Reactant: Brc1nccs1
Reactant: COC(=O)c1ccc(C(C)=O)cc1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(C)(O)c2cncs2)cc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 62.1 %

Procedure:
A flask was charged with 2-bromothiazole (1.386 ml, 15.55 mmol) and THF (30.6 ml) and then sealed and purged with Argon. The solution was cooled to −20° C. and isopropylmagnesium chloride (2 M, 8.16 ml, 16.32 mmol) was added drop wise. The reaction was stirred for 1 hour and then warmed to 0° C. After stirring for 60 minutes, the solution was cooled to −78° C. and methyl 4-acetylbenzoate (3.05 g, 17.10 mmol) in THF (5.11 ml) was added drop wise. The reaction stirred for an additional 30 minutes at −78° C. then warmed to room temperature. After stirring for 1 hour, the reaction was quenched with aqueous saturated NH4Cl and extracted with ethyl acetate (2×). The combined organics were dried over Na2SO4, filtered and concentrated. The crude mixture was purified by flash chromatography on silica (10-75% ethyl acetate/hexanes). The mixed fractions were combined, concentrated and re-purified by column chromatography on silica (10-75% ethyl acetate/hexanes). The desired fractions were combined and concentrated to afford methyl 4-[1-hydroxy-1-(1,3-thiazol-5-yl)ethyl]benzoate (2.54 g, 9.65 mmol, 62.0% yield). MS ESI: [M+H]+ m/z 264.0.
Reaction SMILES: [N:1]1([CH2:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=2)[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9][NH:8][CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:25][OH:26].[F:27][C:28]([F:35])([F:34])[CH2:29][O:30]C(=O)C>C(N(CC)CC)C>[F:35][C:28]([F:27])([F:34])[C:29]([N:4]1[CH2:5][CH2:6][CH2:7][N:8]([C:25](=[O:26])[C:28]([F:35])([F:34])[F:27])[CH2:9][CH2:10][N:11]([C:29](=[O:30])[C:28]([F:35])([F:34])[F:27])[CH2:12][CH2:13][CH2:14][N:1]([CH2:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=2)[CH2:2][CH2:3]1)=[O:30]
Reactant: CC(=O)OCC(F)(F)F
Reactant: O=C(O)c1ccc(CN2CCCNCCNCCCNCC2)cc1
Reactant: CO
Solvent: CCN(CC)CC
Product: O=C(O)c1ccc(CN2CCCN(C(=O)C(F)(F)F)CCN(C(=O)C(F)(F)F)CCCN(C(=O)C(F)(F)F)CC2)cc1
Reaction time: 60 h

Procedure:
To a two-neck round bottom flask purged with argon was added successively 4-(1,4,8,11-tetraazacyclotetradec-1-ylmethyl)-benzoic acid (90 mg, 0.24 mmol), dry methanol (1 ml), dry triethyl amine (0.5 ml) and trifluoroethylacetate (1.7 ml). All following procedures were carried on in argon atmosphere. The mixture was stirred for 60 hours. After that the solvents were removed at reduced pressure and the residue was taken up in dry tetrahydrofurane (5 ml). The THF solution was filtered and the solvent removed at reduced pressure. The residue was dried in vacuo for 4 hours to produce 0.54 g of oily compound. MS m/z 623.5 M[C24H27F9N4O5]+1.
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C@@H:7]1[CH2:12][CH2:11][NH:10][CH2:9][C@H:8]1[OH:13].C1(C)[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C@H:21]1[CH2:26][CH2:25][NH:24]C[C@@H]1O.[C:29]([OH:38])(=[O:37])[C@@H:30]([C@H:32]([C:34]([OH:36])=[O:35])[OH:33])[OH:31].[CH2:39]([OH:41])[CH3:40]>>[C:34]([C@@H:32]([C@H:30]([C:29]([OH:38])=[O:37])[OH:31])[OH:33])([OH:36])=[O:35].[OH:13][C@@H:8]1[C@@H:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[CH3:14])[CH2:12][CH2:11][N:10]([CH2:29][C@H:25]2[CH2:24][C@H:39]([OH:41])[C:40]3=[N:20][CH:19]=[CH:18][CH:17]=[C:16]3[CH2:21][CH2:26]2)[CH2:9]1
Reactant: Cc1ccccc1[C@@H]1CCNC[C@H]1O
Reactant: CCO
Reactant: Cc1ccccc1[C@H]1CCNC[C@@H]1O
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Product: Cc1ccccc1[C@H]1CCN(C[C@@H]2CCc3cccnc3[C@@H](O)C2)C[C@@H]1O

Procedure:
A free amine form of the entitled compound was obtained in the same manner as in Example 15, for which, however, (3R*,4R*)-4-o-tolyl-piperidin-3-ol obtained in Production Example 12 were used in place of (3S*,4S*)-4-o-tolyl-piperidin-3-ol used in Example 15. The obtained free amine compound and the same amount of L-tartaric acid were mixed in ethanol, and crystallized from heptane added thereto to obtain the entitled compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1F.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][N:23]([C:5]2[CH:6]=[CH:7][C:8]([F:10])=[CH:9][C:4]=2[C:3]([O:2][CH3:1])=[O:12])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COC(=O)c1cc(F)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1cc(F)ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 110 °C
Yield: 16.5 %

Procedure:
2,5-Difluorobenzoic acid methyl ester (25 g, 145 mmol), piperazine-1-carboxylic acid tert-butyl ester (27 g, 145 mmol) and K2CO3 (50 g, 363 mmol) are added to 1,4-dioxane and the mixture is heated to 110° C. for 2 days. The reaction mixture is cooled, inorganic salts filtered through sintered funnel and filtrate is concentrated under reduced pressure. Crude compound is purified by column chromatography (silica-gel, 100-200 mesh, eluent; 5% EtOAc in hexane) to afford desired 4-(4-fluoro-2-methoxycarbonyl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester as a syrupy liquid (8.1 g, 16.3%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]([NH:8][CH3:9])=[CH:6][CH:7]=1.[F:10][C:11]([F:33])([F:32])[C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=1)[C:16]([C:29](O)=[O:30])=[CH:15]2.Cl.[CH3:35]N(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>CN(C)C=O.O>[CH3:9][N:8]([CH3:35])[C:5]1[N:4]=[CH:3][C:2]([NH:1][C:29]([C:16]2[N:17]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)[C:18]3[C:14]([CH:15]=2)=[CH:13][C:12]([C:11]([F:33])([F:32])[F:10])=[CH:20][CH:19]=3)=[O:30])=[CH:7][CH:6]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1cc2cc(C(F)(F)F)ccc2n1Cc1cccc(F)c1
Reactant: CNc1ccc(N)cn1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)c1ccc(NC(=O)c2cc3cc(C(F)(F)F)ccc3n2Cc2cccc(F)c2)cn1
Reaction time: 8 h
Yield: 40 %

Procedure:
0.185 g (1.35 mmol) of 3-amino-6-(dimethylamino)pyridine (WO2005/028452) in 2 ml of dry dimethylformamide is added dropwise at 20° C. under argon to a solution of 0.35 g (1.04 mmol) of 5-trifluoromethyl-1-(3-fluorobenzyl)-1H-indole-2-carboxylic acid (WO2006/072736), 0.198 g (1.14 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride and 0.165 g (1.14 mmol) of 1-hydroxybenzotriazole monohydrate in 6 ml of dry dimethylformamide. The reaction mixture is stirred overnight, run onto 100 ml of water and then extracted three times with 50 ml of ethyl acetate. The organic phases are subsequently combined, washed three times with 20 ml of water, dried over sodium sulfate and then concentrated under reduced pressure. The expected product is purified by chromatography on a silica column, elution being carried out with a mixture of dichloromethane and methanol. 0.19 g of the expected compound is thus isolated.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[N:3]=1.[NH2:20][CH:21]1[CH2:24][CH:23]([NH:25]C(=O)OC(C)(C)C)[C:22]1([CH3:34])[CH3:33].CCN(C(C)C)C(C)C>O1CCOCC1>[NH2:20][C@H:21]1[CH2:24][C@H:23]([NH:25][C:2]2[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([NH:10][CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)[N:3]=2)[C:22]1([CH3:34])[CH3:33]
Reactant: N#Cc1cnc(NCCc2cccc(Cl)c2)nc1Cl
Reactant: CC(C)(C)OC(=O)NC1CC(N)C1(C)C
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)[C@@H](Nc2nc(NCCc3cccc(Cl)c3)ncc2C#N)C[C@@H]1N
Temperature: 125 °C
Reaction time: 5 h
Yield: 63.7 %

Procedure:
To a mixture of 4-chloro-2-((3-chlorophenethyl)amino)pyrimidine-5-carbonitrile (600 mg, 2.04 mmol) and tert-butyl (3-amino-2,2-dimethylcyclobutyl)carbamate (490 mg, 2.29 mmol) in dioxane (20 mL) was added DIEA (738 mg, 5.73 mmol). The resulting mixture was stirred at 125° C. under microwave irradiation for 5 h. After removal of the organic solvent under reduced pressure, the residue was diluted with ethyl acetate and the organic layer ws washed with aqueous solution of ammonia chloride. The organic layer was separated and dried over sodium sulfate and concentrated under vacuum to give the crude product, which was purified by silica gel chromatography (10% to 33% ethyl acetate in petroleum) to afford the title compound (610 mg, 1.30 mmol, 63% yield) as a pale yellow solid. The racemic product (500 mg, 1.06 mmol) was separated by chiral preparative supercritical fluid chromatography (chiral column: OJ, Column size: 0.46 cm I.D.×25 cm L, 5 um; Mobile phase: CO2:MeOH:DEA=60:40:0.1, Flow: 2.5 mL/min, 220 nm T=35° C.) to give four isomers: tert-butyl ((1S,3S)-3-((2-((3-chlorophenethyl)amino)-5-cyanopyrimidin-4-yl)amino)-2,2-dimethylcyclobutyl)carbamate (peak 1, 100 mg, 0.21 mmol, 20% yield, RT=7.88 min, d.e.=100%, e.e. =100%), tert-butyl ((1R,3R)-3-((2-((3-chlorophenethyl)amino)-5-cyanopyrimidin-4-yl)amino)-2,2-dimethylcyclobutyl)carbamate (peak 3, 102 mg, 0.22 mmol, 20% yield, RT=9.37 min, d.e.=100%, e.e. =100%), tert-butyl ((1R,3S)-3-((2-((3-chlorophenethyl)amino)-5-cyanopyrimidin-4-yl)amino)-2,2-dimethylcyclobutyl)carbamate (peak 2, 85 mg, 0.18 mmol, 17% yield, RT=8.29 min, d.e.=100%, e.e. =100%) and tert-butyl ((1S,3R)-3-((2-((3-chlorophenethyl)amino)-5-cyanopyrimidin-4-yl)amino)-2,2-dimethylcyclobutyl)carbamate (peak 4, 82 mg, 0.17 mmol, 17% yield, RT=10.96 min, d.e.=100%, e.e. =100%). MS (ESI) m/z 471.2 [M+H]+
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([NH:9][NH2:10])[CH:6]=[CH:7][CH:8]=1.C(Cl)(Cl)(Cl)Cl.C(N(CC)CC)C.C(O[C:26]1([CH:38]=[CH:37][CH:36]=[CH:35][CH2:34]1)[CH:27]=[N:28][C:29](=O)[CH2:30][CH2:31][CH3:32])C>C(Cl)(Cl)Cl>[Br:2][C:3]1[CH:4]=[C:5]([N:9]2[C:29]([CH2:30][CH2:31][CH3:32])=[N:28][C:27]([C:26]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[N:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: NNc1cccc(Br)c1
Reactant: CCCC(=O)N=CC1(OCC)C=CC=CC1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)(Cl)Cl
Product: CCCc1nc(-c2ccccc2)nn1-c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
First, 7.4 g of 3-bromophenyl hydrazine hydrochloride and 80 mL of carbon tetrachloride were put into a 200-mL three-neck flask, 3.5 g of triethylamine (Et3N) was added dropwise to this mixture little by little, and the mixture was stirred at room temperature for 1 hour. After a predetermined time elapsed, 8.8 g of N-(1-ethoxybenzylidene)butyramide obtained in Step 1 of Synthesis Example 1 was added to this mixture, and the mixture was stirred at room temperature for 24 hours. After the stirring, this mixture was dissolved in chloroform and washed with water and saturated saline. After the washing, anhydrous magnesium sulfate was added to the organic layer for drying. This mixture was gravity-filtered, and the obtained filtrate was concentrated to give an oily substance. This oily substance was purified by silica gel column chromatography. As the developing solvent, dichloromethane was used. The obtained fraction was concentrated to give a solid. This solid was recrystallized with a mixed solvent of toluene and hexane to give 1-(3-bromophenyl)-3-phenyl-5-propyl-1H-1,2,4-triazole (white powder, 47% yield). The synthesis scheme of Step 1 is shown in (E-1) below.
Reaction SMILES: [C:1]([O:9][CH2:10]/[CH:11]=[CH:12]/[C:13]1[NH:21][C:20]2[C:19]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:18][CH:17]=[N:16][C:15]=2[CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29](=O)([O-])[O-].[K+].[K+].IC.O>CN(C)C=O>[C:1]([O:9][CH2:10]/[CH:11]=[CH:12]/[C:13]1[N:21]([CH3:29])[C:20]2[C:19]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:18][CH:17]=[N:16][C:15]=2[CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(OC/C=C/c1cc2ncnc(Oc3ccccc3)c2[nH]1)c1ccccc1
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1c(/C=C/COC(=O)c2ccccc2)cc2ncnc(Oc3ccccc3)c21
Temperature: 25 °C
Reaction time: 4 h
Yield: 58 %

Procedure:
(2E)-3-(4-Phenoxy-5H-pyrrolo[3,2-d]pyrimidin-6-yl)-2-propenyl benzoate (500 mg) was dissolved in N,N-dimethylformamide (4 mL), and potassium carbonate (279 mg) and iodomethane (0.1 mL) were sequentially added. After stirring at room temperature for 4 hrs, water (30 mL) was added to the reaction mixture and the mixture was extracted with ethyl acetate (100 mL), dried over magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by basic silica gel column chromatography (eluent, hexane:ethyl acetate=80:20→50:50) to give the title compound (301 mg) as crystals.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][S:5][CH:6]=1.O.O.O.[C:14]([O-])(=[O:16])C.[Na+].C(O)=O>O>[CH:14]([NH:1][C:2]1[C:3]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][S:5][CH:6]=1)=[O:16]
Reactant: COC(=O)c1cscc1N
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: O=CO
Product: COC(=O)c1cscc1NC=O

Procedure:
A stirred solution of methyl 4-amino-3-thenoate (4 g), sodium acetate trihydrate (2.8 g) and formic acid (27 ml) was heated at 95° C. for 1 hour. On cooling the solution was poured into water, and the solution filtered to give the title product as a solid.