Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][O:8][C@H:9]2[CH2:26][CH2:25][C@@:24]3([CH3:27])[C@H:11]([CH2:12][CH2:13][C@@H:14]4[C@@H:23]3[CH2:22][CH2:21][C@@:19]3([CH3:20])[C@:15]4([OH:33])[CH2:16][CH2:17][C@@H:18]3[C:28]3[CH:32]=[CH:31][O:30][CH:29]=3)[CH2:10]2)C(=O)C2=CC=CC=C12.O.NN.O>C(O)C>[NH2:5][CH2:6][CH2:7][O:8][C@H:9]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C@H:11]([CH2:12][CH2:13][C@@H:14]3[C@@H:23]2[CH2:22][CH2:21][C@@:19]2([CH3:20])[C@:15]3([OH:33])[CH2:16][CH2:17][C@@H:18]2[C:28]2[CH:32]=[CH:31][O:30][CH:29]=2)[CH2:10]1
Reactant: C[C@]12CC[C@H](OCCN3C(=O)c4ccccc4C3=O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](c3ccoc3)CC[C@]12O
Agent: NN
Solvent: CCO
Solvent: O
Product: C[C@]12CC[C@H](OCCN)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](c3ccoc3)CC[C@]12O
Yield: 92.7 %

Procedure:
To a solution of 0.50 g of 3β-(2-phthalimidoethoxy)-17β-(3-furyl)-5β-androstan-14β-ol in 50 ml of ethanol (96%) 0.19 g of hydrazine hydrate were added at room temperature. The mixture was kept at reflux for 4 hrs, then 10 ml of water were added and the ethanol distilled under reduced pressure. The residue was extracted with methylene chloride, the organic solution was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The crude residue was purified by flash-chromatography (SiO2) using methylene chloride/methanol 90/10 as eluant to give 0.35 g of the title compound (I-aa) as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH2:13][C@@H:12]3[C@@H:9]([CH2:10][N:11]3C(OC(C)(C)C)=O)[CH2:8]2)[CH:2]=1.O.[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([OH:32])(=[O:31])=[O:30])=[CH:25][CH:24]=1>C(O)C>[CH3:22][C:23]1[CH:24]=[CH:25][C:26]([S:29]([OH:32])(=[O:31])=[O:30])=[CH:27][CH:28]=1.[CH3:22][C:23]1[CH:24]=[CH:25][C:26]([S:29]([OH:32])(=[O:31])=[O:30])=[CH:27][CH:28]=1.[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH2:13][C@@H:12]3[C@@H:9]([CH2:10][NH:11]3)[CH2:8]2)[CH:2]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CN(c3cccnc3)C[C@H]21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: O
Product: c1cncc(N2C[C@@H]3CN[C@@H]3C2)c1
Reaction time: 6 h
Yield: 74.8 %

Procedure:
The product of Example 38K (100 mg, 0.36 mmol) in ethanol (10 mL) was treated with 4-methylbenzenesulfonic acid monohydrate (144 mg, 0.76 mmol) at 80° C. and allowed to stir for 6 hours. The mixture was concentrated under reduced pressure and the residue was diluted with warm methyl tert-butyl ether (20 mL) and stirred at ambient temperature for 10 hours. The precipitate was isolated by filtration and dried under reduced pressure at 40-50° C. to provide the title compound (140 mg, 86% yield). 1H NMR (MeOH-d4, 300 MHz) δ 2.40 (s, 6H), 3.28 (dd, J=10.9, 6.4 Hz, 1H), 3.40 (dd, J=12.9, 5.5 Hz, 1H), 3.60 (m, 1H), 3.78 (dd, J=11.1, 15.0 Hz, 1H), 4.04 (d, J=10.8 Hz, 1H), 4.28 (d, J=12.9 Hz, 1H), 4.30 (m, 1H), 5.14 (dd, J=7.1, 5.4 Hz, 1H), 7.24 (d, J=7.8 Hz, 4H), 7.68 (d, J=8.1 Hz, 4H), 7.88 (dd, J=8.8, 5.4 Hz, 1H), 8.02 (ddd, J=9.1, 2.7, 1.3 Hz, 1H), 8.20 (d, J=5.4 Hz, 1H), 8.34 (d, J=3.0 Hz, 1H); m/z 176 (M+H)+; Anal. calculated for C10H13N3.2.4TsOH.H2O: C, 53.07; H, 5.68; N, 6.93. Found: C, 52.99; H, 5.23; N, 6.62.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=[O:8].[OH:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][OH:21])=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+]>CN(C)C(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]2[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][CH2:20][OH:21])=[CH:16][CH:17]=2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(Br)ccc1F
Reactant: OCCCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=Cc1cc(Br)ccc1Oc1ccc(CCCO)cc1
Yield: 99.4 %

Procedure:
In a manner similar to the method described in Example 50a, 5-bromo-2-fluorobenzaldehyde (5.5 g, 27 mmol) (Alfa) was reacted with 3-(4-hydroxyphenyl)-1-propanol (4.5 g, 30 mmol)(Aldrich) and K2CO3 in N,N-dimethylacetamide to give 5-bromo-2-[4-(3-hydroxy-propyl)-phenoxy]-benzaldehyde as a brown oil (Yield 9 g, 99%).
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.[Li]C(C)(C)C.[CH2:12]([N:14]([CH2:29][CH3:30])[CH2:15][CH2:16][N:17]1[C:27]2[C:22](=[C:23]([Br:28])[CH:24]=[CH:25][CH:26]=2)[C:20](=[O:21])[C:18]1=[O:19])[CH3:13].[NH4+].[Cl-]>C1COCC1>[CH2:29]([N:14]([CH2:12][CH3:13])[CH2:15][CH2:16][N:17]1[C:27]2[C:22](=[C:23]([Br:28])[CH:24]=[CH:25][CH:26]=2)[C:20]([OH:21])([C:2]2[CH:6]=[CH:5][S:4][CH:3]=2)[C:18]1=[O:19])[CH3:30]
Reactant: Brc1ccsc1
Reactant: CCN(CC)CCN1C(=O)C(=O)c2c(Br)cccc21
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCN(CC)CCN1C(=O)C(O)(c2ccsc2)c2c(Br)cccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.7 %

Procedure:
To 3-bromothiophene (105.5 mg, 2.1 eq) in anhydrous THF (2 mL) under a nitrogen atmosphere and with stirring was added t-BuLi (0.38 mL, 2.1 eq, 1.7 M in pentane) at −40° C. (bath temperature). Stirring was continued for 30 minutes after which 1-(2-diethylaminoethyl)-4-bromoisatin (100.0 mg, 3.08×10−4 mol) in anhydrous THF (2 mL) was added dropwise. The resulting red colored solution was stirred at −40° C. for 8 hours. Saturated aqueous NH4Cl (1.5 mL) was added and the reaction mixture was allowed to warm to room temperature. The mixture was extracted with EtOAc and the combined extracts were dried (anhydrous Na2SO4). After filtration the solvent was removed in vacuo. Purification was carried out by column chromatography (silica gel, eluting 1% to 2% MeOH in CHCl3) to give the title compound as a light brown foam (124.5 mg, 99%).
Reaction SMILES: [I:1][C:2]1[CH:7]=[C:6]([C:8]([NH:10][CH2:11][C:12]([F:15])([F:14])[F:13])=[O:9])[CH:5]=[CH:4][C:3]=1[N:16]1[CH:20]=[C:19]([C:21]([OH:23])=O)[N:18]=[N:17]1.[CH:24]1([NH2:27])[CH2:26][CH2:25]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.C(N(CC)CC)C>[CH:24]1([NH:27][C:21]([C:19]2[N:18]=[N:17][N:16]([C:3]3[CH:4]=[CH:5][C:6]([C:8]([NH:10][CH2:11][C:12]([F:14])([F:13])[F:15])=[O:9])=[CH:7][C:2]=3[I:1])[CH:20]=2)=[O:23])[CH2:26][CH2:25]1
Reactant: O=C(NCC(F)(F)F)c1ccc(-n2cc(C(=O)O)nn2)c(I)c1
Reactant: NC1CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NCC(F)(F)F)c1ccc(-n2cc(C(=O)NC3CC3)nn2)c(I)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.2 %

Procedure:
To a solution of 1-(2-iodo-4-{[(2,2,2-trifluoroethyl)amino]carbonyl}phenyl)-1H-1,2,3-triazole-4-carboxylic acid (2.08 g, 4.73 mmol) obtained in Example 379d) in DMF (20 ml) were sequentially added cyclopropylamine (500 mg), triethylamine (1.0 ml), HOBt (360 mg) and WSC (1.4 g), and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column (ethyl acetate/hexane=1/20 to 1/1) to give the title compound as a colorless powder (1.66 g, 73%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:11][CH:10]([O:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[CH2:9]2)[CH:5]=[CH:4][N:3]=1.[NH2:20][C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=1)[C:24]([NH:26][CH3:27])=[O:25].FC(F)(F)C(O)=O>CC(O)C>[F:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][CH:10]2[CH2:11][N:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:20][C:21]4[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=4)[C:24]([NH:26][CH3:27])=[O:25])[N:7]=3)[CH2:9]2)=[CH:14][CH:15]=1
Reactant: CNC(=O)c1cccc(N)c1
Reactant: Fc1ccc(OC2CN(c3ccnc(Cl)n3)C2)cc1
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)c1cccc(Nc2nccc(N3CC(Oc4ccc(F)cc4)C3)n2)c1
Temperature: 84 °C
Yield: 97.8 %

Procedure:
To 2-chloro-4-(3-(4-fluorophenoxy)azetidin-1-yl)pyrimidine (90.0 mg, 0.322 mmol) and 3-amino-N-methylbenzamide (53.2 mg, 0.354 mmol) in a disposable sealed tube in 2-propanol (2.50 mL) was added trifluoroacetic acid (0.074 mL, 0.965 mmol). The resulting reaction mixture was heated at 84° C. for 18 h, cooled to RT, concentrated, taken up in MeOH-DCM, filtered through an SCX-2 column with MeOH. The product was eluted with 2.0 M NH3 in MeOH. Fractions containing the product were concentrated to afford 3-(4-(3-(4-fluorophenoxy)azetidin-1-yl)pyrimidin-2-ylamino)-N-methylbenzamide (123.9 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:20])=[C:4]([CH:14]2[CH2:18][NH:17][C:16](=[O:19])[CH2:15]2)[C:5]([O:11][CH2:12][CH3:13])=[C:6]([CH:8](O)[CH3:9])[CH:7]=1.CN(C)C=O.S(Cl)([Cl:28])=O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([F:20])=[C:4]([CH:14]2[CH2:18][NH:17][C:16](=[O:19])[CH2:15]2)[C:5]([O:11][CH2:12][CH3:13])=[C:6]([CH:8]([Cl:28])[CH3:9])[CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: CCOc1c(C(C)O)cc(Cl)c(F)c1C1CNC(=O)C1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOc1c(C(C)Cl)cc(Cl)c(F)c1C1CNC(=O)C1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 84.8 %

Procedure:
The mixture of diastereoisomers from step 6 were each processed individually to the final products. A solution of 4-[3-chloro-6-ethoxy-2-fluoro-5-(1-hydroxyethyl)phenyl]pyrrolidin-2-one (0.41 g, 1.4 mmol) (from Step 6) in methylene chloride (12 mL) was treated with N,N-dimethylformamide (0.011 mL, 0.14 mmol) followed by thionyl chloride (0.21 mL, 2.9 mmol) dropwise and stirred at 20° C. for 30 min. The reaction mixture was added dropwise to ice cooled saturated sodium bicarbonate solution and extracted with dichloromethane. The organic layer was separated and washed with brine, dried over sodium sulfate, filtered, and concentrated to give the desired products [from peak 1 (0.38 g, 87%); from peak 2 (0.39 g, 89%)] along with 17-18% of the styrene that formed from chloride elimination. These mixtures were used without further purification. From peak 1: LCMS for C14H17Cl2FNO2 (M+H)+: m/z=320.1; Found: 320.0. From peak 2: LCMS for C14H17Cl2FNO2 (M+H)+: m/z=320.1; Found: 320.0.
Reaction SMILES: [CH3:1][C:2]1[C:12]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[F:19][C:20]([F:45])([F:44])[CH2:21][NH:22][C:23]([C:25]1([CH2:39][CH2:40][CH2:41][CH2:42]Br)[C:38]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[O:32][C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:24]>>[CH2:1]=[C:2]1[C:12]([N:13]2[CH2:14][CH2:15][N:16]([CH2:42][CH2:41][CH2:40][CH2:39][C:25]3([C:23](=[O:24])[NH:22][CH2:21][C:20]([F:45])([F:19])[F:44])[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:31]=4[O:32][C:33]4[C:38]3=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH2:17][CH2:18]2)=[CH:11][CH:10]=[CH:9][CH:3]1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)c1cccc(N2CCNCC2)c1C
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2Oc2ccccc21
Product: C=C1C(N2CCN(CCCCC3(C(=O)NCC(F)(F)F)c4ccccc4Oc4ccccc43)CC2)=CC=CC1C(=O)OCC

Procedure:
The procedure of step (b) of Example 1 was repeated, except that the compound prepared in step (a) of Example 53 and the compound prepared in step (a) of Example 96 were used as the starting compounds. Thus, ethyl 2-methyly-3-[4-[4-[9-(2,2,2-trifluoroethylcarbamoyl)-9H-xanthen-9-yl]butyl]piperazin-1-yl]benzoate was obtained.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[C:8](=[O:21])[C:9]([O:19][CH3:20])=[C:10]([O:17][CH3:18])[C:11]2=[O:16].C(O)(=O)C.[ClH:26]>O>[Cl:26][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[C:8](=[O:21])[C:9]([O:19][CH3:20])=[C:10]([O:17][CH3:18])[C:11]2=[O:16]
Reactant: Cl
Reactant: COC1=C(OC)C(=O)c2c(N)cccc2C1=O
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COC1=C(OC)C(=O)c2c(Cl)cccc2C1=O
Temperature: -5 °C

Procedure:
A solution of sodium nitrite (0.69 g, 10 mmol) in water (5 ml) was added at 0°-5° C. to a solution of 5-amino-2,3-dimethoxy-1,4-naphthoquinone (1.17 g, 5 mmol) in 5:1 acetic acid:water (25 ml) containing concentrated hydrochloric acid (1.7 ml). A further quantity of sodium nitrite (0.69 g) was then added to the reaction mixture after cooling to -5° C., followed by a solution of cuprous chloride (0.6 g) in concentrated hydrochloric acid (5 ml). The mixture was allowed to warm to 22° C. and solid cuprous chloride was added portionwise until the mixture assumed a green color. Water was then added to the reaction mixture and the precipitated yellow solid filtered off, washed with water and recrystallized from methanol:water (2:1) giving 1.01 g of 5-chloro-2,3-dimethoxy-1,4-naphthoquinone, mp 120°-121° C.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH:17][C:18](=[O:29])[C@@H:19]([NH:23][S:24]([CH2:27][CH3:28])(=[O:26])=[O:25])[CH:20]([CH3:22])[CH3:21])=[CH:11][C:10]=1[O:30][CH3:31])C1C=CC=CC=1.[H][H]>O1CCCC1.[Pd]>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH:17][C:18](=[O:29])[C@@H:19]([NH:23][S:24]([CH2:27][CH3:28])(=[O:26])=[O:25])[CH:20]([CH3:21])[CH3:22])=[CH:11][C:10]=1[O:30][CH3:31]
Reactant: CCS(=O)(=O)N[C@H](C(=O)NCCc1ccc(OCc2ccccc2)c(OC)c1)C(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCS(=O)(=O)N[C@H](C(=O)NCCc1ccc(O)c(OC)c1)C(C)C

Procedure:
14.5 g of (S)-2-(ethylsulfonylamino)-3-methyl-butyric acid N-[2-(4-benzyloxy-3-methoxy-phenyl)-ethyl]-amide are dissolved in 420 ml of tetrahydrofuran and, together with 3 g of 5% palladium on active carbon, shaken in a hydrogenation vessel for 5 hours in a hydrogen atmosphere under normal pressure. The catalyst is then filtered off. The filtrate is concentrated. The residue is purified by flash chromatography on silica gel with ethyl acetate/n-hexane 3:1, yielding (S)-2-(ethylsulfonylamino)-3methyl-butyric acid N-[2-(4-hydroxy-3-methoxy-phenyl)-ethyl]-amide in the form of a colourless oil.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[O:7][N:6]=[C:5]([C:8]2[S:12][C:11]([C:13](Cl)=[O:14])=[CH:10][CH:9]=2)[C:4]=1[CH3:16].Cl.[NH:20]1[CH2:25][CH2:24][CH2:23][C@H:22]([CH2:26][OH:27])[CH2:21]1>>[OH:27][CH2:26][C@H:22]1[CH2:23][CH2:24][CH2:25][N:20]([C:13]([C:11]2[S:12][C:8]([C:5]3[C:4]([CH3:16])=[C:3]([C:2]([F:18])([F:17])[F:1])[O:7][N:6]=3)=[CH:9][CH:10]=2)=[O:14])[CH2:21]1
Reactant: Cc1c(-c2ccc(C(=O)Cl)s2)noc1C(F)(F)F
Reactant: OC[C@H]1CCCNC1
Agent: Cl
Product: Cc1c(-c2ccc(C(=O)N3CCC[C@H](CO)C3)s2)noc1C(F)(F)F

Procedure:
Prepared from 5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carbonyl chloride (74 mg, 0.25 mmol, as prepared in Example 2 Method B) and (S)-1-piperidin-3-yl-methanol, hydrochloride (76 mg, 0.5 mmol) by the method used in Example 46 for the achiral isomer. Gummy solid (70 mg, 74%). LC/MS 5.85 min, [M+1]+ 375.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@H:4]([CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)[NH2:5].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=O>>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:22]2[C:8]3[NH:9][C:10]4[C:15]([C:7]=3[CH2:6][CH:4]([C:3]([O:2][CH3:1])=[O:16])[NH:5]2)=[CH:14][CH:13]=[CH:12][CH:11]=4)[CH:24]=[CH:25][CH:26]=1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: COc1cccc(C=O)c1
Product: COC(=O)C1Cc2c([nH]c3ccccc23)C(c2cccc(OC)c2)N1

Procedure:
The same method but starting from racemic tryptophan methyl ester and 3-methoxybenzaldehyde gave the title compound as white crystals m.p.: 146° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:12])[C:7]=1[CH2:8][C:9]([OH:11])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:25]1([CH2:30][C:31]2[C:36]([O:37][CH3:38])=[CH:35][CH:34]=[CH:33][C:32]=2[CH2:39][CH2:40][NH2:41])[CH2:29][CH2:28][CH2:27][CH2:26]1.C(N(CC)CC)C>C1COCC1>[CH:25]1([CH2:30][C:31]2[C:36]([O:37][CH3:38])=[CH:35][CH:34]=[CH:33][C:32]=2[CH2:39][CH2:40][NH:41][C:9](=[O:11])[CH2:8][C:7]2[C:6]([Cl:12])=[CH:5][N:4]=[CH:3][C:2]=2[Cl:1])[CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: COc1cccc(CCN)c1CC1CCCC1
Reactant: O=C(O)Cc1c(Cl)cncc1Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cccc(CCNC(=O)Cc2c(Cl)cncc2Cl)c1CC1CCCC1
Yield: 85.7 %

Procedure:
By working in a way similar to that described in example 4 but using (3,5-dichloro-pyridin-4-yl)-acetic acid (356 mg, 1.73 mmoles), carbonyldiimidazole (308 mg, 1.9 mmoles), THF (15 ml), 2-(2-cyclopentylmethyl-3-methoxy-phenyl)-ethylamine (390 mg, 1.44 mmoles), obtained as described in example 49, and triethylamine (0.24 ml, 1.73 mmoles), 520 mg of the title compound were obtained (yield: 86%).
Reaction SMILES: Cl[CH2:2][N:3]1[CH:7]=[N:6][C:5]([C:8]([F:11])([F:10])[F:9])=[N:4]1.[F:12][C:13]([F:22])([F:21])[CH2:14][CH2:15][CH:16]([C:19]#[N:20])[C:17]#[N:18].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:9][C:8]([F:11])([F:10])[C:5]1[N:6]=[CH:7][N:3]([CH2:2][C:16]([CH2:15][CH2:14][C:13]([F:12])([F:21])[F:22])([C:17]#[N:18])[C:19]#[N:20])[N:4]=1
Reactant: FC(F)(F)c1ncn(CCl)n1
Reactant: N#CC(C#N)CCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cn1cnc(C(F)(F)F)n1
Yield: 5.7 %

Procedure:
1.56 g of 1-(chloromethyl)-3-(trifluoromethyl)-1H-1,2,4-triazole and 1.38 g of (3,3,3-trifluoropropyl)malononitrile were dissolved in 25 ml of N,N-dimethylformamide. 2.35 g of potassium carbonate was added to the solution under ice cooling with stirring, followed by stirring at room temperature for 4 hours. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized from hexane-MTBE to obtain 0.15 g of {[3-(trifluoromethyl)-1H-1,2,4-triazole-1-yl]methyl}(3,3,3-trifluoropropyl)malononitrile (referred as the compound of the present invention (33), hereinafter) shown by below formula.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:19][CH:20]=[CH2:21])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].C(=O)([O-])[O-].[Na+].[Na+].[N+:28]([O-])([N+]([O-])=O)=[O:29]>O1CCCC1.C(Cl)Cl>[Cl:1][CH2:2][CH2:3][N:4]([N:28]=[O:29])[C:5]([N:7]([CH2:19][CH:20]=[CH2:21])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: C=CCN(C(=O)NCCCl)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Reactant: O=[N+]([O-])[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: C=CCN(C(=O)N(CCCl)N=O)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Yield: 71.7 %

Procedure:
3.2 g of 1-(2-chloroethyl)-3-(2-propenyl)-3-D-galactopyranosylurea are dissolved in a mixture of 60 ml of tetrahydrofuran and 60 ml of methylene chloride, and 15 g of sodium carbonate anhydrate are added thereto. 5 g of nitrogen tetroxide gas are introduced into the mixture for 10 minutes under ice-cooling and stirring. The mixture is treated in the same manner as described in Example 2. 2.5 g of 1-(2-chloroethyl)-1-nitroso-3-(2-propenyl)-3-D-galactopyranosylurea are thereby obtained as yellow caramel.
Reaction SMILES: [CH:1]1([CH2:7][NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[Cl:18][C:19]1[N:24]=[C:23](Cl)[C:22]([N+:26]([O-:28])=[O:27])=[CH:21][N:20]=1>ClCCl>[Cl:18][C:19]1[N:24]=[C:23]([NH:8][CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:22]([N+:26]([O-:28])=[O:27])=[CH:21][N:20]=1
Reactant: NCC1CCCCC1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=[N+]([O-])c1cnc(Cl)nc1NCC1CCCCC1
Yield: 25.6 %

Procedure:
Cyclohexylmethylamine (3.11 g) and N,N-diisopropylethylamine (6.2 ml) were dissolved into 45 ml dichloromethane. The mixture was added dropwise to a solution of 2,4-dichloro-5-nitropyrimidine (4.85 g) in dichloromethane (30 ml) at 0° C. After the completion of the dropwise addition, the mixture was kept at the same temperature to react for 20 min. Purification was conducted by a column chromatography to obtain a bright-yellow sheet-like solid (1.73 g) in a yield of 26%. ESI-MS (m/z, %) 272 (M−H)+. 1H NMR (400 MHz, CDCl3): δ 9.03 (s, 1H), 8.48 (s, 1H), 3.52 (m, 2H), 1.78-1.64 (m, 7H), 1.33-1.14 (m, 4H), 1.08-1.00 (m, 2H).
Reaction SMILES: [CH:1]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:20]=[C:21]1[C:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:25][CH2:24][CH2:23][N:22]1[CH2:39][C:40](O)=[O:41].Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[CH:1]([N:14]1[CH2:19][CH2:18][N:17]([C:40](=[O:41])[CH2:39][N:22]2[CH2:23][CH2:24][CH2:25][C:26]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]2=[O:20])[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCCC(c2ccccc2)(c2ccccc2)C1=O)N1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-benzhydrylpiperazine (1.63 g, 6.46 mmol) in dichloromethane (75 mL) under nitrogen was added the product of Example 68E (2.00 g, 6.46 mmol) followed by N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (2.48 g, 12.93 mmol) and N,N-dimethylpyridin-4-amine (0.079 g, 0.65 mmol). The reaction mixture was stirred overnight at room temperature. The reaction was concentrated and the residue was partitioned in ethyl acetate/water (8:2, 400 mL). The organic layer was washed with water followed by brine, dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography eluting with ethyl acetate/hexane (1:3) gave the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.38-7.42 (m, 4H), 7.25-7.31 (m, 12H), 7.16-7.24 (m, 4H), 4.23 (s, 1H), 4.20 (s, 2H), 3.64 (t, J=4.7 Hz, 2H), 3.47 (t, J=6.5 Hz, 2H), 3.41-3.45 (m, 2H), 2.60-2.65 (m, 2H), 2.34-2.42 (m, 4H), 1.78-1.87 (m, 2H); MS (DCI+) m/z 544 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([N:15]([CH3:25])[S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)(=[O:18])=[O:17])[CH:14]=1)[NH:11][C:10]([C:26]1[S:27][CH2:28][C@@H:29]([C:31](O)=[O:32])[N:30]=1)=[CH:9]2.[NH4+].[N:35]1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>CN(C)C=O>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([N:15]([CH3:25])[S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)(=[O:17])=[O:18])[CH:14]=1)[NH:11][C:10]([C:26]1[S:27][CH2:28][C@@H:29]([C:31]([NH2:35])=[O:32])[N:30]=1)=[CH:9]2
Reactant: On1nnc2ccccc21
Reactant: COCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C3=N[C@H](C(=O)O)CS3)cc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C3=N[C@H](C(N)=O)CS3)cc2c1
Yield: 37.4 %

Procedure:
A solution of (4R)-2-{5-(2-methoxyethoxy)-7-[methyl(pyridin-2-ylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazole-4-carboxylic acid (0.15 g), 1H-1,2,3-benzotriazol-1-ol ammonium salt (0.072 g), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.090 g) and triethylamine (0.086 mL) in N,N-dimethylformamide (5 mL) was stirred at room temperature for 3 hr. The reaction mixture was concentrated, water was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with 1N hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography, and eluted with ethyl acetate to give the title compound (0.056 g, yield 37%) as colorless crystals.