Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C@@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)([CH3:3])[CH3:2].[ClH:19].[CH:20]1([C:23]2[C:24]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)=[N:25][CH:26]=[C:27]([CH:29]3[CH2:31][CH2:30]3)[CH:28]=2)[CH2:22][CH2:21]1>>[ClH:19].[CH:20]1([C:23]2[C:24]([N:32]3[CH2:33][CH2:34][N:35]([C:14]([C:13]4[CH:12]=[CH:11][C:10]([N:5]5[C@H:4]([CH:1]([CH3:2])[CH3:3])[CH2:8][O:7][C:6]5=[O:9])=[CH:18][CH:17]=4)=[O:16])[CH2:36][CH2:37]3)=[N:25][CH:26]=[C:27]([CH:29]3[CH2:31][CH2:30]3)[CH:28]=2)[CH2:21][CH2:22]1
Reactant: CC(C)[C@@H]1COC(=O)N1c1ccc(C(=O)O)cc1
Reactant: c1nc(N2CCNCC2)c(C2CC2)cc1C1CC1
Agent: Cl
Product: CC(C)[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C4CC4)cc3C3CC3)CC2)cc1
Yield: 45.9 %

Procedure:
By reaction and treatment in the same manner as in Example 87 and using (R)-4-(4-isopropyl-2-oxooxazolidin-3-yl)benzoic acid (499 mg) described in Preparation Example 18 and 1-(3,5-dicyclopropylpyridin-2-yl)piperazine hydrochloride (560 mg) described in Preparation Example 50, the title compound (469 mg) was obtained.
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[F:17][C:18]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([F:28])[C:19]=1[CH:20]=O>O1CCCC1.C(OCC)(=O)C>[F:17][C:18]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([F:28])[C:19]=1[CH2:20][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: COc1cc(F)c(C=O)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1c(F)cc(OC)cc1F
Yield: 55 %

Procedure:
A solution of ethyl diethylphosphonoacetate (2.34 g, 10.4 mmol) and 60% sodium hydride (0.38 g, 9.50 mmol) in tetrahydrofuran (40 ml) was stirred under ice-cooling for 10 min. 2,6-Difluoro-4-methoxybenzaldehyde (1.5 g, 8.71 mmol) was added, and the mixture was stirred while elevating the temperature to room temperature for 4 hrs. The reaction solution was diluted with ethyl acetate, washed successively with aqueous citric acid solution, water and aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography (ethyl acetate:hexane=1:10-1:5), and then subjected to catalytic reduction in the same manner as in Reference Example 172 to give the title compound (1.17 g) as a colorless oil. yield 52%. MS 245.0 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C@@H:11]2[CH2:15][CH2:14][C@H:13]([C:16]3[CH:21]=[CH:20][C:19](OC)=[C:18]([O:24][CH3:25])[CH:17]=3)[NH:12]2)=O)=[CH:4][C:3]=1[O:26][CH3:27].C1(C)C=CC=CC=1.C1C[O:38][CH2:37]C1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C@@H:11]2[CH2:15][CH2:14][C@H:13]([C:16]3[CH2:17][C:18]([O:24][CH3:25])([O:38][CH3:37])[CH:19]=[CH:20][CH:21]=3)[NH:12]2)=[CH:4][C:3]=1[O:26][CH3:27]
Reactant: C1CCOC1
Reactant: COc1cc(NC(=O)[C@@H]2CC[C@H](c3ccc(OC)c(OC)c3)N2)ccc1Cl
Solvent: Cc1ccccc1
Product: COc1cc(NC[C@@H]2CC[C@H](C3=CC=CC(OC)(OC)C3)N2)ccc1Cl
Temperature: 0 °C
Yield: 67 %

Procedure:
(2S,5R)5-(3,4-Dimethoxy-phenyl)-pyrrolidine-2-carboxylic acid (4-chloro-3-methoxy-phenyl)amide was dissolved in anhydrous THF and cooled to 0° C. in an ice bath. A 0.5M solution of alane complex in toluene (42.6 ml, 21.3 mmol, 3.0 equivalents) was added slowly and the reaction was allowed to stir and warm to room temperature overnight. The reaction was quenched upon addition of ethyl acetate:methanol (1:1, 5 ml). The resulting slurry was filtered through Celite and rinsed with ethyl acetate. The filtrate was concentrated in vacuo to afford (2S,R)(4-chloro-3-methoxy-phenyl)-[5-(3,3-dimethoxy-phenyl)-pyrrolidin-2-ylmethyl]-amine (1.80 g, 4.78 mmol, 67% yield). Analysis H1 NMR (400 MHz, CDCl3): 7.12 (1H, d), 6.98-6.90 (3H, m), 6.23 (1H, s), 6.19 (1H, d) 4.39-4.15 (2H, m), 3.76-3.53 (1H, m), 3.30-2.97 (2H, m), 2.34-1.55 (6H, m). MS (LC-MS): Calculated for C20H25ClN2O3 376.16, found 377.21 (M+H)+.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([CH3:20])=[C:18](Cl)[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[Cl:22][C:23]1[N:28]=[C:27]([CH3:29])[C:26]([OH:30])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([CH3:20])=[C:18]([O:30][C:26]3[C:27]([CH3:29])=[N:28][C:23]([Cl:22])=[CH:24][CH:25]=3)[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: Cc1c(Cl)ncnc1OC1CCN(C(=O)OC(C)C)CC1
Reactant: Cc1nc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(Cl)ccc1Oc1ncnc(OC2CCN(C(=O)OC(C)C)CC2)c1C
Temperature: 150 °C
Yield: 70.8 %

Procedure:
A mixture of 4-(6-chloro-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylic acid isopropyl ester (1.03 g, 3.27 mmol), 6-chloro-2-methyl-pyridin-3-ol (470 mg, 3.27 mmol), and potassium carbonate (903 mg, 6.53 mmol) in 15 mL DMF were heated in microwave for 1 hour at 150° C. The mixture was purified to give Compound C65 as a white solid (0.975 g, 71%). 1H NMR (CDCl3, 400 MHz) δ 0.92-0.94 (d, 6H), 1.74-1.82 (m, 2H), 1.95-2.02 (m, 2H), 2.19 (s, 3H), 2.47 (s, 3H), 3.39-3.45 (m, 2H), 3.74-3.79 (m, 2H), 4.91-4.97 (m, 1H), 5.33-5.36 (m, 1H), 7.21-7.23 (d, 1H), 7.36-7.38 (d, 1H), 8.19 (s, 1H). Exact mass calculated for C20H25ClN4O4 420.16, found 421.3 (MH+).
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[CH2:14][NH:13][CH2:12][CH2:11]2.Br[C:19]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[C:22]([NH:29][C:30](=[O:36])[CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[C:21]([Cl:37])[CH:20]=1>C1(C)C=CC=CC=1>[Cl:37][C:21]1[CH:20]=[C:19]([N:13]2[CH2:12][CH2:11][C:10]3[C:15](=[CH:16][CH:17]=[C:8]([F:7])[CH:9]=3)[CH2:14]2)[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[C:22]=1[NH:29][C:30](=[O:36])[CH2:31][C:32]([CH3:34])([CH3:33])[CH3:35]
Reactant: Fc1ccc2c(c1)CCNC2
Reactant: CC(C)(C)CC(=O)Nc1c(Cl)cc(Br)cc1C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C)(C)CC(=O)Nc1c(Cl)cc(N2CCc3cc(F)ccc3C2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Bis(dibenzylidineacetone)palladium (2 mg, 0.0035 mmol) and (2′-dicyclohexyl phosphanyl biphenyl-2-yl)dimethylamine (3.3 mg, 0.0084 mmol) were added to dry toluene (10 mL purged with argon) and stirred for 15 minutes under argon. Potassium tert-butoxide (122 mg, 1.08 mmol), 6-fluoro-1,2,3,4-tetrahydroisoquinoline (96 mg, 0.65 mmol), and N-(4-bromo-2-chloro-6-(trifluoromethyl)phenyl)-3,3-dimethylbutanamide (200 mg, 0.54 mmol) were then added, and the reaction mixture was stirred at 90° C. overnight. The reaction mixture was then cooled to room temperature, concentrated, and purified by thin layer chromatography (dichloromethane:methanol 5%) to afford the title compound as a solid. m/z=441 [M−1]−.
Reaction SMILES: [CH3:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([CH3:13])=[C:7]2[C:3]=1[CH:4](SC)[C:5](=[O:14])[NH:6]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.C1(C)C(S(O)(=O)=O)=CC=CC=1.O>ClCCl>[CH3:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([CH3:13])=[C:7]2[C:3]=1[CH2:4][C:5](=[O:14])[NH:6]2
Reactant: COc1cc(C)c2c(c1C)C(SC)C(=O)N2
Agent: Cc1ccccc1S(=O)(=O)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: COc1cc(C)c2c(c1C)CC(=O)N2
Reaction time: 3 h
Yield: 86.5 %

Procedure:
To a solution of 4,7-dimethyl-5-methoxy-3-(methylthio)-1,3-dihydro-2H-indol-2-one (17.8 g, 75 mmol) in dichloromethane (350 ml) were added triphenylphosphine (23.6 g, 90 mmol) and toluenesulfonic acid monohydrate (17.1 g, 90 mmol) at room temperature and stirred for 3 hours. The reaction mixture was poured into a cold water, and the precipitated crystals were collected by filtration. After washing with dichloromethane and water, 12.4 g of the title compound was obtained.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[NH2:11][C:12]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][CH2:31][CH3:32])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21]#[N:22])[CH:19]=2)[NH:14][C:13]1=[O:23]>N1C=CC=CC=1>[C:21]([C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:23])[C:12]2([NH:11][C:2](=[O:3])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[O:30][CH2:31][CH3:32])#[N:22]
Reactant: CCOc1ccccc1C1(N)C(=O)Nc2ccc(C#N)cc21
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Product: CCOc1ccccc1C1(NC(=O)Oc2ccccc2)C(=O)Nc2ccc(C#N)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 111 %

Procedure:
1.2 ml (9.38 mMol) of phenyl chloroformate were added dropwise to 2.5 g (8.5 mMol) of product 2a dissolved in 50 ml of pyridine at 0° C. The reaction solution was then stirred at room temperature for 16 h. The solution was subsequently poured into ice-water, and the aqueous phase was extracted with ethyl acetate (AcOEt). The organic phase was washed several times with water, dried and concentrated in vacuo. 3.9 g of the product were obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]([CH:8]=[CH:9][CH:10]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:14]([CH2:16][C:17]([N-:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])#[N:15]>>[CH2:20]([NH:19][C:17](/[C:16](=[CH:10]/[CH:9]=[CH:8]/[C:7]1[CH:12]=[CH:13][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)/[C:14]#[N:15])=[O:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: N#CCC(=O)[N-]Cc1ccccc1
Reactant: O=CC=Cc1ccc([N+](=O)[O-])cc1
Product: N#C/C(=C\C=C\c1ccc([N+](=O)[O-])cc1)C(=O)NCc1ccccc1
Yield: 82.5 %

Procedure:
The compound was prepared as described in Example 3 by adding 4-nitrocinnamaldehyde (0.022 g, 0.12 mmol) to N-(cyanoacetyl)benzylamide (Example 4, 0.022 g, 0.12 mmol). After refluxing for 1 h, the product was purified by silica gel chromatography (CHCl3-MeOH, 5:1) to give a yellow solid (0.033 g, 81%). The product gave the following analytical data:
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[C:12]([C:19]4[S:20][CH:21]=[CH:22][CH:23]=4)=[N:13][N:14]([CH3:18])[C:15]=3[CH:16]=[O:17])=[CH:10][C:5]=2[CH2:4][CH2:3][CH2:2]1.[Cl:24]N1C(=O)CCC1=O>C(#N)C>[Cl:24][C:21]1[S:20][C:19]([C:12]2[C:11]([C:9]3[CH:8]=[CH:7][C:6]4[O:1][CH2:2][CH2:3][CH2:4][C:5]=4[CH:10]=3)=[C:15]([CH:16]=[O:17])[N:14]([CH3:18])[N:13]=2)=[CH:23][CH:22]=1
Reactant: Cn1nc(-c2cccs2)c(-c2ccc3c(c2)CCCO3)c1C=O
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: Cn1nc(-c2ccc(Cl)s2)c(-c2ccc3c(c2)CCCO3)c1C=O
Yield: 102 %

Procedure:
A solution of 4-(3,4-dihydro-2H-1-benzopyran-6-yl)-1-methyl-3-(thiophen-2-yl)-1H-pyrazole-5-carbaldehyde (3d) (166 mg, 0.51 mmol) and N-chlorosuccinimide (67 mg, 0.50 mmol) in acetonitrile (18 mL) was heated overnight at 60° C. The reaction mixture was concentrated in vacuo. Water (10 mL) was added and the aqueous layer was extracted with ethyl acetate (2×12 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative TLC (cyclohexane/ethyl acetate 80/20), to provide 3-(5-chlorothiophen-2-yl)-4-(3,4-dihydro-2H-1-benzopyran-6-yl)-1-methyl-1H-pyrazole-5-carbaldehyde (36a) (183 mg, 0.51 mmol, 99%).
Reaction SMILES: [F:1][C:2]1[C:15]([N:16]2[C:21](=[O:22])[CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[NH:18][C:17]2=[O:27])=[CH:14][C:5]2[N:6]([CH:10]([CH2:12][CH3:13])[CH3:11])[C:7](=[O:9])[S:8][C:4]=2[CH:3]=1.[H-].[Na+].[N+:30](C1C=C([N+]([O-])=O)C=CC=1ON)([O-])=O.O>CN(C)C=O>[F:1][C:2]1[C:15]([N:16]2[C:21](=[O:22])[CH:20]=[C:19]([C:23]([F:24])([F:25])[F:26])[N:18]([NH2:30])[C:17]2=[O:27])=[CH:14][C:5]2[N:6]([CH:10]([CH2:12][CH3:13])[CH3:11])[C:7](=[O:9])[S:8][C:4]=2[CH:3]=1
Reactant: NOc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: CCC(C)n1c(=O)sc2cc(F)c(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)cc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(C)n1c(=O)sc2cc(F)c(-n3c(=O)cc(C(F)(F)F)n(N)c3=O)cc21
Yield: 19.3 %

Procedure:
To a solution of 1-[6-fluoro-3-sec-butyl-2(3H)-benzothiazolon-5-yl]-4-trifluoromethyl-1,2,3,6-tetrahydropyrimidine-2,6-dione (2.0 g) in dimethylformamide (10 g), sodium hydride (0.3 g) and 2,4-dinitrophenoxyamine (1.8 g) were added, and the resultant mixture was heated at 40 to 60° C. for 3 hours. After completion of the reaction, the reaction mixture was poured into water, extracted with ethyl acetate and concentrated. The residue was purified by silica gel column chromatography to give 1-[6-fluoro-3-sec-butyl-2(3H)-benzothiazolon-5-yl]-3-amino-4-trifluoromethyl-1,2,3,6-tetrahydropyrimidine-2,6-dione (0.4 g).
Reaction SMILES: [CH2:1]([N:8]([C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[C:24](=[O:28])[NH:23][CH2:22][CH2:21]2)[S:9]([C:12]1[CH:16]=[CH:15][N:14]([CH3:17])[N:13]=1)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH2:32][CH3:33]>C1COCC1>[CH2:1]([N:8]([C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[C:24](=[O:28])[N:23]([CH2:32][CH3:33])[CH2:22][CH2:21]2)[S:9]([C:12]1[CH:16]=[CH:15][N:14]([CH3:17])[N:13]=1)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1ccc(S(=O)(=O)N(Cc2ccccc2)c2ccc3c(c2)CCNC3=O)n1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN1CCc2cc(N(Cc3ccccc3)S(=O)(=O)c3ccn(C)n3)ccc2C1=O
Temperature: 110 °C
Yield: 42.8 %

Procedure:
To a suspension of 1-methyl-1H-pyrazole-3-sulfonic acid benzyl-(1-oxo-1,2,3,4-tetrahydro-isoquinolin-6-yl)-amide (9 mg, 0.022 mmol) and sodium hydride (2 mg of a 60% dispersion in mineral oil, 0.045 mmol) in anhydrous THF (0.5 ml) was added iodoethane (2 μl, 0.045 mmol) and the reaction heated to 110° C. in a microwave for 0.5 hrs. The solvent was evaporated in vacuo and the resulting residue purified by preparative HPLC (Method B) to yield the title compound as a colourless solid (4 mg, 24%). HPLC retention time 4.14 min. Mass spectrum (ES+) m/z 425 (M+H).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH:10]([CH3:12])[CH3:11])=[N:5][CH:6]=[CH:7][CH:8]=1.C([O:15][C:16](=[O:28])[C:17]([CH3:27])([CH3:26])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)C>>[CH:10]([S:9][C:4]1[C:3]([CH2:2][O:25][C:22]2[CH:21]=[CH:20][C:19]([CH2:18][C:17]([CH3:27])([CH3:26])[C:16]([OH:28])=[O:15])=[CH:24][CH:23]=2)=[CH:8][CH:7]=[CH:6][N:5]=1)([CH3:12])[CH3:11]
Reactant: CCOC(=O)C(C)(C)Cc1ccc(O)cc1
Reactant: CC(C)Sc1ncccc1CCl
Product: CC(C)Sc1ncccc1COc1ccc(CC(C)(C)C(=O)O)cc1
Yield: 81.5 %

Procedure:
3-Chloromethyl-2-isopropylsulfanyl-pyridine (0.02 g, 0.099 mmol) obtained in Step C of Preparation Example 1 and 3-(4-hydroxy-phenyl)-2,2-dimethyl-propionic acid ethyl ester (0.022 g, 0.099 mmol) obtained in Step D of Preparation Example 39 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.029 g, 81%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[C:14]([F:15])=[CH:13][CH:12]=[C:11]([F:16])[N:10]=2)=[CH:4][C:5](F)=[N:6][CH:7]=1.[NH2:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([NH2:24])[CH2:20][CH2:19]1>CS(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([C:9]2[C:14]([F:15])=[CH:13][CH:12]=[C:11]([F:16])[N:10]=2)=[CH:4][C:5]([NH:17][C@H:18]2[CH2:23][CH2:22][C@H:21]([NH2:24])[CH2:20][CH2:19]2)=[N:6][CH:7]=1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: Fc1cc(-c2nc(F)ccc2F)c(Cl)cn1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N[C@H]1CC[C@H](Nc2cc(-c3nc(F)ccc3F)c(Cl)cn2)CC1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a solution of 5′-chloro-2′,3,6-trifluoro-2,4′-bipyridine (95 mg, 0.388 mmol) in DMSO (2.5 mL) was added trans-1,4-diaminocyclohexane (177 mg, 1.55 mmol). The mixture was stirred at 90° C. for 2 hr. The cooled reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried (Na2SO4), filtered, and concentrated to give 137 mg of crude trans-N1-(5′-chloro-3,6-difluoro-2,4′-bipyridin-2′-yl)cyclohexane-1,4-diamine which was used without further purification. LCMS (m/z): 339.0 (MH+), retention time=0.54 min
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[C:14]([NH:19]/[C:20](/[NH:32]C(=O)OCC2C=CC=CC=2)=[N:21]/C(=O)OCC2C=CC=CC=2)[C:15]([CH3:18])=[N:16][CH:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[N:16][C:15]([CH3:18])=[C:14]([NH:19][C:20]([NH2:32])=[NH:21])[CH:13]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1ncc(CCCNC(=O)OC(C)(C)C)cc1N/C(=N/C(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: Cc1ncc(CCCNC(=O)OC(C)(C)C)cc1NC(=N)N
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.3 %

Procedure:
To a solution of dibenzyl {(Z)-[(5-{3-[(tert-butoxycarbonyl)amino]propyl}-2-methylpyridin-3-yl)amino]methylylidene}biscarbamate (3.34 g, 5.80 mmol) in MeOH (100 mL) was added palladium hydroxide on carbon (0.41 g). The reaction vessel was flushed with hydrogen gas and then allowed to stir at rt under an atmosphere of hydrogen gas overnight. The reaction mixture was filtered over a pad of Celite® and the filtrate was concentrated to give tert-butyl[3-(5-{[amino(imino)methyl]amino}-6-methylpyridin-3-yl)propyl]carbamate (1.77 g, 5.76 mmol, 99%) as a white solid. LCMS (FA): Rt=0.76 min, m/z=308.0 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:15]=[CH:14][C:10](C(O)=O)=[CH:9][CH:8]=2)[N:5]=[C:4]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:3]=1.[CH3:20][O:21]C1C=CC(NN)=CC=1>>[C:16]([C:4]1[CH:3]=[C:2]([NH2:1])[N:6]([C:7]2[CH:8]=[CH:9][C:10]([O:21][CH3:20])=[CH:14][CH:15]=2)[N:5]=1)([CH3:17])([CH3:18])[CH3:19]
Reactant: CC(C)(C)c1cc(N)n(-c2ccc(C(=O)O)cc2)n1
Reactant: COc1ccc(NN)cc1
Product: COc1ccc(-n2nc(C(C)(C)C)cc2N)cc1

Procedure:
The title compound was prepared in the same manner as described for 4-(5-amino-3-tert-butyl-pyrazol-1-yl)benzoic acid, replacing 4-hydrazinobenzoic acid with 4-methoxyphenylhydrazine. 1H-NMR (DMSO-d6) δ 7.40 (d, J=5.1 Hz, 2H), 6.98 (d, J=4.8 Hz, 2H), 5.32 (s, 1H), 5.05 (s, 2H), 3.77 (s, 3H), 1.20 (s, 9H); MS LC-MS [M+H]+=246, RT=1.76 min.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.Br[C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[O:17])=[CH:12][C:11]=1[F:32]>>[CH3:30][C:29]1[C:24]([N:21]2[CH2:22][CH2:23][N:18]([C:16]([C:13]3[CH:14]=[CH:15][C:10]([N:7]4[C@H:3]([CH2:2][OH:1])[CH2:4][CH2:5][C:6]4=[O:8])=[C:11]([F:32])[CH:12]=3)=[O:17])[CH2:19][CH2:20]2)=[N:25][CH:26]=[C:27]([CH3:31])[CH:28]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)c(F)c3)CC2)c(C)c1
Reactant: O=C1CC[C@@H](CO)N1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)CC[C@H]4CO)c(F)c3)CC2)c(C)c1
Yield: 36.4 %

Procedure:
Using (S)-5-hydroxymethylpyrrolidin-2-one (127 mg) and (4-bromo-3-fluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (392 mg) described in Preparation Example 125 and by the reaction and treatment in the same manner as in Example 1, the title compound (155 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-])=O)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]>[Pd].CO>[NH2:1][C:2]1[C:10]([NH2:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Nc1c(C(=O)O)cccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Nc1cccc(C(=O)O)c1N
Reaction time: 2 h
Yield: 67.7 %

Procedure:
Palladium on carbon catalyst (10% Pd, ~200 mg) was added cautiously, as a slurry in methanol (10ml), to a solution of 3-nitroanthranilic acid (2.44 g, 13 mmol) in methanol (120 ml), and the mixture was stirred under a hydrogen atmosphere for 2 hours until the absorption of gas ceased. The catalyst was removed by filtration through Celite, and the filtrate was evaporated to dryness under reduced pressure to afford the crude product. Purification by column chromatography on silica gel, with dichloromethane:methanol (4:1) as eluent, gave 2,3-diaminobenzoic acid as a red solid (1.34 g, 66%). vmax /cm-1 3433.73, 2882.02, 2602.30 and 1658.99; δH (d6 -DMSO, 200 MHz) 5.8-7.4 (4H, br s, 2×NH2), 6.45 (1H, t, Ar-5H), 6.75 (1H, d, Ar-4H), 7.20 (1H, d, Ar-6H); δC (d6 -DMSO) 110.31, 115.45, 118.33, 120.55, 135.03, 140.36, 170.68; m/z (EI) 152 (M+), 134, 106, 79.
Reaction SMILES: Br.[NH2:2][CH:3]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]2[NH:12][C:13]3[C:18]([C:19]=2[CH:20]=1)=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:4]([OH:6])=[O:5].C(=O)([O-])O.[Na+].O1CCOCC1.Cl[C:33]([O:35][CH2:36][CH:37]1[C:49]2[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=2[C:43]2[C:38]1=[CH:39][CH:40]=[CH:41][CH:42]=2)=[O:34]>O>[CH:10]1[C:11]2[NH:12][C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:19]=2[CH:20]=[C:8]([CH2:7][CH:3]([NH:2][C:33]([O:35][CH2:36][CH:37]2[C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][C:43]=3[C:44]3[C:49]2=[CH:48][CH:47]=[CH:46][CH:45]=3)=[O:34])[C:4]([OH:6])=[O:5])[CH:9]=1
Reactant: NC(Cc1ccc2[nH]c3ccccc3c2c1)C(=O)O
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(NC(Cc1ccc2[nH]c3ccccc3c2c1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Temperature: 0 °C

Procedure:
Crude 2-Amino-3-(9H-carbazol-3-yl)-propionic acid HBr salt (50 mg, 0.15 mmol) was combined with aqueous sodium hydrogen carbonate (2 mL of a saturated solution) and dioxane (2 mL) and stirred at about 0° C. 9-Fluorenylmethyl chloroformate (100 mg, 0.39 mmol) was added and the reaction stirred at room temperature for about 8 h. The reaction mixture was diluted with water (25 mL), and extracted with diethyl ether (2×25 mL). The aqueous layer was acidified with hydrochloric acid to pH 3, and extracted with ethyl acetate (3×25 mL). The combined ethyl acetate extracts were concentrated under reduced pressure and dried in vacuo. The crude product was purified using column chromatography on silica gel with 10% methanol in dichloromethane as eluant to afford rac-3-(9H-Carbazol-3-yl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-propionic acid (ES-MS (M+H)+ 477.2 (calc. 477.17)), which was utilized directly in the synthesis of peptide analogs by solid phase peptide synthesis protocols.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:15][C:16](=[O:20])OCC)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:26]=[CH:27][CH:28]=1>>[CH3:1][O:2][C:3]1[C:4]([NH:15][C:16]([N:32]2[CH2:31][CH2:30][N:29]([C:25]3[CH:26]=[CH:27][CH:28]=[C:23]([O:22][CH3:21])[CH:24]=3)[CH2:34][CH2:33]2)=[O:20])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2
Reactant: COc1cccc(N2CCNCC2)c1
Reactant: CCOC(=O)Nc1nc2ccc(OC)cc2nc1OC
Product: COc1cccc(N2CCN(C(=O)Nc3nc4ccc(OC)cc4nc3OC)CC2)c1
Yield: 90 %

Procedure:
Ethyl N-(3,6-dimethoxyquinoxalin-2-yl)carbamate and 1-(3-methoxyphenyl)piperazine were reacted by the same way with the example 148 to obtain the titled compound (yield, 90%). 1H NMR (300 MHz, CDCl3): δ 3.27 (s, 4H), 3.75 (s, 4H), 3.79 (s, 3H), 3.89 (s, 3H), 4.12 (s, 3H), 6.44-6.57 (m, 3H), 7.14-7.22 (m, 4H), 7.72-7.75 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[NH:7][C:6]=2[CH:5]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:3]=1.Br[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:26].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[N:7]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[C:6]=2[CH:5]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:3]=1
Reactant: Clc1ccccc1CBr
Reactant: Cc1nc2c(Br)cc(N3CCOCC3)cc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc2c(Br)cc(N3CCOCC3)cc2n1Cc1ccccc1Cl
Temperature: 90 °C
Reaction time: 4 h
Yield: 84.5 %

Procedure:
To the mixture of 4-(4-bromo-2-methyl-1H-benzo[d]imidazol-6-yl)morpholine (0.8 g, 2.70 mmol) in N,N-Dimethylformamide (DMF) (10 mL) was added 1-(bromomethyl)-2-chlorobenzene (0.666 g, 3.24 mmol) and potassium carbonate (1.120 g, 8.10 mmol). The resulting reaction mixture was stirred at 90° C. for 4 h. It was cooled to room temperature and poured into water (100 mL). The aqueous mixture was extracted with DCM (100 mL×2). The combined organic phases were washed with Brine (100 mL) and concentrated. The crude material was purified on silica column (20˜70% EtOAc in Hexane) to give the product as solid (0.96 g, 84%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.56 (s, 3H) 2.89-3.18 (m, 4H) 3.66-3.91 (m, 4H) 5.34 (s, 2H) 6.35-6.50 (m, 1H) 6.57 (d, J=2.27 Hz, 1H) 7.00-7.21 (m, 2H) 7.21-7.33 (m, 1H) 7.47 (dd, J=7.82 1.11 Hz, 1H); MS (ES+) m/e 420.0 [M+H]+.