Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[C:12]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([Cl:30])[CH:23]=2)=[N:13][C:14](S(C)=O)=[N:15][CH:16]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH:32]12[CH2:37][CH:36]1[CH2:35][NH:34][CH2:33]2.C(N(CC)CC)C>C1COCC1>[CH2:1]([NH:8][C:9]([C:11]1[C:12]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([Cl:30])[CH:23]=2)=[N:13][C:14]([N:34]2[CH2:35][CH:36]3[CH:32]([CH2:37]3)[CH2:33]2)=[N:15][CH:16]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1NCC2CC12
Reactant: COc1ccc(CNc2nc(S(C)=O)ncc2C(=O)NCc2ccccc2)cc1Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(CNc2nc(N3CC4CC4C3)ncc2C(=O)NCc2ccccc2)cc1Cl
Reaction time: 5 h
Yield: 23.9 %

Procedure:
In absolute THF (15 mL) were dissolved N-benzyl-4-((3-chloro-4-methoxybenzyl)amino)-2-(methylsulfinyl)pyrimidine-5-formamide (200 mg, 0.45 mmol) and 3-azabicyclo[3.1.0]hexane hydrochloride salt (81 mg, 0.68 mmol). Triethylamine (137 mg, 1.35 mmol) was added dropwisely. The reaction was conducted at ambient temperature for 5 h. The solvent was removed by rotary evaporation, followed by addition of water and extraction with DCM. The organic phase was dried over sodium sulfate and concentrated. The obtained solid was purified by silica gel column chromatography (DCM/methanol=50/1) to give a yellow solid (50 mg, 24% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([OH:19])=O)[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C(=O)CCC1=O.C1CCC(N=C=NC2CCCCC2)CC1.[NH:43]1[CH2:49][CH2:48][CH2:47][C@H:44]1[CH2:45][OH:46]>C1COCC1>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([N:43]1[CH2:49][CH2:48][CH2:47][C@H:44]1[CH:45]=[O:46])=[O:19])[CH2:13][CH:14]([CH3:15])[CH3:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC[C@@H]1CCCN1
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: C1CCOC1
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C=O
Temperature: 4 °C
Reaction time: 21 h

Procedure:
In 200 ml of THF was dissolved 26.5 g of N-benzyloxycarbonyl-leucin. To this solution were added under cooling with edible salt and ice 11.5 g of HOSu and 20.6 g of DCC, and the mixture was stirred for 21 hours at 4° C. The reaction liquid was filtered and the filtrate was evaporated whereby a semi-solid substance was obtained. This substance was recrystallized from isopropyl alcohol to obtain a white solid substance which was then dissolved in 400 ml of THF. To this solution was added 7.9 g of L-prolinol, and the mixture was stirred for 72 hours at room temperature. After removal of THF by distillation, the residue was dissolved in 300 ml of ethyl acetate and the solution was washed with 100 ml of 1-M Na2CO3, dehydrated with anhydrous Na2SO4 and evaporated until dryness. To the resultant oily substance were added 33.5 g of WSCD-HCl and 140 ml of redistilled DMSO, and the mixture was stirred for 10 minutes. Subsequently, 6.2 ml of a DMSO solution of 2 -M anhydrous H3PO4 was added and the mixture was stirred for further 2 hours. The reaction was stopped with 300 ml of a buffer solution of 1-M potassium phosphate of pH 7.5. The reaction mixture was extracted with 300 ml of ethyl acetate, and the extract was dried over anhydrous Na2SO4. The ethyl acetate was distilled off and the residue was dissolved in 300 ml of ethanol. To this solution was added 200 g of NaHSO3 in 350 ml of water, and the mixture was stirred vigorously for 10 minutes. After concentration of the ethanol up to about 350 ml, unreacted materials were eliminated twice with 100 ml of ether, and solid Na2CO3 was added until the pH value of the liquid became 9. After 5 minutes, the reaction liquid was extracted twice with 100 ml of ether, and the ether was then distilled off to leave an oily substance. Yield 4.2 g (12.1%).
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[C:15]([C:17]([O:19]CC)=O)[N:14]=[N:13]2)=[C:8]([OH:22])[CH:7]=1)=[O:5])[CH3:2].[CH:23]1([NH2:26])[CH2:25][CH2:24]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.O.C(N(CC)CC)C>[CH:23]1([NH:26][C:17]([C:15]2[N:14]=[N:13][N:12]([C:9]3[CH:10]=[CH:11][C:6]([C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:7][C:8]=3[OH:22])[CH:16]=2)=[O:19])[CH2:25][CH2:24]1
Reactant: CCNC(=O)c1ccc(-n2cc(C(=O)OCC)nn2)c(O)c1
Reactant: NC1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCNC(=O)c1ccc(-n2cc(C(=O)NC3CC3)nn2)c(O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
The product obtained in the same manner as in Example 133e) from ethyl 1-{4-[(ethylamino)carbonyl]-2-hydroxyphenyl}-1H-1,2,3-triazole-4-carboxylate (2.37 g) obtained in Example 133c) was dissolved in DMF (18 ml), cyclopropylamine (0.51 ml), triethylamine (1.01 ml), HOBt (1.12 g) and WSC (1.40 g) were successively added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was acidified with 1N hydrochloric acid. The precipitated crystals were collected by filtration and washed with water to give the title compound as a pale-brown powder (1.41 g, yield in 2 steps 59%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]>C1C=CC=CC=1.C(OCC)C>[N:1]1([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: CCOC(=O)CBr
Solvent: c1ccccc1
Solvent: CCOCC
Product: CCOC(=O)CN1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.8 %

Procedure:
Piperidine(1.87 ml, 18.9 mmol) was added dropwise to a solution of ethyl bromoacetate(1 ml, 9.0 mmol) in benzene(9 ml), stirred for 2 hours at a room temperature, diluted with ethyl ether, washed with saturated NaCl solution. The separated organic layer was dried over anhydrous sodium sulfate and concentrated under a reduced pressure to give 1.26 g of the titled compound. (Yield 81.8%)
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][OH:6])[CH3:2].[Cl:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([Cl:15])=[CH:10][C:9]=1[S:16](Cl)(=[O:18])=[O:17]>>[Cl:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([Cl:15])=[CH:10][C:9]=1[S:16]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][OH:6])(=[O:18])=[O:17]
Reactant: O=S(=O)(Cl)c1cc(Cl)c(Cl)cc1Cl
Reactant: CCNCCO
Product: CCN(CCO)S(=O)(=O)c1cc(Cl)c(Cl)cc1Cl

Procedure:
The title compound was prepared from 2-ethylamino ethanol and 2,4,5trichlorophenylsulfonylchloride using the method described in Description 1.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=1[NH2:14].C(N(CC)CC)C.ClC(Cl)(O[C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.[NH2:35][C:36]1[CH:41]=[N:40][CH:39]=[CH:38][N:37]=1>C1(C)C=CC=CC=1>[CH3:15][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=1[NH:14][C:27]([NH:35][C:36]1[CH:41]=[N:40][CH:39]=[CH:38][N:37]=1)=[O:33]
Reactant: Cc1ccc(OCCCN(C)C)c(N)c1
Reactant: Nc1cnccn1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1ccc(OCCCN(C)C)c(NC(=O)Nc2cnccn2)c1
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 35 %

Procedure:
To a stirred, cooled (about 0° C.) solution of 2-(3-dimethylamino-propoxy)-5-methyl-phenylamine (208 mg, 1.0 mmol) in toluene (3.0 mL) was added triethylamine (140 μL, 1.0 mmol) and triphosgene (98 mg, 0.33 mmol). After stirring for 30 minutes, amino pyrazine (95 mg, 1.0 mmol) was added and the reaction was heated to 65 degrees C. After stirring for 4 hours, the reaction was cooled to room temperature and stirred for 8 hours. The precipitate that formed was filtered, rinsed with toluene (2×1mL), and dried under reduced pressure (35% yield).
Reaction SMILES: [CH:1]1([N:4]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[C:5]([C:7]2[CH:8]=[N:9][C:10]([N:13]3[CH:17]=[CH:16][N:15]=[C:14]3[CH3:18])=[N:11][CH:12]=2)=[O:6])[CH2:3][CH2:2]1.F[C:26]1[C:31]([F:32])=[CH:30][C:29]([C:33]([F:36])([F:35])[F:34])=[CH:28][N:27]=1.C(N(C(C)C)C(C)C)C>CN1CCCC1=O>[CH:1]1([N:4]([CH:19]2[CH2:24][CH2:23][N:22]([C:26]3[C:31]([F:32])=[CH:30][C:29]([C:33]([F:36])([F:34])[F:35])=[CH:28][N:27]=3)[CH2:21][CH2:20]2)[C:5]([C:7]2[CH:12]=[N:11][C:10]([N:13]3[CH:17]=[CH:16][N:15]=[C:14]3[CH3:18])=[N:9][CH:8]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: Cc1nccn1-c1ncc(C(=O)N(C2CCNCC2)C2CC2)cn1
Reactant: Fc1cc(C(F)(F)F)cnc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cc1nccn1-c1ncc(C(=O)N(C2CC2)C2CCN(c3ncc(C(F)(F)F)cc3F)CC2)cn1
Temperature: 200 °C

Procedure:
A mixture of 2-(2-methyl-imidazol-1-yl)-pyrimidine-5-carboxylic acid cyclopropyl-piperidin-4-yl-amide (44 mg), 2,3-difluoro-5-(trifluoromethyl)pyridine (22 mg), and ethyldiisopropylamine (35 μL) in N-methyl-2-pyrrolidinone (1 mL) is heated to 200° C. for 0.5 h in a microwave oven. The reaction mixture is concentrated and the crude product is purified by preparative HPLC (MeOH/H2O/ammonia). LC (method 16): tR=1.29 min; Mass spectrum (ESI+): m/z=490 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[C:6]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)=[O:7].[C-:18]#[N:19].[K+].CCOCC>O1CCOCC1.O>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]([C:5]2[CH:4]=[C:3]([CH2:2][C:18]#[N:19])[CH:17]=[CH:16][CH:15]=2)=[O:7])=[CH:9][CH:10]=1
Reactant: O=C(c1ccc(Cl)cc1)c1cccc(CBr)c1
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOCC
Product: N#CCc1cccc(C(=O)c2ccc(Cl)cc2)c1
Reaction time: 6 h
Yield: 68.4 %

Procedure:
A solution of 17 g of 3-bromomethyl-4'-chlorobenzophenone in 75 cc of dioxane at 70° C. was added to the solution of 26.5 g of potassium cyanide in 75 cc of water and the mixture was refluxed with stirring for 6 hours. After cooling, 500 cc of ether were added to the mixture and the aqueous phase was decanted off. The organic phase was washed with water until the wash waters were neutral, dried over magnesium sulfate, treated with activated carbon, filtered and evaporated to dryness under reduced pressure. The residue was crystallized from methanol to obtain 9.61 g of 3-p-chlorobenzoyl phenyl acetonitrile melting at 86° to 90° C.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][N:6]1[C:10]([CH2:11]O)=[C:9]([CH2:13][O:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]3=[N:25][N:26]=[C:27]([C:28]4[CH:32]=[C:31]([CH3:33])[O:30][N:29]=4)[N:17]3[N:16]=2)[N:8]=[N:7]1.ClCC1N=NNC=1.[NH:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1>C(Cl)Cl>[CH3:33][C:31]1[O:30][N:29]=[C:28]([C:27]2[N:17]3[N:16]=[C:15]([O:14][CH2:13][C:9]4[N:8]=[N:7][N:6]([CH3:5])[C:10]=4[CH2:11][N:41]4[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]4)[C:24]4[C:19]([C:18]3=[N:25][N:26]=2)=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:32]=1
Reactant: Cc1cc(-c2nnc3c4ccccc4c(OCc4nnn(C)c4CO)nn23)no1
Reactant: C1CCNCC1
Agent: ClCc1c[nH]nn1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1cc(-c2nnc3c4ccccc4c(OCc4nnn(C)c4CN4CCCCC4)nn23)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 16 %

Procedure:
Thionyl chloride (625 μl, 8.6 mmol) was added to a stirred suspension of [1-methyl-4-({[3-(5-methylisoxazol-3-yl)[1,2,4]triazolo[3,4-α]phthalazine-6-yl]oxy}methyl)-1H-[1,2,3]triazol-5-yl]methanol (672 mg, 1.71 mmol) in CH2Cl2 (50 ml) and the mixture was stirred at room temperature for 1 h under N2, during which period the solid dissolved and then precipitated. The reaction mixture was concentrated under reduced pressure and then azeotroped with toluene (2×50 ml) and used without further purification. A portion of the crude chloromethyltriazole (125 mg, 0.30 mmol) and piperidine (0.30 ml, 3.0 mmol) in CH2Cl2 (6ml) were stirred at room temperature for 48 h under N2. The mixture was then concentrated under reduced pressure while dry loading onto silica and purified by column chromatography on silica using 2% MeOH/CH2Cl2 containing 1% NH3 solution as eluent to yield the desired phthalazine (126 mg, 90%), which was then recrystallised CH2Cl2/iso-hexanes. 1H NMR (360 MHz, CDCl3) δ 8.67 (1H, d, J=8.0 Hz), 8.14 (1H, d, J=8.0 Hz), 7.93 (1H, t, J=8.0 Hz), 7.75 (1H, d, J=8.0 Hz), 6.94 (1H, s), 5.77 (2H, s), 4.12 (3H, broad s), 3.70-3.60 (2H, m), 2.59 (3H, s), 2.40-2.30 (4H, m), 1.75-1.33 (6H, m).
Reaction SMILES: [F:1][C:2]([F:26])([O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[N:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=3)=[N:15]2)=[CH:10][CH:9]=1)[C:3]([F:6])([F:5])[F:4].Cl[C:28]([O:30][C:31]1[CH:36]=CC([N+]([O-])=O)=C[CH:32]=1)=[O:29].[N+]([C:43]1C=CC(NC(=O)[O-])=CC=1)([O-])=O.CC(O)(C)C.[H-].[Na+]>C1COCC1>[C:31]([O:30][C:28](=[O:29])[NH:25][C:22]1[CH:23]=[CH:24][C:19]([C:16]2[N:17]=[CH:18][N:14]([C:11]3[CH:12]=[CH:13][C:8]([O:7][C:2]([F:1])([F:26])[C:3]([F:6])([F:5])[F:4])=[CH:9][CH:10]=3)[N:15]=2)=[CH:20][CH:21]=1)([CH3:36])([CH3:43])[CH3:32]
Reactant: O=C([O-])Nc1ccc([N+](=O)[O-])cc1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccc(-c2ncn(-c3ccc(OC(F)(F)C(F)(F)F)cc3)n2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ncn(-c3ccc(OC(F)(F)C(F)(F)F)cc3)n2)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 23.5 %

Procedure:
A solution of 4-[1-(4-pentafluoroethyloxyphenyl)-1H-[1,2,4]triazol-3-yl]-phenylamine (1.0 g, 2.7 mmol) in dry THF (8 mL) was stirred while p-nitrophenyl chloroformate (0.60 g, 3 mmol) was added in one portion and the solution was allowed to stir for 3 h. The resulting solid was filtered and air-dried. A smaller portion of the p-nitrophenylcarbamate (152 mg, 0.28 mmol) was suspended in dry THF (3 mL). To this were added 2-methyl-2-propanol (41 mg, 0.32 mmol) in dry THF (1 mL) followed by NaH (60% mineral oil dispersion; 26 mg, 0.67 mmol) in one portion. Additional dry THF (1 mL) was used to rinse joints, etc. The solution was heated to 60° C. (external) for 1.5 h, at which point TLC (3:3:3:1 EtOAc/hexanes/CH2Cl2/acetone) showed no starting material. The mixture was cooled and allowed to stir at 25° C. for 20 h. The mixture was cooled, poured on to ice-water (50 mL), and extracted with EtOAc (3×50 mL). The combined extracts were washed with satd aq NaCl (75 mL), dried (Na2SO4), filtered and concentrated. RP-HPLC (acid-free medium water-acetonitrile gradient) provided the title compound (31 mg, 23%) as an off-white solid: mp 205-209° C.; 1H NMR (400 MHz, CDCl3) δ 8.55 (s, 1H), 8.12 (d, J=9.0 Hz, 2H), 7.80 (d, J=9.3 Hz, 2H), 7.48 (d, J=8.8 Hz, 2H), 7.38 (d, J=9.0 Hz, 2H), 6.58 (s, 1H), 1.54 (s, 9H); ESIMS m/z 471 (M+H), 469 (M−H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][S@](C(C)(C)C)=O)[CH3:9])=[C:4]([F:17])[CH:3]=1.Cl.O1CCOCC1>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH2:10])[CH3:9])=[C:4]([F:17])[CH:3]=1
Reactant: C[C@@H](N[S@@](=O)C(C)(C)C)c1ccc(Cl)cc1F
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: C[C@@H](N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (S)-N-((R)-1-(4-chloro-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (5.4 g, 19.4 mmol) in methanol (150 mL) at 0° C. was added a solution of hydrochloric acid in p-dioxane (4.0 M in p-dioxane, 19.4 mL, 77.6 mmol). The reaction was slowly warmed to room temperature and stirred at room temperature for 18 h. The solvent removed in vacuo, and the crude material was dissolved in saturated aqueous sodium bicarbonate and dichloromethane. The mixture was stirred for 45 min to give a clear solution. The phases were separated, and the aqueous layer was extracted with dichloromethane (2×100 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was used without further purification (3.1 g, 92%, >96% ee, determined by Mosher's method).
Reaction SMILES: C([O:8][C:9]1[CH:115]=[CH:114][C:12]([CH2:13][C@@H:14]([C:28]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([CH:37]([C:76]3[CH:81]=[CH:80][C:79]([NH:82][C:83](=[O:113])[C@H:84]([CH2:98][C:99]4[CH:104]=[CH:103][C:102]([O:105]CC5C=CC=CC=5)=[CH:101][CH:100]=4)[NH:85][C:86](=[O:97])[CH2:87][C:88]4[C:96]5[C:91](=[CH:92][CH:93]=[CH:94][CH:95]=5)[NH:90][CH:89]=4)=[CH:78][CH:77]=3)[C:38]3[CH:43]=[CH:42][C:41]([NH:44][C:45](=[O:75])[C@H:46]([CH2:60][C:61]4[CH:66]=[CH:65][C:64]([O:67]CC5C=CC=CC=5)=[CH:63][CH:62]=4)[NH:47][C:48](=[O:59])[CH2:49][C:50]4[C:58]5[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=5)[NH:52][CH:51]=4)=[CH:40][CH:39]=3)=[CH:33][CH:32]=2)=[O:29])[NH:15][C:16](=[O:27])[CH2:17][C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][CH:19]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1>CO.CN(C)C=O.[C].[Pd]>[NH:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18]([CH2:17][C:16]([NH:15][C@H:14]([C:28]([NH:30][C:31]2[CH:32]=[CH:33][C:34]([CH:37]([C:38]3[CH:43]=[CH:42][C:41]([NH:44][C:45](=[O:75])[C@H:46]([CH2:60][C:61]4[CH:62]=[CH:63][C:64]([OH:67])=[CH:65][CH:66]=4)[NH:47][C:48](=[O:59])[CH2:49][C:50]4[C:58]5[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=5)[NH:52][CH:51]=4)=[CH:40][CH:39]=3)[C:76]3[CH:77]=[CH:78][C:79]([NH:82][C:83](=[O:113])[C@H:84]([CH2:98][C:99]4[CH:104]=[CH:103][C:102]([OH:105])=[CH:101][CH:100]=4)[NH:85][C:86](=[O:97])[CH2:87][C:88]4[C:96]5[C:91](=[CH:92][CH:93]=[CH:94][CH:95]=5)[NH:90][CH:89]=4)=[CH:80][CH:81]=3)=[CH:35][CH:36]=2)=[O:29])[CH2:13][C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:115][CH:114]=2)=[O:27])=[CH:19]1
Reactant: O=C(Cc1c[nH]c2ccccc12)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)Nc1ccc(C(c2ccc(NC(=O)[C@H](Cc3ccc(OCc4ccccc4)cc3)NC(=O)Cc3c[nH]c4ccccc34)cc2)c2ccc(NC(=O)[C@H](Cc3ccc(OCc4ccccc4)cc3)NC(=O)Cc3c[nH]c4ccccc34)cc2)cc1
Agent: [Pd]
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(Cc1c[nH]c2ccccc12)N[C@@H](Cc1ccc(O)cc1)C(=O)Nc1ccc(C(c2ccc(NC(=O)[C@H](Cc3ccc(O)cc3)NC(=O)Cc3c[nH]c4ccccc34)cc2)c2ccc(NC(=O)[C@H](Cc3ccc(O)cc3)NC(=O)Cc3c[nH]c4ccccc34)cc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 4.2 %

Procedure:
The tris[4-[O-benzyl-N-[2-(1H-indol-3-yl)acetyl]-L-tyrosyl]aminophenyl]methane (70 mg) obtained in Example 92 was dissolved in a mixed solvent of methanol (4 ml) and N,N-dimethylformamide (4 ml), 10% palladium carbon (25 mg) was added, and then the mixture was stirred for 3 days at room temperature under a hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. A portion of the residue was purified by preparative high performance liquid chromatography using methanol/trifluoroacetic acid (100/0.1) and water/trifluoroacetic acid (100/0.1) as a mixed eluent, to obtain 2.4 mg of the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][NH:9][CH2:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[CH:2]=1.C(N(C(C)C)C(C)C)C.CN(C=O)C.[Cl:31][CH2:32][CH2:33][CH2:34]I>O>[Cl:31][CH2:32][CH2:33][CH2:34][N:9]([CH2:8][CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH2:10][C:11]1[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=1
Reactant: c1cncc(CCNCc2ccncc2)c1
Reactant: ClCCCI
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: ClCCCN(CCc1cccnc1)Cc1ccncc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(2-Pyridin-3-yl-ethyl)-pyridin-4-ylmethyl-amine (210 mg) and N-ethyldiisopropylamine (0.34 ml) were added to a DMF solution (2 ml) of 1-chloro-3-iodopropane (0.16 ml). The mixture was stirred at room temperature overnight. Water was added to the reaction mixture, followed by extraction using ethyl acetate. The organic layer was washed with water and then saturated saline, and dried with anhydrous sodium sulfate. After condensation under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate:methanol=20:1→4:1). The purified product was condensed under reduced pressure to give the title compound (74 mg) as a colorless oily matter.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][CH:2]=1.C1([Li])C=CC=CC=1.C1CCCCC1.[C:21]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCCC1.CCOCC>[C:29]1([C:21]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)([OH:28])[CH2:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: Cc1ccncc1
Agent: [Li]c1ccccc1
Solvent: C1CCOC1
Solvent: C1CCCCC1
Solvent: CCOCC
Product: OC(Cc1ccncc1)(c1ccccc1)c1ccccc1
Reaction time: 0.5 h
Yield: 93.7 %

Procedure:
A flame-dried, 12-L flask equipped with a mechanical stirrer, thermometer, and dropping funnel was charged under argon with 252.5 g of 4-picoline and 2.50 L of tetrahydrofuran. The solution was cooled in an ice bath to below 20° and maintained at 15°-20° during the addition over 15 minutes, of 1.315 L of 1.85M phenyllithium in 70:30 cyclohexane:ether solution. The mixture was stirred at 15°-20° for 30 minutes and then cooled to -5°-0° in an acetone-ice bath. The temperature was maintained in this range during the rapid addition of a solution of 494.2 g of benzophenone in 1.50 L tetrahydrofuran. A bright blue color persisted after the addition of just a little of the benzophenone solution. The cooling bath was removed and the mixture was stirred at ambient temperature for 3 hours. To the flask was added 1.0 L of deionized water and 2.0 L of tetrahydrofuran. The mixture was warm gently on a steam bath to dissolve all the solids. The aqueous phase was separated and extracted with 2.0 L of tetrahydrofuran. The combined organic solutions were dried over sodium sulfate and stripped of solvent on a rotary evaporator at 45°. The resulting solid was triturated at reflux with 1.60 L of hexanes. The suspension was stored at 4° overnight and filtered. The solids were washed with a total of 1.0 L of boiling point 35°-60° petroleum ether and dried in a forced air oven at 75° to give 699.6 g (94% yield) of alpha,alpha-diphenyl-4-pyridineethanol as a pale-yellow solid, mp 154°-155°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH:13]=O)[C@H:10]([C:15]([CH3:23])([CH3:22])[O:16][SiH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:24]([NH2:27])([CH3:26])[CH3:25].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC#N.O>ClCCCl.O.CC#N>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][NH:27][CH:24]([CH3:26])[CH3:25])[C@H:10]([C:15]([CH3:23])([CH3:22])[O:16][SiH2:17][C:18]([CH3:20])([CH3:19])[CH3:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)N
Reactant: CC(C)(C)OC(=O)N1C[C@@H](C=O)[C@H](C(C)(C)O[SiH2]C(C)(C)C)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCCl
Solvent: O
Product: CC(C)NC[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1C(C)(C)O[SiH2]C(C)(C)C

Procedure:
The title compound is prepared in a similar manner as described for Example 9/reaction step F, from (3S*,4S*)-3-(tert-butyl-dimethyl-silanyloxymethyl)-4-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester (19.3 g, 56.1 mmol), isopropylamine (14.5 mL, 168 mmol) and NaBH(OAc)3 (29.7 g, 140 mmol) in 1,2-dichloroethane (0.5 L) as a yellowish oil. MS: 387.2 [M+H]+. tR (HPLC, C18 column, 5-100% CH3CN/H2O/6 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA, flow: 1 mL/min): 5.34 min.