Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.II.O=[C:13]([CH:15]=[C:16]([CH3:18])[CH3:17])[CH3:14]>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[NH:9][C:16]([CH3:18])([CH3:17])[CH:15]=[C:13]2[CH3:14]
Reactant: CC(=O)C=C(C)C
Reactant: COc1ccc(N)cc1
Agent: II
Product: COc1ccc2c(c1)C(C)=CC(C)(C)N2

Procedure:
Skraup reaction of 4-anisidine (5.0 g) and iodine (1.7 g) in mesityl oxide (25 ml) was performed according to the method described in example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21](O)=O)[C:9]=2[CH2:24][CH3:25])=[CH:4][CH:3]=1.Cl.[NH2:27][C:28]([CH3:33])([CH3:32])[C:29]([NH2:31])=[O:30]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]3[NH:31][C:29](=[O:30])[C:28]([CH3:33])([CH3:32])[N:27]=3)[C:9]=2[CH2:24][CH3:25])=[CH:6][CH:7]=1
Reactant: CCc1c(C(=O)O)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reactant: CC(C)(N)C(N)=O
Agent: Cl
Product: CCc1c(C2=NC(C)(C)C(=O)N2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1

Procedure:
Compound 24 was synthesized from 4c (1.0 g, 2.53 mmol) and 5i (0.56 g, 4.07 mmol) as a white solid (0.58 g, 50%) in a manner similar to that described in Example 53. 1H NMR (400 MHz, CDCl3) δ 7.43 (d, 1H), 7.30 (d, 2H), 7.30˜7.27 (m, 2H), 7.07 (d, 2H), 7.00 (br s, 1H), 2.78 (q, 2H), 1.81 (s, 6H), 1.20 (t, 3H); ESMS m/z: 461.0 (M+1).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[N:15]=[N:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([CH:22]4[CH2:27][CH2:26][CH:25]([CH2:28][C:29]([NH2:31])=O)[CH2:24][CH2:23]4)=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.C1COCC1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(N(CC)CC)C>[F:33][C:2]([F:1])([F:32])[C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[N:15]=[N:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([CH:22]4[CH2:23][CH2:24][CH:25]([CH2:28][C:29]#[N:31])[CH2:26][CH2:27]4)=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)=[CH:5][CH:4]=1
Reactant: NC(=O)CC1CCC(c2ccc(-c3ccc(Nc4ccc(C(F)(F)F)nc4)nn3)cc2)CC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: N#CCC1CCC(c2ccc(-c3ccc(Nc4ccc(C(F)(F)F)nc4)nn3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2-(4-{4-[6-(6-Trifluoromethyl-pyridin-3-ylamino)-pyridazin-3-yl]-phenyl}-cyclohexyl)-acetamide (0.18 g, 0.41 mmol, 1.0 equiv) in 3 Ml THF was added trifluoroacetic anhydride (0.068 Ml, 0.49 mmol, 1.2 equiv) followed by triethylamine (0.12 Ml, 0.90 mmol, 2.2 equiv). The reaction was stirred at ambient temperature overnight, and then concentrated in vacuo. Purification by silica gel chromatography (10-50% EtOAc in hexanes) afforded the title compound: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.39-1.50 (m, J=12.82, 12.54, 12.54, 3.54 Hz, 2H) 1.69-1.80 (m, J=12.88, 12.69, 12.69, 3.41 Hz, 2H) 1.86-1.97 (m, J=11.91, 11.91, 6.06, 5.87, 2.91 Hz, 1H) 2.09 (d, J=15.92 Hz, 1H) 2.09 (dd, J=5.94, 3.66 Hz, 3H) 2.76 (t, J=3.03 Hz, 1H) 7.53 (d, J=9.35 Hz, 1H) 7.59 (d, J=8.34 Hz, 2H) 8.08 (d, J=8.59 Hz, 1H) 8.20 (d, J=8.34 Hz, 2H) 8.30 (d, J=9.35 Hz, 1H) 8.91 (dd, J=8.59, 2.27 Hz, 1H) 9.16 (d, J=2.53 Hz, 1H) 10.25 (s, 1H); (M+H)+438.3.
Reaction SMILES: [CH2:1]([C:3]([CH2:10][OH:11])([CH2:6][CH2:7][CH2:8][CH3:9])[CH:4]=[O:5])[CH3:2]>[Ni]>[CH2:6]([C:3]([CH2:1][CH3:2])([CH2:4][OH:5])[CH2:10][OH:11])[CH2:7][CH2:8][CH3:9]
Reactant: CCCCC(C=O)(CC)CO
Agent: [Ni]
Product: CCCCC(CC)(CO)CO

Procedure:
continuously feeding the organic phase of step (8) to a hydrogenation zone wherein the 2-ethyl-2-(hydroxymethyl)hexanal is contacted with a supported nickel hydrogenation catalyst at a total pressure of about 21 to 36 bars absolute and at a hydrogenation zone exit temperature of about 150° to 170° C. to produce 2-butyl-2-ethyl-1,3-propanediol.
Reaction SMILES: CO[C:3](=[O:20])[C:4]([NH2:19])([CH2:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)[CH2:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1.[CH3:21][CH:22]1[CH:27]2[C:28]([CH3:30])([CH3:29])[CH:25]([CH2:26]2)[CH2:24][CH:23]1[CH2:31][N:32]=[C:33]=[S:34]>C(O)C>[N:16]1[CH:15]=[CH:14][C:13]([CH2:12][C:4]2([CH2:5][C:6]3[CH:7]=[CH:8][N:9]=[CH:10][CH:11]=3)[NH:19][C:33](=[S:34])[N:32]([CH2:31][CH:23]3[CH2:24][CH:25]4[CH2:26][CH:27]([C:28]4([CH3:30])[CH3:29])[CH:22]3[CH3:21])[C:3]2=[O:20])=[CH:18][CH:17]=1
Reactant: COC(=O)C(N)(Cc1ccncc1)Cc1ccncc1
Reactant: CC1C(CN=C=S)CC2CC1C2(C)C
Solvent: CCO
Product: CC1C(CN2C(=O)C(Cc3ccncc3)(Cc3ccncc3)NC2=S)CC2CC1C2(C)C
Temperature: 75 °C
Reaction time: 16 h
Yield: 80.3 %

Procedure:
2-Amino-3-pyridin-4-yl-2-pyridin-4-ylmethyl-propionic acid methyl ester (2.50 g, 9.23 mmol) was dissolved in absolute ethanol (50 ml). To the reaction was added 5.01 g (23.9 mmol) of (+)-3-pinanemethyl isothiocyanate. The reaction was then heated to 75° C. under an atmosphere of dry N2. After stirring for 16 hours, the reaction was subsequently concentrated under vacuum. The resulting oil was chromatographed on silica gel using a gradient of neat ethyl acetate to 5% methanol in ethyl acetate to give 3.32 g (7.41 mmol) of the titled compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]2[N:9]=[CH:10][CH:11]=[C:4]2[N:3]=1.[Br-].[C:13]([C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18][Zn+])#[N:14].[NH4+].[Cl-]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C>[Cl:8][C:6]1[N:5]2[N:9]=[CH:10][CH:11]=[C:4]2[N:3]=[C:2]([CH2:18][C:17]2[CH:16]=[C:15]([CH:22]=[CH:21][CH:20]=2)[C:13]#[N:14])[CH:7]=1
Reactant: N#Cc1cccc(C[Zn+])c1
Reactant: Clc1cc(Cl)n2nccc2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: N#Cc1cccc(Cc2cc(Cl)n3nccc3n2)c1
Temperature: 60 °C
Yield: 64 %

Procedure:
To the reaction flask, 5,7-dichloropyrazolo[1,5-a]pyrimidine (452 mg, 2.4 mmol) was added along with (3-cyanobenzyl)zinc(II) bromide (6 mL, 3.75 mmol, 0.625M in DMF), Pd(PPh3)4 (110 mg, 0.1 mmol), and DMF (10 mL). The reaction was heated at 60° C. for 4 hours then cooled to room temperature. The reaction mixture was poured into saturated aqueous NH4Cl solution and ice and extracted with ethyl acetate. The combined extracts were washed with water, saturated NaCl solution, and then dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by column chromatography on silica using 35% ethyl acetate/hexanes as the eluent. The product, 3-((7-chloropyrazolo[1,5-a]pyrimidin-5-yl)methyl)benzonitrile, was recovered in 64% yield. LCMS (M+1=269)
Reaction SMILES: C1(NC(N)=N)CC1.[CH:8]([NH:11][C:12]1[N:17]=[C:16]([C:18]2[C:19]([CH:27]([CH3:29])[CH3:28])=[N:20][N:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=23)[CH:15]=[CH:14][N:13]=1)([CH3:10])[CH3:9]>>[CH:8]1([NH:11][C:12]2[N:17]=[C:16]([C:18]3[C:19]([CH:27]([CH3:29])[CH3:28])=[N:20][N:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=34)[CH:15]=[CH:14][N:13]=2)[CH2:10][CH2:9]1
Reactant: CC(C)Nc1nccc(-c2c(C(C)C)nn3ccccc23)n1
Agent: N=C(N)NC1CC1
Product: CC(C)c1nn2ccccc2c1-c1ccnc(NC2CC2)n1

Procedure:
Cyclopropyl-[4-(2-isopropyl-pyrazolo[1,5-a]pyridin-3-yl)-pyrimidin-2-yl]-amine was prepared from 3-dimethylamino-1-(2-isopropyl-pyrazolo[1,5-a]pyridin-3-yl)-propenone and N-cyclopropyl-guanidine following the method used in Step 4 of the synthesis of Isopropyl-[4-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-pyrimidin-2-yl]-amine (Example 66), except preparative-HPLC purification was used in the place of recrystallization (34 mg, 7%). 1H-NMR (250 MHz, DMSO-d6) δ 8.86 (d, J=6.8 Hz, 1H), 8.57 (d, J=8.3 Hz, 1H), 8.27 (d, J=6.5 Hz, 1H), 7.59 (t, J=7.9 Hz, 1H), 7.19-7.10 (m, 2H), 4.62 (broad s, 1H), 3.86-3.78 (m, 1H), 2.80-2.72 (m, 1H), 1.38 (d, J=6.5 Hz, 6H), 0.90-0.84 (m, 2H), 0.70-0.64 (m, 2H); LC/MS 294.2 m/z (M+H+). Compound 1136.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([Cl:12])[C:6]=2[CH2:13]Cl.[Na].CN(C)[CH:18]=[O:19]>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([Cl:12])[C:6]=2[CH2:13][O:19][C:18]1[CH:9]=[CH:8][C:7]([Cl:12])=[CH:6][CH:5]=1
Reactant: CN(C)C=O
Reactant: ClCc1c(Cl)ccc2cc(Cl)cnc12
Agent: [Na]
Product: Clc1ccc(OCc2c(Cl)ccc3cc(Cl)cnc23)cc1

Procedure:
24.6 parts of 3,7-dichloro-8-chloromethylquinoline (Example 1) and 15 parts of sodium p-chlorophenate in 200 parts of dimethylformamide were stirred at 100° C. for 10 hours. The solvent was distilled off, water was added to the residue and the solid was filtered off with suction, dried and recrystallized from a suitable solvent. 32 parts of 3,7-dichloro-8-p-chlorophenoxymethylquinoline of melting point 110° C. were obtained. The yield corresponds to 95% of theory.
Reaction SMILES: [C:1]([BH3-])#[N:2].[Na+].[CH:5]([O:8][C:9]1[CH:16]=[CH:15][C:12](C=O)=[CH:11][CH:10]=1)([CH3:7])[CH3:6].C([O-])(=O)C.[NH4+].Cl>CO>[CH:5]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:1][NH2:2])=[CH:11][CH:10]=1)([CH3:7])[CH3:6]
Reactant: [BH3-]C#N
Reactant: CC(C)Oc1ccc(C=O)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: CO
Product: CC(C)Oc1ccc(CN)cc1
Temperature: 25 °C
Reaction time: 40 h
Yield: 14.2 %

Procedure:
Sodium cyanoborohydride (330 mg) was added to a solution of 770 mg of p-isopropoxybenzaldehyde and 4.0 g of ammonium acetate in 20 ml of methanol, and the mixture was stirred at room temperature for 40 hours. The reaction mixture was adjusted to pH 2 or less by addition of concentrated hydrochloric acid, and then concentrated. The residue was dissolved in water and the solution was washed with ethyl acetate. The aqueous layer was adjusted to pH 11 or more by addition of solid potassium hydroxide, and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated aqueous solution of sodium chloride in that order, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 110 mg of p-isopropoxybenzylamine.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=1)=O.[NH:17]1[CH2:27][CH2:26][CH:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:19][CH2:18]1.C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>ClCCl.CO.[Ti](Cl)(Cl)(Cl)Cl.C(OCC)(=O)C.C1(C)C=CC=CC=1.C(N(CC)CC)C>[F:1][C:2]([F:16])([F:15])[CH:3]([N:17]1[CH2:27][CH2:26][CH:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:19][CH2:18]1)[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=1
Reactant: CCOC(=O)C1CCNCC1
Reactant: O=C(c1cccc(C(F)(F)F)c1)C(F)(F)F
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: CO
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCN(C(c2cccc(C(F)(F)F)c2)C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.355 ml of 2,2,2-trifluoro-1-(3-(trifluoromethyl)phenyl)ethanone in 12 ml of dichloromethane were added 0.32 ml of ethyl isonipecotate, 0.58 ml of triethylamine and 1.05 ml of a toluene solution containing 1 M titanium(IV) chloride at room temperature, followed by stirring the reaction mixture at room temperature overnight. To the reaction mixture was added a solution of 392 mg of sodium cyanoborohydride in 5 ml of methanol at room temperature, followed by stirring the reaction mixture at room temperature for 6 hours. Ethyl acetate and saturated aqueous sodium bicarbonate solution were added to the reaction mixture. An insoluble matter was filtered off using Celite. The ethyl acetate layer was separated, washed with brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated in vacuo. The resulting residue was purified by a silica gel column chromatography (eluent: hexane to hexane/ethyl acetate=4/1) to give the title compound as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[C:13]([F:15])[C:12]([Si](C)(C)C)=[CH:11][C:10]=2[F:20])[N:5]=[C:4]([C:21]([O:23][CH3:24])=[O:22])[C:3]=1[Cl:25].[I:26]Cl.[O-]S([O-])=O.[Na+].[Na+]>C(Cl)Cl>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[C:13]([F:15])[C:12]([I:26])=[CH:11][C:10]=2[F:20])[N:5]=[C:4]([C:21]([O:23][CH3:24])=[O:22])[C:3]=1[Cl:25]
Reactant: ClI
Reactant: COC(=O)c1nc(-c2cc(F)c([Si](C)(C)C)cc2F)c(F)c(N)c1Cl
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1nc(-c2cc(F)c(I)cc2F)c(F)c(N)c1Cl
Temperature: 20 °C
Reaction time: 8 h
Yield: 74.4 %

Procedure:
To a solution of methyl 4-amino-3-chloro-6-(2,5-difluoro-4-(trimethylsilyl)phenyl)-5-fluoropicolinate (0.280 g, 0.720 mmol) in CH2Cl2 (2.88 mL) at 20° C. was added iodine monochloride (0.144 mL, 2.880 mmol). The reaction mixture was stirred at 20° C. overnight. The mixture was then poured into a 10% aqueous solution of Na2SO3, extracted with EtOAc (3×), dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (SiO2, hexanes/EtOAc gradient) to afford the title compound as a white solid (0.237 g, 0.536 mmol, 74.4%).
Reaction SMILES: [Br:1][C:2]1(Br)[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[Br:12])[C:3]1=[O:13]>O>[Br:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[Br:12])[C:3]1=[O:13]
Reactant: O=C1c2cccc(Br)c2CCC1(Br)Br
Solvent: O
Product: O=C1c2cccc(Br)c2CCC1Br
Yield: 98.5 %

Procedure:
A clear yellow solution of 5-bromo-3,4-dihydro-1(2H)-naphthalenone (12.09 g, 53.7 mmol) in freshly opened Et2O (220 mL) under an N2 atmosphere was chilled to −5° C. HCl was bubbled in subsurface for 1 min, causing no visible change. The dropwise addition of a solution of Br2 (8.58 g, 53.7 mmol) in CH2Cl2 (20 mL) and Et2O (2 mL) to the vigorously stirring solution of 5-bromo-3,4-dihydro-1(2H)-naphthalenone over 2 h (each drop was allowed to fully decolorize before adding the next) produced a product mixture that assayed by HPLC. Peak area showed 79.4% title compound, 9.5% unreacted 5-bromo-3,4-dihydro-1(2H)-naphthalenone, 0.6% unidentified, and 9.4% 2,2,5-tribromo-1-tetralone. The addition of H2O produced a top light brown organic phase, and a clear, colorless bottom aqueous phase which was separated. After drying with MgSO4, the organic layer was concentrated under vacuum at room temperature to give the crude intermediate title compound as a light brown oil (16.08 g, 98.5%).
Reaction SMILES: [NH2:1][C@H:2]([C:15]([NH2:17])=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=1.[C:18]([N:28]([CH3:36])[C@H:29]([C:33](O)=[O:34])[CH:30]([CH3:32])[CH3:31])([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].O>C1COCC1>[C:18]([N:28]([CH3:36])[C@H:29]([C:33]([NH:1][C@H:2]([C:15]([NH2:17])=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([CH3:14])([CH3:12])[CH3:13])[CH:5]=1)=[O:34])[CH:30]([CH3:32])[CH3:31])([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]
Reactant: CC(C)(C)c1cc(C[C@H](N)C(N)=O)ccc1O
Reactant: CC(C)[C@@H](C(=O)O)N(C)C(=O)OCc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[C@@H](C(=O)N[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)N(C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.1 %

Procedure:
To a solution of the thus obtained Tyr(3-tBu)-NH2 (1 g, 4.23 mmol), Z-N-Me-Val-OH (1.23 g, 4.63 mmol) and CMPI (1.2 g, 4.69 mmol) in THF (20 ml), TEA (1.8 ml) was added under cooling with ice and stirred at room temperature for 4 hours. The reaction mixture was mixed with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate and evaporated to remove the solvent under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=2:1), giving Z-N-Me-Val-Tyr(3-tBu)-NH2 (1.7 g, 83%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:25])([C@H:16]([O:18]C1CCCCO1)[CH3:17])[CH2:10][N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1.FC(F)(F)C(O)=O>C(O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:25])([C@H:16]([OH:18])[CH3:17])[CH2:10][N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: C[C@@H](OC1CCCCO1)C(O)(Cn1ccnc1)c1ccc(F)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: C[C@@H](O)C(O)(Cn1ccnc1)c1ccc(F)cc1F
Reaction time: 0.17 h
Yield: 131.4 %

Procedure:
In ethanol (8.5 ml) was dissolved (3R)-2-(2,4-difluorophenyl)-1-(1-imidazolyl)-3-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)-2-butanol (1.7 g) followed by addition of trifluoroacetic acid (8.5 ml) at 0° C. After 10 minutes, the temperature was adjusted to 20° C. and the mixture was allowed to stand for 1 hour. The reaction mixture was then concentrated under reduced pressure and the residue was subjected to silica gel chromatography (2 cm×10 cm) using methanol-methylene chloride (1:9) as the eluent. The desired fraction was concentrated to give (3R)-2-(2,4-difluorophenyl)-1-(1-imidazolyl)-2,3-butanediol (1.7 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[Mg+].[C:24]([O:30][CH2:31][CH3:32])(=[O:29])[CH2:25]C([O-])=O.Cl>O1CCCC1.C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH2:25][C:24]([O:30][CH2:31][CH3:32])=[O:29])=[O:8])=[CH:9][CH:10]=1
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: O=C(O)c1ccc(Cl)cc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Mg+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(=O)c1ccc(Cl)cc1
Reaction time: 6 h

Procedure:
To a solution of 4-chlorobenzoic acid (15.77 g, 100.7 mmol) in tetrahydrofuran (100 ml) was added 1,1′-carbonyldiimidazole (18.0 g, 111 mmol) at room temperature and the mixture was stirred as it was for 6 hrs. To the mixture was added monoethyl malonate monomagnesium salt (15.9 g, 55.4 mmol) at room temperature and the mixture was stirred at 60° C. for 3 hrs. The reaction solution was diluted with ethyl acetate and water and acidified with conc. hydrochloric acid. The ethyl acetate layer was separated and the aqueous layer was extracted with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane/ethyl acetate=6/1) to give the objective substance.
Reaction SMILES: [CH:1]1([NH2:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH2:12]([N:14]=[C:15]=[O:16])[CH3:13]>CCOCC>[CH2:12]([NH:14][C:15]([NH:11][CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1)=[O:16])[CH3:13]
Reactant: CCN=C=O
Reactant: NC1CCCc2ccccc21
Solvent: CCOCC
Product: CCNC(=O)NC1CCCc2ccccc21

Procedure:
To a solution containing 7.4 grams (0.05 mole) of 1,2,3,4-tetrahydro-1-naphthylamine in 150 ml. anhydrous ether is added dropwise with stirring 3.6 grams (0.05 mole) ethyl isocyanate in 10 ml. ether. After the addition, the mixture is heated under reflux for 3 hours, the mixture cooled, and the solid collected by filtration. Recrystallization of the crude product from aqueous methanol gives analytically pure 1-ethyl-3-(1,2,3,4-tetrahydro-1-naphthyl)urea, melting point 178° to 179° C. Other aprotic solvents such as acetone; tetrahydrofuran and benzene may be used as solvents for this reaction. Temperatures employed for the reaction are in the range of 0° to 100° C.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].[OH:7][CH2:8][CH2:9][NH:10][CH2:11][CH2:12][CH2:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1.C(N(CC)CC)C>ClCCl.O>[C:18]([C:17]1[CH:20]=[CH:21][C:14]([CH2:13][CH2:12][CH2:11][N:10]([CH2:9][CH2:8][OH:7])[C:3]([N:2]([CH3:6])[CH3:1])=[O:4])=[CH:15][CH:16]=1)#[N:19]
Reactant: N#Cc1ccc(CCCNCCO)cc1
Reactant: CN(C)C(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C(=O)N(CCO)CCCc1ccc(C#N)cc1
Reaction time: 8 h
Yield: 101.7 %

Procedure:
N,N-Dimethylcarbamoyl chloride (3.9 g, 0.0368 mol) was added to a mixture of 4-[3-(2-hydroxyethylamino)propyl]benzonitrile (5 g, 0.025 mol; see step (i) above) and triethylamine (3.7 g, 0.368 mol) in dichloromethane (100 mL) at 0° C. Stirring was then continued at room temperature overnight. The reaction mixture was diluted with water and extracted with dichloromethane. The organic layer was washed with water and brine and dried over sodium sulfate. Solvent evaporation under reduced pressure, followed by purification by column chromatography (using 4% methanol in dichloromethane) yielded 7 g of the sub-title compound as a pale yellow, gummy liquid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:19]([S:28]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)(=[O:30])=[O:29])[C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=2[F:27])=[CH:4][C:5]([NH:8][CH2:9][CH2:10][NH:11]C(=O)OC(C)(C)C)=[N:6][CH:7]=1.[ClH:38].CO>>[ClH:1].[ClH:38].[Cl:1][C:2]1[C:3]([CH:19]([S:28]([C:31]2[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=2)(=[O:30])=[O:29])[C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=2[F:27])=[CH:4][C:5]([NH:8][CH2:9][CH2:10][NH2:11])=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCNc1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)c(Cl)cn1
Agent: Cl
Solvent: CO
Product: NCCNc1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)c(Cl)cn1
Reaction time: 1 h
Yield: 76 %

Procedure:
To t-butyl 2-[[5-chloro-4-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridin-2-yl]amino]ethylcarbamate (146 mg, 0.25 mmol) was added a 20% hydrochloric acid-methanol solution (1 ml). The resulting mixture was stirred for 1 hour. The residue obtained by concentrating the reaction mixture under reduced pressure was crystallized from ethanol to give the title compound (106 mg, 76%).
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([NH:12]C(=O)OC(C)(C)C)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[N+:2]=[N-:3].O1CCOCC1>C1COCC1.Cl.CCOCC>[N:1]([CH2:4][C@@H:5]([NH2:12])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[N+:2]=[N-:3]
Reactant: CC(C)(C)OC(=O)N[C@H](CN=[N+]=[N-])c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: CCOCC
Product: [N-]=[N+]=NC[C@@H](N)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
To a solution of tert-butyl [(1S)-2-azido-1-phenylethyl]carbamate (210 mg, 0.8 mmol, 1.0 eq.) in THF (2 ml), 4.0M hydrogen chloride in dioxane (2.0 ml, 8.0 mmol, 10.0 eq.) was added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with ether. The precipitate was filtered and washed with ether to yield (S)-2-Azido-1-phenyl-ethylamine 40 as a white solid in 85% yield. LC-MS [163 (M+1)]
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH:4]=[CH2:5].[NH2:7][CH2:8][CH:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([F:19])[CH:16]=2)[O:11][CH2:10]1>CO>[F:19][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[O:11][CH2:10][CH:9]([CH2:8][NH:7][CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:6])[CH2:18]2
Reactant: C=CC(=O)OC
Reactant: NCC1COc2ccc(F)cc2C1
Solvent: CO
Product: COC(=O)CCNCC1COc2ccc(F)cc2C1
Yield: 65 %

Procedure:
While stirring at a temperature of from 0° to 5°, a solution of 1.42 g (16.4 mmol) of acrylic acid methyl ester in 10 ml of methanol is added dropwise within a period of 15 minutes to a solution of 3.0 g (16.5 mmol) of 3-aminomethyl-6-fluoro-chroman in 80 ml of methanol. The reaction mixture is then stirred for 16 hours at from 0° to 5° and then concentrated by evaporation in vacuo. The oily residue is chromatographed on 250 g of silica gel (0.040-0.063 mm) with ethyl acetate as eluant, yielding 2.85 g of N-[(6-fluorochroman-3-yl)methyl]-N-(2-methoxycarbonylethyl)-amine in the form of a light-yellow oil. The N-[(6-fluorochroman-3-yl)methyl]-N-(2-methoxycarbonylethyl)-amine hydrochloride, prepared therefrom with hydrochloric acid in diethyl ether, crystallizes from acetone/diethyl ether and melts at 163°-165°. The N-[(6-fluorochroman-3-yl)methyl]-N-(2-methoxycarbonylethyl)-amine cyclamate, prepared from the crude base with N-cyclohexyl-sulfamic acid, crystallizes from acetone and melts at 155°-156°.