Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([Cl:9])=[C:7]([Cl:10])[CH:6]=[CH:5][C:4]=1[Cl:11].[NH2:12][C:13]1[N:18]=[C:17]([SH:19])[N:16]=[C:15]([OH:20])[CH:14]=1.C(N(CC)CC)C>C(O)C>[NH2:12][C:13]1[N:18]=[C:17]([S:19][CH2:2][C:3]2[C:4]([Cl:11])=[CH:5][CH:6]=[C:7]([Cl:10])[C:8]=2[Cl:9])[N:16]=[C:15]([OH:20])[CH:14]=1
Reactant: Nc1cc(O)nc(S)n1
Reactant: Clc1ccc(Cl)c(CBr)c1Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Nc1cc(O)nc(SCc2c(Cl)ccc(Cl)c2Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.6 %

Procedure:
A mixture of 2-(bromomethyl)-1,3,4-trichlorobenzene (580 mg, 2.1 mmol), 6-amino-2-sulfanylpyrimidin-4-ol (290 mg, 1.8 mmol), and triethylamine (280 μL, 2.0 mmol) in absolute ethanol (10 mL) was stirred at room temperature overnight. The solvent was evaporated under reduced pressure. The solid product was suspended in water (50 mL). The solid material was recovered by filtration, washed with water (1×20 mL) and diethyl ether (2×20 mL), and dried in vacuo, affording the title compound (325 mg, 54% yield); 1H NMR (400 MHz, DMSO-d6): δ 4.64 (s, 2H), 5.03 (s, 1H), 6.57 (s (br), 2H), 7.54 (d, 1H, J=8.8 Hz), 7.64 (d, 1H, J=8.8 Hz); M+ 337; HPLC purity: 95.5%.
Reaction SMILES: [CH2:1]([O:3]CC)C.Br[C:7]1[CH:8]=[CH:9][C:10]([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[N:11][CH:12]=1.C([Li])CCC.CN(C)C=O>O>[F:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][CH2:13][C:10]2[N:11]=[CH:12][C:7]([CH:1]=[O:3])=[CH:8][CH:9]=2)=[CH:16][CH:17]=1
Reactant: CCOCC
Reactant: Fc1ccc(OCc2ccc(Br)cn2)cc1
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(COc2ccc(F)cc2)nc1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 30.5 %

Procedure:
To a diethyl ether (100 mL) solution of 5-bromo-2-(4-fluoro-phenoxymethyl)-pyridine (4.00 g, 14.2 mmol) described in Manufacturing Example 72-1-1 was added dropwise n-butyl lithium (2.55 M n-hexane solution, 6.13 mL, 15.6 mmol) on a dry ice-ethanol bath (−78° C.) under nitrogen atmosphere, which was stirred for 40 minutes at −78° C. N,N-dimethylformamide (1.32 mL, 17.0 mmol) was then added dropwise and stirred for 5 minutes at −78° C. The reaction solution was cooled to room temperature and water was added, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:4) to obtain the title compound (1.00 g, 30.5%).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:3]([N:5]1[CH2:10][CH2:9][N:8]([CH:11]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)=[O:4].[C:30]([O:34][C:35]1[CH:42]=[CH:41][C:38]([CH:39]=O)=[CH:37][CH:36]=1)([CH3:33])([CH3:32])[CH3:31].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl.CCOC(C)=O>[F:18][C:15]1[CH:14]=[CH:13][C:12]([CH:11]([C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)[N:8]2[CH2:7][CH2:6][N:5]([C:3](=[O:4])[C@@H:2]([NH:1][CH2:39][C:38]3[CH:41]=[CH:42][C:35]([O:34][C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:36][CH:37]=3)[CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:10][CH2:9]2)=[CH:17][CH:16]=1
Reactant: CC(C)C[C@H](N)C(=O)N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Reactant: CC(C)(C)Oc1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)C[C@H](NCc1ccc(OC(C)(C)C)cc1)C(=O)N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.1 %

Procedure:
(S)-2-Amino-1-{4-[bis-(4-fluoro-phenyl)-methyl]-piperazin-1-yl}4-methyl-pentan-1-one (0.500 g, 1.25 mmol, Example 53) and 4-(tert-butoxy)benzaldehyde (0.229 mL, 1.25 mmol, Lancaster) were mixed in CH2Cl2 (6 mL). After stirring at ambient temperature under nitrogen atmosphere for 30 minutes, the solution was cooled to 0° C. in an ice-water bath. To this solution was added sodium triacetoxyborohydride (0.396 g, 1.87 mmol). The resulting reaction mixture was stirred for, in succession, 30 minutes at 0° C. and 12 hours at ambient temperature. Twenty milliliters of saturated aqueous NaHCO3 solution was added to the reaction mixture, and the resulting mixture was stirred for 25 minutes. The 2 layers were separated, and the aqueous layer was extracted with CH2Cl2 (2×20 mL). The combined organic solution was dried over Na2SO4. TLC (50% EtOAc in Hexanes as the eluant) showed two spots with Rf values 0.9 and 0.55. The solution was concentrated in vacuo affording a viscous oil. The lower spot on TLC (Rf=0.55) was isolated by flash chromatography (30% EtOAc in hexanes). Forty-four percent (0.311 g) of the pure titled compound was obtained as a white foam: mp 56-61° C. APCI-MS m/z 564.5 (MH+).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:7]2[CH:8]=[C:9](B(O)O)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:15])[O:3]1.Br[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1>>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:9]2[CH:10]=[CH:11][C:6]3[NH:5][C:4](=[O:15])[O:3][C:2]([CH3:16])([CH3:1])[C:7]=3[CH:8]=2)=[CH:19][CH:20]=1
Reactant: Fc1ccc(Br)cc1
Reactant: CC1(C)OC(=O)Nc2ccc(B(O)O)cc21
Product: CC1(C)OC(=O)Nc2ccc(-c3ccc(F)cc3)cc21

Procedure:
6-(4-Fluoro-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one was prepared, according to the procedure of Example 5 from (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid and 1-bromo-4-fluorobenzene, as off-white crystals: mp 232-233° C.; 1H-NMR (DMSO-d6) δ10.3 (s, 1H), 7.74 (m, 2H), 7.53 (m, 2H), 7.28 (m, 2H), 6.96 (d, 1H, J=8.9 Hz), 1.63 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[CH:9][CH2:10][CH2:11][CH2:12][C:13]([O:15]C)=[O:14])=[CH:4][CH:3]=1.[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:4][CH:3]=2)(=[O:32])=[O:31])=[CH:26][CH:25]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)CCCC=C(c1ccc(N)cc1)c1cccnc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)Nc2ccc(C(=CCCCC(=O)O)c3cccnc3)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 3 g of methyl 6-(4-aminophenyl)-6-(3-pyridyl)-hex-5-enoate, 1.9 g of 4-methylbenzene-sulphonic acid chloride and 5 ml of triethylamine in 100 ml of methylene chloride is stirred for one hour at ambient temperature. The organic phase is washed with water, evaporated down and the residue is purified pyer a silica gel column with ethyl acetate. The product fraction is evaporated down and heated in a mixture of 50 ml of ethanol and 3 ml of 10N sodium hydroxide solution to 50° C. for one hour. The reaction mixture is diluted with water and neutralised by the addition of citric acid. The agueous phase is extracted with ethyl acetate, dried and evaporated down. The residue is recrystallised from ethyl acetate/diisopropylether.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH2:10]([CH:12]1[O:14][CH2:13]1)[Cl:11].Cl>C(O)C>[Cl:11][CH2:10][CH:12]([OH:14])[CH2:13][NH:4][C:3]1[CH:5]=[CH:6][C:7]([Cl:9])=[CH:8][C:2]=1[Cl:1]
Reactant: ClCC1CO1
Reactant: Nc1ccc(Cl)cc1Cl
Agent: Cl
Solvent: CCO
Product: OC(CCl)CNc1ccc(Cl)cc1Cl
Reaction time: 288 h
Yield: 41.1 %

Procedure:
324.0 Grams (2.0 mol) of 2,4-dichloroaniline, 400 ml absolute ethanol, 185.1 g (2.0 mol) of epichlorohydrin and 3 g of conc. hydrochloric acid are added together in this sequence with stirring and then allowed to stand for 12 days. The solution is thereafter concentrated in vacuum to a brown oily residue which is distilled in high vacuum. The main fraction, which boils between 130° C. and 153° C./0.01 Torr, is collected and redistilled, yielding 209 g of N-(3-chloro-2-hydroxypropyl)-2,4-dichloroaniline as a clear liquid, boiling at 142°-145° C./0.01 Torr.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([NH:15][C:16]([O:18][CH2:19][CH:20]([CH3:22])[CH3:21])=[O:17])[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4].CN(C)C=O.[H-].[Na+].I[CH2:31][CH3:32]>O>[CH3:1][O:2][C:3]([C:5]1([N:15]([CH2:31][CH3:32])[C:16]([O:18][CH2:19][CH:20]([CH3:22])[CH3:21])=[O:17])[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4]
Reactant: CCI
Reactant: COC(=O)C1(NC(=O)OCC(C)C)CCc2ccccc2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(C(=O)OCC(C)C)C1(C(=O)OC)CCc2ccccc2C1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To an ice cooled solution of ester from Example 53D (101 mg, 0.33 mmol) and anhydrous N,N-dimethylforamide (1.5 mL) under N2 was added 60% dispersion sodium hydride (35 mg, 0.825 mmol) and then stirred for 15 minutes. Iodoethane (40 μL, 0.495 mmol) was added. The reaction was stirred at room temperature for 18 hours, diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column (20% ethyl acetate/hexane) to provide the titled compound as a clear, colorless syrup (51 mg, 46%). 1H NMR (δ, CDCl3): 7.07–7.15 (m, 4H), 3.90 (dd, 2H), 3.71 (s, 3H), 3.35–3.5 (m, 2H), 3.00–3.08 (m, 2H), 7.75–2.8 (m, 2H), 2.55–2.6 (m, 1H), 2.19–2.3 (m 1H), 1.88–2.0 (m, 1H), 1.14 (t, 3H), 0.95 (d, 6H). MS (DCI/NH3): 334.2 (M+1).
Reaction SMILES: [CH2:1]([O:3][C@@H:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18]/[CH:19]=[CH:20]/[C:21]2[CH:22]=[C:23]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:24]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:26]=2)=[CH:13][CH:12]=1)[C:5]([O:7]CC)=[O:6])[CH3:2].[OH-].[Na+]>>[CH2:1]([O:3][C@@H:4]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:18]/[CH:19]=[CH:20]/[C:21]2[CH:26]=[C:25]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:24]=[C:23]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:22]=2)=[CH:15][CH:16]=1)[C:5]([OH:7])=[O:6])[CH3:2]
Reactant: CCOC(=O)[C@H](Cc1ccc(OC/C=C/c2cc(-c3ccccc3)cc(-c3ccccc3)c2)cc1)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCO[C@@H](Cc1ccc(OC/C=C/c2cc(-c3ccccc3)cc(-c3ccccc3)c2)cc1)C(=O)O
Yield: 91.9 %

Procedure:
The title compound was prepared from (E)-(S)-ethyl 2-ethoxy-3-[4-(3-[1,1′;3′,1″]terphenyl-5′-yl-allyloxy)-phenyl]-propionate (Example 109) (405 mg, 0.8 mmol) and sodium hydroxide (1M, 1.6 ml, 1.6 mmol) by a procedure analogous to that described in example 51, yielding (E)-(S)-2-ethoxy-3-[4-(3-[1,1′;3′,1″]terphenyl-5′-yl-allyloxy)-phenyl]-propionic acid (352 mg, 92%) as a colourless glass.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][NH:4][C:3]=1[C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16])=[O:8].[H-].[Na+].C1(C)C=C(C)C=C(C)C=1S(O[NH2:31])(=O)=O>CN(C=O)C>[NH2:31][N:4]1[CH:5]=[CH:6][C:2]([CH3:1])=[C:3]1[C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16])=[O:8]
Reactant: Cc1ccccc1NC(=O)c1[nH]ccc1C
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccccc1NC(=O)c1c(C)ccn1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.9 %

Procedure:
3-Methyl-N-o-tolyl-1H-pyrrole-2-carboxamide (1.5 g, 7.00 mmol) was dissolved in 60 mL of DMF. 294 mg (7.35 mmol) of sodium hydride (60 wt % dispersion in mineral oil) were added and the reaction mixture was stirred at room temperature for 1 hour. Then O-(mesitylsulfonyl)hydroxylamine (1.658 g, 7.70 mmol) was added and the reaction mixture was stirred for 30 minutes. The solvent was evaporated to dryness and the crude product was purified by flash chromatography (0 to 50% heptane/AcOEt) to give 1.17 g (73% yield) of the title compound as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([OH:13])=O)[NH:6]2.Cl.Cl.Cl.[NH2:17][CH:18]1[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][N:26]2[CH:31]3[CH2:32][CH2:33][CH:27]2[CH2:28][CH:29]([OH:34])[CH2:30]3)[CH2:20][CH2:19]1>>[OH:34][CH:29]1[CH2:30][CH:31]2[N:26]([CH2:25][CH2:24][N:21]3[CH2:22][CH2:23][CH:18]([NH:17][C:11]([C:5]4[NH:6][C:7]5[C:3]([CH:4]=4)=[C:2]([Br:1])[CH:10]=[CH:9][CH:8]=5)=[O:13])[CH2:19][CH2:20]3)[CH:27]([CH2:33][CH2:32]2)[CH2:28]1
Reactant: O=C(O)c1cc2c(Br)cccc2[nH]1
Reactant: NC1CCN(CCN2C3CCC2CC(O)C3)CC1
Agent: Cl
Product: O=C(NC1CCN(CCN2C3CCC2CC(O)C3)CC1)c1cc2c(Br)cccc2[nH]1

Procedure:
This compound is synthesized from 4-Bromo-1H-indole-2-carboxylic acid and amine 24 analogously to the method described for 194 (see example 156).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[N:6][CH:5]=1.C([O-])([O-])=O.[K+].[K+].Cl.Cl[CH2:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=1>CN(C=O)C>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:20][C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]=2)=[N:6][CH:5]=1
Reactant: COC(=O)c1ccc(O)nc1
Reactant: ClCc1ccc2ccccc2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCc2ccc3ccccc3n2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.2 %

Procedure:
To a solution of 6-hydroxynicotinic acid methyl ester (10.0g, 0.0652 mol), prepared as in step 1, in DMF (350 ml) at room temperature was added anhydrous K2CO3 (19.0 g, 0.137 mol) followed by 2-chloromethylquinoline hydrochloride (14.0 g, 0.0652 mol), and the mixture was allowed to stir at room temperature overnight. Once the starting material was consumed, water (700 ml) was added to the mixture, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The resulting white precipitate was filtered and washed with hexanes to give 15.20 g of 6-(quinol-2-ylmethoxy)nicotinic acid methyl ester.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][C:17](O)=[O:18].[CH:20]([NH:23][NH:24][C:25](=[O:37])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32][CH2:33][CH2:34][O:35][CH3:36])([CH3:22])[CH3:21].C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][C:17]([N:23]([CH:20]([CH3:22])[CH3:21])[NH:24][C:25](=[O:37])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32][CH2:33][CH2:34][O:35][CH3:36])=[O:18]
Reactant: Cc1cccc(-c2ccccc2CCC(=O)O)c1C
Reactant: COCCOc1ccccc1C(=O)NNC(C)C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCCOc1ccccc1C(=O)NN(C(=O)CCc1ccccc1-c1cccc(C)c1C)C(C)C
Yield: 35.8 %

Procedure:
A solution of 3-(2′,3′-dimethyl-biphenyl-2-yl)-propionic acid (110 mg, 0.44 mmoles) and 2-(2-methoxy-ethoxy)-benzoic acid-N′-isopropyl hydrazide (100 mg, 0.40 mmoles) in DMF (3 mL) was treated with triethylamine (0.16 mL, 1.19 mmoles), HOBT (64 mg, 0.48 mmoles) and EDCI (91 mg, 0.48 mmoles) at room temperature for 48 h. The reaction mixture was partitioned between 1N HCl and ethyl acetate. The organic layer was washed successively with water, 1N NaOH and brine, then dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with 10% ethyl acetate/hexanes to afford the product (70 mg, 36%). LC-MS m/e 489.39 (M+H+)
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[S:7][CH:8]=[C:9]([C:11]3[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][N:12]=3)[N:10]=2)[CH2:3][CH2:2]1.N.[H][H]>[Ni].CO>[NH2:16][CH2:15][C:14]1[CH:13]=[N:12][C:11]([C:9]2[N:10]=[C:6]([NH:5][CH2:4][CH:1]3[CH2:3][CH2:2]3)[S:7][CH:8]=2)=[CH:18][CH:17]=1
Reactant: N#Cc1ccc(-c2csc(NCC3CC3)n2)nc1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCc1ccc(-c2csc(NCC3CC3)n2)nc1
Temperature: 40 °C
Reaction time: 6 h
Yield: 51.7 %

Procedure:
Add 6-[2-(cyclopropylmethylamino)-thiazol-4-yl]-nicotinonitrile (2.0 g, 7.8 mmol), Raney Nickel (2.0 mL), and 2M ammonia in methanol (200 mL) to a pressure vessel under a nitrogen atmosphere. Pressurize the vessel to 60 psi with hydrogen, and stir the mixture for 6 h at 40° C. Filter the mixture through Celite® and concentrate in vacuo to an oil. Dissolve the oil in EtOAc (300 mL) and saturated ammonium hydroxide (50 mL). Stir the solution for 20 h in a sealed flask at room temperature. Collect the organic layer and concentrate in vacuo. Purify the crude mixture by SCX chromatography followed by chromatography on silica gel (150 g) eluting with DCM/2M ammonia in methanol (99:1 to 85:15 gradient) to obtain the title compound (1.05 g, 51%). MS (ES+) m/z: 261 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:32])[C@@H:13]([NH:24]C(OC(C)(C)C)=O)[CH2:14][CH2:15][O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(O)(C(F)(F)F)=O>ClCCl>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:32])[C@@H:13]([NH2:24])[CH2:14][CH2:15][O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCOCc2ccccc2)NC(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)N1CCN(C(=O)[C@@H](N)CCOCc2ccccc2)CC1
Reaction time: 12 h

Procedure:
To a solution of 1.23 g 4-((S)-4-benzyloxy-2-tert-butoxycarbonylamino-butyryl)-piperazine-1-carboxylic acid ethyl ester in 7 ml dichloromethane were added 2 ml TFA. After stirring for 12 h and evaporation of the solvents the crude trifluoroacetate salt was obtained as colorless oil. Yield: 1.30 g.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][CH:9]=1)(=[O:3])[CH3:2].[N:27]1[CH:32]=[CH:31][CH:30]=[C:29](B(O)O)[CH:28]=1>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:29]2[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=2)=[CH:10][CH:9]=1)(=[O:3])[CH3:2]
Reactant: OB(O)c1cccnc1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(I)cc1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(-c2cccnc2)cc1
Yield: 79 %

Procedure:
By carrying out the operation analogously to example 1, starting from 4-iodophenyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation II, and 3-pyridineboronic acid, the expected product is obtained in the form of a yellow solid with a yield of 79%.
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[CH3:27][CH:28]([CH3:34])[CH2:29][CH2:30][C:31](O)=[O:32]>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:31](=[O:32])[CH2:30][CH2:29][CH:28]([CH3:34])[CH3:27])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Reactant: CC(C)CCC(=O)O
Agent: Cl
Product: CC(C)CCC(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (77 mg, 73%), MS (ISP) m/z=427.4 [(M+H)+], mp 188° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydro chloride (intermediate B) (100 mg, 0.25 mmol) and 4-methyl-pentanoic acid.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:15]([O:17]CC)=O)=[C:4]([C:7](=O)[C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[S:5][CH:6]=1.[CH3:20][NH:21][NH2:22]>CCO>[Br:1][C:2]1[C:3]2[C:15](=[O:17])[N:21]([CH3:20])[N:22]=[C:7]([C:8]3[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=3)[C:4]=2[S:5][CH:6]=1
Reactant: CNN
Reactant: CCOC(=O)c1c(Br)csc1C(=O)c1ccncc1
Solvent: CCO
Product: Cn1nc(-c2ccncc2)c2scc(Br)c2c1=O
Yield: 44.8 %

Procedure:
A suspension of ethyl 4-bromo-2-isonicotinoylthiophene-3-carboxylate (5.2 g, 15.94 mmol) and methyl-hydrazine (2.2 g, 47.8 mmol) in EtOH (40 mL) was heated to reflux overnight. After removal of the solvent, the crude product was purified by silica gel column and eluted with 5:1 PE/EtOAc to give the title compound as a white solid (2.3 g, 44.8% yield). LC-MS (Method C): m/z 322 (M+H)+, Rt: 1.75 min. 1H NMR (400 MHz, DMSO-d6): δ=8.80-8.78 (m, 2H), 8.28 (s, 1H), 7.81-7.80 (m, 1H), 3.81 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[C:14]([OH:16])=[O:15])[CH:6]=[CH:7][CH:8]=1.S(=O)(=O)(O)O.[CH2:24](O)[CH3:25]>>[CH2:24]([O:15][C:14]([C:10]1[CH:11]=[N:12][O:13][C:9]=1[C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:17])[F:18])[CH:4]=1)=[O:16])[CH3:25]
Reactant: CCO
Reactant: O=C(O)c1cnoc1-c1cccc(C(F)(F)F)c1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cnoc1-c1cccc(C(F)(F)F)c1
Yield: 80 %

Procedure:
A portion of the 5-(3'-trifluoromethylphenyl)-4-isoxazolecarboxylic acid (2.5 g.; 0.01 mol.) in 25 ml. of ethanol and 2 ml. of sulfuric acid were heated at reflux for 4 hours. The reaction mixture was cooled, concentrated to one-half its initial volume, then diluted with 175 ml. of methylene chloride. The organic solution was washed with water, sodium bicarbonate, again with water, dried over magnesium sulfate, filtered and concentrated to give an oil. The oil was distilled through a Vigreux column to yield ethyl-5-(3'-trifluoromethylphenyl)-4-isoxazolecarboxylate (2.2 g.; 80% yield) as a colorless oil (b.p.=88°-90° C. at 0.15 torr.) having the following analysis:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].C1C(=O)N([Br:22])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>>[Br:22][CH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc([N+](=O)[O-])cc1C(F)(F)F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: O=[N+]([O-])c1ccc(CBr)c(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 12 h
Yield: 98.1 %

Procedure:
1-Methyl-4-nitro-2-(trifluoromethyl)benzene (25 g, 122 mmol) was stirred in a solvent of dichloethane (300 mL). The reaction solution was added with NBS (21.7 g, 122 mmol) and AIBN (2.0 g, 12.2 mmol), followed by stirring for about 12 hours at 80° C. The solid thus obtained was filtered under reduced pressure and dried with warm wind in an oven (40° C.) for 3 hours or more to obtain the title compound (34 g, 98%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]([NH2:10])[CH2:7][CH2:8][CH2:9][C:2]1=2.[C:11]([NH:19][C@H](C(O)=O)CCC(O)=O)(=[O:18])C1C=CC=CC=1>>[S:1]1[CH:5]=[CH:4][C:3]2[CH:6]([NH:10][C:11]([NH2:19])=[O:18])[CH2:7][CH2:8][CH2:9][C:2]1=2
Reactant: O=C(O)CC[C@H](NC(=O)c1ccccc1)C(=O)O
Reactant: NC1CCCc2sccc21
Product: NC(=O)NC1CCCc2sccc21

Procedure:
Similarly, the salt of (+)-4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine and (S)-(-)-N-benzoyl glutamic acid is treated in the above manner to afford (+)-4,5,6,7-tetrahydrobenzo[b]thien-4-ylurea, melting point 218° C. to 220° C.; [α]58925 +60°, [α]436 +149.8°, [α]365 +272.5°.