Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:27][C:28]3[CH:29]=[N:30][C:31](Br)=[CH:32][CH:33]=3)[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:35]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1B(O)O)[CH3:36].C(=O)([O-])[O-].[Na+].[Na+]>C(O)(C)C.C1(C)C=CC=CC=1>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:27][C:28]3[CH:29]=[N:30][C:31]([C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=4[CH2:35][CH3:36])=[CH:32][CH:33]=3)[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccc(Br)nc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: CCc1ccccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: CCc1ccccc1-c1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)OC(C)(C)C)cn1
Temperature: 80 °C
Reaction time: 20 h
Yield: 77 %

Procedure:
To a stirred slurry of 1.75 g (3.35 mmol) of (S)-tert-butyl 2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(6-bromo-pyridin-3-yl)propanoate and 1.005 g (6.70 mmol, 2 eq.) of 2-ethylphenylboronic acid in 50 mL of 1:1 isopropanol/toluene was added 25.0 mL of 2 M aqueous sodium carbonate solution. The reaction mixture was purged twice with argon and evacuated and then 124 mg (0.167 mmol, 0.05 equivalents) of bis(tricyclohexylphosphine)palladium(II)chloride was added and the mixture was again purged with argon and evacuated. The rapidly stirred mixture was heated at 80° C. under argon. After 20 h, the reaction mixture was cooled to room temperature and partially concentrated to remove isopropanol. The residue was partitioned between ethyl acetate and water and the aqueous phase was extracted once more with ethyl acetate. The organic extracts were combined, dried over magnesium sulfate, filtered and concentrated to give a brown oil. Purification by chromatography on silica gel using ethyl acetate/dichloromethane (1:9) as eluant (5×15 cm column), gave the desired compound as a colorless oil, 1.25 g, 77% yield.
Reaction SMILES: [S:1]([CH2:8][C:9]([OH:11])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=S(Cl)[Cl:14]>>[C:2]1([S:1][CH2:8][C:9]([Cl:14])=[O:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CSc1ccccc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)CSc1ccccc1
Yield: 98 %

Procedure:
To thiophenoxyacetic acid (8 g, 0.05 mol) was added SOCl2 (8 mL) and the reaction mixture was heated to reflux for 1 h. TLC showed disappearance of the starting material. The excess SOCl2 was removed in vacuo (hood|) and the product distilled to give 8.6 g (98%) of the title compound: bp 85°-86° C., 4-5 Torr (lit. 117°-119° C., 6 Torr (Mooradian, A.; Cavallito, C. J.; Bergman, A. J.; Lawson, E. J.; Suter, C. M. J. Am. Chem. Soc. 1949, 3372)); 1H NMR (CDCl3) δ7.48-7.34 (m, 5H), 4.06 (m, 2H); 13C NMR (CDCl3) δ169.75, 132.83, 131.44, 129.35, 128.22, 48.48; MS (EI, m/z) 186 (M+).
Reaction SMILES: O[C:2]1(CNC(C)C)COC2C=CC(O)=CC=2OC1.[CH:19]([N:22]1[CH2:26][C:25]2([CH2:32][O:31][C:30]3[CH:33]=[CH:34][C:35]([OH:37])=[CH:36][C:29]=3[O:28][CH2:27]2)[O:24][C:23]1=[O:38])([CH3:21])[CH3:20]>>[CH:19]([N:22]1[CH2:26][C:25]2([CH2:32][O:31][C:30]3[CH:33]=[CH:34][C:35]([O:37][CH3:2])=[CH:36][C:29]=3[O:28][CH2:27]2)[O:24][C:23]1=[O:38])([CH3:21])[CH3:20]
Reactant: CC(C)NCC1(O)COc2ccc(O)cc2OC1
Reactant: CC(C)N1CC2(COc3ccc(O)cc3OC2)OC1=O
Product: COc1ccc2c(c1)OCC1(CO2)CN(C(C)C)C(=O)O1

Procedure:
This compound is prepared by employing the same reactants, reaction conditions and procedure outlined in Example 90 except the 3,7-dihydroxy-3-isopropylaminomethyl-3,4-dihydro-2H-1,5-benzodioxepin is replaced by an equivalent quantity of 3'-isopropyl-7-hydroxy-3,4-dihydro-2H-1,5-benzodioxepin-3-spiro-5'-oxazolidin-2'-one from Example 94, Step A.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=2)=[CH:10][CH:11]=1)[CH:2]([CH3:4])[CH3:3].[Cl:22][C:23]1[C:24]([F:33])=[C:25]([S:29](Cl)(=[O:31])=[O:30])[CH:26]=[CH:27][CH:28]=1.C(N(CC)C(C)C)(C)C>ClCCl>[Cl:22][C:23]1[C:24]([F:33])=[C:25]([S:29]([N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[CH2:6][C:7]2[S:8][C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=3)=[CH:10][CH:11]=2)(=[O:31])=[O:30])[CH:26]=[CH:27][CH:28]=1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1F
Reactant: CC(C)CNCc1ccc(-c2cccc(S(C)(=O)=O)c2)s1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CN(Cc1ccc(-c2cccc(S(C)(=O)=O)c2)s1)S(=O)(=O)c1cccc(Cl)c1F

Procedure:
In analogy to example 13, step 2, isobutyl-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-amine (example 15, step 2) was reacted with 3-chloro-2-fluorophenylsulfonyl chloride and N,N-diisopropyl ethyl amine in dichloromethane to give 3-chloro-2-fluoro-N-isobutyl-N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-benzenesulfonamide as a colorless oil. MS: 532.7 ([M+NH4]+)
Reaction SMILES: [BrH:1].[Br:2][CH2:3][C:4]([C:6]1[N:7]=[C:8]([NH:11][C:12]([NH2:14])=[NH:13])[S:9][CH:10]=1)=O.[CH:15]([NH2:17])=[S:16]>CN(C)C=O>[BrH:2].[BrH:1].[NH:11]([C:8]1[S:9][CH:10]=[C:6]([C:4]2[N:17]=[CH:15][S:16][CH:3]=2)[N:7]=1)[C:12]([NH2:14])=[NH:13]
Reactant: N=C(N)Nc1nc(C(=O)CBr)cs1
Reactant: NC=S
Agent: Br
Solvent: CN(C)C=O
Product: N=C(N)Nc1nc(-c2cscn2)cs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.4 %

Procedure:
A mixture of 1.8 g (5.2 mmol) of 2-bromo-1-(2-guanidino-4-thiazolyl)ethanone hydrobromide, 0.34 g (5.5 mmol) of thioformamide, and 10 ml of dimethylformamide was stirred at room temperature for 2 hours. The mixture was concentrated and the residue was triturated with acetonitrile. The resulting precipitate was collected by filtration, washed with acetonitrile, and dried to afford 1.74 g (85%) of 2-guanidino-4-(4-thiazolyl)thiazole dihydrobromide. This was dissolved in 10 ml of water, and 1 ml of saturated sodium bicarbonate solution was added. The resulting precipitate was collected by filtration, washed well with water, then acetonitrile, then dried in vacuo to afford 1.17 g of 2-guanidino-4-(4-thiazoyl)thiazole as a white solid, mp 220°-222°; nmr (DMSO-d6) (δ): 8.96 (s, 1H); 7.96 (s, 1H); 7.18 (s, 1H); 7.0 (b, 4H); calcd. for C7H7N5S2 : C, 37.32; H, 3.13; N, 31.09; found: 36.94; H, 3.52; N, 29.74.
Reaction SMILES: [O:1]=[C:2]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[CH2:3][N:4]1C(=O)C2C(=CC=CC=2)C1=O.[BH4-].[Na+].Cl>C(O)(C)C>[NH2:4][CH2:3][CH:2]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[OH:1]
Reactant: O=C(CN1C(=O)c2ccccc2C1=O)c1cccnc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: NCC(O)c1cccnc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of crude 2-(2-oxo-2-pyridin-3-ylethyl)isoindole-1,3-dione (Preparation 97, 5.0 g, ˜19.0 mmol) in aqueous isopropanol (210 ml, water/IPA:1/6) was added sodium borohydride (10.2 g, 270 mmol) in 2 portions. The mixture was stirred at rt for 12 h before being carefully acidified (pH 2) with dilute hydrochloric acid (1M). After removal of the solvent the residue was taken up in destillated water (100 mL) and passed down a column filled with ion-exchange resin (Amberlite IR 120, H+-form, 300 g, eluent: 500 mL water then 1L of 2 M aqueous ammonia solution). Concentration of the alkaline fractions gave the title compound as a yellow oil. δH (d6 DMSO): 2.74, 2.85 (2H, 2m), 4.66 (11H, m), 5.15 (3H, br s), 7.36 (1H, dd), 7.75 (1H, m), 8.46 (1H, m), 8.56 (1H, m); m/z (ES+)=139.11 [M+H]+; RT=0.21 min.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[C:16]3[N:15]=[CH:14][C:13](=[O:17])[NH:12][C:11]=3[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[F:20].[C:21]([C:25]1[CH:29]=[C:28]([N:30]=[C:31]=[O:32])[N:27]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:26]=1)([CH3:24])([CH3:23])[CH3:22]>>[C:21]([C:25]1[CH:29]=[C:28]([NH:30][C:31]([NH:1][C:2]2[CH:19]=[CH:18][C:5]([O:6][C:7]3[C:16]4[N:15]=[CH:14][C:13](=[O:17])[NH:12][C:11]=4[N:10]=[CH:9][CH:8]=3)=[CH:4][C:3]=2[F:20])=[O:32])[N:27]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:26]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: Nc1ccc(Oc2ccnc3[nH]c(=O)cnc23)cc1F
Reactant: CC(C)(C)c1cc(N=C=O)n(-c2ccccc2)n1
Product: CC(C)(C)c1cc(NC(=O)Nc2ccc(Oc3ccnc4[nH]c(=O)cnc34)cc2F)n(-c2ccccc2)n1

Procedure:
Method F2 was used with 8-(4-amino-3-fluorophenoxy)pyrido[2,3-b]pyrazin-3(4H)-one and 3-tert-butyl-5-isocyanato-1-phenyl-1H-pyrazole to afford the title compound. Yield: 50 mg (60%) of a cream colored solid.
Reaction SMILES: FC(F)(F)C(O)=O.C(O[C:13](=O)[N:14]([C@@H:16]([C:28](=[O:51])[N:29]([C@H:31]([CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:32]([N:34]1[CH2:39][CH2:38][CH2:37][C@@H:36]([CH2:40][N:41]([CH3:43])[CH3:42])[CH2:35]1)=[O:33])[CH3:30])[CH2:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=1)C)(C)(C)C>ClCCl>[CH2:44]([C@@H:31]([N:29]([CH3:30])[C:28](=[O:51])[C@H:16]([NH:14][CH3:13])[CH2:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=1)[C:32]([N:34]1[CH2:39][CH2:38][CH2:37][C@@H:36]([CH2:40][N:41]([CH3:42])[CH3:43])[CH2:35]1)=[O:33])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: CN(C)C[C@@H]1CCCN(C(=O)[C@@H](Cc2ccccc2)N(C)C(=O)[C@@H](Cc2ccc3ccccc3c2)N(C)C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)[C@H](Cc1ccccc1)C(=O)N1CCC[C@@H](CN(C)C)C1
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 79.7 %

Procedure:
At 0° C., trifluoroacetic acid (20 ml) was added to a solution of N-((1R)-1-{N-[(1R)-1-benzyl-2-((3S)-3-((dimethylamino)methyl)piperidin-1-yl)-2-oxoethyl]-N-methylcarbamoyl}-2-(2-naphthyl)ethyl)-N-methylcarbamic acid tert-butyl ester (1.189, 1.92 mmol) in dichloromethane (20 ml). The reaction mixture was stirred for 50 min at 0° C. The solvent was removed in vacuo. The residue was dissolved in dichloromethane (80 ml) and the solvent was removed in vacuo. The latter procedure was repeated two times. The crude product was purified by flash chromatography on silica (40 g), using dichloromethane/methanol/25% aqueous ammonia (100:10:1) as eluent, to give 788 mg of (2R)-N-[(1R)-1-benzyl-2-((3S)-3-((dimethylamino)m ethyl)piperidin-1-yl)-2-oxoethyl]-N-methyl-2-(methylamino)-3-(2-naphthyl)propionamide.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH3:12][C@H:13]1[CH2:41][O:40][C@@:16]2([O:20][C@H:19]3[CH2:21][C@H:22]4[C@@H:27]5[CH2:28][CH2:29][C@H:30]6[CH2:35][C@@H:34]([OH:36])[CH2:33][CH2:32][C@:31]6([CH3:37])[C@H:26]5[CH2:25][CH2:24][C@:23]4([CH3:38])[C@H:18]3[C@@H:17]2[CH3:39])[CH2:15][CH2:14]1>C(Cl)Cl.CCOCC>[CH3:39][C@@H:17]1[C@:16]2([O:40][CH2:41][C@H:13]([CH3:12])[CH2:14][CH2:15]2)[O:20][C@H:19]2[CH2:21][C@@H:22]3[C@@:23]([CH3:38])([C@@H:18]12)[CH2:24][CH2:25][C@H:26]1[C@H:27]3[CH2:28][CH2:29][C@@H:30]2[C@:31]1([CH3:37])[CH2:32][CH2:33][C:34](=[O:36])[CH2:35]2
Reactant: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5C[C@@H](O)CC[C@]5(C)[C@H]4CC[C@]3(C)[C@H]1[C@@H]2C
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5CC(=O)CC[C@]5(C)[C@H]4CC[C@]3(C)[C@H]1[C@@H]2C
Reaction time: 5 h
Yield: 90.4 %

Procedure:
Pyridinium chlorochromate (PCC) was added to a mixture of tigogenin (50.00 g, 120.0 mmol), celite (160 g), in CH2Cl2 (1000 mL) at 0° C. The reaction was allowed to come to ambient temperature and was stirred for 5 hours. The reaction was diluted with 1000 4 mL Et2O and was filtered through a silica gel plug. The plug was washed with an additional 6000 mL Et2O. The filtrate was concentrated in vacuo to afford 45.00 g of the title compound (90.4%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:18]#[N:19].[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:24][NH2:25]>>[Cl:20][C:21]1[CH:22]=[C:23]([CH2:24][NH:25][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:18]#[N:19])[CH:26]=[CH:27][C:28]=1[Cl:29]
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: CCOc1cc2ncc(C#N)c(Cl)c2cc1OCC
Product: CCOc1cc2ncc(C#N)c(NCc3ccc(Cl)c(Cl)c3)c2cc1OCC

Procedure:
In the manner of Example 61 reaction of 4-chloro-6,7-diethoxy-3-quinolinecarbonitrile with 3,4-dichlorobenzylamine gave the title compound as a tan solid, mp 163-165° C.
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[S:10][C:6]=2[C:5]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[CH:4][N:3]=1.[NH2:18][C:19]1[S:20][CH:21]=[C:22]([CH3:24])[N:23]=1>>[CH3:11][C:9]1[S:10][C:6]2[C:5]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)=[CH:4][N:3]=[C:2]([NH:18][C:19]3[S:20][CH:21]=[C:22]([CH3:24])[N:23]=3)[C:7]=2[N:8]=1
Reactant: Cc1nc2c(Cl)ncc(-c3cccnc3)c2s1
Reactant: Cc1csc(N)n1
Product: Cc1csc(Nc2ncc(-c3cccnc3)c3sc(C)nc23)n1

Procedure:
The title compound, MS: m/e=340.1 (M+H+), was prepared in accordance with the general method of example 2, step 2 from 4-chloro-2-methyl-7-pyridin-3-yl-thiazolo[4,5-c]pyridine and 2-amino-4-methylthiazole.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:12])=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](O)=[O:6].ClC([N:18](C)C)=C(C)C.N>>[NH2:1][C:2]1[C:3]([F:12])=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([NH2:18])=[O:6]
Reactant: Nc1c(Cl)ccc(C(=O)O)c1F
Reactant: CC(C)=C(Cl)N(C)C
Agent: N
Product: NC(=O)c1ccc(Cl)c(N)c1F
Yield: 69 %

Procedure:
The sub-title compound is prepared from 3-amino-4-chloro-2-fluoro-benzoic acid, (1-chloro-2-methyl-propenyl)-dimethyl-amine and conc. NH3 in analogy to step Ac.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].[H-].[Na+].I[CH2:13][C:14]([NH2:16])=[O:15]>CN(C=O)C>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH2:13][C:14]([NH2:16])=[O:15]
Reactant: NC(=O)CI
Reactant: Cc1cccc(O)c1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(OCC(N)=O)c1C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 83 %

Procedure:
2.1 19.95 g of 2,3-dimethylphenol 6 are dissolved in 250 ml of DMF, 6.4 g of NaH (60% suspension in paraffin oil) are carefully added with cooling, and the mixture is stirred at RT for 45 min. 31.4 g of 2-iodoacetamide 2 are then added, and the reaction mixture is stirred overnight. The mixture is subsequently subjected to conventional work-up, giving 23.8 g (83%) of 2-(2,3-dimethylphenoxy)acetamide 7; MS-EI (M+)=179.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([OH:14])=[CH:13][C:8]=2[O:7][CH2:6]1.[CH3:16][C:17]1[CH:22]=[C:21]([O:23][CH2:24][CH2:25][CH2:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:20]=[C:19]([CH3:31])[C:18]=1[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38]O)[CH:33]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CCCCCC>[CH3:31][C:19]1[CH:20]=[C:21]([O:23][CH2:24][CH2:25][CH2:26][S:27]([CH3:30])(=[O:28])=[O:29])[CH:22]=[C:17]([CH3:16])[C:18]=1[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][O:14][C:12]2[CH:11]=[CH:10][C:9]3[C@H:5]([CH2:4][C:3]([O:2][CH3:1])=[O:15])[CH2:6][O:7][C:8]=3[CH:13]=2)[CH:33]=1
Reactant: COC(=O)C[C@@H]1COc2cc(O)ccc21
Reactant: Cc1cc(OCCCS(C)(=O)=O)cc(C)c1-c1cccc(CO)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(OCCCS(C)(=O)=O)cc4C)c3)ccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82.1 %

Procedure:
A solution of methyl[(3S)-6-hydroxy-2,3-dihydro-1-benzofuran-3-yl]acetate (0.208 g, 1.00 mmol), {2′,6′-dimethyl-4′-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}methanol (0.348 g, 1.00 mmol) and tributylphosphine (0.324 g, 1.60 mmol) in toluene (15 mL) was stirred, 1,1′-(azodicarbonyl)dipiperidine (0.404 g, 1.60 mmol) was added, and the mixture was stirred at room temperature for 1.5 hr under nitrogen atmosphere. Hexane (8 mL) was added to the reaction mixture, the precipitated insoluble substance was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=40:60-80:20) to give the title compound (0.442 g, yield 82%) as a colorless oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]#[C:8][C:9]2[CH:10]=[C:11]([C:19]3[N:20]=[C:21]([CH2:24][N:25]4[CH:29]=[C:28]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:27]=[N:26]4)[S:22][CH:23]=3)[CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=2)[CH:2]=1.N1C=CC=CC=1>C(O)C.S([O-])([O-])(=O)=O.[Ba+2].[Pd+2].S([O-])([O-])(=O)=O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3](/[CH:7]=[CH:8]\[C:9]2[CH:10]=[C:11]([C:19]3[N:20]=[C:21]([CH2:24][N:25]4[CH:29]=[C:28]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:27]=[N:26]4)[S:22][CH:23]=3)[CH:12]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:14]=2)[CH:2]=1
Reactant: CCOC(=O)c1cnn(Cc2nc(-c3cc(C#Cc4cccnc4)cc(C(F)(F)F)c3)cs2)c1
Agent: [Pd+2]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: CCO
Solvent: c1ccncc1
Product: CCOC(=O)c1cnn(Cc2nc(-c3cc(/C=C\c4cccnc4)cc(C(F)(F)F)c3)cs2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 46.4 %

Procedure:
To a solution (10 mL) of the compound (980 mg, 2.0 mmol) obtained in Example 87a in ethanol were added pyridine (480 mg, 6.1 mmol) and palladium-barium sulfate (490 mg), and the mixture was stirred at room temperature for 5 hr under a hydrogen atmosphere (1 atm). Palladium-carbon was removed and the solvent was evaporated under reduced pressure. The resulting crude title compound was purified by column chromatography (hexane-hexane/ethyl acetate=35/65) to give the title compound (450 mg, 46%) as colorless crystals.
Reaction SMILES: [C:1]([OH:20])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH2:21]([CH2:23][NH2:24])[OH:22].O>CCCCCC>[C:1]([NH:24][CH2:23][CH2:21][OH:22])(=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Reactant: NCCO
Solvent: CCCCCC
Solvent: O
Product: CCCCCCCC/C=C\CCCCCCCC(=O)NCCO

Procedure:
In an exemplary embodiment, 1 mmol oleic acid was reacted with 1 mmol ethanolamine in 1.5 mL hexane at 65° C. for 3 hours in the presence 30% lipase and 10 μL water. N-oleoyl ethanolamine with 96.6% purity was obtained and all oleic acid was consumed. In another exemplary embodiment, when the synthesis was conducted on a large scale (50 mmol of each of the reactants), the purity of N-oleoyl ethanolamine after crystallization purification was 96.1%. More examples of reacting the alkanolamine and the fatty acid to prepare the high-purity fatty acid N-acylalkanolamine in a high yield are described in Examples 9-18.
Reaction SMILES: O=[C:2]([CH2:8][CH3:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[C:13]([Cl:18])[C:12]=1[NH:19][NH2:20].C1C=CC=CC=1>O>[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[C:13]([Cl:18])[C:12]=1[NH:19][N:20]=[C:2]([CH2:8][CH3:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(=O)CC
Reactant: NNc1c(Cl)cc(Cl)cc1Cl
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)C(CC)=NNc1c(Cl)cc(Cl)cc1Cl

Procedure:
A reaction mixture consisting of 11 g. (0.085 mole) ethyl 2-oxobutyrate, 17 g. (0.077 mole) (2,4,6-trichlorophenyl)hydrazine, and 200 ml. benzene was heated at the reflux temperature with a Dean and Stark water trap attached to the reaction vessel. When all the water produced by the reaction had been removed, the benzene was removed by evaporation under reduced pressure. The oily residue that remained was dissolved in hot technical hexane, and this solution was allowed to cool. Crystals of the desired product separated and 15.2 g. were recovered. Recrystallization from methanol gave an analytical sample of ethyl 2-oxobutyrate 2-(2,4,6-trichlorophenyl)hydrazone having a melting point at 97° to 99° C.
Reaction SMILES: O=[C:2]1[NH:7][C:6]2[S:8][C:9]([C:11]([O:13][CH3:14])=[O:12])=[CH:10][C:5]=2[N:4]=[CH:3]1.P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:2]1[N:7]=[C:6]2[S:8][C:9]([C:11]([O:13][CH3:14])=[O:12])=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1cc2ncc(=O)[nH]c2s1
Product: COC(=O)c1cc2ncc(Cl)nc2s1
Yield: 39.4 %

Procedure:
A mixture of 91 (6.66 mmol, 1.4 g) in phosphorus oxychloride (21.46 mmol, 2 mL) was heated to reflux for 5 days. Reaction mixture was concentrated under reduced pressure and co-evaporated with toluene (3×). The crude product was purified by chromatography (heptane/ethyl acetate 9/1) to give methyl 3-chlorothieno[2,3-b]pyrazine-6-carboxylate 92 (0.6 g, 40%). NMR (400 MHz, CDCl3) 4.01 (s, 3H), 8.18 (s, 1H), 8.71 (s, 1H). (m/z)=229 (M+H)+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[C:12]2[CH2:13][NH:14][CH2:15][CH2:16][S:17][C:11]=2[CH:10]=[CH:9][CH:8]=1.Cl.C(N(CC)CC)C>ClCCl>[Cl:6][C:7]1[C:12]2[CH2:13][N:14]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:15][CH2:16][S:17][C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: Clc1cccc2c1CNCCS2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CCSc2cccc(Cl)c2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of methanesulphonyl chloride (3.43 g) in dichloromethane (30 ml) was added dropwise at room temperature to a stirred solution of 6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine (5.2 g, prepared in a similar manner to its hydrochloride, Example 1 above) and triethylamine (3.03 g, 0.03 ml) in dichloromethane (100 ml). The reaction mixture was stirred at room temperature for one hour, washed with water, dried and the solvent was removed by evaporation. Purification of the residue by flash chromatography using dichloromethane as eluent gave 6-chloro-4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine, which was recrystallised from hexane. Yield 6.06 g (m.p. 85°-86° C.).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12](Cl)[C:11]([Cl:15])=[C:10]([Cl:16])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[OH-:18].[K+]>>[C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([OH:18])[C:11]([Cl:15])=[C:10]([Cl:16])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [OH-]
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(Cl)c(Cl)c1
Agent: [K+]
Product: CC(C)(C)OC(=O)Nc1cc(O)c(Cl)c(Cl)c1
Temperature: 90 °C

Procedure:
In analogy to Example 63A, tert-butyl(3,4,5-trichlorophenyl)carbamate from Example 66A (3.98 g, 13.4 mmol) was reacted with potassium hydroxide (1.77 g, 26.8 mmol). The reaction mixture was heated to 80° C. overnight and subsequently to 90° C. for 3 h. The product was isolated by preparative HPLC to yield 760 mg (20%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].[Br:18]N1C(=O)CCC1=O.O.C(=O)(O)[O-].[Na+]>CN(C=O)C>[Br:18][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([CH2:8][CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[CH:4]=1
Reactant: CC(C)(C)[Si](C)(C)OCCc1ccccc1N
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCc1cc(Br)ccc1N
Temperature: 25 °C
Reaction time: 24 h
Yield: 73.1 %

Procedure:
To a DMF (50 ml) solution of 1-Amino-2-[2-(tert-butyldimethylsilyloxy)ethyl]benzene (3.96 g, 0.015 mol) [European journal of organic chemistry, 2001, issue 48, 2447-2462] was added N-bromosuccinimide (2.67 g, 0.015 mol) and the mixture was stirred at ambient temperature for 24 hours. Then, the reaction was poured onto saturated aqueous sodium bicarbonate water and extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtration and evaporation. The crude material was purified through silica gel column chromatography eluting with hexane/ethyl acetate (10:1 to 5:1) to afford 3.62 g (73% yield) of the title compound as brown oil.