Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.[Br:21][C:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[O:24][C:23]=1[CH3:31]>ClC1C=CC=CC=1>[Br:21][C:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[O:24][C:23]=1[CH2:31][Br:1]
Reactant: Cc1oc2ccccc2c1Br
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: Clc1ccccc1
Product: BrCc1oc2ccccc2c1Br
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 77.8 %

Procedure:
2.7 g (15.3 mmoles) of N-bromosuccinimide and 0.4 g (2.7 mmoles) of azobisisobutyronitrile were added to a solution of 2.8 g (13.3 mmoles) of 3-bromo-2-methylbenzofuran dissolved in 30 ml of monochlorobenzene. The mixture was stirred at 80° C. for 30 minutes to give rise to a reaction. After confirmation of the disappearance of the raw materials, the reaction mixture was cooled to room temperature. The insolubles were removed by filtration. The filtrate was subjected to vacuum distillation to remove the solvent contained therein. The residue was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 3.0 g (yield: 79.0%) of 3-bromo-2-bromomethylbenzofuran.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16](=O)[CH2:17][CH2:18][C:19]([O:21]C)=O)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[NH2:24][NH2:25].CCCCCC.C(OCC)(=O)C>C(O)C>[C:1]([C:5]1[CH:6]=[C:7]([C:16]2[CH2:17][CH2:18][C:19](=[O:21])[NH:24][N:25]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)CCC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: NN
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CCCCCC
Product: CC(C)(C)c1cc(C2=NNC(=O)CC2)cc(C(C)(C)C)c1O
Yield: 85 %

Procedure:
A mixture of 22 g (0.07 mol) methyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-4-oxo-butanoate and 6.8 g (0.18 mol) of 85% aqueous hydrazine in 250 ml of ethanol is heated under reflux. The reaction is considered complete by the disappearance of the starting material as indicated by TLC analysis (silica gel; 7/3: hexane/ethyl acetate). Upon cooling the reaction mixture, 18.0 g (85% yield) of white crystals are collected by filtration: mp 200°-203° C.; IR (CH2Cl2) 3640, 3420, 3250 and 1680 cm-1.
Reaction SMILES: [C:1]([C:4]1[CH:18]=[CH:17][C:7]2[CH:8]=[CH:9][N:10]3[CH:16]=[CH:15][CH:14]=[C:11]3[C:12](=[O:13])[C:6]=2[CH:5]=1)(=[O:3])N.S(=O)(=O)(O)[OH:20].N([O-])=O.[Na+]>O>[C:1]([C:4]1[CH:18]=[CH:17][C:7]2[CH:8]=[CH:9][N:10]3[CH:16]=[CH:15][CH:14]=[C:11]3[C:12](=[O:13])[C:6]=2[CH:5]=1)([OH:20])=[O:3]
Reactant: NC(=O)c1ccc2ccn3cccc3c(=O)c2c1
Reactant: O=S(=O)(O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccc2ccn3cccc3c(=O)c2c1

Procedure:
To 9-carbamoyl-11H-pyrrolo[2,1-b] [3]-benzazepin-11-one (27 g., 0.112 moles) in 300 ml. of 50% sulfuric acid maintained at 50° C. is added slowly 25 g. of sodium nitrite in 75 ml. of water. At the end of the addition, the solid is filtered, washed with water and air-dried to yield 9-carboxy-11H-pyrrolo[2,1-b] [3]benzazepin-11-one.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:13])[CH:7]=[CH:8][N:9]2[CH3:12])=[CH:4][CH:3]=1.[Cl:14][S:15](O)(=[O:17])=[O:16]>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:13])[C:7]([S:15]([Cl:14])(=[O:17])=[O:16])=[CH:8][N:9]2[CH3:12])=[CH:4][CH:3]=1
Reactant: O=S(=O)(O)Cl
Reactant: Cn1ccc(=O)c2ccc(Cl)cc21
Product: Cn1cc(S(=O)(=O)Cl)c(=O)c2ccc(Cl)cc21
Temperature: 25 °C

Procedure:
7-Chloro-1-methyl-4-quinolone (6.9 g) and chlorosulphonic acid (14 ml) were stirred and heated at 140° for 2 hours. The reaction mixture was cooled to room temperature and carefully added dropwise to ice water (200 ml). The solid which formed was collected, washed with water and dried in air to give the novel compound 7-chloro-1-methyl-4-oxo-1,4-dihydroquinoline-3-sulphonyl chloride, m.p. >300°.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[CH:24]1([NH2:27])[CH2:26][CH2:25]1>>[CH:24]1([NH:27][C:19](=[O:21])[C:18]2[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:16][CH:17]=2)[CH2:26][CH2:25]1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: NC1CC1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NC2CC2)cn1
Yield: 68 %

Procedure:
As described for example 12, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.64 mmol) was converted using cyclopropylamine instead of 2,2,2-trifluoroethylamine to the title compound (SiO2, heptane:ethyl acetate=80:20 to 20:80, 148 mg, 68%) which was obtained as a white solid. MS: m/e=350.2 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=1[CH2:6][N:7]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]1)([O-:3])=[O:2].C(N(CC)CC)C.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1(C)C=CC=CC=1>[C:25]([O:13][CH:10]1[CH2:11][CH2:12][N:7]([CH2:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[N+:1]([O-:3])=[O:2])[CH2:8][CH2:9]1)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=[N+]([O-])c1ccccc1CN1CCC(O)CC1
Reactant: O=C(Cl)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(OC1CCN(Cc2ccccc2[N+](=O)[O-])CC1)c1ccccc1
Yield: 67.1 %

Procedure:
0.5 g (0.00212 mol) of 1-(2-nitro-benzyl)-piperidin-4-ol and 0.595 ml (0.00424 mol) of triethylamine were dissolved in 15 ml of toluene, treated with 0.295 ml (0.00254 mol) of benzoyl chloride and boiled at reflux for 18 hrs. The reaction mixture was concentrated and the residue was chromatographed over silica gel with ethyl acetate/hexane (1 :2). 0.484 g (75%) of 1-(2-nitro-benzyl)-piperidin-4-yl benzoate was obtained as a yellow oil. MS: me/e=341 (C19H21N2O4+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.[CH3:13][C:14]1[N:15]=[CH:16][N:17]([C:19]2[S:20][CH:21]=[CH:22][C:23]=2[NH2:24])[CH:18]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([NH:24][C:23]2[CH:22]=[CH:21][S:20][C:19]=2[N:17]2[CH:18]=[C:14]([CH3:13])[N:15]=[CH:16]2)=[O:12])=[CH:7][CH:8]=1
Reactant: COc1ccc(CC(=O)O)cc1
Reactant: Cc1cn(-c2sccc2N)cn1
Product: COc1ccc(CC(=O)Nc2ccsc2-n2cnc(C)c2)cc1
Yield: 6 %

Procedure:
2-(4-methoxyphenyl)-N-(2-(4-methyl-1H-imidazol-1-yl)thiophen-3-yl)acetamide was prepared from 2-(4-methoxyphenyl)acetic acid and 2-(4-methyl-1H-imidazol-1-yl)thiophen-3-amine according to the procedure described in Example 9.7.3., above. Purification by flash column chromatography afforded the final product (silica, 75:25 ethyl acetate/hexane) (77 mg, 6%). Method [7] m/z 328.0 (M+H); retention time=1.001. 1H-NMR (CDCl3) δ 8.00 (broad s, 1H), 7.77 (d, J=6.4 Hz, 1H), 7.16 (s, 1H), 7.13 (d, J=8.7 Hz, 2H), 6.85 (d, J=8.7 Hz, 2H), 6.50 (s, 1H), 3.81 (s, 3H), 3.65 (s, 2H), 2.15 (d, J=0.9 Hz, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.[CH3:13][C:14]([Si:17](Cl)([CH3:19])[CH3:18])([CH3:16])[CH3:15].N1C=CN=C1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[C:14]([Si:17]([O:12][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=2)[CH:8]=1)([CH3:19])[CH3:18])([CH3:16])([CH3:15])[CH3:13]
Reactant: Oc1ccc2cc(Br)ccc2c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc2cc(Br)ccc2c1
Reaction time: 3 h
Yield: 96.3 %

Procedure:
To a solution of 6-bromo-2-naphthol (13.68 g, 61.33 mmol) and TBDMS-Cl (11.09 g, 73.6 mmol) in DMF (50 mL) was added imidazole (10.2 g, 150 mmol). The solution was stirred for 3 hr, mixed with sodium bicarbonate solution (250 mL), and extracted with 50% ethyl acetate-hexanes (3×250 mL). The combined organic layers were washed with water, dried over magnesium sulfate, filtered and evaporation of the solvent yielded a tan oil which was dried under vacuum to yield 19.92 g (97%) of the title compound as a white solid:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[N:12][C:13]=1[CH3:14])[N:10]([CH2:15][CH3:16])[CH:9]=[C:8]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:7]2=[O:22])[CH3:2].S1(CCCC1)(=O)=[O:24].[Se](=O)=O>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[N:12][C:13]=1[CH:14]=[O:24])[N:10]([CH2:15][CH3:16])[CH:9]=[C:8]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:7]2=[O:22])[CH3:2]
Reactant: O=S1(=O)CCCC1
Reactant: CCOC(=O)c1cn(CC)c2nc(C)c(OCC)cc2c1=O
Agent: O=[Se]=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn(CC)c2nc(C=O)c(OCC)cc2c1=O

Procedure:
A mixture of 30.4 g of ethyl 1,4-dihydro-6-ethoxy-1-ethyl-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylate (Compound VIII where R1 =R2 =R3 =C2H5) and 100 ml of sulfolane was stirred at 140°-145° C. and 22 g of selenium dioxide in limited amounts was added thereto. After reacting the mixture under the same conditions for 5 hours and then allowing it to cool, chloroform was added thereto. The insoluble materials were removed by filtration. The filtrate was washed successively with 3% sodium carbonate solution, water, dried over anhydrous sodium sulfate and evaporated. To the residue was added isopropanol and the precipitated crystals were collected by filtration to obtain 22.0 g of ethyl 1,4-dihydro-6-ethoxy-1-ethyl-7-formyl-4-oxo-1,8-naphthyridine-3-carboxylate, m.p. 169°-170° C.
Reaction SMILES: [F-].[NH4+].[CH3:3][O:4][C:5](=[O:44])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][C@H:15]([NH:17][CH2:18][C@H:19]([O:36][Si](C(C)(C)C)(C)C)[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[C:22]([CH2:34][OH:35])[CH:21]=2)[CH3:16])[CH:9]=1>O.CO>[NH3:17].[CH3:3][O:4][C:5](=[O:44])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][C@H:15]([NH:17][CH2:18][C@@H:19]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[C:22]([CH2:34][OH:35])[CH:21]=2)[OH:36])[CH3:16])[CH:9]=1
Reactant: COC(=O)CCc1cccc(C[C@@H](C)NC[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(OCc3ccccc3)c(CO)c2)c1
Agent: [F-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: COC(=O)CCc1cccc(C[C@@H](C)NC[C@H](O)c2ccc(OCc3ccccc3)c(CO)c2)c1
Product: N
Temperature: 40 °C
Yield: 178 %

Procedure:
Ammonium fluoride (2.80 g, 75.5 mmol) was added in one portion to a solution of methyl-3-(3-{(2R)-2-[(2R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-2-(4-[benzyloxy]-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-propanoate (Preparation 53) (4.47 g, 7.55 mmol) in water (20 ml) and methanol (30 ml) at room temperature. The reaction was heated at 40° C. for 18 hours and then allowed to cool to room temperature. The methanol was removed in vacuo and the resulting aqueous extracted with dichloromethane (3×75 ml), the combined organics were washed with water (25 ml), dried (sodium sulfate) and the solvent removed in vacuo to yield an orange foam. This was purified by flash column chromatography on silica gel eluting with dichloromethane:methanol: 880 ammonia (95:5:0.5 by volume) to give the title compound as a yellow oil (3.21 g).
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:23]=[CH:22][C:7]2[CH:8]=[C:9]([C:11]([NH:13][C@@H:14]3[CH:19]4[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]4)[CH2:15]3)=[O:12])[S:10][C:6]=2[CH:5]=1.C(N(CC)CC)C.[CH:31]1([N:37]=[C:38]=[O:39])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>C1COCC1.CN(C=O)C>[ClH:1].[N:16]12[CH2:21][CH2:20][CH:19]([CH2:18][CH2:17]1)[C@@H:14]([NH:13][C:11]([C:9]1[S:10][C:6]3[CH:5]=[C:4]([NH:3][C:38]([NH:37][CH:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)=[O:39])[CH:23]=[CH:22][C:7]=3[CH:8]=1)=[O:12])[CH2:15]2
Reactant: Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Reactant: O=C=NC1CCCCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1)NC1CCCCC1
Reaction time: 18 h

Procedure:
A solution of 40 mg (0.11 mmol) of 6-amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide dihydrochloride in 2 ml of THF and 0.2 ml of DMF is mixed with 29.8 μl (0.21 mmol) of triethylamine and 26.8 mg (0.21 mmol) of, cyclohexyl isocyanate. After 18 h at room temperature, the product is purified by preparative HPLC. The concentrated product fraction is dissolved in a mixture of methanol and 1 N hydrochloric acid (2:1), again concentrated and dried under high vacuum. 23.4 mg (47.3% of theory) of the title compound are obtained.
Reaction SMILES: [C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:20][CH2:21][CH2:22][C:23]#[N:24].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(O)CCC.O1CCOCC1>[C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:8][CH2:9][N:10]([CH2:20][CH2:21][CH2:22][C:23]#[N:24])[CH2:11][CH2:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(C2(c3ccccc3)CCNCC2)cc1
Reactant: N#CCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCCCO
Product: N#CCCCN1CCC(c2ccccc2)(c2ccccc2)CC1
Temperature: 25 °C
Yield: 87.3 %

Procedure:
A suspension of 4,4-diphenylpiperidine (4.15 g, 17.5 mmol, 1.00 equiv), 4-bromobutyronitrile (2.10 mL, 21.0 mmol, 1.20 equiv, Aldrich), potassium carbonate (4.85 g, 35.0 mmol, 2.00 equiv), and potassium iodide (581 mg, 3.50 mmol, 0.20 equiv) in n-butanol (20 mL) and 1,4-dioxane (20 mL) was stirred at reflux under argon for 48 hours. The mixture was cooled to room temperature and concentrated. Water (50 mL) was added and the mixture was extracted with CH2Cl2 (4×150 mL) . The combined organic solutions were dried over MgSO4 and concentrated. The residue was purified by flash chromatography (SiO2, EtOAc) to afford 4.65 g (87%) of white solid, which was characterized spectroscopically.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([O:8][CH2:9][CH2:10][C@@H:11]([C:19]([OH:21])=[O:20])[NH:12]C(=O)C(F)(F)F)=[O:7])[C@@H:3]([CH3:5])[OH:4].ClCC(O)=O.[N:27]([O-])=O.[Na+]>O>[N+:1](=[C:2]([C@H:3]([OH:4])[CH3:5])[C:6]([O:8][CH2:9][CH2:10][C@@H:11]([C:19]([OH:21])=[O:20])[NH2:12])=[O:7])=[N-:27]
Reactant: O=N[O-]
Reactant: C[C@@H](O)[C@H](N)C(=O)OCC[C@H](NC(=O)C(F)(F)F)C(=O)O
Agent: O=C(O)CCl
Agent: [Na+]
Solvent: O
Product: C[C@@H](O)C(=[N+]=[N-])C(=O)OCC[C@H](N)C(=O)O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 4.8 %

Procedure:
To a solution of O-L-threonyl-N-trifluoroacetyl-L-homoserine (800 mg) and 4M aqueous chloroacetic acid (100 μl) in water (10 ml) was added sodium nitrite (345 mg) at room temperature. After stirring for 15 minutes at room temperature, the reaction mixture was neutrized with 2M tris buffer solution to pH 7.0 to 7.3 and then Acylase I (acylase, Sigma A-7264, made by Sigma Chemicals) (100 mg) was added. The mixture was stirred for 5 hours at 35° C. and chromatographed on carbon (50 ml) eluting successively with water and a 9:1 mixture of water and acetone to give O-[2-diazo-3(R)-hydroxy-1-oxobutyl]-L-homoserine (28 mg).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:21]1([C:25]([NH:27][NH2:28])=[O:26])[CH2:24][CH2:23][CH2:22]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:28][NH:27][C:25]([CH:21]1[CH2:24][CH2:23][CH2:22]1)=[O:26])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: NNC(=O)C1CCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C(NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1)C1CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.9 %

Procedure:
To a mixture of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0250 g, 0.905 mmol) in DCM (15.0 mL) were added cyclobutanecarbohydrazide 199 (0.155 g, 1.358 mmol), 1-hydroxybenzotriazole (0.186 g, 1.358 mmol) and 1-ethyl-(3-dimethylamino propyl) carbodiimide hydrochloride (0.260 g, 1.358 mmol) sequentially at room temperature. The mixture was stirred at room temperature overnight, diluted with DCM and concentrated to provide a residue, which was subjected to chromatography to give 200 (0.34 g, quant. yield) as a white foam.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[Cl:9][C:10]1[CH:11]=[C:12](B(O)O)[CH:13]=[CH:14][CH:15]=1>>[Br:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:14]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:9])[CH:15]=2)[CH:7]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: Brc1cncc(Br)c1
Product: Clc1cccc(-c2cncc(Br)c2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using the following starting materials: 3,5-dibromo-pyridine and 3-chlorophenylboronic acid.
Reaction SMILES: [C:1]([CH:5](O)[C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:4])([CH3:3])[CH3:2].P(Br)(Br)[Br:12]>C1C=CC=CC=1>[C:1]([CH:5]([Br:12])[C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C(O)C(C)(C)C
Reactant: BrP(Br)Br
Solvent: c1ccccc1
Product: CC(C)(C)C(Br)C(C)(C)C
Temperature: 0 °C

Procedure:
The alcohol is dissolved in benzene and stirred at 0° C. under argon. A solution of phosphorus tribromide in benzene is added and the mixture is stirred for 2 hours and then heated to 60° C. for 4 hours. The mixture is cooled, poured into ice and extracted with ether. The organic layer is washed with saturated NaHCO3, dried over MgSO4 and evaporated to give di-t-butylmethyl bromide.
Reaction SMILES: Cl.[CH3:2][N:3]([CH2:5][C:6]([NH2:8])=[S:7])[CH3:4].Br[CH2:10][C:11](=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13].C(O)C>CCOCC.O>[CH3:2][N:3]([CH2:5][C:6]1[S:7][CH:10]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:8]=1)[CH3:4]
Reactant: CCOC(=O)C(=O)CBr
Reactant: CN(C)CC(N)=S
Agent: Cl
Solvent: O
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)c1csc(CN(C)C)n1
Temperature: 2.5 °C

Procedure:
A reaction mixture was prepared containing 15.5 g. of dimethylaminothioacetamide hydrochloride, 20.5 g. of ethyl bromopyruvate and 100 ml. of ethanol. The reaction mixture was heated to refluxing temperature for about four hours after which time the solvent was removed in vacuo in a rotary evaporator. The residue, containing ethyl 2-dimethylaminomethyl-4-thiazolecarboxylate formed in the above reaction, was dissolved in a mixture of ether and water. The aqueous layer was separated. The ether layer was extracted with an equal volume of water and then discarded. The two aqueous layers were combined and washed with ether. The ether layer was again discarded and the aqueous layer cooled to a temperature in the range of 0-5° C. Solid potassium carbonate was added until the aqueous layer gave a basic reaction to litmus. An oil separated comprising ethyl 2-dimethylaminomethyl-4-thiazolecarboxylate free base. The oily layer was extracted with ether and the ether extract separated and dried. The ether was removed by evaporation in vacuo. The resulting residue was purified by gradient high pressure liquid chromatography (silica ethyl acetate). Ethyl 2-dimethylaminomethyl-4-thiazolecarboxylate thus obtained had the following physical characteristics:
Reaction SMILES: [F:1][C:2]1[CH:12]=[C:11]([CH2:13][CH2:14][CH:15]([OH:31])[C:16]2[S:17][C:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)=[CH:19][CH:20]=2)[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7].[H-].[Na+].[CH2:34](Br)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH2:34]([O:31][CH:15]([C:16]1[S:17][C:18]([C:21]2[CH:22]=[CH:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=2)=[CH:19][CH:20]=1)[CH2:14][CH2:13][C:11]1[CH:10]=[CH:9][C:3]([O:4][CH2:5][C:6]([OH:8])=[O:7])=[C:2]([F:1])[CH:12]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(O)COc1ccc(CCC(O)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)cc1F
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Product: O=C(O)COc1ccc(CCC(OCc2ccccc2)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)cc1F

Procedure:
2-(4-(3-(Benzyloxy)-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)-2-fluoro-phenoxy)acetic acid is prepared from 2-(2-fluoro-4-(3-hydroxy-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)phenoxy)acetic acid using 2.2 equivalents of sodium hydride and 2.2 equivalents of benzyl bromide according to general procedure H.
Reaction SMILES: CN(C)C(N(C)C)=N.[C:9]([O:13][C:14]([CH:16](P(OC)(OC)=O)[C:17]([O:19][CH3:20])=[O:18])=[O:15])([CH3:12])([CH3:11])[CH3:10].[Cl:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][C:29]=1[F:36].O>C(Cl)Cl>[C:9]([O:13][C:14](/[C:16](=[CH:32]\[C:31]1[CH:34]=[CH:35][C:28]([Cl:27])=[C:29]([F:36])[CH:30]=1)/[C:17]([O:19][CH3:20])=[O:18])=[O:15])([CH3:10])([CH3:11])[CH3:12]
Reactant: COC(=O)C(C(=O)OC(C)(C)C)P(=O)(OC)OC
Reactant: O=Cc1ccc(Cl)c(F)c1
Agent: CN(C)C(=N)N(C)C
Solvent: O
Solvent: ClCCl
Product: COC(=O)/C(=C/c1ccc(Cl)c(F)c1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71.1 %

Procedure:
1,1,3,3-tetramethylguanidine (2.11 ml, 16.8 mmol) was added to a 0° C. solution of methyl 2-(tert-butoxycarbonyl)-2-(dimethoxyphosphoryl)-acetate (5.00 g, 16.8 mmol) in DCM (70 mL). The reaction mixture stirred at 0° C. for 30 minutes, then a solution of 4-chloro-3-fluorobenzaldehyde (2.67 g, 16.8 mmol) in DCM (10 mL) was added by syringe. The reaction mixture was stirred for 10 minutes. The reaction mixture was then warmed to room temperature and stirred for 1 hour. H2O was then added, and the mixture was extracted with DCM. The combined extracts were dried (Na2SO4), filtered, and concentrated. The resulting solids were recrystallized from IPA to give (Z)-methyl 2-(tert-butoxycarbonyl)-3-(4-chloro-3-fluorophenyl)acrylate (3.76 g, 67.8% yield) as a white powder (2 crops). LCMS (APCI−) m/z 328 [M−H]−.
Reaction SMILES: [CH2:1]([O:4][C@@H:5]1[C@H:9]([CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)[S:8][C:7]2[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:6]1=2)[CH:2]=[CH2:3].ClC1C=C(C=CC=1)C(OO)=[O:26]>C(Cl)Cl>[CH2:1]([O:4][C@@H:5]1[C@H:9]([CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)[S:8](=[O:26])[C:7]2[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:6]1=2)[CH:2]=[CH2:3]
Reactant: C=CCO[C@H]1c2ccc(Cl)cc2S[C@H]1Cn1ccnc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: C=CCO[C@H]1c2ccc(Cl)cc2S(=O)[C@H]1Cn1ccnc1
Reaction time: 1 h

Procedure:
Dissolve 21.7 g. (70.7 mmole) of (±)-cis-3-allyloxy-6-chloro-2,3-dihydro-2-(1H-1-imidazolylmethyl) benzo[b]thiophene in 500 mL of CH2Cl2 and cool the solution to 0°-5°. Added 14.6 g (70.7 mmole) of m-chloroperoxybenzoic acid (tech. 80-85%) and stir the reaction mixture at 0°-5° for 1 hour. Extract the reaction mixture with 500 mL of 5% aqueous NaHCO3 followed by 500 mL of H2O. Dried the CH2Cl2 layer over anhydrous MgSO4 and concentrate it to give (±)-cis-3-allyloxy-6-chloro-2,3-dihydro-2-(1H-1-imidazolylmethyl)benzo[b]thiophene-1-oxide, a gum, m/e 322.
Reaction SMILES: [BH4-].[Li+].Cl[Si](C)(C)C.[F:8][C:9]([F:19])([F:18])[CH2:10][C@@H:11]([CH3:17])[C@@H:12]([C:14](O)=[O:15])[NH2:13].CO>C1COCC1>[NH2:13][C@@H:12]([C@H:11]([CH3:17])[CH2:10][C:9]([F:8])([F:18])[F:19])[CH2:14][OH:15]
Reactant: C[C@H](CC(F)(F)F)[C@H](N)C(=O)O
Agent: C[Si](C)(C)Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H](CC(F)(F)F)[C@H](N)CO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirring solution of lithium borohydride (14.5 mL of a 2M solution in THF, 29 mmol) at 0° C. was added chlorotrimethylsilane (7.38 mL, 58 mmol) dropwise over a period of 30 min. The ice bath was removed and the resulting slurry was stirred at 25° C. for 30 min. The reaction mixture was cooled to 0° C. and 5,5,5-trifluoro-L-alloisoleucine (2.7 g, 16.98 mmol) was added in portions as a solid over a period of 15 min. The reaction mixture was allowed to warm slowly to 25° C. as the ice bath melted. After 3 days at 25° C., the reaction mixture was cooled to 0° C., and methanol (22 mL) was carefully added over a period of 30 min. The solution was stirred at 25° C. for an additional 40 min, then concentrated under reduced pressure in a water bath at 60° C. The resulting slurry was made basic with 20% sodium hydroxide (10 mL). Water (10 mL) was added, and the entire aqueous layer was extracted with methylene chloride (100 mL) and dried over MgSO4. The organic phase was filtered and evaporated to produce (2S,3R)-2-amino-5,5,5-trifluoro-3-methylpentan-1-ol as a crude oil (2.6 g, 89.6%).