Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C(OC([N:9]1[CH2:13][C@@H:12]([S:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[CH2:11][C@H:10]1[C:24](=[O:28])[NH:25][CH2:26][CH3:27])=O)(C)(C)C.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH2:26]([NH:25][C:24]([C@@H:10]1[CH2:11][C@H:12]([S:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[CH2:13][NH:9]1)=[O:28])[CH3:27]
Reactant: CCNC(=O)[C@@H]1C[C@H](SCc2ccc(OC)cc2)CN1C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCNC(=O)[C@@H]1C[C@H](SCc2ccc(OC)cc2)CN1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.5 %

Procedure:
41.19 ml of a 4N ethyl acetate solution of hydrogen chloride were added to a solution of 13.00 g of (2S, 4S)-1-t-butoxycarbonyl-2-ethylcarbamoyl-4-(4-methoxybenzylthio)pyrrolidine dissolved in 100 ml of ethyl acetate, and the mixture was stirred at room temperature for 3 hours. At the end of this time, the reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The aqueous layer was saturated with ammonium chloride and extracted with tetrahydrofuran. The combined extracts were washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was removed by distillation under reduced pressure. The residue was subjected to column chromatography through silica gel (eluted with a 87:13 by volume mixture of ethyl acetate and methanol) to afford 8.00 g of the title compound as pale brown crystals, melting at 67-68° C.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:9]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:10]>B#[W]>[C:9](=[O:10])([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Oc1ccccc1
Agent: B#[W]
Product: O=C(Oc1ccccc1)Oc1ccccc1

Procedure:
Example 1 was repeated with 14.1 g of a powdered tungsten monoboride from Strem at 140° C. After 2 hours' reaction time, phenol conversion was 17.3%, wherein 4.8 g of phenyl chloroformate and 24.2 g of diphenyl carbonate were formed. Selectivity for carbonates was approximately 99%.
Reaction SMILES: C(N(CC)CC)C.[C:8]([NH:15][C@H:16]([C:25](O)=[O:26])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].C(OC(Cl)=O)C(C)C.[BH4-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O.C1COCC1>[C:8]([NH:15][C@H:16]([CH2:25][OH:26])[CH2:17][C:18]1[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=1)([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(F)cc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H](CO)Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
At from -5° C. to -10° C. 9.66 ml (69 mmol) of triethylamine are added to a solution of 17.9 g (63 mmol) of N-Boc-(p-fluorophenylalanine) in 73 ml of abs. THF, and a solution of 9.05 ml (69 mmol) of chloroformic acid isobutyl ester in 44 ml of abs. THF is added dropwise thereto. After stirring for 0.5 h at RT, the resulting precipitate is filtered off with suction. The filtrate is added dropwise, with cooling, to 4.77 g (126 mmol) of sodium borohydride in 28 ml of water. The mixture is stirred for 4 h at RT and acidified with 10% citric acid, the THF is partially removed by evaporation using a RE and the residue is partitioned between 3 portions of ethyl acetate and 2 portions of 2N sodium hydroxide solution, water, saturated sodium hydrogen carbonate solution and brine. The organic phases are dried with sodium sulfate, concentrated by evaporation, dissolved in a small amount of methylene chloride and crystallised by the addition of hexane to yield the title compound: TLC Rf (N)=0.36; tRet (I)=16.8 min; 1H-NMR (200 MHz, CD3OD): 7.24 (dd, 8 and 5 Hz, 2H), 6.98 (t, 8 Hz, 2H), 3.73 (m, 1H), 3.47 (d, 5 Hz, 2H), 2.88 (dd, 13 and 6 Hz, 1H), 2.62 (dd, 13 and 8 Hz, 1H), 1.36 (s, 9H).
Reaction SMILES: [NH2:1][C:2](=[N:24]O)[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:23]=[CH:22][C:12]([O:13][CH2:14][C:15]([CH3:21])([CH3:20])[C:16]([O:18][CH3:19])=[O:17])=[CH:11][CH:10]=2)=[N:7][CH:8]=1.C(OC(=O)C)(=O)C>C(O)(=O)C>[C:16]([OH:18])(=[O:17])[CH3:15].[NH2:24][C:2](=[NH:1])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[CH:11][C:12]([O:13][CH2:14][C:15]([CH3:20])([CH3:21])[C:16]([O:18][CH3:19])=[O:17])=[CH:22][CH:23]=2)=[N:7][CH:8]=1
Reactant: COC(=O)C(C)(C)COc1ccc(-c2ccc(C(N)=NO)cn2)cc1
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: COC(=O)C(C)(C)COc1ccc(-c2ccc(C(=N)N)cn2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 186.7 %

Procedure:
In acetic acid (60 mL) was dissolved methyl 3-(4-{5-[amino(hydroxyimino)methyl]-pyridin-2-yl}phenoxy)-2,2-dimethylpropanoate (5.8 g), acetic anhydride (4 mL) was added to the solution and the mixture was stirred at room temperature for 2 hours. To the residue obtained by concentrating the mixture under reduced pressure were added methanol (300 mL) and tetrahydrofuran (70 mL), and 10% palladium carbon (1.2 g) was added to the mixture under nitrogen atmosphere. The atmosphere of the reaction mixture was made hydrogen atmosphere, and the mixture was stirred at room temperature for 2 hours. After replacing the atmosphere with nitrogen, the mixture was filtered using Celite. The filtrate was concentrated under reduced pressure, ether was added to the obtained residue to pulverize the solid, and the solid was collected by filtration and dried to obtain methyl 3-(4-{5-[amino(imino)methyl]pyridin-2-yl}-phenoxy)-2,2-dimethylpropanoate acetate (6.11 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH3:22]I.[Cl-].[Na+].Cl>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([N:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH3:22])[C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)c1cccc(Br)c1
Agent: Cl
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)C(C(=O)O)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
To a solution of (3-bromo-phenyl)-tert-butoxycarbonylamino-acetic acid (490 mg, 1.49 mmol) in THF (10 mL) at room temperature was added sodium hydride (125 mg, 60% inmineral oil, 3.1 mmol) and the resulting pale yellow suspension was stirred at room temperature for 3 hours. Methyl iodide (528 mg, 3.7 mmol) was added and the resulting mixture was stirred overnight. Satuated sodium chloride (10 mL) was added and the aqueous phase pH was adjusted to 5 by addition of 1 N hydrochloric acid. The resulting mixture was extracted with ethyl acetate (10 mL×3) and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified using a gradient of methanol in dichloromethane to afford (3-bromo-phenyl)-(tert-butoxy-carbonyl-methyl-amino)-acetic acid (390 mg, 76%) as an oil. MS: m/z 344 (M+H+).
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:8]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[N:9][N:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=12)=O.Cl.[CH:29]1([NH:34][C:35]([NH2:37])=[NH:36])[CH2:33][CH2:32][CH2:31][CH2:30]1.C(=O)([O-])[O-].[K+].[K+].CCOCC>CN1CCCC1=O.O>[CH:29]1([NH:34][C:35]2[N:37]=[C:5]([C:7]3[C:8]([C:20]4[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=4)=[N:9][N:10]4[CH:15]=[C:14]([C:16]([F:18])([F:17])[F:19])[CH:13]=[CH:12][C:11]=34)[CH:4]=[CH:3][N:36]=2)[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: CN(C)/C=C/C(=O)c1c(-c2ccc(F)cc2)nn2cc(C(F)(F)F)ccc12
Reactant: N=C(N)NC1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCOCC
Product: Fc1ccc(-c2nn3cc(C(F)(F)F)ccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Temperature: 140 °C
Yield: 55.7 %

Procedure:
To a solution of (2E)-3-(dimethylamino)-1-[2-(4-fluorophenyl)-6-(trifluoromethyl)-pyrazolo[1,5-α]pyridin-3-yl]-2-propen-1-one (314 mg, 0.83 mmol)) in 1-methyl-2-pyrrolidinone (3 mL) was added N-cyclopentylguanidine hydrochloride (271 mg, 1.66 mmol) and potassium carbonate (229 mg, 1.66 mmol). The mixture was heated at 140° C. for 8 hours. Upon cooling to room temperature, ether was added followed by water. The organics were washed with brine, and the aqueous layer was extracted with ether. The combined organics were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica (4:1 hexanes-ethyl acetate) to give N-cyclopentyl-4-[2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-α]pyridin-3-yl]-2-pyrimidinamine (204 mg, 56%) as a white solid. 1H NMR (CDCl3): δ 8.84 (s, 1H), 8.51 (d, 1H), 8.11 (d, 1H), 7.64 (dd, 2 H), 7.44 (dd, 1H), 7.17 (t, 2H), 6.33 (d, 1H), 5.17 (d, 1H), 4.34 (m, 1H), 2.15–2.06 (m, 2 ),H 1.84–1.52 (m, 6H); 19F NMR (CDCl3): δ−62.70, −112.25; MS m/z 442 (M+1); mp 155–156° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.[C:12]([C:14]1([CH3:38])[S:18][C:17]([C:19]2[NH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][C:22]=3[N:28]([CH3:37])[S:29]([C:32]2[S:33][CH:34]=[CH:35][CH:36]=2)(=[O:31])=[O:30])=[N:16][CH2:15]1)#[N:13].[OH-].[Na+]>C(O)C>[NH2:13][CH2:12][C:14]1([CH3:38])[S:18][C:17]([C:19]2[NH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][C:22]=3[N:28]([CH3:37])[S:29]([C:32]2[S:33][CH:34]=[CH:35][CH:36]=2)(=[O:31])=[O:30])=[N:16][CH2:15]1
Reactant: CN(c1cccc2cc(C3=NCC(C)(C#N)S3)[nH]c12)S(=O)(=O)c1cccs1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCO
Product: CN(c1cccc2cc(C3=NCC(C)(CN)S3)[nH]c12)S(=O)(=O)c1cccs1
Reaction time: 0.25 h
Yield: 56.9 %

Procedure:
To a mixture of lithium aluminum hydride (0.05 g) and tetrahydrofuran (6 mL) was added N-[2-(5-cyano-5-methyl-4,5-dihydro-1,3-thiazol-2-yl)-1H-indol-7-yl]-N-methylthiophene-2-sulfonamide (0.40 g) at 0° C., and the mixture was stirred for 15 min. Ethanol (2 mL) and 1N aqueous sodium hydroxide solution (0.2 mL) were successively added, and the resulting inorganic salt was removed by filtration. The filtrate was concentrated, and the residue was subjected to basic silica gel column chromatography to give the title compound (0.23 g, yield 57%) as colorless crystals from a fraction eluted with ethyl acetate. melting point 164-165° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[C:28]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[C:30]([NH2:36])[CH:29]=1.[N-:37]=[C:38]=[O:39].[K+]>O.C(O)(=O)C.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]([C:28]2[CH:29]=[C:30]([NH:36][C:38]([NH2:37])=[O:39])[CH:31]=[C:32]([O:34][CH3:35])[CH:33]=2)=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[N:5]=[CH:6][N:7]=1
Reactant: [N-]=C=O
Reactant: COc1cc(N)cc(-c2c(N)ncnc2N[C@@H](C)c2nn3ccc(C)c3c(=O)n2-c2ccccc2)c1
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1cc(NC(N)=O)cc(-c2c(N)ncnc2N[C@@H](C)c2nn3ccc(C)c3c(=O)n2-c2ccccc2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 57.1 %

Procedure:
(S)-2-(1-((6-Amino-5-(3-amino-5-methoxyphenyl)pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (87 mg, 0.18 mmol) was suspended in a mixture of water (1.5 ml) and acetic acid (1.5 ml) and cooled in an ice bath to 0° C. This mixture was treated with a solution of potassium isocyanate (29 mg, 0.36 mmol) in water (0.5 ml). The reaction mixture was stirred at 0° C. for 1 h and then led to warm to room temperature. The crude was diluted with ethyl acetate and washed with saturated ammonium chloride solution and brine. After evaporation of the solvent, the residue was purified by flash chromatography (50 to 100%, hexane-ethyl acetate) using SP1® Purification System to give 54 mg (57% yield) of the title compound as a solid. Purity 99%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[S:20][C:16]=3[C:15]([Br:25])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:5]=[C:4]([Br:26])[C:3]=1[OH:27].C[O:29][C:30](=[O:45])[C@@H:31](O)[CH2:32][CH2:33][N:34]1[CH2:42][C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35]1=[O:43].BrBr>>[Br:26][C:4]1[CH:5]=[C:6]([C:8]2[C:17]3[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[S:20][C:16]=3[C:15]([Br:25])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:7]=[C:2]([Br:1])[C:3]=1[O:27][C@H:31]([CH2:32][CH2:33][N:34]1[CH2:42][C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35]1=[O:43])[C:30]([OH:45])=[O:29]
Reactant: COC(=O)[C@@H](O)CCN1Cc2ccccc2C1=O
Reactant: Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br
Agent: BrBr
Product: O=C(O)[C@@H](CCN1Cc2ccccc2C1=O)Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br

Procedure:
Prepared from of 2,6-dibromo-4-(6-bromo-benzo[b]naphtho[2,3-d]thiophen-1 1-yl)-phenol (Example 21) and (S)-(+)-α-hydroxy-1-oxo-2-isoindolinebutyric acid methyl ester (Example 106). White solid: mp 239-241° C.: NMR (CDCl3); δ8.34 (d, J =8 Hz, 1 H), 7.90 (d, J=8 Hz, 1 H), 7.80 (d, J=8 Hz, 1 H), 7.66 (ddd, J=8, 7, 1 Hz, 1 H), 7.62-7.58 (m, 4 H), 7.52-7.47 (m, 3 H), 7.39 (ddd, J=8, 7, 1 Hz, 1 H), 7.14 (ddd, J =8, 7, 1 Hz, 1 H), 6.72 (d, J=8, Hz, 1 H), 5.39 (t, J=7 Hz, 1 H), 4.59 (m, 2 H), 4.22-3.93 (m, 2 H), 2.65 (t, J=6 Hz, 2 H); MS (+FAB): [M+H]+, 3 bromine isotope pattern, 778, 780, 782, 784); Anal. Calc. for C34H22Br3NO4S: C, 52.33, H, 2.84, N, 1.79. Found: C, 52.11, H, 2.73, N, 1.79.
Reaction SMILES: C(OC([N:7]1[CH2:11][C@@H:10]([N:12](C(OCC=C)=O)[CH3:13])[CH2:9][C@H:8]1[CH:20]=[C:21]([C:23]1[CH2:29][C@H:28]2[N:25]([C:26](=[O:33])[C@@H:27]2[C@H:30]([OH:32])[CH3:31])[C:24]=1[C:34]([O:36]CC=C)=[O:35])[CH3:22])=O)C=C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)(=O)C>O1CCCC1.C(O)C.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>[OH:32][C@@H:30]([C@H:27]1[C:26](=[O:33])[N:25]2[C@@H:28]1[CH2:29][C:23]([C:21]([CH3:22])=[CH:20][C@@H:8]1[CH2:9][C@H:10]([NH:12][CH3:13])[CH2:11][NH:7]1)=[C:24]2[C:34]([OH:36])=[O:35])[CH3:31]
Reactant: C=CCOC(=O)C1=C(C(C)=C[C@@H]2C[C@H](N(C)C(=O)OCC=C)CN2C(=O)OCC=C)C[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CN[C@@H]1CN[C@H](C=C(C)C2=C(C(=O)O)N3C(=O)[C@H]([C@@H](C)O)[C@H]3C2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.2 %

Procedure:
To a solution of allyl (5R,6S)-3-[2-{(2S,4S)-1-allyloxycarbonyl-4-(N-allyloxycarbonyl-N-methylamino)-pyrrolidin-2-yl}-1-methylethenyl]-6-[(1R)-1hydroxyethyl]-7-oxo-1-azabicyclo [3.2.0]hept-2-ene-2-carboxylate (0.495 g) in a mixture of tetrahydrofuran (5 ml) and ethanol (2.5 ml) were added successively triphenylphosphine (96 mg), 5.5-dimethyl-1,3-cyclohxanedione (dimedone)(0.38 g), acetic acid (54.7 μl), and tetrakis(triphenylphosphine)palladium(0) (85 mg). Stirring at ambient temperature for 1 hour gave a precipitate, which was coolected by filtration, washed with ethyl acetate and dissolved in water (70 ml). The solution was washed with ethyl acetate (30 ml×3) and concentrated in vacuo. The residue was chromatographed on nonionic adsorption resin "Diaion HP-20" (Trademark, made by Mitsubishi Chemical Industries)(70 ml) eluting with aqueous isopropyl alcohol (3%-20%). The fractions containing the desired compound were collected and lyophilized to give (5R,6S)-6-[(1R)-1-hydroxyethyl]-3-[2-{(2S,4S)-4-(methylamino)-pyrrolidin-2-yl}-1-methylethenyl]-7-oxo-1-azabicyclo-[3.2.0]hept-2-ene-2-carboxylic acid (135 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[O:6][C@@H:5]2[CH:7]=[CH:8][C@H:9]([OH:10])[C@@H:4]2[O:3]1.N1C=CC=CC=1.Cl[C:19]([O:21][CH3:22])=[O:20]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:19](=[O:20])([O:21][CH3:22])[O:10][C@@H:9]1[C@H:4]2[C@H:5]([O:6][C:2]([CH3:11])([CH3:1])[O:3]2)[CH:7]=[CH:8]1
Reactant: COC(=O)Cl
Reactant: CC1(C)O[C@H]2[C@@H](O)C=C[C@H]2O1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)O[C@H]1C=C[C@H]2OC(C)(C)O[C@@H]12
Temperature: 0 °C

Procedure:
(3aS,4S,6aR)-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-ol (2-1) (9.76 g, 62.5 mmol, 1.0 equiv) was dissolved in DCM (200 mL). Pyridine (7.58 mL, 94.0 mmol, 1.5 equiv) was added and the mixture stirred at 0° C. After 1 hour DMAP (3.05 g, 25.0 mmol, 0.4 equiv) was added followed by methyl chloroformate (19.4 mL, 250 mmol, 4 equiv). The resulting mixture was stirred overnight, and the temperature was allowed to slowly increase to room temperature. The reaction was partitioned between DCM and water, and the organic layer was separated and washed with water, dried (MgSO4), and concentrated to yield desired (3aR,4S,6aR)-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl methyl carbonate (2-2) as a colorless oil. 1H NMR (500 MHz, CDCl3): δ 6.10 (d, J=5.9 Hz, 1H); 5.91 (d, J=5.9 Hz, 1H); 5.30 (d, J=5.4 Hz, 1H); 5.03 (d, J=5.7 Hz, 1H); 4.92 (t, J=5.5 Hz, 1H); 3.83 (s, 3H); 1.40 (s, 3H); 1.38 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[C:9]2[O:14][C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1)([O-:3])=[O:2].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][C:24]=1[C:32]([F:35])([F:34])[F:33]>O1CCCC1>[N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[C:9]2[O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:30]([NH:29][C:26]2[CH:27]=[CH:28][C:23]([Cl:22])=[C:24]([C:32]([F:34])([F:33])[F:35])[CH:25]=2)=[O:31])=[CH:17][CH:16]=1)([O-:3])=[O:2]
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: Nc1ccc(Oc2ccnc3c([N+](=O)[O-])cccc23)cc1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Oc2ccnc3c([N+](=O)[O-])cccc23)cc1)Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 88.4 %

Procedure:
4-(8-Nitroquinolin-4-yloxy)phenylamine (7.5 mg, 0.027 mmol) and 4-chloro-3-(trifluoromethyl)phenyl isocyanate (11.8 mg, 0.054 mmol) were dissolved in tetrahydrofuran, and stirred at room temperature for 12 hours. When the reaction was completed, the solvent was removed by vacuum distillation, and a white solid product was filtered to obtain 12.0 mg of the desired compound (yield 88.9%).
Reaction SMILES: [C:1]([Mg]Br)#[CH:2].[F:5][C:6]([F:14])([F:13])[C:7]([C:9]([F:12])([F:11])[F:10])=[O:8]>>[F:5][C:6]([F:14])([F:13])[C:7]([C:9]([F:12])([F:11])[F:10])([OH:8])[C:1]#[CH:2]
Reactant: O=C(C(F)(F)F)C(F)(F)F
Reactant: C#C[Mg]Br
Product: C#CC(O)(C(F)(F)F)C(F)(F)F

Procedure:
To a 100 ml solution of ethynyl magnesium bromide (0.5 M in THF) in an acetone-ethanol dry ice bath was bubbled hexafluoro acetone gas (6.1 g, 36.7 mmol) over 2 h. The reaction mixture was warmed to r.t and then refluxed for 0.5 h. The reaction mixture was quenched with aqueous NH4Cl solution and extracted with ether. The combined organic phases were washed with brine, and dried over MgSO4. A liquid mixture of 1,1,1-trifluoro-2-trifluoromethyl-but-3-yn-2-ol with THF at b.p. 100-103° C. (4.7 g, contained about 68 mol % THF) was obtained by distillation (12 inch Vigreux column).
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[Cl:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][C:18]=1[F:19])[NH2:15]>>[N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[NH:3][C:2]=1[NH:15][C:14]1[CH:16]=[CH:17][C:18]([F:19])=[C:12]([Cl:11])[CH:13]=1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: Nc1ccc(F)c(Cl)c1
Product: Fc1ccc(Nc2nc3ccccc3[nH]2)cc1Cl

Procedure:
The title compound was prepared from 2-chlorobenzimidazole and 3-chloro-4-fluoroaniline by Procedure A. The product was isolated by filtration to give the title compound as a hydrochloride salt (white solid, mp 306-307° C.). MS(ES+) m/z 262 ([M+1]+, 100).
Reaction SMILES: [CH3:1][C:2]1[C:3](N2C=NC=N2)=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.[Na].C(O)(=O)C.[CH2:19]([OH:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O>[CH2:19]([O:26][C:3]1[C:2]([CH3:1])=[CH:7][NH:6][C:5](=[O:8])[N:4]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: OCc1ccccc1
Reactant: Cc1c[nH]c(=O)nc1-n1cncn1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: Cc1c[nH]c(=O)nc1OCc1ccccc1
Temperature: 100 °C
Yield: 67.9 %

Procedure:
1.06 g (6 mmol) of 5-methyl-4-(1,2,4-triazol-1-yl)-pyrimidin-2(1H)-one are added to a solution of 2.34 g (18 mmol) of sodium benzylate in 25 ml of dry benzyl alcohol and 25 ml of dry dimethylformamide are added. The mixture is heated for 2 hours with stirring to 100° C. The cooled solution is neutralized with acetic acid, concentrated and chromatographed on silica gel using ethylacetate/methanol 9/1. 880 mg (67.9% of theory) of 4-benzyloxy-5-methylpyrimidin-2(1H)-one are obtained with melting point 181°-182°C. 1H NMR (270 MHz, d6 -DMSO), δ[ppm]: 11.14 (s, 1H), 7.56 (d, 1H), 7.41 (m, 5H), 5.35 (s, 2H), 1.87 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH2:11][O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[C:9]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(Cl)(=O)C(Cl)=O.[C:29]1(=O)[CH2:34][CH2:33][CH2:32][CH2:31][C:30]1=[O:35].C(N(CC)CC)C>CN(C)C=O.C(Cl)Cl>[Cl:1][C:2]1[C:10]([CH2:11][O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[C:9]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][C:34]1[CH2:33][CH2:32][CH2:31][C:30](=[O:35])[CH:29]=1)=[O:5]
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1COC1CCCCC1
Reactant: O=C1CCCCC1=O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(C(=O)OC2=CC(=O)CCC2)c(Cl)c1COC1CCCCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.53 g (1.53 mmol) of 2-chloro-3-cyclohexanyloxymethyl-4-methylsulfonylbenzoic acid was treated with 2 drops of N,N-dimethylformamide and 0.59 g (4.58 mmol) of oxalyl chloride in 23 ml of methylene chloride and the mixture was refluxed for 2.5 h. It was then stripped off on a rotary evaporator, the residue was taken up in 23 ml of methylene chloride and the mixture was treated at 0° C. with 0.19 g (1.68 mmol) of cyclohexanedione and 0.46 g (4.58 mmol) of triethylamine. It was stirred at room temperature for 4 h. It was then concentrated on a rotary evaporator and purified by chromatography (silica gel, ethyl acetate:hexane=1:1).
Reaction SMILES: [CH2:1]([O:23][CH:24]([CH3:32])[C:25]([O:27]C(C)(C)C)=[O:26])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6]/[CH:7]=[CH:8]\[CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH3:22].[CH:33](O)=O>C(OCC)C>[CH2:1]([O:23][CH:24]([CH2:32][CH3:33])[C:25]([OH:27])=[O:26])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6]/[CH:7]=[CH:8]\[CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH3:22]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCOC(C)C(=O)OC(C)(C)C
Reactant: O=CO
Solvent: CCOCC
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCOC(CC)C(=O)O
Temperature: 40 °C
Reaction time: 6 h
Yield: 58 %

Procedure:
A mixture of tert-butyl 2-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaen-1-yloxy)propanoate (2.09 g, 4.58 mmol) in HCOOH (9 ml) was stirred at 40° C. under N2-atmosphere for 6 hrs. The reaction mixture was diluted with diethyl ether (100 mL), washed with water (30 mL), dried (MgSO4), filtered and evaporated under reduced pressure. Dry-flash on silica gel (50 g) eluting with toluene-toluene (85:15) yielded 1.44 g of the crude title compound. Flash chromatography on silica gel (30 g) eluting with heptane-heptane/(EtOAc w/5% HCCOH) 98:2-95:5-80:20 yielded 1.07 g (58% yield) of the title compound as a liquid. 1H NMR (200 MHz, CDCl3) δ 0.97 (t, 3H), 0.99 (t, 3H), 1.64-1.91 (m, 4H), 2.00-2.23 (m, 4H), 2.78-2.87 (m, 10H), 3.42-3.66 (m, 2H), 3.85 (dd, 1H), 5.26-5.46 (m, 12H). MS (electrospray) (neg): 399 (M−H)−.