Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]2[C:13](=[O:17])[CH2:14][CH2:15][S:16][CH:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]1([Mg]Br)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.BrC1C=CC=CC=1.[Mg].[Cl-].[NH4+]>C(OCC)C>[OH:17][C:13]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:11]2[CH:10]([CH2:9][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:12]2)[S:16][CH2:15][CH2:14]1
Reactant: Br[Mg]c1ccccc1
Reactant: O=C1CCSC2CN(Cc3ccccc3)CC12
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: Brc1ccccc1
Solvent: CCOCC
Product: OC1(c2ccccc2)CCSC2CN(Cc3ccccc3)CC21
Reaction time: 3 h

Procedure:
A solution of 21.15 g of (4aRS,7aSR)6-benzyl-4-oxoperhydrothiopyrano[2,3-c]pyrrole in 150 cm3 of anhydrous ethyl ether are added over 30 minutes to a solution of phenylmagnesium bromide prepared from 19.8 cm3 of bromobenzene and 4.52 g of dry magnesium in 120 cm3 of anhydrous ethyl ether. The reaction mixture is stirred at the reflux temperature for 3 hours, and then for 20 hours at 20° C. The mixture, to which 200 cm3 of ethyl ether has been added, is stirred with 600 cm3 of a saturated aqueous solution of ammonium chloride. The aqueous phase is extracted with 200 cm3 of ethyl ether, the two pooled etherial extracts are washed twice with 300 cm3 of a saturated aqueous solution of sodium chloride and then dried over magnesium sulphate and concentrated to dryness under reduced pressure (5.4 kPa) at 35° C. 12.2 g of (4RS,4aSR,7aRS)-4-hydroxy-4-phenyl6-benzylperhydrothiopyrano[2,3-c]pyrrole are obtained in the form of a white solid; melting point 137° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:15])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.C([N:24]=[C:25]=[S:26])(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:25]([NH2:24])=[S:26])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Reactant: O=C(N=C=S)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine (500 mg, 2.46 mmol) in THF (30 ml) at 0° C. was slowly added benzoyl isothiocyanate (0.366 ml, 2.583 mmol) and the reaction mixture was stirred at rt for 2 hours. The solvents were evaporated and the residue was dissolved in methanol (50 ml). A solution of potassium carbonate (1.02 g, 7.38 mmol) in water (23 ml) was added dropwise at rt, the reaction mixture was stirred for 3 h at rt. The methanol was evaporated, water (10 ml) was added and stirred at rt for 1 hour. The solids were filtered off, washed with diethyl ether and dried in vacuo. After trituration with diethyl ether the title compound was obtained as light yellow solid (490 mg, 76%). MS ISP (m/e): 263.1 (100) [(M+H)+].
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]([C:7]2[CH:8]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH:17]=O.CO.[C:21]([O:25][CH3:26])(=[O:24])[NH:22][NH2:23]>C(O)(=O)C>[CH3:26][O:25][C:21](=[O:24])[NH:22][N:23]=[CH:17][C:3]1[N:4]=[C:5]([C:7]2[CH:8]=[C:9]([C:13]([F:14])([F:15])[F:16])[CH:10]=[CH:11][CH:12]=2)[NH:6][C:2]=1[CH3:1]
Reactant: Cc1[nH]c(-c2cccc(C(F)(F)F)c2)nc1C=O
Reactant: COC(=O)NN
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)NN=Cc1nc(-c2cccc(C(F)(F)F)c2)[nH]c1C
Yield: 90.1 %

Procedure:
A mixture of 5-methyl-2-(α,α,α-trifluoro-m-tolyl)imidazole-4-carboxaldehyde (20.0 g, 0.0787 mole), methanol (500 ml), methyl carbazate (7.8 g) and glacial acetic acid (0.5 ml) is refluxed overnight. The solution is then concentrated to afford 23.14 g of title product. A sample is recrystallized from methanol-acetone, m.p. 251°-251.5° C.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([Br:12])[N:3]=1.[CH2:13]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[CH3:14].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:12][C:4]1[N:3]=[C:2]([N:18]2[CH2:19][CH2:20][N:15]([CH2:13][CH3:14])[CH2:16][CH2:17]2)[C:11]2[C:6]([CH:5]=1)=[CH:7][CH:8]=[CH:9][CH:10]=2
Reactant: Brc1cc2ccccc2c(Br)n1
Reactant: CCN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN1CCN(c2nc(Br)cc3ccccc23)CC1
Yield: 73.3 %

Procedure:
1,3-Dibromoisoquinoline (2.70 g), N-ethylpiperazine (1.16 g) and potassium carbonate (3.50 g) were reacted in DMF (30 ml) at 80° C. for 5 hr. The reaction solution was evaporated, and then partitioned between ethyl acetate and water. The resulting organic layer was washed with water, dried and evaporated. The resulting residue was purified by NH silica gel column chromatography (ethyl acetate/n-hexane system), to give the title compound (2.21 g) as a pale yellow oil.
Reaction SMILES: Cl.C([N:9]([CH2:23][C@@H:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=1)[OH:25])[CH:10]1[CH2:16][CH2:15][CH2:14][C:13]2[CH:17]=[CH:18][C:19]([O:21][CH3:22])=[CH:20][C:12]=2[CH2:11]1)C1C=CC=CC=1.ClC1C=CC=CC=1>[Pd].CO>[ClH:32].[CH3:22][O:21][C:19]1[CH:18]=[CH:17][C:13]2[CH2:14][CH2:15][CH2:16][CH:10]([NH:9][CH2:23][C@@H:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=3)[OH:25])[CH2:11][C:12]=2[CH:20]=1
Reactant: COc1ccc2c(c1)CC(N(Cc1ccccc1)C[C@H](O)c1cccc(Cl)c1)CCC2
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: Clc1ccccc1
Product: COc1ccc2c(c1)CC(NC[C@H](O)c1cccc(Cl)c1)CCC2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 173 %

Procedure:
A mixture of (1R)-2-[N-benzyl-N-(3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-1-(3-chlorophenyl)ethanol hydrochloride (0.20 g), chlorobenzene (0.86 ml) and 10% palladium on carbon (0.01 g) in methanol (4 ml) was stirred at room temperature under hydrogen atmosphere for 1.5 hours. The catalyst was filtered off and washed with methanol. The filtrate was evaporated in vacuo, and the residue was powdered from diisopropyl ether to afford (1R)-2-[(3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-amino]-1-(3-chlorophenyl)ethanol hydrochloride (0.14 g).
Reaction SMILES: [C:1](=O)([O:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([Cl:12])=[C:7]([Cl:13])[N:6]=1)OC.ClC[C:17]([O:19][CH3:20])=[O:18]>>[Cl:11][C:10]1[C:5]([O:4][CH2:1][C:17]([O:19][CH3:20])=[O:18])=[N:6][C:7]([Cl:13])=[C:8]([Cl:12])[CH:9]=1
Reactant: COC(=O)CCl
Reactant: COC(=O)Oc1nc(Cl)c(Cl)cc1Cl
Product: COC(=O)COc1nc(Cl)c(Cl)cc1Cl

Procedure:
Mixtures of 2.56 g (0.01 g mole) of methyl 3,5,6-trichloro-2-pyridyl carbonate, 0.01 to 0.1 g mole of methyl chloroacetate, and initiator as noted were heated at 100° C. until gas evolution had stopped. Unreacted methyl chloroacetate was then removed from the reaction mixture using a rotary evaporator. The crude product remaining was analyzed by gas chromatography. In each case, a good yield (about 2.8 g of crude product) of the expected 3,5,6-trichloro-2-pyridoxyacetic acid, methyl ester (III) was found with only small amounts of by-products IV, V, and VI as shown schematically below. ##STR2## The reaction conditions and results are listed in detail in Table II.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH3:38][CH:39]1[CH2:44][CH:43]([CH3:45])[CH2:42][NH:41][CH2:40]1>>[CH3:38][CH:39]1[CH2:44][CH:43]([CH3:45])[CH2:42][N:41]([C:21]2[N:20]=[C:19]([O:18][C:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:29]=[C:30]([N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)[CH:31]=[C:2]([F:1])[CH:3]=4)=[CH:9][CH:10]=3)[CH:24]=[CH:23][N:22]=2)[CH2:40]1
Reactant: CC1CNCC(C)C1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Product: CC1CC(C)CN(c2nccc(Oc3ccc(NC(=O)c4cc(F)cc(N5CCOCC5)c4)c4ccccc34)n2)C1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and 3,5-dimethylpiperidine according to conditions described in general procedure C. Mp: 102-104° C.; 1H NMR (400 MHz, DMSO-d6) δ 0.76-0.88 (m, 6 H), 1.33-3.22 (m, 8 H), 3.27 (m, 4 H), 3.77 (m, 4H), 6.17 (d, J=5.5 Hz, 1H), 7.02-7.06 (m, 1 H), 7.27 (d, J=8.8 Hz, 1H), 7.41 (d, J=8.0 Hz, 1 H), 7.25-7.62 (m, 4H), 7.62-7.83 (m, 1 H), 7.99-8.01 (m, 1 H), 8.24 (d, J=5.5 Hz, 1 H), 10.47 (s, 1 H).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([C:6]([O:8][CH3:9])=[O:7])=[N:2]1.[N+:10]([C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Br)=[CH:15][CH:14]=1)([O-:12])=[O:11].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[N+:10]([C:13]1[CH:20]=[CH:19][C:16]([CH2:17][N:2]2[C:3]([C:6]([O:8][CH3:9])=[O:7])=[N:4][CH:5]=[N:1]2)=[CH:15][CH:14]=1)([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: COC(=O)c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ncnn1Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 12.4 %

Procedure:
A mixture of methyl 1H-1,2,4-triazole-3-carboxylate (7.06 g), 4-nitrobenzyl bromide (10 g), potassium carbonate (16.6 g) and N,N-dimethylformamide (60 ml) was stirred at room temperature for 4 hrs. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to give methyl 1-(4-nitrobenzyl)-1H-1,2,4-triazole-5-carboxylate (1.50 g, 12%) as crystals from a fraction eluted with hexane-ethyl acetate (1:1, v/v). Recrystallization thereof from ethyl acetate-hexane gave colorless prism crystals. melting point: 126-130° C.
Reaction SMILES: Cl.Cl.[CH2:3]1[C:11]2[C:6](=[C:7]([N: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)[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH3:34][N:35]([CH3:39])[C:36](Cl)=[O:37]>ClCCl>[CH2:3]1[C:11]2[C:6](=[C:7]([N:12]3[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:36]([N:35]([CH3:39])[CH3:34])=[O:37])[CH2:24][CH2:25]4)[CH2:16][CH2:17]3)[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4]1
Reactant: CN(C)C(=O)Cl
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3CCC4)CC2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3CCC4)CC2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
0.4 g (1 mmol) trans-4-{2-[4-(indan-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl-amine dihydrochloride was suspended in dichloromethane (30 ml), triethylamine (0.56 ml, 4 mmol) was added followed by 0.12 ml (1.3 mmol) N,N-dimethylcarbamoylchloride. The reaction mixture was stirred for 24 hours at room temperature. The solution was extracted with water (2×8 ml), dried and evaporated in vacuo. The residue was purified using flash chromatography giving the title compound (0.2 g, 50%), melting at 150-2° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:33]([NH2:36])[CH2:34][CH3:35]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([NH:36][CH2:33][CH2:34][CH3:35])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Reactant: CCCN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCCNC(=O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A mixture of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid 5.0 g (0.0174 mole) and 1,1'-carbonyldiimidazole (2.82 g, 0.0174 mole) in 150 ml of tetrahydrofuran was stirred at room temperature for 2.5 hrs with a stream of nitrogen bubbling through it. The n-propylamine (2.06 g, 0.0348 mole) was added dropwise and the reaction mixture was allowed to stir at room temperature under nitrogen atmosphere overnight. The tetrahydrofuran was evaporated and the residue was triturated with water. The solid was collected and dried under high vacuum at 50° C. overnight. The solid was dissolved in isopropyl alcohol, filtered, diluted with water, and placed in the freezer overnight. The crystalline precipitate was collected by filtration, washed with water, and dried at 50° C. under high vacuum overnight to give 3.6 g (63%), m.p. 220°-21° C.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[CH2:5]([NH2:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[C:1]([CH2:2][CH2:3][N:12]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][CH2:2][C:1]#[N:4])#[N:4]
Reactant: NCc1ccccc1
Reactant: C=CC#N
Product: N#CCCN(CCC#N)Cc1ccccc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 93.5 %

Procedure:
18.58 g of acrylonitrile was added dropwise to an aqueous solution (80 mL) of 10.71 g of benzylamine at room temperature over 1 hour and 20 minutes. Thereafter, the mixture was heated and stirred at 70° C. for 8 hours. After the reaction mixture was concentrated to dryness, 100 mL of water was added thereto, followed by extraction of the mixture with ethyl acetate (150 mL). After the organic layer obtained was washed with water, it was dried with anhydrous magnesium sulfate. The solvent was distilled off to give 19.93 g of the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:11][CH3:12])[CH:3]=1.[Cl:13]N1C(=O)CCC1=O>C(#N)C>[Cl:1][C:2]1[C:10]([Cl:13])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: COc1cc(Cl)ccc1C(=O)O
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: COc1cc(Cl)c(Cl)cc1C(=O)O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 4-chloro-2-methoxybenzoic acid (5 g, 26.8 mmol) in 200 mL of acetonitrile was added N-chlorosuccinimide (17.9 g, 134 mmol). The mixture was allowed to stir for 72 hours at ambient temperature and was quenched with 50 mL of H2O. The layers were separated and the aqueous layer was extracted with three 25 mL portions of CH2Cl2. The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Purification via column chromatography (SiO2, 25% hexanes in ethyl acetate) afforded the title compound. MS (DCI/NH3) m/z 238 (M+NH4)+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10]CC)=O)[CH2:4][CH2:3]1.C1(C)C=CC=CC=1>O>[CH:2]12[CH2:7][CH2:6][CH:5]([CH2:4][CH2:3]1)[C:8](=[O:10])[NH:1]2
Reactant: CCOC(=O)C1CCC(N)CC1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1NC2CCC1CC2
Temperature: 25 °C
Yield: 68.7 %

Procedure:
A solution of ethyl 4-aminocyclohexanecarboxylate (0.6 g, 3.49 mmol), toluene (1 mL) in oil bath (170° C.) was heated for 2-3 h to dryness. After cooling to rt, the reaction mixture was diluted with water and extracted with ethyl acetate (3×30 mL). The combined organic layers were dried over Na2SO4. After filtration and concentration, 300 mg of the desired product was obtained by column chromatography purification. MS (ESI): 126 (MH+).
Reaction SMILES: O[C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:15])[C:4]=2[CH:3]=1.C1(=O)[O:20][CH2:19][CH2:18][O:17]1>C(N(CC)CC)C>[OH:17][CH2:18][CH2:19][O:20][C:3]1[C:4]2[C:5](=[O:15])[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:12]=2[CH:13]=[CH:14][CH:2]=1
Reactant: O=C1OCCO1
Reactant: O=C1c2ccccc2-c2ccc(O)cc21
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2-c2cccc(OCCO)c21
Yield: 63 %

Procedure:
Following the procedure described in Example 29, 2-hydroxyfluoren-9-one (Aldrich) was reacted with ethylene carbonate and triethylamine to obtain 2-hydroxyethoxyfluoren-9-one (63% yield), with a melting point of 118-119° C. The title compound, with a melting point of 131.5-133° C., was obtained in 96% yield by the previously described DBU-catalyzed reaction with VDM in heptane.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7](=O)[CH2:8][C:9]([O:11]CC)=O)=[CH:3][CH:2]=1.Cl.[C:16]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)(=[NH:18])[NH2:17].C(=O)([O-])[O-].[K+].[K+].C(O)C>C(O)(=O)C>[N:21]1[CH:22]=[CH:23][CH:24]=[C:19]([C:16]2[NH:18][C:9](=[O:11])[CH:8]=[C:7]([C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)[N:17]=2)[CH:20]=1
Reactant: N=C(N)c1cccnc1
Reactant: CCOC(=O)CC(=O)c1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CC(=O)O
Product: O=c1cc(-c2ccncc2)nc(-c2cccnc2)[nH]1
Temperature: 75 °C
Yield: 50.2 %

Procedure:
ethyl 3-(4-pyridyl)-3-oxopropionate (0.60 g), 3-amidinopyridine hydrochloride (0.54 g) and potassium carbonate (1.15 g) were added to 5 ml of ethanol, and the mixture was heated under reflux at 75° C. for 20 hours. Acetic acid was added to the reaction mixture, and the solvent was removed by distillation. The residue was added with water and then with acetic acid, and the resulting solid was separated by filtration, washed with water and ethyl acetate, and dried to obtain 0.39 g of the desired compound.
Reaction SMILES: CCO.[N+:4]([C:7]1[CH:8]=[N:9][C:10]2[C:15]([C:16]=1[N:17]1[CH2:22][CH2:21][CH2:20][C@H:19]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:18]1)=[CH:14][CH:13]=[CH:12][CH:11]=2)([O-])=O.[NH4+].[Cl-]>[Fe].O>[NH2:4][C:7]1[CH:8]=[N:9][C:10]2[C:15]([C:16]=1[N:17]1[CH2:22][CH2:21][CH2:20][C@H:19]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[CH2:18]1)=[CH:14][CH:13]=[CH:12][CH:11]=2
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c([N+](=O)[O-])cnc3ccccc23)C1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c(N)cnc3ccccc23)C1
Temperature: 80 °C
Reaction time: 1 h
Yield: 33.7 %

Procedure:
EtOH (5.00 mL) followed by water (1.00 mL) were added to a vial containing tert-butyl [(3S)-1-(3-nitroquinolin-4-yl)piperidin-3-yl]carbamate (118.9 mg, 0.3193 mmol), iron powder (199.0 mg, 3.563 mmol) and NH4Cl (288.9 mg, 5.401 mmol). The mixture was stirred at 80° C. for 1 h. The reaction mixture was filtered through a pad of diatomaceous earth. The pad was eluted with a 10% aq. K3PO4 (20 mL), and EtOAc (20 mL). The organic layer was washed with brine (20 mL), dried over Na2SO4, and concentrated under reduced pressure. The resulting residue was purified by chromatography on silica gel (0-100% EtOAc in hexanes) to give the sub-title compound as a pale yellow solid (36.9 mg, 34%). LCMS calc. for C19H27N4O2 (M+H)+: m/z=343.2. found 343.2.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]#[C:10][C:11]#[C:12][C@@H:13]2[O:15][C@H:14]2[CH:16]=[CH:17][CH2:18][OH:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O:24]O)(C)(C)C>C1C=CC=CC=1.C/C(/O)=C\C(C)=O.C/C(/O)=C\C(C)=O.O=[V]>[C:1]1([C:7]#[C:8][C:9]#[C:10][C:11]#[C:12][CH:13]2[O:15][CH:14]2[C@@H:16]2[O:24][C@H:17]2[CH2:18][OH:19])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OO
Reactant: OCC=C[C@@H]1O[C@H]1C#CC#CC#Cc1ccccc1
Agent: O=[V]
Agent: CC(=O)/C=C(\C)O
Solvent: c1ccccc1
Product: OC[C@@H]1O[C@H]1C1OC1C#CC#CC#Cc1ccccc1
Reaction time: 4 h

Procedure:
To a stirred solution of 22 mg (0.089 mmole) of (trans)-3-[3-(6-phenyl-1,3,5-hexatriynyl)oxiranyl]-2-propen-1-ol (see Example 6) in 5 ml of dry benzene was added 2 mg of vanadyl acetylacetonate and 50 μl (0.26 mmole) of a 5.43M solution of t-butylhydroperoxide in benzene. The mixture was stirred for 4 hours. The mixture was concentrated and the residue was purified via preparative thin layer chromatography (silica gel; ethyl acetate-hexane 1:1) to afford 11 mg of the title compound as an approximately 1:1 mixture of diastereomers.
Reaction SMILES: C(OP([CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]#[C:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH:25]([F:27])[F:26])=[CH:20][CH:19]=2)[CH:11]=1)[F:9])OCC)C.[Li+].CC([N-]C(C)C)C.[CH:36]1([CH:39]=O)[CH2:38][CH2:37]1.Cl>O.C1COCC1>[CH:36]1([CH:39]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]#[C:17][C:18]3[CH:19]=[CH:20][C:21]([O:24][CH:25]([F:26])[F:27])=[CH:22][CH:23]=3)[CH:11]=2)[F:9])[CH2:38][CH2:37]1
Reactant: CCOP(OCC)C(F)c1cccc(C#Cc2ccc(OC(F)F)cc2)c1
Reactant: O=CC1CC1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: FC(=CC1CC1)c1cccc(C#Cc2ccc(OC(F)F)cc2)c1
Reaction time: 0.5 h

Procedure:
Into a cold solution of diethyl[(3-{[4-(difluoromethoxy)phenyl]ethynyl}phenyl)(fluoro)methyl]phosphonite (2.0 g, 4.08 mmol) and THF (20 mL) was added dropwise LDA (14.64 mL, 1.0M). The mixture was stirred for 30 minutes and then cyclopropanecarbaldehyde (410 mg, 5.8 mmol) was added and the mixture was allowed to come to room temperature and stirred for 24 hours. Then, HCl (5 mL, 2N) was added and the mixture was stirred for 30 minutes, poured into water and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and purification by ICSO (hexane/EtOAc 20/1) gavel-(2-cyclopropyl-1-fluorovinyl)-3-{[4-(difluoromethoxy)phenyl]ethynyl}benzene 1:1 Z/E isomers as a yellow oil (0.72 g); MS m/e (M)+ 328.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].[C:10](OC(=O)C)(=[O:12])[CH3:11]>>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:10](=[O:12])[CH3:11])[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: Nc1ccc(F)c(F)c1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(F)c(F)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 3,4-difluoroaniline (28.2 g) was added acetic anhydride (30 ml) slowly. After allowed to stand for 30 minutes, the reaction mixture was poured into ice water (100 ml). The resulting precipitate was collected by filtration and washed with water sufficiently to give the title compound (34.7 g) as colorless needles, mp 127°-127.5° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[C@@H:4]([NH2:8])[CH:5]([CH3:7])[CH3:6].[F:10][C:11]([F:17])([F:16])[CH:12](OC)O>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][O:2][C:3](=[O:9])[C@@H:4]([N:8]=[CH:12][C:11]([F:17])([F:16])[F:10])[CH:5]([CH3:7])[CH3:6]
Reactant: COC(O)C(F)(F)F
Reactant: COC(=O)[C@@H](N)C(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H](N=CC(F)(F)F)C(C)C
Temperature: 25 °C
Yield: 56.7 %

Procedure:
A solution of (S)-2-amino-3-methyl-butyric acid methyl ester hydrochloride (6.72 g, 40 mmol) in water (50 mL) was partitioned between saturated sodium hydrogen carbonate solution and dichloromethane. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated to afford (S)-2-amino-3-methyl-butyric acid methyl ester (40 mmol). A solution of (S)-2-amino-3-methyl-butyric acid methyl ester (40 mmol), 2,2,2-trifluoro-1-methoxy-ethanol (5.2 g, 3.8 mL, 40 mmol) and 4-toluenesulfonic acid hydrate (100 mg) in toluene (125 mL) was heated at reflux using a Dean-Stark apparatus for 3 h. The reaction mixture was cooled to room temperature and the solvent was evaporated. The residue was purified by silica gel chromatography using a gradient of iso-hexanes/ethyl acetate 10:1 to 5:1 to afford the title compound (4.79 g, 56%) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 0.94 (d, J=7.1 Hz, 3H), 0.97 (d, J=7.1 Hz, 3H), 2.32-2.44 (m, 1H), 3.73-3.77 (m, 4H), 7.67 (q, J=3.3 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:10][CH:9]([C:11]([F:14])([F:13])[F:12])[O:8][C:7]([CH3:16])([CH3:15])[C:6]=2[CH:17]=1.Br[C:19]1[CH:20]=[C:21]([C:24]#[N:25])[S:22][CH:23]=1>>[CH3:15][C:7]1([CH3:16])[C:6]2[CH:17]=[C:2]([C:19]3[CH:20]=[C:21]([C:24]#[N:25])[S:22][CH:23]=3)[CH:3]=[CH:4][C:5]=2[NH:10][CH:9]([C:11]([F:14])([F:13])[F:12])[O:8]1
Reactant: N#Cc1cc(Br)cs1
Reactant: CC1(C)OC(C(F)(F)F)Nc2ccc(Br)cc21
Product: CC1(C)OC(C(F)(F)F)Nc2ccc(-c3csc(C#N)c3)cc21

Procedure:
Prepared using the coupling procedure for Example 13 starting with 6-bromo-4,4-dimethyl-2-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazine and 4-bromo-2-thiophenecarbonitrile. A yellow solid: 1H-NMR (DMSO-d6) δ 8.43 (s, 1H), 8.19 (s, 1H), 7.54 (d, 1H, J=1.98 Hz), 7.46 (dd, 1H, J=8.33, 1.98 Hz), 6.90 (s, 1H), 6.83 (d, 1H, J=8.33 Hz), 5.35 (d, 1H, J=3.57 Hz), 1.59 (s, 3H), 1.57 (s, 3H); MS (ES) m/z 337 ([M−H]−).