Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C:9]([F:14])([F:13])[CH2:8][N:7]([CH2:15][CH2:16][C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[C:6]=2[N:22]=1.[C:23](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C)C=O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:23])[C:10](=[O:12])[C:9]([F:13])([F:14])[CH2:8][N:7]([CH2:15][CH2:16][C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[C:6]=2[N:22]=1
Reactant: O=C1Nc2cnc(Cl)nc2N(CCc2cccs2)CC1(F)F
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN1C(=O)C(F)(F)CN(CCc2cccs2)c2nc(Cl)ncc21
Reaction time: 4 h
Yield: 102.2 %

Procedure:
To a solution of 0.51 g (0.0015 mole) of 2-chloro-7,7-difluoro-9-(2-thiophen-2-yl-ethyl)-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-269) in 12 mL of dimethylformamide was added 0.58 g (0.0023 mole) of cesium carbonate, followed by 0.28 mL (0.0045 mole) of iodomethane. After stirring four hours, the mixture filtered and then concentrated under reduced pressure. Ice water and dichloromethane were added. The mixture was extracted with dichloromethane twice. The combined organic layers were washed three times with sodium carbonate, three times with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 0.55 g of 2-chloro-7,7-difluoro-5-methyl-9-(2-thiophen-2-yl-ethyl)-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-269) as a sticky solid.
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].[H-].[Na+].[C:14]1([CH:26]2[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]2)[N:15]=[N:16][N:17]2[C:22]=1[C:21]1[CH:23]=[CH:24][NH:25][C:20]=1[N:19]=[CH:18]2.O>O1CCCC1>[C:14]1([CH:26]2[CH2:31][CH2:30][C:29](=[CH:3][C:1]#[N:2])[CH2:28][CH2:27]2)[N:15]=[N:16][N:17]2[C:22]=1[C:21]1[CH:23]=[CH:24][NH:25][C:20]=1[N:19]=[CH:18]2
Reactant: O=C1CCC(c2nnn3cnc4[nH]ccc4c23)CC1
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: N#CC=C1CCC(c2nnn3cnc4[nH]ccc4c23)CC1
Reaction time: 0.5 h
Yield: 91.8 %

Procedure:
Diethyl (cyanomethyl)phosphonate (37.0 μL, 0.235 mmol) in tetrahydrofuran (1 mL) was mixed with sodium hydride (55 wt % dispersion in mineral oil, 10.0 mg, 0.235 mmol) under cooling with ice and then stirred for 30 minutes. The reaction mixture was mixed with 4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexanone (20.0 mg, 0.0783 mmol) obtained in Synthetic Examplea 82 and then stirred at room temperature for 30 minutes. After addition of water, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/2→1/1→1/0 (v/v)) to give the title compound as a colorless solid (20.0 mg, yield 92%).
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5]1.I[CH3:16].O>O1CCCC1>[CH3:16][O:3][CH:4]1[CH2:5][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC1CN(C(=O)OC(C)(C)C)C1
Yield: 33.3 %

Procedure:
A suspension of sodium hydride (2.89 g) in tetrahydrofuran (50 ml) was stirred while cooling in an ice bath. A solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (5.00 g) in tetrahydrofuran (50 ml) was gradually added thereto, followed by stirring at the same temperature for 30 min. Then, the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was again stirred while cooling in an ice bath for 15 min. To the reaction mixture was added dropwise iodomethane (3.09 ml), followed by stirring for 2 hr. Water was gradually added to the reaction mixture. When bubbling stopped, the organic layer was separated. The aqueous layer was extracted with ethyl acetate. The organic layer was combined, washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (eluent; heptane:ethyl acetate=3:1, 2:1, 1:1, then ethyl acetate). Fractions containing the target compound were concentrated to provide the titled compound as a colorless oil (1.80 g, 33.3%). Fractions containing the starting material were concentrated for recovery (2.10 g, 42.0%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH2:7][O:6][C:5](=[O:8])[CH:4]=1.[F:9][C:10]([F:20])([F:19])[C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH:13]=[O:14].O.[OH-].[Li+].O>C(#N)C>[OH:14][CH:13]([C:12]1[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=1[C:10]([F:9])([F:19])[F:20])[CH:7]1[O:6][C:5](=[O:8])[CH:4]=[C:3]1[O:2][CH3:1]
Reactant: O=Cc1ccccc1C(F)(F)F
Reactant: COC1=CC(=O)OC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: COC1=CC(=O)OC1C(O)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59 %

Procedure:
A mixture of 4-methoxy-5H-furan-2-one (2.00 g, 17.5 mmol), 2-(trifluoromethyl)-benzaldehyde (3.05 g, 17.5 mmol) and lithium hydroxide monohydrate (0.148 g, 3.53 mmol) in acetonitrile is stirred at room temperature for 0.5 h, treated with water, stirred for 0.5 h and concentrated in vacuo. The resultant residue is diluted with water and filtered. The filtercake is dried in vacuo to give the title product as a white solid, 3.00 g (59% yield), mp 126-128° C., identified by NMR and mass spectral analyses.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([NH:8][C:9](=[O:15])[C:10](=[O:14])[NH:11]2)=[C:6]([CH2:16][NH:17][C:18](=[O:26])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2O)[CH:5]=1)([O-:3])=[O:2].[C:27]([O:30]CC)(=[O:29])[CH3:28].CO>>[N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([NH:8][C:9](=[O:15])[C:10](=[O:14])[NH:11]2)=[C:6]([CH2:16][NH:17][C:18](=[O:26])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:30][C:27](=[O:29])[CH3:28])[CH:20]=2)[CH:5]=1)([O-:3])=[O:2]
Reactant: CCOC(C)=O
Reactant: O=C(NCc1cc([N+](=O)[O-])cc2[nH]c(=O)c(=O)[nH]c12)c1ccccc1O
Solvent: CO
Product: CC(=O)Oc1cccc(C(=O)NCc2cc([N+](=O)[O-])cc3[nH]c(=O)c(=O)[nH]c23)c1

Procedure:
N-(7-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-ylmethyl)-(2-hydroxy)-benzoic acid amide, ESCl+ -MS: (M+H)+ =357; TLC: ethyl acetate/methanol (1:1+2% acetic acid) Rf 0.33.
Reaction SMILES: O1C2(CC[N:8]([C:11](=[O:31])[CH2:12][C:13]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:30][CH2:29][C:24]5([O:28][CH2:27][CH2:26][O:25]5)[CH2:23][CH2:22]4)=[CH:17][CH:16]=3)=O)CC2)OCC1.[NH2:32]N>C(O)C.O1CCCC1>[O:28]1[C:24]2([CH2:29][CH2:30][N:21]([C:18]3[CH:17]=[CH:16][C:15]([C:13]4[NH:32][NH:8][C:11](=[O:31])[CH:12]=4)=[CH:20][CH:19]=3)[CH2:22][CH2:23]2)[O:25][CH2:26][CH2:27]1
Reactant: NN
Reactant: O=C(CC(=O)N1CCC2(CC1)OCCO2)c1ccc(N2CCC3(CC2)OCCO3)cc1
Solvent: CCO
Solvent: C1CCOC1
Product: O=c1cc(-c2ccc(N3CCC4(CC3)OCCO4)cc2)[nH][nH]1
Temperature: 25 °C
Yield: 79.6 %

Procedure:
1-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-3-[4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-phenyl]-propane-1,3-dione (which was obtained in Example 143) (0.43 g, 1 mmol) was dissolve in a mixture of ethanol (10 mL) and tetrahydrofuran (4 mL). The solution was treated with 0.08 mL (2.4 mmol) of hydrazine and heated at reflux for 4 days. After cooling to room temperature, the resulting suspension was filtered, and the precipitate was washed with ethanol and dried in vacuo to give 0.24 g of light yellow solid; 1H NMR (DMSO-d6) δ 1.67–1.71 (t, 4 H), 3.29–3.32 (t, 4 H), 3.91 (s, 4 H), 5.72 (s, 1 H), 6.97 (d, 2 H), 7.48 (d, 2 H), 9.50 (brs, 1 H), 11.80 (brs, 1 H); MS (ES) m/z: 302 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:62])[NH:4][C@@H:5]([CH:59]([CH3:61])[CH3:60])[C:6](=[O:58])[N:7]1[CH2:11][CH2:10][CH2:9][C@@:8]1([C:55](=[O:57])[NH2:56])[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:22]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[C:21]([C:30]3[CH:35]=[CH:34][C:33]([C@:36]4([C:52](=[O:54])[NH2:53])[CH2:40][CH2:39][CH2:38][N:37]4[C:41](=[O:51])[C@@H:42]([NH:46][C:47](=[O:50])[O:48][CH3:49])[CH:43]([CH3:45])[CH3:44])=[CH:32][CH:31]=3)=[CH:20][CH:19]=2)=[CH:14][CH:13]=1.[Br:63]N1C(=O)CCC1=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:62])[NH:4][C@@H:5]([CH:59]([CH3:61])[CH3:60])[C:6](=[O:58])[N:7]1[CH2:11][CH2:10][CH2:9][C@@:8]1([C:55](=[O:57])[NH2:56])[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:22]([C:23]3[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=3)[C:21]([C:30]3[CH:35]=[CH:34][C:33]([C@:36]4([C:52](=[O:54])[NH2:53])[CH2:40][CH2:39][CH2:38][N:37]4[C:41](=[O:51])[C@@H:42]([NH:46][C:47](=[O:50])[O:48][CH3:49])[CH:43]([CH3:45])[CH3:44])=[CH:32][CH:31]=3)=[C:20]([Br:63])[CH:19]=2)=[CH:14][CH:13]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@@]1(C(N)=O)c1ccc(-c2ccc(-c3ccc([C@]4(C(N)=O)CCCN4C(=O)[C@@H](NC(=O)OC)C(C)C)cc3)n2-c2ccc(F)cc2)cc1)C(C)C
Solvent: ClCCl
Product: COC(=O)N[C@H](C(=O)N1CCC[C@@]1(C(N)=O)c1ccc(-c2cc(Br)c(-c3ccc([C@]4(C(N)=O)CCCN4C(=O)[C@@H](NC(=O)OC)C(C)C)cc3)n2-c2ccc(F)cc2)cc1)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.9 %

Procedure:
To a suspension of the product from Example 51 (455 mg, 0.534 mmol) in CH2Cl2 (2.7 mL) was added a mixture of 1-bromopyrrolidine-2,5-dione (95 mg, 0.534 mmol) in CH2Cl2 (2.7 mL). The mixture was stirred overnight at room temperature then concentrated under reduced pressure and triturated with diethyl ether to provide a mixture of compounds that was subjected to reverse phase HPLC purification eluted with a gradient of 60-100% MeOH in 10 mM ammonium acetate to afford the title compound (84 mg, 17% yield). 1H NMR (free base) (400 MHz, DMSO-D6) δ 10.06 (s, 1H), 10.02 (s, 1H), 7.46 (d, J=8.7, 2H), 7.41 (d, J=8.7, 2H), 7.30 (d, J=7.7, 2H), 7.15-7.03 (m, 6H), 6.98 (d, J=8.7, 2H), 6.53 (s, 1H), 4.45-4.33 (m, 2H), 4.01 (t, J=7.7, 2H), 3.85-3.73 (m, 2H), 3.66-3.54 (m, 2H), 3.51 (s, 6H), 2.20-2.05 (m, 2H), 2.03-1.77 (m, 8 H), 0.97-0.79 (m, 12H). MS (ESI; M+H) m/z=933.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([OH:23])=[O:22])[CH2:9]2)=[CH:4][CH:3]=1.[CH2:24](O)[CH3:25].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:24]([O:22][C:21]([C:10]1[CH2:9][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[N:11]=1)=[O:23])[CH3:25]
Reactant: O=C(O)C1=NN(c2ccc(Cl)cc2Cl)C(c2ccc(Cl)cc2)C1
Reactant: CCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1=NN(c2ccc(Cl)cc2Cl)C(c2ccc(Cl)cc2)C1
Temperature: 80 °C

Procedure:
5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-pyrazole-3-carboxylic acid (0.55 g, 1.50 mmol) was dissolved in 20 mL of toluene and (2 mL) ethanol and (0.05 g) of p-toluenesulfonic acid monohydrate were added. The mixture was heated at 80° C. for 72 hours. After cooling to room temperature, the reaction mixture washed with sodium hydrogen carbonate solution and water, dried over sodium sulphate and evaporated to dryness to give the title compound in form of oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:17]=[C:16]([CH2:18]Br)[CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1.[CH2:20]([O:22][P:23]([O:27]CC)[O:24][CH2:25][CH3:26])[CH3:21]>>[CH2:20]([O:22][P:23]([CH2:18][C:16]1[CH:15]=[CH:14][C:12]2[N:13]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[O:10][C:11]=2[CH:17]=1)([O:24][CH2:25][CH3:26])=[O:27])[CH3:21]
Reactant: CCOP(OCC)OCC
Reactant: COc1ccc(-c2nc3ccc(CBr)cc3o2)cc1
Product: CCOP(=O)(Cc1ccc2nc(-c3ccc(OC)cc3)oc2c1)OCC
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 88.9 %

Procedure:
A round bottom flask is charged with 38 g (0.12 mole) of 2-(p-methoxyphenyl)-6-bromomethyl-benzoxazole (compound of the formula (221)) in 38 ml of triethylphosphite and the reaction mixture is heated to 150° C., kept for 30 minutes at this temperature and then excess triethylphosphite is distilled off in vacuo (10 mm). The residue, a brown oil, congeals after 10 hours. The crude product (44.5 g =98.9% of theory) is stirred with hexane in a mixer. The fine crystalline suspension is filtered by suction and the filter cake is washed with hexane, affording 40 g (88.9% of theory) of 6-(diethylphosphonomethyl)-2-(p-methoxyphenyl)-benzoxazole of the formula ##STR63## in the form of light beige-coloured crystals with a melting point of 86°-88° C.
Reaction SMILES: [N:1]#[C:2]Br.O.[NH2:5][C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][C:16]=1[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([OH:24])[CH2:20][CH2:19]1)[C:9]([O:11][CH2:12][CH3:13])=[O:10]>C(#N)C.CO>[NH2:1][C:2]1[N:17]([C@H:18]2[CH2:23][CH2:22][C@H:21]([OH:24])[CH2:20][CH2:19]2)[C:16]2[CH:15]=[CH:14][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][C:6]=2[N:5]=1
Reactant: CCOC(=O)c1ccc(N[C@H]2CC[C@H](O)CC2)c(N)c1
Reactant: N#CBr
Solvent: O
Solvent: CC#N
Solvent: CO
Product: CCOC(=O)c1ccc2c(c1)nc(N)n2[C@H]1CC[C@H](O)CC1

Procedure:
5.0 M cyanogen bromide in acetonitrile (1.0 mL) was added to water (35 mL) in a 250 mL round-bottom flask at room temperature with stirring. To this was added dropwise via an addition funnel ethyl 3-amino-4-(trans-4-hydroxycyclohexylamino)benzoate (0.91 g, 0.0033 mol) in methanol (70 mL) over 1 hour. After 3 hours the reaction mixture was concentrated to an off white residue. The residue was triturated with ethyl acetate and dried overnight in vacuo to give the title compound (0.97 g, 98%) as an off white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([NH:25][C:26](=[O:29])[CH2:27][CH3:28])[CH:22]=[CH:21][C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH2:8][CH2:7]1)=[O:5].[CH3:30]I>>[CH3:30][N:25]([C:23]1[CH:22]=[CH:21][C:3]([C:4]([N:6]2[CH2:7][CH2:8][N:9]([CH2:12][CH2:13][C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[CH2:10][CH2:11]2)=[O:5])=[C:2]([Cl:1])[CH:24]=1)[C:26](=[O:29])[CH2:27][CH3:28]
Reactant: CCC(=O)Nc1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)c(Cl)c1
Reactant: CI
Product: CCC(=O)N(C)c1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)c(Cl)c1

Procedure:
In a manner analogous to that described in Example 5, 0.8 g of 1-[2-chloro-4-(N-propionylamino)benzoyl]-4-[2-(4-chlorophenyl)ethyl]-piperazine is methylated with 0.29 g of methyl iodide to form 1-[4-(N-methyl-N-propionylamino)-2-chlorobenzoyl]-4-[2-(4-chlorophenyl)ethyl]-piperazine and converted into the hydrochloride having a melting point of 135°.
Reaction SMILES: C([O:3][C:4](=[O:39])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:37])[C:13]([C:21]2[N:22]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)[N:23]=[C:24]3[C:29]=2[CH2:28][CH2:27][CH2:26][CH2:25]3)([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[OH:14])=[C:7]([F:38])[CH:6]=1)C.[OH-].[Li+]>C1COCC1.CO>[Cl:36][C:33]1[CH:32]=[CH:31][C:30]([N:22]2[C:21]([C:13]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)([OH:14])[C:12]([NH:11][C:8]3[CH:9]=[CH:10][C:5]([C:4]([OH:39])=[O:3])=[CH:6][C:7]=3[F:38])=[O:37])=[C:29]3[C:24]([CH2:25][CH2:26][CH2:27][CH2:28]3)=[N:23]2)=[CH:35][CH:34]=1
Reactant: CCOC(=O)c1ccc(NC(=O)C(O)(c2c3c(nn2-c2ccc(Cl)cc2)CCCC3)C2CCCCC2)c(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(NC(=O)C(O)(c2c3c(nn2-c2ccc(Cl)cc2)CCCC3)C2CCCCC2)c(F)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 121 %

Procedure:
To a solution of 4-{2-[2-(4-chloro-phenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-2-cyclohexyl-2-hydroxy-acetylamino}-3-fluoro-benzoic acid ethyl ester (6 mg, 11 μmol) in THF/MeOH 1/1 (0.2 ml) was a added a 1 N aqueous lithium hydroxide solution (60 μl, 60 μmol) at ambient temperature under an argon atmosphere. The reaction mixture was stirred for 12 h at ambient temperature and poured onto ice water/1 N aqueous NaOH solution 1/1. The layers were separated, the aqueous layer was acidified with ice cold 1 N aqueous HCl solution and extracted two times with iPrOAc. The combined extracts were washed with ice water/brine 1/1 and dried over Na2SO4. After filtration the solvent was removed under reduced pressure to give the title compound (7 mg; quant.) as yellow solid. MS: m/e=526.4 [M+H+].
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]([F:20])([F:19])[F:18])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[CH:7]=[CH:6]2)#[N:2].[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=O)=[CH:24][C:23]=1[F:31]>>[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]2[O:15][N:14]=[C:13]([CH2:12][N:8]3[C:9]4[C:5](=[C:4]([C:17]([F:19])([F:20])[F:18])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)[CH:6]=[CH:7]3)[N:16]=2)=[CH:24][C:23]=1[F:31]
Reactant: O=C(O)c1ccc(Cl)c(F)c1
Reactant: N#Cc1ccc2c(ccn2CC(=N)NO)c1C(F)(F)F
Product: N#Cc1ccc2c(ccn2Cc2noc(-c3ccc(Cl)c(F)c3)n2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 241 from 2-[5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide and 4-chloro-3-fluorobenzoic acid: MS (ES) m/z 421
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:8][O:9][C:10](=[O:23])[C@@H:11]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([O:21][CH3:22])[CH:15]=1)[NH2:12].ClCCl.[Cl:27][CH2:28][C:29](Cl)=[O:30]>O>[CH3:8][O:9][C:10](=[O:23])[C@H:11]([NH:12][C:29](=[O:30])[CH2:28][Cl:27])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([O:21][CH3:22])[CH:15]=1
Reactant: O=C(Cl)CCl
Reactant: COC(=O)[C@H](N)Cc1ccc(C)c(OC)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: COC(=O)[C@@H](Cc1ccc(C)c(OC)c1)NC(=O)CCl
Reaction time: 0.5 h

Procedure:
Potassium carbonate (1.70 g) was added by small portions with ice-cooling to a mixture of 3-methoxy-4-methyl-D-phenylalanine methyl ester hydrochloride (1.60 g) in mixed solvents of dichloromethane (7 ml) and water (9 ml). Chloroacetyl chloride (0.66 ml) was added to the mixture below 5° C. over 15 minutes and then the whole was stirred for 30 minutes. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated under reduced pressure to give an oil of (2R)-2-[N-(chloroacetyl)-amino]-3-(3-methoxy-4-methylphenyl)propionic acid methyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1.O.ON1C2C=CC=C[C:19]=2N=N1.C(N(CC)CC)C>CN(C=O)C>[CH:3]12[CH2:7][CH:6]([CH:5]=[CH:4]1)[CH2:12][CH2:13]2.[CH3:19][C:12]1[CH:13]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=1[CH:7]=[CH:8][C:9]([O-:11])=[O:10]
Reactant: On1nnc2ccccc21
Reactant: COc1ccc(C=CC(=O)O)cc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: C1=CC2CCC1C2
Product: COc1ccc(C=CC(=O)[O-])c(C)c1

Procedure:
(exo-rich)5-norbornene-2-methanol (15 g, 0.121 mol) that was synthesized in (2), 4-methoxy cinnamic acid (Aldrich, 21.5 g, 0.121 mol), EDC [1-(3-dimethylaminopropyl)-3-ethylcarboimide hydrochloride] (Aldrich, 37 g, 0.194 mol), and HOBT (1-hydroxybenzotriazol hydrate) (Aldrich, 24.5 g, 0.182 mol) were put into the two-neck flask having the volume of 250 ml and then dissolved in 100 ml of DMF. After the temperature was reduced to 0° C., triethyl amine (Aldrich, 75 ml, 0.605 mol) was slowly dropped. The temperature was increased to normal temperature and maintained for 3 hours. When the reaction was finished, the extraction was performed by using a great amount of ethyl acetate. The resulting substance was washed by using a NaHCO3 aqueous solution, dried by using anhydrous MgSO4, and filtered to remove the solvent by using the rotary evaporator, thereby manufacturing the yellow product oil. The purification was performed by using the column chromatography (hexane:ethylacetate=10:1) to obtain 5-norbornene-2-methyl-(4-methoxy cinnamate) that was the pure product (yield: 80%). The molar ratio (mol %) of the exo isomer and the endo isomer of the product was 58:42.
Reaction SMILES: C[O:2][C:3](=[O:23])[C@@H:4]([N:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[C:18]([F:21])([F:20])[F:19])[C:10]1=[O:22])[CH2:5][CH2:6][S:7][CH3:8].O.[OH-].[Li+]>O1CCCC1.O>[CH3:8][S:7][CH2:6][CH2:5][C@H:4]([N:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[C:18]([F:20])([F:21])[F:19])[C:10]1=[O:22])[C:3]([OH:23])=[O:2]
Reactant: COC(=O)[C@H](CCSC)N1Cc2c(cccc2C(F)(F)F)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CSCC[C@@H](C(=O)O)N1Cc2c(cccc2C(F)(F)F)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.9 %

Procedure:
A solution of (S)-4-methylsulfanyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-butyric acid methyl ester (134 mg, 0.39 mmol) in tetrahydrofuran/water (6 mL, 1:1) was treated with lithium hydroxide monohydrate (33 mg, 0.78 mmol) at room temperature. The reaction mixture was then stirred at room temperature for 2 h. After this time, the reaction mixture was concentrated in vacuo to remove the tetrahydrofuran. The resulting material was then diluted with a 1N aqueous hydrochloric acid solution and then extracted with ethyl acetate. The organic layers were combined and then dried over magnesium sulfate, filtered to remove the drying agent, and the filtrate was concentrated in vacuo to afford (S)-4-methylsulfanyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-butyric acid (126 mg, 97%) as a white foam: HR-ES(+) m/e calcd for C14H14NO3SF3 [M+H]+ 334.0719, observed 334.0717; 1H NMR (400 MHz, CHLOROFORM-d) δ 8.07 (d, J=7.46 Hz, 1H), 7.83 (d, J=7.67 Hz, 1H), 7.59-7.71 (m, 1H), 5.25 (dd, J=4.48, 10.44 Hz, 1H), 4.79 (d, J=17.47 Hz, 1H), 4.56 (d, J=17.47 Hz, 1H), 2.41-2.66 (m, 3H), 2.20-2.35 (m, 1H), 2.13 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[CH3:16][NH:17][N:18]1[CH:22]=[CH:21][CH:20]=[CH:19]1.O>C(O)C>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([N:17]([CH3:16])[N:18]2[CH:22]=[CH:21][CH:20]=[CH:19]2)[CH:7]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: CNn1cccc1
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: O
Product: CN(c1cc(Cl)ncn1)n1cccc1
Temperature: 80 °C
Yield: 31.7 %

Procedure:
To a solution of 4,6-dichloropyrimidine (5.0 g), in 50 ml absolute ethanol was added triethylamine (5.8 ml), followed by a solution of N-methyl-1H-pyrrol-1-amine (3.2 g), in 30 ml ethanol. After stirring at 80° C. for twenty hours, the mixture was poured into 300 ml water, stirred for five minutes, and the resultant tan precipitate collected and dried to give 2.4 g, m.p. 88°-89° C. This material was sublimed at 75° C./1.0 mm Hg to give 2.2 g (31%) of 6-Chloro-N-methyl-N-(1H-pyrrol-1-yl)-4-pyrimidinamine, m.p. 88°-89° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[CH2:12][CH2:13][NH2:14].[C:15](Cl)(=[O:25])[C:16]1[C:17](=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:18](Cl)=[O:19].CCN(C(C)C)C(C)C>C(#N)C>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[CH2:12][CH2:13][N:14]1[C:18](=[O:19])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]2[C:15]1=[O:25]
Reactant: O=C(Cl)c1ccccc1C(=O)Cl
Reactant: COc1cc(Br)c(CCN)cc1OC
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1cc(Br)c(CCN2C(=O)c3ccccc3C2=O)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Bromo-4,5-dimethoxylbenzeneethanamine (3.5 g 13.2 mmol) was dissolved and stirred in 50 mL dry acetonitrile. 2.14 mL (1.1 equiv) phthaloyl dichloride and 7 mL (3 equiv) Hünig's base were added. The mixture was stirred at room temperature overnight. Acetonitrile was then removed, and the remaining product was taken up in dichloromethane and washed with basic water (pH=11). The aqueous wash was extracted with dichloromethane 3×15 mL. The organic fractions were combined and dried over sodium sulfate. Solvent was removed to give the crude product, which was then purified by column chromatography. Calculated yield: 1.8 g (34%).