Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]([C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[CH2:3][N:4]([CH2:12][C@H:13]1[CH2:22][CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([I:23])[CH:19]=2)[O:14]1)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[CH3:30][C:31]([Si:34](Cl)([CH3:36])[CH3:35])([CH3:33])[CH3:32].N1C=CN=C1.C([O-])(O)=O.[Na+]>CN(C=O)C>[Si:34]([O:1][C@H:2]([C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[CH2:3][N:4]([CH2:12][C@H:13]1[CH2:22][CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([I:23])[CH:19]=2)[O:14]1)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:8])[CH3:9])([C:31]([CH3:33])([CH3:32])[CH3:30])([CH3:36])[CH3:35]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)N(C[C@H]1CCc2cc(I)ccc2O1)C[C@H](O)c1cccnc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(C[C@H]1CCc2cc(I)ccc2O1)C[C@H](O[Si](C)(C)C(C)(C)C)c1cccnc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of tert-butyl (2R)-2-hydroxy-2-(3-pyridinyl)ethyl([(2R)-6-iodo-3,4-dihydro-2H-chromen-2-yl]methyl}carbamate (Example 37, Method A, 6.35 g, 12.4 mmol), TBDMSCl (2.25 g, 14.9 mmol) and imidazole (2.10 g, 30.9 mmol) in DMF (10 mL) was stirred at room temperature under argon for 24 hours. The reaction mixture was then poured into a saturated NaHCO3 solution (50 mL). The mixture was extracted with ether (100 mL×2). The ether layer was washed with water (50 mL) and dried over anhydrous sodium sulfate. Removal of the solvent in vacuo afforded a near white syrup which was purified by column chromatography (silica gel, hexanes/ethyl acetate (5/1, v/v)) giving the desired compound as a colorless oil. LC-MS m/z 625.0 (MH+), RT=4.09 minutes.
Reaction SMILES: CC(C)([O-])C.[K+].[OH:7][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][CH2:12][CH:13]2[N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.Br[CH2:25][CH2:26][CH2:27][N:28]1[C:32](=[O:33])[C:31]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]2[C:29]1=[O:38]>CN(C)C=O>[C:29]1(=[O:38])[N:28]([CH2:27][CH2:26][CH2:25][O:7][C:8]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:9]=2[CH2:10][CH2:11][CH2:12][CH:13]3[N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:32](=[O:33])[C:31]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]12
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: Oc1cccc2c1CCCC2N1CCOCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCOc1cccc2c1CCCC2N1CCOCC1
Reaction time: 48 h
Yield: 85.3 %

Procedure:
Potassium t-butoxide (7.8 g) is added to a stirred solution of 5-hydroxy-1-morpholinyl-1,2,3,4-tetrahydronaphthalene (14.7 g) dissolved in dimethylformamide (150 ml) and the reaction solution stirred for a few minutes. N-(3-bromopropyl) phthalimide (33.8 g) is added to the reaction mixture and stirring is continued at RT for 2 days. The reaction mixture is partitioned between H2O and ether, the layers separated and the aqueous layer adjusted to a pH >10 with sodium hydroxide solution and extracted with additional diethyl ether. The combined ether layers are washed with H2O and aqueous 5% hydrochloric acid. The acidic aqueous extracts are made strongly alkaline with sodium hydroxide solution, resulting in an oily precipitate which is extracted with ether and methylene chloride. The combined organic layers are washed with 5% aqueous sodium hydroxide and saturated sodium chloride, dried over sodium sulfate, filtered, and evaporated, resulting in 22.6 g of an amber oil as the crude product used in the next step.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][C:4]=1[O:15]C)[CH3:2].B(Br)(Br)Br>C(Cl)Cl>[CH2:13]([O:12][C:10](=[O:11])[CH2:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[C:4]([OH:15])[CH:5]=1)[CH3:14]
Reactant: CCOC(=O)Cc1ccc(CC)c(OC)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)Cc1ccc(CC)c(O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.1 %

Procedure:
A solution of ethyl 4-ethyl-3-methoxyphenylacetate (10; 3.0 g; 13.50 mmol) and CH2Cl2 (80 mL) was cooled to −78° C. and a solution of BBr3 (5.10 mL; 53.94 mmol; 1.0 M in CH2Cl2) over 30 min. After 1 h at −78° C. the reaction was allowed to warm to rt and stirred for 12 h. The reaction was cooled in an ice-water bath and the reaction quenched with 20 mL of water. The aqueous phase was extracted with CH2Cl2:EtOAc (4:1 v/v), dried (Na2SO4), filtered and evaporated. The crude product was purified by silica gel chromatography and eluting with a CH2Cl2:EtOAc gradient (100:1 to 100:4) to yield 12a (2.0 g; 71%): ms 209.2 (M+H)+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21]5[CH:22]=[N:23][N:24]([CH2:26][C:27]([O:29]CC)=[O:28])[CH:25]=5)=[CH:19][CH:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH-].[Li+].Cl>CO.O>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21]5[CH:22]=[N:23][N:24]([CH2:26][C:27]([OH:29])=[O:28])[CH:25]=5)=[CH:19][CH:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)Cn1cc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)Cn1cc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 40.5 %

Procedure:
To a solution of Example 154 (0.085 g, 0.218 mmol) in methanol (1.4 ml), lithium hydroxide (0.026 g, 1.09 mmol) in water (0.36 ml) was added and stirred at RT. After 12 h, the pH was adjusted to 7-7.5 using 0.5N HCl and the solid precipitated was filtered, washed with ethyl acetate and petroleum ether and dried under to afford the title compound as a yellow solid (0.034 g, 38%). M.P.: >270° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.87 (d, J=2.7 Hz, 1H), 8.47 (d, J=8.7 Hz, 1H), 8.39 (m, 2H), 8.08 (s, 1H), 8.00 (s, 1H), 7.99 (d, J=7.1 Hz, 1H), 7.82 (t, J=8.9 Hz, 2H), 7.52 (q, J=4.1 Hz, 1H), 6.10 (s, 2H), 4.48 (s, 2H). MS (m/z): 385.87 (M+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)[CH:5]=[C:4]([CH3:16])[N:3]=1.[Br:17][C:18]1[N:19]=[CH:20][NH:21][CH:22]=1>>[Br:17][C:18]1[N:19]=[CH:20][N:21]([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=3)[CH:5]=[C:4]([CH3:16])[N:3]=2)[CH:22]=1
Reactant: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(Cl)n1
Reactant: Brc1c[nH]cn1
Product: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(-n2cnc(Br)c2)n1

Procedure:
The title compound was prepared from 2-chloro-4-(3,4-dichloro-phenyl)-6-methyl-pyrimidine (example A.41) (0.4 g, 1.46 mmol) and commercially available 4-bromo-imidazole (0.32 g, 2.18 mmol) according to the general procedure IVa. Obtained as a light brown solid (0.33 g, 59%). MS (ISP) 385.0 [(M+H)+]; mp 219.5° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N+:3]=1[O-].[N+:10]([O-])([OH:12])=[O:11].S(=O)(=O)(O)O>>[CH3:1][C:2]1[CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=[C:4]([CH3:8])[N:3]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1cccc(C)[n+]1[O-]
Agent: O=S(=O)(O)O
Product: Cc1cc([N+](=O)[O-])cc(C)n1

Procedure:
The 4-nitro substituted starting material is prepared by contacting 2,6-dimethylpyridine N-oxide with nitric acid and sulfuric acid thereby forming the 2,6-dimethyl-4-nitropyridine. The N-oxide is reduced to the pyridine compound with phosphorous trichloride and then oxidized to the 4-nitropyridine 2,6-dicarboxylic acid with potassium permanganate.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4](=[O:31])[CH2:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:30])[CH2:20][CH2:21][NH:22]C(OC(C)(C)C)=O)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1>O1CCOCC1.C(OCC)(=O)C>[ClH:1].[CH3:2][O:3][C:4](=[O:31])[CH2:5][C@H:6]1[CH2:7][CH2:8][C@H:9]([C:12]2[CH:13]=[CH:14][C:15]([NH:18][C:19](=[O:30])[CH2:20][CH2:21][NH2:22])=[CH:16][CH:17]=2)[CH2:10][CH2:11]1
Reactant: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)CCNC(=O)OC(C)(C)C)cc2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)CCN)cc2)CC1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
0.4M hydrogen chloride solution dissolved in 1,4-dioxane (3.2 mL) was added to trans-{4-[4-(3-tert-butoxycarbonylaminopropionylamino)phenyl]cyclohexyl}acetic acid methyl ester (800 mg, 1.91 mmol) dissolved in ethyl acetate (16 mL). The reaction mixture was stirred at 50° C. for 4 hours and slowly cooled up to 25° C. The product was collected through filtration and washed with ethyl acetate. The product was dried under vacuum to obtain the desired compound (615 mg, 91%) as a white solid.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:10]=[N:11][C:12]([Cl:15])=[CH:13][CH:14]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].CI.[C:18]([O-])([O-])=O.[K+].[K+]>CC(C)=O>[C:1]([N:5]([CH3:18])[S:6]([C:9]1[CH:10]=[N:11][C:12]([Cl:15])=[CH:13][CH:14]=1)(=[O:7])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(Cl)nc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CN(C(C)(C)C)S(=O)(=O)c1ccc(Cl)nc1
Yield: 64.4 %

Procedure:
A mixture of 0.97 g (3.9 mmol) of N-tert-butyl-6-chloropyridine-3-sulfonamide, 2.43 mL (39 mmol) of methyl iodide and 5.4 g (39 mmol) of K2CO3 in 40 mL of acetone is refluxed for 12 hours. The reaction medium is filtered at room temperature, and the filtrate is concentrated under reduced pressure. The residue obtained is purified on silica gel, eluting with a cyclohexane/EtOAc gradient of from 0 to 20% EtOAc, to give 0.66 g of N-tert-butyl-6-chloro-N-methylpyridine-3-sulfonamide in the form of a yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[CH3:9][N:10](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[C:9]([C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1)#[N:10]
Reactant: CN(C)C=O
Reactant: Cc1ccnc(Cl)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: Cc1ccnc(C#N)n1
Temperature: 180 °C
Yield: 54 %

Procedure:
To a solution of 2-chloro-4-methylpyrimidine (1 g, 7.78 mmol) and zinc cyanide (475 mg, 4.04 mmol) in anhydrous DMF (10 ml) was added Pd(PPh3)4 (449 mg, 0.366 mmol) and nitrogen flushed through the mixture for 5 min. The mixture was heated at 180° C. for 30 min in a microwave reactor. The reaction was repeated on the same scale and the reaction mixtures were combined. The mixture was partitioned between EtOAc and water (filtered through celite to remove some insolubles), and the organic layer washed with sat. NaCl, dried over MgSO4, filtered and evaporated. The residue was purified by MPLC (Biotage Horizon: FLASH 25+M) eluent: 100% Hexanes (90 ml), gradient rising from 100% Hexanes to 15% EtOAc in Hexanes (900 ml), then 15% EtOAc in Hexanes (500 ml) to give 1 g of the title compound (54%) as an off-white solid. 1H NMR (CDCl3): 2.62 (s, 3H), 7.42 (d, J5.1 Hz, 1H), 8.69 (d, J5.1 Hz, 1H).
Reaction SMILES: O.[C:2]([OH:6])(=[O:5])[CH:3]=[O:4].[CH3:7][C:8]([CH3:13])([CH2:11]O)[CH2:9][OH:10]>C1C=CC=CC=1>[C:2]([CH:3]1[O:10][CH2:9][C:8]([CH3:13])([CH3:11])[CH2:7][O:4]1)([OH:6])=[O:5]
Reactant: CC(C)(CO)CO
Reactant: O=CC(=O)O
Solvent: O
Solvent: c1ccccc1
Product: CC1(C)COC(C(=O)O)OC1
Yield: 73.4 %

Procedure:
Following a general procedure,23 a mixture of glyoxylic acid monohydrate (5.0 g, 54 mmol), 2,2-dimethyl 1,3-propanediol (8.5 g, 81 mmol) and Amberlyst-15 ion-exchange resin (100 mg) in benzene (140 mL) was refluxed for 15 h in a flask fitted with a Dean-Stark apparatus. The reaction mixture was filtered. The filtrate was concentrated and then refluxed with 20% aqueous NaOH (50 mL) for 30 min. The resulting alkaline solution was extracted with ether and neutralized in the cold with dilute HCl. At the end the pH was brought to ˜1.0 using H3PO4. The acidified aqueous layer was extracted with ether. The extracts were combined, dried (Na2SO4) and concentrated to afford a white solid (6.349 g, 73%): mp 58-60° C.; 1H NMR δ0.80 (s, 3H), 1.22 (s, 3H), 3.57 (d, J=12.0 Hz, 2H), 3.79 (d, J=12.0 Hz, 2H), 4.97 (s, 1H); 13C NMR δ169.1, 124.7, 95.8, 77.5, 30.6, 23.0, 21.9; FAB-MS obsd 161.0806, calcd 161.0814 (C7H12O4).
Reaction SMILES: [CH:1]([NH:4][C:5]([NH:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[S:6])([CH3:3])[CH3:2].Cl[CH2:13][N:14]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)[C:15](Cl)=[O:16]>>[C:8]([N:7]=[C:5]1[N:4]([CH:1]([CH3:3])[CH3:2])[C:15](=[O:16])[N:14]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH2:13][S:6]1)([CH3:9])([CH3:11])[CH3:10]
Reactant: CC(C)NC(=S)NC(C)(C)C
Reactant: O=C(Cl)N(CCl)c1ccc(F)cc1
Product: CC(C)N1C(=O)N(c2ccc(F)cc2)CSC1=NC(C)(C)C

Procedure:
In a similar manner, 1.7 g (0.01 mole) of 1-isopropyl-3-t-butylthiourea was reacted with 2.2 g (0.01 mole) of N-chloromethyl-N-(p-fluorophenyl)-carbamoyl chloride to obtain 2-t-butylimino-3-isopropyl 5-(p-fluorophenyl)-tetrahydro-1,3,5-thiadiazin-4-one (compound No. 282): ##STR140## in the form of hydrochloride melting at 160°-195° C. Yield 2.8 g (80%). The crystals were suspended in 20 ml of water and treated in a manner similar to that described above to obtain white crystals of the free base melting at 109°-110° C. (isopropanol). Yield 2.0 g (63%).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C)C=O.ClCCl>[C:22]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4]1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(OCc1ccccc1)c1ccc2[nH]ccc2c1
Reactant: O=C(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1ccc2c(ccn2C(=O)c2ccccc2)c1
Reaction time: 0.5 h
Yield: 117.8 %

Procedure:
Sodium hydride (58 mg) was added to a solution of benzyl 1H-indole-5-carboxylate (300 mg) in N,N-dimethylformamide (2 ml) with ice cooling, and then stirred for 30 minutes. Benzoyl chloride (202 mg) was added thereto, and the mixture was stirred for 2 hours. The reaction mixture was diluted with dichloromethane, and the organic phase was washed with 2 N hydrochloric acid, a saturated sodium bicarbonate solution and a saturated saline solution. The organic phase was dried over sodium sulfate anhydrous. The product was concentrated under reduced pressure to give benzyl 1-benzoyl-1H-indole-5-carboxylate (500 mg, Y.:quant.) as pale orange crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:34][C:11]3[C:12](=[O:33])[N:13]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH2:22][C@H:23]([OH:30])[CH2:24][S:25]([CH2:28][CH3:29])(=[O:27])=[O:26])=[C:17]([O:31][CH3:32])[CH:16]=4)[CH2:14][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.[NH:35]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[C@H:36]([C:40](O)=[O:41])[CH:37]([CH3:39])[CH3:38].CC(C)N=C=NC(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:46]([O:45][C:43]([NH:35][C@@H:36]([CH:37]([CH3:39])[CH3:38])[C:40]([O:30][C@H:23]([CH2:24][S:25]([CH2:28][CH3:29])(=[O:26])=[O:27])[CH2:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([N:13]2[CH2:14][C:10]3[CH:9]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[S:34][C:11]=3[C:12]2=[O:33])=[CH:16][C:17]=1[O:31][CH3:32])=[O:41])=[O:44])([CH3:49])([CH3:48])[CH3:47]
Reactant: CCS(=O)(=O)C[C@@H](O)COc1ccc(N2Cc3cc(-c4ccc(Cl)cc4)sc3C2=O)cc1OC
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCS(=O)(=O)C[C@H](COc1ccc(N2Cc3cc(-c4ccc(Cl)cc4)sc3C2=O)cc1OC)OC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C
Yield: 79 %

Procedure:
To a suspension of (S)-2-(4-chlorophenyl)-5-(4-(3-(ethylsulfonyl)-2-hydroxypropoxy)-3-methoxyphenyl)-4H-thieno[2,3-c]pyrrol-6(5H)-one) (46.0 mg, 0.088 mmol), DMAP (5.47 mg, 0.045 mmol) and BOC-Val-OH (22.96 mg, 0.106 mmol) in CH2Cl2 (0.401 mL) at RT was added DIC (0.022 mL, 0.141 mmol) dropwise over a period of 1 h. After stirring for an additional 2H, the reaction mixture was filtered and the filtrate was washed with cold 1N HCl (3×10 mL) and cold 10% NaHCO3 (3×10 mL) prior to drying over anhydrous Na2SO4 and concentrating under vacuum. The residue was purified by flash chromatography (silica gel, hexanes:EtOAc, 100:0 to 0:100) to afford 50.4 mg (79% yield) of the title compound as a yellow solid: HPLC retention time: 4.153 min., LCMS (ES): m/z 721 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](Cl)(=[O:14])=[O:13])[CH:7]=1.[CH3:17][NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.N1C=CC=CC=1>ClCCl>[CH3:1][O:2][C:3](=[O:16])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](=[O:14])(=[O:13])[N:18]([CH3:17])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:7]=1
Reactant: CNc1ccccc1
Reactant: COC(=O)C=Cc1cccc(S(=O)(=O)Cl)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)C=Cc1cccc(S(=O)(=O)N(C)c2ccccc2)c1
Yield: 27.8 %

Procedure:
A solution of 3-(3-chlorosulfonylphenyl)acrylic acid methyl ester (3) (0.440 g, 1.68 mmol) in dichloromethane (2 ml) was added to a mixture of N-methylaniline (0.364 g, 3.40 mmol) and pyridine (0.5 ml), and the resultant solution was stirred at 50° C. for one hour. The reaction mixture was evaporated and the residue was partitioned between ethyl acetate and 10% HCl. The organic layer was washed successively with water, saturated NaCl, and dried (Na2SO4). The solvent was removed and the residue was chromatographed on silica gel with chloroform-ethyl acetate (15:1, v/v) as eluent. The obtained product was washed with diethyl ether to give the title compound (0.155 g, 28%). 1H NMR (CDCl3, HMDSO), δ: 3.12 (3H, s); 3.74 (3H, s); 6.34 (1H, d, J=16.0 Hz); 6.97-7.74 (10H, m).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:13](OC(=O)C)(=[O:15])[CH3:14]>>[OH:1][C:2]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:15])[CH3:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(N)ccc1O
Reactant: CC(=O)OC(C)=O
Product: COC(=O)c1cc(NC(C)=O)ccc1O
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 74 %

Procedure:
Methyl 2-hydroxy-5-aminobenzoate (10 g, 60 mmole) was mixed with acetic anhydride (10 ml) and heated with stirring to 100° C. for 5 minutes. Subsequently the reaction mixture was cooled and concentrated to dryness, in vacuo. The remaining material was recrystallized from ethanol-water (1:1) with activated carbon, to give the title compound (9.7 g, 74%), m.p. 147°-148° C. Found (Calc. for C10H11NO4) C 57.01 (57.42), H 5.27 (5.26), N 6.76 (6.70).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[F:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][C:12]=1[CH3:18]>>[Cl:1][C:2]1[N:7]=[C:6]([NH:15][C:14]2[CH:16]=[CH:17][C:11]([F:10])=[C:12]([CH3:18])[CH:13]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Cc1cc(N)ccc1F
Product: Cc1cc(Nc2nc(Cl)ncc2F)ccc1F

Procedure:
In a like manner to the preparation of 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and 4-fluoro-3-methylaniline were reacted to provide 2-chloro-5-fluoro-N4-(4-fluoro-3-methylphenyl)-4-pyrimidineamine. 1H NMR (CDCl3): δ 8.06 (d, 1H, J=2.4 Hz), 7.48-7.43 (m, 1H), 7.39 (dd, 1H, J=2.7 and 6.3 Hz), 7.03 (t, 1H, J=9.0 Hz), 6.84 (bs, 1H), 2.30 (d, 1H, J=1.8 Hz); 19F NMR (282 MHz, CDCl3): −34285, −44676; LCMS: purity: 95%; MS (m/e): 257 (MH+).
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16]([O:19][S:20]([CH3:23])(=[O:22])=[O:21])([CH3:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:24](N1CC(O)(CCC)C1)(C1C=CC=CC=1)[C:25]1C=CC=CC=1>>[CH:1]([N:14]1[CH2:17][C:16]([O:19][S:20]([CH3:23])(=[O:21])=[O:22])([CH2:18][CH2:24][CH3:25])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(OS(C)(=O)=O)CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CCCC1(O)CN(C(c2ccccc2)c2ccccc2)C1
Product: CCCC1(OS(C)(=O)=O)CN(C(c2ccccc2)c2ccccc2)C1

Procedure:
1-Benzhydryl-3-methanesulphonyloxy-3-propylazetidine was prepared under the conditions described for 1-benzhydryl-3-methanesulphonyloxy-3-methylazetidine in Patent Application EP 406,112, but starting with 2.4 g of 1-benzhydryl-3-hydroxy-3-propylazetidine. 2.4 g of 1-Benzhydryl-3-methanesulphonyloxy-3-propylazetidine are obtained in the form of a colorless solid, melting point 70° C.
Reaction SMILES: [C:1]([O:20][CH2:21][C:22]([O:24]CC)=[O:23])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CCO>[C:1]([O:20][CH2:21][C:22]([OH:24])=[O:23])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 1 h
Yield: 98 %

Procedure:
To a suspension of ethyl 2-(trityloxy)acetate (8.2 g, 23.67 mmol) in EtOH (350 ml), NaOH 6M (7.89 ml, 47.3 mmol) was added at RT. The suspension slowly turned into a solution. After 1 hour, EtOH was removed under vacuum and the remaining crude was partitioned between HCl 2N and DCM. The organic phase was separated, dried over Na2SO4 and evaporated under vacuum. 2-(Trityloxy)acetic acid was obtained (7.42 g, 23.31 mmol, 98% yield) and used as such in the following reaction without further purification.
Reaction SMILES: C(OCC)C.[CH2:6]([C:8]1[O:9][C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[CH:12]=1)[CH3:7].[Br:17]Br>C(OCC)(=O)C>[Br:17][C:12]1[C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[O:9][C:8]=1[CH2:6][CH3:7]
Reactant: BrBr
Reactant: CCc1cc2ccccc2o1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCc1oc2ccccc2c1Br
Temperature: 0 °C

Procedure:
To a 250 mL flask equipped with magnetic stirring is added 100 mL of diethyl ether and 2-ethylbenzofuran (20.00 g, 136.8 mmol). The reaction flask is cooled to 0° C. and bromine (8.40 mL, 164.2 mmol) is added to an addition funnel containing 50 mL of ethyl acetate. The mixture is added dropwise to the reactor while maintaining the 0° C. temperature. The addition funnel is rinsed with an additional 20 mL of ethyl acetate. The resulting mixture is stirred for 2 hours and the temperature maintained at 0° C. The reaction is quenched with 50 mL of water. The contents of the reactor are then transferred to a 1 L separatory funnel and rinsed with 2×50 mL of water. The organic layers are combined and rinsed with 200 mL of a saturated sodium thiosulfate solution. The layers are separated and the organic layer is dried over MgSO4 to give an amber colored solution. The solvent is removed in vacuo to give the product, 3-bromo-2-ethylbenzofuran, as a pale yellow liquid which is used without further purification (yield: 27.1 g, 88 percent).