Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)=O.[N:13]#[C:14][C:15]#[N:16].CN(C)C1C=CC=CC=1>CN(C)C=O>[C:14]([C:15]1[NH:2][CH:3]=[C:4]([C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=2)[N:16]=1)#[N:13]
Reactant: N#CC#N
Reactant: Cc1ccc(C(=O)CN)cc1
Agent: Cl
Solvent: CN(C)c1ccccc1
Solvent: CN(C)C=O
Product: Cc1ccc(-c2c[nH]c(C#N)n2)cc1
Temperature: 100 °C
Yield: 70 %

Procedure:
15 g (81 mmol) of 2-amino-4'-methylacetophenone hydrochloride was measured out in a 200-ml four-necked flask. To the material was then added 121 ml (121 mmol) of a 1 mol/l N,N-dimethylformamide solution of cyanogen. The mixture was then stirred. To the mixture was then added 29.4 g (243 mmol) of N,N-dimethylaniline. The mixture was then heated at a temperature of 100° C. with stirring for 3 hours. N,N-dimethylaniline was then distilled off from the reaction mixture under a pressure of 30 mmHg. The reaction mixture was then allowed to cool to room temperature. 200 ml of water was then poured into the reaction mixture. The reaction mixture was acidified with hydrochloric acid, and a precipitate was recovered by filtration. The filtration residue was dissolved in 200 ml of a 5% aqueous solution of sodium hydroxide, and the solution was filtered. The filtrate was then acidified with hydrochloric acid. 2-Cyano-4-(p-tolyl)imidazole as a desired compound was then recovered by filtration. The material was then dried to obtain 12.43 g of a desired compound with a purity of 83.4% (yield: 70.0%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[C:24]([CH3:37])=[C:25]([CH3:36])[C:26]4[O:30][C:29]([CH3:32])([CH3:31])[C:28](=[O:33])[C:27]=4[C:34]=3[CH3:35])[CH2:19][CH2:18]2)=[CH:13][CH:12]=1>CCCCCC>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C:28]2([OH:33])[C:27]3[C:34]([CH3:35])=[C:23]([N:20]4[CH2:21][CH2:22][N:17]([C:14]5[CH:15]=[CH:16][C:11]([O:10][CH3:9])=[CH:12][CH:13]=5)[CH2:18][CH2:19]4)[C:24]([CH3:37])=[C:25]([CH3:36])[C:26]=3[O:30][C:29]2([CH3:31])[CH3:32])=[CH:3][CH:4]=1
Reactant: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(=O)C(C)(C)O4)CC2)cc1
Reactant: Clc1ccc(Br)cc1
Solvent: CCCCCC
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(O)(c3ccc(Cl)cc3)C(C)(C)O4)CC2)cc1
Yield: 71 %

Procedure:
Using 1-bromo-4-chlorobenzene and 4-(4-methoxyphenyl)-1-(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-on-5-yl)piperazine obtained in Reference Example 13, the title compound was synthesized in the same manner as in Example 33. Yield 71%. mp. 153–155° C. (hexane).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:13]2[NH:17][C:16]3[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:15]=3[N:14]=2)[CH2:12][CH2:11][O:10][CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:22][C:20]1[CH:19]=[CH:18][C:16]2[NH:17][C:13]([C:8]3([NH2:7])[CH2:12][CH2:11][O:10][CH2:9]3)=[N:14][C:15]=2[CH:21]=1
Reactant: CC(C)(C)OC(=O)NC1(c2nc3cc(Cl)ccc3[nH]2)CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1(c2nc3cc(Cl)ccc3[nH]2)CCOC1
Reaction time: 2 h

Procedure:
[3-(5-Chloro-1H-benzoimidazol-2-yl)-tetrahydro-furan-3-yl]-carbamic acid tert-butyl ester (2.09 g, 6.19 mmol) is dissolved in DCM (100 mL) and treated with TFA (10 mL). Stirring is continued for 2 h. Volatiles are evaporated under reduced pressure and the resulting residue taken up twice with ethyl ether and evaporated under reduced pressure to give 3-(5-Chloro-1H-benzoimidazol-2-yl)-tetrahydro-furan-3-ylamine as trifluoroacetic salt crude (2.2 g).
Reaction SMILES: [CH:1]1([C:6]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=2[NH:15][C:16](=[O:30])[NH:17][C:18]2[S:19][CH:20]=[C:21]([CH2:23][CH2:24]OS(C)(=O)=O)[N:22]=2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:31]1[CH:35]=[CH:34][N:33]=[C:32]1[SH:36]>>[CH:1]1([C:6]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=2[NH:15][C:16]([NH:17][C:18]2[S:19][CH:20]=[C:21]([CH2:23][CH2:24][S:36][C:32]3[NH:31][CH:35]=[CH:34][N:33]=3)[N:22]=2)=[O:30])=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Sc1ncc[nH]1
Reactant: Cc1ccc(NC(=O)Nc2nc(CCOS(C)(=O)=O)cs2)c(C(=O)C2CCCC2)c1
Product: Cc1ccc(NC(=O)Nc2nc(CCSc3ncc[nH]3)cs2)c(C(=O)C2CCCC2)c1
Yield: 49.9 %

Procedure:
1-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-3-{4-[2-(1H-imidazol-2-ylsulfanyl)-ethyl]-thiazol-2-yl}-urea (25 mg, 50%) was prepared from methanesulfonic acid 2-{2-[3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-4-yl}-ethyl ester (0.05 g, 0.11 mmol) and 1H-imidazol-2-thiol (0.009 g, 0.11 mmol) following the general procedure Z.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([O:9][C:10]([N:12]1[CH2:16][C@@H:15]([S:17][C:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:14][C@H:13]1[CH2:37][OH:38])=[O:11])[CH:7]=[CH2:8].C(N(CC)CC)C>C(Cl)Cl>[CH2:6]([O:9][C:10]([N:12]1[CH2:16][C@@H:15]([S:17][C:18]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:14][C@H:13]1[CH2:37][O:38][S:2]([CH3:1])(=[O:4])=[O:3])=[O:11])[CH:7]=[CH2:8]
Reactant: C=CCOC(=O)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCOC(=O)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1COS(C)(=O)=O
Reaction time: 0.5 h
Yield: 94 %

Procedure:
A solution of methanesulfonyl chloride (20.5 ml, 265 mmol) in methylene chloride (20 ml) was dropwise added to a solution of (2S,4S)-N-allyloxycarbonyl-2-hydroxymethyl-4-tritylthiopyrrolidine (119 g, 259 mmol, compound of Reference Example 3-1 of Japanese Patent Application No. 192,093/1990) and triethylamine (40.3 ml, 289 mmol) in methylene chloride (1 l) under cooling with ice, and the mixture was stirred at the same temperature for 30 minutes. The reaction solution was washed sequentially with water (500 ml), a saturated sodium hydrogen carbonate aqueous solution (250 ml) and a saturated sodium chloride aqueous solution (250 ml), then dried over anhydrous sodium sulfate and concentrated. To the residue, ethyl acetate (30 ml) and diisopropyl ether (270 ml) were added, and the precipitated crystals were collected by filtration to obtain (2S,4S)-N-allyloxycarbonyl-2-methanesulfonyloxymethyl-4-tritylthiopyrrolidine (130.8 g, yield: 94%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7](Cl)=[N:8][OH:9].[C:12]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)#[CH:13].N>>[F:1][C:2]1[CH:11]=[C:6]([C:7]2[CH:13]=[C:12]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[O:9][N:8]=2)[CH:5]=[N:4][CH:3]=1
Reactant: ON=C(Cl)c1cncc(F)c1
Reactant: C#Cc1cccnc1
Agent: N
Product: Fc1cncc(-c2cc(-c3cccnc3)on2)c1

Procedure:
The titled compound was prepared according to Method CB using the product of Example 28B (88 mg, 0.5 mmol) and 3-ethynylpyridine (Aldrich, 52 mg, 0.5 mmol). 1H NMR (300 MHz, MeOH-d4) 87.59 (s, 1H), 7.63 (ddd, J=8.0, 5.1, 0.8 Hz, 1H), 8.19 (ddd, J=9.3, 2.8, 1.8 Hz, 1H), 8.36 (dt, J=7.9, 2.0 Hz, 1H), 8.62 (d, J=2.8 Hz, 1H), 8.68 (dd, J=5.2, 1.6 Hz, 1H), 8.99 (t, J=1.6 Hz, 1H), 9.12 (d, J=2.4 Hz, 1H) ppm; MS (DCI/NH3) m/z 242 (M+H)+.
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:2].[Na+].[Na+].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH:21]=[O:22])=[CH:16][CH:15]=1.C1(C)C=CC=CC=1>O>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([OH:2])=[O:22])=[CH:16][CH:15]=1
Reactant: COc1ccc(CC=O)cc1
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(CC(=O)O)cc1
Temperature: 20 °C
Reaction time: 17 h
Yield: 9896.6 %

Procedure:
1.44 equivalents (7.7 g) of sodium periodate NaIO4, 0.6 mol % (0.045 g) of sodium dichromate Na2Cr2O72H2O and 3 g of 1N sulfuric acid H2SO4 (12 mol %) were dissolved in 50 ml of water. To this solution were added 25 mmol (3.75 g) of 4-methoxyphenylacetaldehyde and 25 ml of toluene, whereupon the reaction mixture was stirred for 17 h at 20° C. The phases were then separated and the aqueous phase was extracted with 2×10 ml of toluene. 30 ml of 1N NaOH were added to the combined toluene phases. The basic water phase was made acidic with 3 g of conc. H2SO4 and extracted with 2×25 ml of toluene. The combined organic phases were washed 3× with H2O, dried over Na2SO4 and evaporated to dryness. 17 mmol (2.82 g) of p-methoxyphenylacetic acid (yield 68% of theory) with a purity of 98% were obtained.
Reaction SMILES: Cl.[C:2](=[NH:7])(OCC)[CH3:3].C(N(CC)CC)C.Cl.[CH2:16]([O:18][C:19]([NH:21][C:22]1([CH2:28][N:29]2[CH2:34][CH2:33][N:32]([S:35]([C:38]3[CH:47]=[CH:46][C:45]4[C:40](=[CH:41][CH:42]=[C:43]([Cl:48])[CH:44]=4)[CH:39]=3)(=[O:37])=[O:36])[CH2:31][C:30]2=[O:49])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=[O:20])[CH3:17]>CO>[ClH:48].[C:2]([N:25]1[CH2:26][CH2:27][C:22]([CH2:28][N:29]2[CH2:34][CH2:33][N:32]([S:35]([C:38]3[CH:47]=[CH:46][C:45]4[C:40](=[CH:41][CH:42]=[C:43]([Cl:48])[CH:44]=4)[CH:39]=3)(=[O:36])=[O:37])[CH2:31][C:30]2=[O:49])([NH:21][C:19]([O:18][CH2:16][CH3:17])=[O:20])[CH2:23][CH2:24]1)(=[NH:7])[CH3:3]
Reactant: CCOC(C)=N
Reactant: CCOC(=O)NC1(CN2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2=O)CCNCC1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CCOC(=O)NC1(CN2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2=O)CCN(C(C)=N)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 162.1 %

Procedure:
A 4N hydrochloric acid solution in ethyl acetate (30 ml) and ethanol (6 ml) were added to 1-[1-(tert-butoxycarbonyl)-4-ethoxycarbonylamino-4-piperidylmethyl]-4-(6-chloronaphthalene-2-sulfonyl)-2-piperazinone (5.21 g), and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated, the precipitated crystals were filtered, washed with ethyl acetate-ethanol, and dried to obtain 1-[4-ethoxycarbonylamino-4-piperidinylmethyl]-4-(6-chloronaphthalene-2-sulfonyl)-2-piperazinone hydrochloride (3.71 g). Ethyl acetimidate hydrochloride(148 mg) and triethylamine (0.337 ml) were added to a solution of 1-[4-ethoxycarbonylamino-4-piperidinylmethyl]-4-(6-chloronaphthalene-2-sulfonyl)-2-piperazinone hydrochloride (218 mg) in methanol (10 ml) under ice-cooling, and the mixture was stirred at room temperature overnight. After distillation of the solvent, purification by CHP20 column chromatography (water:acetonitrile:1N hydrochloric acid=100:0:0→60:40:0.5) afforded the colorless amorphous title compound (190 mg).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][N:14]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:24])=[CH:6][CH:5]=1.[CH3:25][N:26]([CH3:30])[C:27](Cl)=[S:28]>CN(C=O)C>[O:24]=[C:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:22](=[O:23])[N:14]1[CH2:13][CH2:12][CH2:11][CH2:10][C:7]1[CH:8]=[CH:9][C:4]([O:3][C:27](=[S:28])[N:26]([CH3:30])[CH3:25])=[CH:5][CH:6]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCc1ccc(O)cc1
Reactant: CN(C)C(=S)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)C(=S)Oc1ccc(CCCCN2C(=O)c3ccccc3C2=O)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 59.4 %

Procedure:
A suspension of sodium hydride (60% in mineral oil, 0.44 g, 0.11 mmol) in anhydrous DMF (10 mL) was cooled to 0° C. and added to a solution of 2-[4-(4-hydroxyphenyl)-butyl]isoindole-1,3-dione 8 (2.95 g, 10 mmol) in DMF (15 mL). The mixture was stirred at 0° C. for 30 min and then at room temperature for an additional one hour. A solution of dimethylthiocarbamic acid chloride (1.35 g, 11 mmol) in DMF (10 mL) was then added. The reaction mixture was stirred at room temperature first for 16 h and then at 50° C. for 1 h, cooled back to room temperature and quenched with methanol (10 mL). The mixture was concentrated under vacuum and the residue was purified by flash silica gel column chromatography eluting with CH2Cl2/hexanes/EtOAc (10:1:0.2, v/v) to give the desired product 9 as a yellowish solid (2.27 g, 59% yield). 1H NMR (300 MHz, CDCl3) δ 1.72 (m, 4H), 2.67 (m, 2H), 3.33 (s, 3H), 3.45 (s, 3H), 3.71 (m, 2H), 6.95 (d, 2H), 7.18 (d, 2H), 7.70 (m, 2H), 7.84 (m, 2H). m/z (ESI): 383 [C21H22N2O3S+H]+.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.CO.[CH3:13][NH2:14]>C(O)C>[CH3:13][NH:14][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2
Reactant: Clc1ncnc2nc[nH]c12
Reactant: CN
Solvent: CO
Solvent: CCO
Product: CNc1ncnc2[nH]cnc12
Temperature: 120 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
In 20 mL of a 40% methylamine methanol solution and 20 mL of ethanol, 12.5 g (79 mmol) of 6-chloropurin was dissolved and the solution was sealed in a tube and stirred in the tube at 120° C. for four hours. The reaction solution was concentrated, and then triturated with water and collected on a filter, washed with water, and then vacuum dried to obtain 10.78 g (90%) of methyl-(9H-purin-6-yl)amine as a white solid.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][C@H:5]1[C:18](=[O:19])[CH2:17][C@H:16]2[N:7]([CH2:8][CH2:9][C:10]3[C:15]2=[CH:14][C:13]([O:20][CH3:21])=[C:12]([O:22][CH3:23])[CH:11]=3)[CH2:6]1)[CH3:3].[BH4-].[Na+]>CCO>[CH2:4]([C@@H:5]1[CH2:6][N:7]2[CH2:8][CH2:9][C:10]3[C:15]([C@H:16]2[CH2:17][C@H:18]1[OH:19])=[CH:14][C:13]([O:20][CH3:21])=[C:12]([O:22][CH3:23])[CH:11]=3)[CH:2]([CH3:3])[CH3:1].[CH2:4]([C@@H:5]1[CH2:6][N:7]2[CH2:8][CH2:9][C:10]3[C:15]([C@H:16]2[CH2:17][C@@H:18]1[OH:19])=[CH:14][C:13]([O:20][CH3:21])=[C:12]([O:22][CH3:23])[CH:11]=3)[CH:2]([CH3:3])[CH3:1]
Reactant: COc1cc2c(cc1OC)[C@H]1CC(=O)[C@H](CC(C)C)CN1CC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1cc2c(cc1OC)[C@H]1C[C@@H](O)[C@H](CC(C)C)CN1CC2
Product: COc1cc2c(cc1OC)[C@H]1C[C@H](O)[C@H](CC(C)C)CN1CC2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
(3R,11bR)-Tetrabenazine 1c.1 (2 g, 6.3 mmol) was dissolved in EtOH (70 mL) and cooled to 0° C. Sodium borohydride (261 mg, 6.9 mmol) was then added in portions at 0° C. The reaction was complete after 30 minutes and quenched with saturated NH4Cl (4 mL). The white precipitate formed was filtered and washed with EtOH (5 mL, 2×). The EtOH was removed in vacuo and the aqueous layer extracted 3× with CH2Cl2 (50 mL). The organic layers were combined, dried over MgSO4 and concentrated. The crude product was purified via flash column chromatography (0.5:9.5 MeOH:CH2Cl2) to give 1.6 g (5 mmol) of (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol ((2R,3R,11bR)-dihydrotetrabenazine) 1d.1 and 410 mg (1.3 mmol) of (2S,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol ((2S,3R,1bR)-dihydrotetrabenazine) 1d.2. (2R,3R,11bR)-Dihydrotetrabenazine 1d.1: MS calcd: (319); Found 320.3 (M+H). (2S,3R,11bR)-Dihydrotetrabenazine 1d.2: MS calcd: (319); Found 320.3 (M+H).
Reaction SMILES: [CH3:1][C:2]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])[CH3:3].[CH:9]1([C@H:12]2[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:15]([CH2:24][OH:25])[CH:14]([OH:26])[CH2:13]2)[CH2:11][CH2:10]1>N1C=CC=CC=1.C(Cl)Cl>[Si:5]([O:25][CH2:24][CH:15]1[CH:14]([OH:26])[CH2:13][C@@H:12]([CH:9]2[CH2:10][CH2:11]2)[N:16]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])([C:2]([CH3:4])([CH3:3])[CH3:1])([CH3:7])[CH3:6]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)N1C(CO)C(O)C[C@H]1C1CC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C(CO[Si](C)(C)C(C)(C)C)C(O)C[C@H]1C1CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
TBSCl (1.35 g, 9.00 mmol) was added to a solution of (5S)-tert-butyl 5-cyclopropyl-3-hydroxy-2-(hydroxymethyl)pyrrolidine-1-carboxylate (32) (1.93 g, 7.50 mmol) in pyridine (15 mL) and the resulting solution was stirred at rt for 18 h. The reaction mixture was diluted with CH2Cl2 (20 mL) and washed with 1 N aq. HCl (10 mL). The organic phase was dried (Na2SO4), filtered and concentrated under vacuum to give (5S)-tert-butyl 2-((tert-butyldimethylsilyloxy)methyl)-5-cyclopropyl-3-hydroxypyrrolidine-1-carboxylate (33). Retention time (min)=3.261 method [1], MS (m/z) 394.2 (M+Na)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[C:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[NH:11][N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:28][C:29]1[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=1>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[C:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[N:11]([CH2:28][C:29]3[CH:30]=[CH:31][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:37][CH:38]=3)[N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)c1cc(-c2cc(Cl)cc(Cl)c2)n[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cn2nc(-c3cc(Cl)cc(Cl)c3)cc2C(=O)OC(C)(C)C)cc1
Reaction time: 3 h

Procedure:
To a solution of the product from step D (6.8 g, 21.7 mmol) in 50 mL of N,N-dimethylformamide was added cesium carbonate (10.6 g, 32.6 mmol) and the resultant mixture stirred at ambient temperature for 15 min. Methyl 4-(bromo-methyl)benzoate (5.46 g, 23.9 mmol) was added and stirring continued for 3 h. The reaction mixture was diluted with ethyl acetate and the organic layer washed successively with six portions of water and one portion of brine then dried over magnesium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (SiO2, 5% ethyl acetate/hexanes) to give the title compound as a light tan solid. 1H NMR (500 MHz, CDCl3) δ; 8.03 (d, J=8.4 Hz, 2H); 7.75 (d, J=1.8 Hz, 2H); 7.35 (m, 3H); 7.12 (s, 1H); 5.88 (s, 2H); 3.94 (s, 3H); 1.57 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH2:10][C:11]([C:13]1[CH:14]=[CH:15][C:16]2[O:21][CH2:20][C:19](=[O:22])[N:18]([CH3:23])[C:17]=2[CH:24]=1)=[O:12].[H-].[Na+].[CH3:27]I>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:27])[C:11]([C:13]1[CH:14]=[CH:15][C:16]2[O:21][CH2:20][C:19](=[O:22])[N:18]([CH3:23])[C:17]=2[CH:24]=1)=[O:12]
Reactant: CI
Reactant: COc1ccc(CC(=O)c2ccc3c(c2)N(C)C(=O)CO3)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(C(C)C(=O)c2ccc3c(c2)N(C)C(=O)CO3)c(Cl)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 54 %

Procedure:
To a solution of 6-[2-(2-chloro-4-methoxy-phenyl)-acetyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (5.9 g, 17 mmol) in tetrahydrofuran (380 ml) was added sodium hydride (60% dispersion in mineral oil, 0.72 g, 17.9 mmol). The mixture was stirred at room temperature for 1.5 h and then placed in an ice bath. A solution of methyl iodide (2.54 g, 17.9 mmol) in tetrahydrofuran (15 ml) was added dropwise (5 min). The ice bath was removed and the mixture was stirred at 35° C. for 3.5 h. The reaction mixture was poured on ice-water and extracted twice with AcOEt. The organic phases were washed with water and brine, dried (MgSO4), filtered and concentrated. The product was purified by column chromatography (SiO2, heptane/EtOAc 2:1) to give the title compound (3.3 g) as a light yellow foam. MS (m/e)=360.2 [M+H+].
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1.[CH3:13][Si:14]([C:17]#[CH:18])([CH3:16])[CH3:15].C(N(CC)CC)C>CN(C=O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[CH3:9][O:8][C:6]1[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=[C:2]([C:18]#[C:17][Si:14]([CH3:16])([CH3:15])[CH3:13])[N:7]=1
Reactant: COc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COc1nc(C#C[Si](C)(C)C)ccc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 50.3 %

Procedure:
Bis(triphenylphosphine)palladiumdichloride (0.082 g, 0.118 mmol) was added to a solution of 6-chloro-2-methoxy-3-nitropyridine (0.554 g, 2.94 mmol), trimethylsilylacetylene (0.623 mL, 4.41 mmol), triethylamine (1.843 mL, 13.22 mmol) and copper iodide (0.022 g, 0.118 mmol) in DMF (10.1 mL). The reaction mixture was heated at 80° C. for 1 hour. The reaction mixture was diluted with water and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by Biotage silica gel column chromatography eluting with cyclohexane/EtOAc (99/1) to afford the title compound as a yellow oil (370 mg, 50%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:14]=[C:13]([NH2:15])[NH:12][N:11]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:16][S:17]([C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1)(=[O:19])=[O:18].Cl>CO.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:14]=[C:13]([NH:15][CH2:24][C:23]3[CH:22]=[CH:21][C:20]([S:17]([CH3:16])(=[O:19])=[O:18])=[CH:27][CH:26]=3)[NH:12][N:11]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CS(=O)(=O)c1ccc(C=O)cc1
Reactant: Nc1nc(Nc2cc(Cl)cc(Cl)c2)n[nH]1
Agent: Cl
Solvent: CC(=O)O
Solvent: CO
Product: CS(=O)(=O)c1ccc(CNc2nc(Nc3cc(Cl)cc(Cl)c3)n[nH]2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67 %

Procedure:
To a solution of N3-(3,5-dichlorophenyl)-1H-1,2,4-triazole-3,5-diamine Intermediate 2 (200 mg, 819 μmol) in MeOH (5 mL) was added a suspension of 4-methylsulfonylbenzaldehyde (158 mg, 860 μmol) in acetic acid (75 μl) and MeOH (2 mL). The reaction was stirred at room temperature for 15 minutes, 2-picoline borane complex (140 mg, 1.31 mmol, Aldrich) was added and the stirring was continued for 3 days. The reaction mixture was diluted with MeOH (6 mL) and poured into 0.1N HCl solution (10 ml). The resulting suspension was filtered and washed with water to give an off white solid as desired product (228 mg, 67% yield). MS +m/z: 412 (M+H)+
Reaction SMILES: Cl[CH:2]([CH2:6][CH:7]=O)[C:3](=[O:5])[CH3:4].[NH2:9][C:10]1[N:15]=[CH:14][CH:13]=[CH:12][N:11]=1>C(O)C>[CH3:7][C:6]1[N:9]=[C:10]2[N:15]=[CH:14][CH:13]=[CH:12][N:11]2[C:2]=1[C:3](=[O:5])[CH3:4]
Reactant: CC(=O)C(Cl)CC=O
Reactant: Nc1ncccn1
Solvent: CCO
Product: CC(=O)c1c(C)nc2ncccn12
Temperature: 102.5 °C
Yield: 21.8 %

Procedure:
3-Chloro-2,5-pentanedione (2) (106 mL, 119 g, 887 mmol, 1.2 eq) was dissolved in 650 mL of anhydrous ethanol. 2-Aminopyrimidine (1) (71.5 g×97%=69.36 g, 729 mmol) was added to above stirred solution. The resulting mixture was refluxed for 40 h at an oil bath temperature of 100-105° C. The black reaction mixture was cooled and concentrated under reduced pressure. The residue was treated with saturated sodium bicarbonate solution (˜500 mL) in portions, and swelled the flask to mix well. The mixture was extracted with dichloromethane (×6). The extracts were washed with sodium bicarbonate solution and brine. The organic phase was dried and concentrated. The residue was purified by flash chromatography on a silica gel column (7×30 cm) by gradient elution using n-hexane-ethyl acetate (3:1, 2:1, 1:1, 1:2 and 0:1) and then dichloromethane-methanol (30:1, 20:1, 10:1 and 5:1). The product fractions were collected (TLC, Rf 0.36, 100% ethyl acetate) and concentrated providing a light black solid. Other fractions contained products were collected and re-purified again by the same way. 27.84 g (21.8%) of the final product was obtained. Portion of the product was re-crystallized from small amount of acetonitrile to give red to light brown crystals 4, m.p. 255.6-256.6° C. 1H NMR (CDCl3) δ 2.65 (s, 3H, 3-COCH3), 2.86 (s, 3H, 2-CH3), 7.04-7.12 (m, 1H, 6-H), 7.70-7.74 (m, 1H), 9.96-10.00 (m, 1H).