Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Mg]Br)#[CH:2].[NH:5]1[CH:9]=[N:8][C:7]([C:10](=[O:12])[CH3:11])=[N:6]1>C1COCC1>[NH:5]1[CH:9]=[N:8][C:7]([C:10]([OH:12])([C:1]#[CH:2])[CH3:11])=[N:6]1
Reactant: CC(=O)c1nc[nH]n1
Reactant: C#C[Mg]Br
Solvent: C1CCOC1
Product: C#CC(C)(O)c1nc[nH]n1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
This compound was prepared according to a procedure similar to that described in Procedure A. Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed ethynylmagnesium bromide (45 mL, 2.50 equiv). This was followed by the addition of a solution of 1-(1H-1,2,4-triazol-3-yl)ethan-1-one (1000 mg, 9.00 mmol, 1.00 equiv) in THF (2 mL) dropwise with stirring at 0° C. The resulting solution was stirred for 10 min at 0° C. The resulting solution was allowed to react with stiffing for an additional 6 h at room temperature. The reaction was then quenched by the addition of 10 mL of sat. aq. NH4Cl. The resulting solution was extracted with 2×50 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate. The residue was applied onto a silica gel column with petroleum ether:ethyl acetate (1:1). This resulted in 0.4 g (32%) of 2-(1H-1,2,4-triazol-3-yl)but-3-yn-2-ol as a white solid.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:24](O)=[O:25])[CH2:20][CH:21]([CH3:23])[CH3:22])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2N=CC=CC=2N=N1.[F:60][C:61]([F:92])([F:91])[CH2:62][CH:63]([NH:69][CH2:70][C:71]1[C:86]([O:87][CH3:88])=[CH:85][C:74]([O:75][CH2:76][CH2:77][CH2:78][CH2:79][C:80]([O:82][CH2:83][CH3:84])=[O:81])=[CH:73][C:72]=1[O:89][CH3:90])[CH:64]([O:67][CH3:68])[O:65][CH3:66].C(N(C(C)C)CC)(C)C>ClCCl>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:24]([N:69]([CH2:70][C:71]3[C:72]([O:89][CH3:90])=[CH:73][C:74]([O:75][CH2:76][CH2:77][CH2:78][CH2:79][C:80]([O:82][CH2:83][CH3:84])=[O:81])=[CH:85][C:86]=3[O:87][CH3:88])[CH:63]([CH:64]([O:65][CH3:66])[O:67][CH3:68])[CH2:62][C:61]([F:91])([F:92])[F:60])=[O:25])[CH2:20][CH:21]([CH3:23])[CH3:22])=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: CCOC(=O)CCCCOc1cc(OC)c(CNC(CC(F)(F)F)C(OC)OC)c(OC)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1cnc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)CCCCOc1cc(OC)c(CN(C(=O)[C@H](CC(C)C)NC(=O)OCC2c3ccccc3-c3ccccc32)C(CC(F)(F)F)C(OC)OC)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.6 %

Procedure:
A solution of 6.6 g (18.7 mmol) of N-[(9-fluorenyl)-methoxycarbonyl]-L-leucine and 9.7 g (18.7 mmol) of 7-azabenzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate in 50 ml of anhydrous dichloromethane was stirred at room temperature for 15 minutes. To this mixture were then added 6.0 g (12.4 mmol) of ethyl 5-[4-[[3,3,3-trifluoro-1(RS)-(dimethoxymethyl)propylamino]methyl]-3,5-dimethoxyphenoxy]valerate and 4.3 ml of (24.8 mmol) diisopropylethylamine. After stirring overnight at 25° C. the mixture was diluted with dichloromethane and washed in sequence with water, 10% citric acid solution, saturated sodium hydrogen carbonate solution and saturated sodium chloride solution, then dried over anhydrous magnesium sulphate and filtered. The solvent was removed by evaporation and the residue was chromatographed on silica gel using 30% ethyl acetate in hexane for the elution. There were obtained 8.06 g of ethyl 5-[4-[[N-[N-[(9-fluorenyl)methoxycarbonyl]-L-leucyl]-N-[3,3,3-trifluoro-1(RS)-(dimethoxymethyl)propyl]amino]methyl]-3,5-dimethoxyphenoxy]valerate; MS: m/e 839.4 [M+Na], 855.3 [M+K].
Reaction SMILES: N1CCCC1.[CH3:6][S:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]2[O:18][C:17]([CH3:20])([CH3:19])[N:16]([C:21](=[O:23])[CH3:22])[C@H:15]2[CH:24]=[O:25])=[CH:10][CH:9]=1.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[CH3:6][S:7][C:8]1[CH:9]=[CH:10][C:11]([C@@H:14]2[O:18][C:17]([CH3:19])([CH3:20])[N:16]([C:21](=[O:23])[CH3:22])[C@@H:15]2[CH:24]=[O:25])=[CH:12][CH:13]=1
Reactant: CSc1ccc([C@@H]2OC(C)(C)N(C(C)=O)[C@H]2C=O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCNC1
Product: CSc1ccc([C@@H]2OC(C)(C)N(C(C)=O)[C@@H]2C=O)cc1

Procedure:
Pyrrolidine (9.6 mg; 0.065 mmol) was added at 25° C. to a solution of compound 4 (see example 3) (100 mg, 0.34 mmol) in toluene (2 ml) kept under magnetic stirring and under nitrogen. At the end of the addition the mixture was kept at 25° C. under stirring for 14 hours. The reaction mixture was then poured into 10% NaHCO3 ; after separation of the phases, the aqueous phase was extracted with CH2Cl2. The combined organic phases were dried over sodium sulphate and evaporated to dryness under vacuum.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].[CH:9]1(B(O)O)[CH2:11][CH2:10]1.C(=O)([O-])[O-].[Na+].[Na+].ClC(Cl)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:9]1([N:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=[N:7]2)[CH2:11][CH2:10]1
Reactant: OB(O)C1CC1
Reactant: O=[N+]([O-])c1cn[nH]c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CC(Cl)Cl
Product: O=[N+]([O-])c1cnn(C2CC2)c1
Temperature: 70 °C
Yield: 27.3 %

Procedure:
A 100-mL three-neck round-bottomed flask equipped with a reflux condenser and magnetic stirrer was purged with nitrogen and charged with 4-nitropyrazole (500 mg, 4.42 mmol), cyclopropylboronic acid (760 mg, 8.84 mmol), sodium carbonate (937 mg, 8.84 mmol), 2,2′-bipryidyl (690 mg, 4.42 mmol), and dichloroethane (45 mL). After bubbling nitrogen through the resulting suspension for 30 min, copper (II) acetate (802 mg, 4.42 mmol) was added, and the reaction mixture was heated at 70° C. (oil bath temperature) for 6 h. After this time, the mixture was cooled to room temperature and filtered. The filtrate was diluted with ethyl acetate (150 mL) and water (30 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 0% to 50% ethyl acetate/hexanes) to afford a 37% yield (185 mg) of 109a as an off-white solid: mp 44-45° C.; 1H NMR (500 MHz, CDCl3) δ 8.18 (s, 1H), 8.03 (s, 1H), 3.67 (s, 1H), 1.16 (m, 4H); MS (APCI+) m/z 154.1 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:17][CH2:18][C:19]([OH:21])=[O:20])=[O:16])[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[C:22]1([CH2:28][CH2:29]O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:22]1([CH2:28][CH2:29][O:20][C:19](=[O:21])[CH2:18][NH:17][C:15](=[O:16])[C@H:13]([CH3:14])[NH:12][C:10](=[O:11])[CH2:9][C:4]2[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: OCCc1ccccc1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NCC(=O)O
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NCC(=O)OCCc1ccccc1

Procedure:
Following General Procedure X and using N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]glycine (prepared from N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]glycine benzyl ester (from Example 73 below) using General Procedure O) and 2-phenylethanol (Aldrich), the title compound was prepared as a solid (mp=154.0-155.2° C.). The reaction was monitored by tlc (Rf=0.15 in 15% EtOAc/hexanes) and the product was purified by flash chromotography using 15% EtOAc/hexanes as the eluent.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.Cl.[C:11]([O:15][C:16](=[O:20])[CH2:17][NH:18][CH3:19])([CH3:14])([CH3:13])[CH3:12]>>[C:11]([O:15][C:16](=[O:20])[CH2:17][N:18]([C:6]1[CH:5]=[C:4]([CH3:9])[N:3]=[C:2]([Cl:1])[N:7]=1)[CH3:19])([CH3:14])([CH3:13])[CH3:12]
Reactant: Cc1cc(Cl)nc(Cl)n1
Reactant: CNCC(=O)OC(C)(C)C
Agent: Cl
Product: Cc1cc(N(C)CC(=O)OC(C)(C)C)nc(Cl)n1
Yield: 52 %

Procedure:
Prepared in analogy to example 98a), using 2,4-dichloro-6-methylpyrimidine and sarcosine tert-butyl ester hydrochloride. The title compound was isolated as a slightly yellow oil in a yield of 52%. MS ISP (m/e): 272.2 & 274.0 (25 & 10) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=6.23 (s broad, 1H), 4.21 (s broad, 2H), 3.10 (s broad, 3H), 2.36 (s, 3H), 1.46 (s, 9H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([OH:12])=O.C(Cl)(=O)C(Cl)=O.[CH3:19][N:20]([CH3:36])[CH:21]1[CH2:25][CH2:24][N:23]([C:26]2[S:27][C:28]3[CH:34]=[C:33]([NH2:35])[CH:32]=[CH:31][C:29]=3[N:30]=2)[CH2:22]1>>[CH3:19][N:20]([CH3:36])[CH:21]1[CH2:25][CH2:24][N:23]([C:26]2[S:27][C:28]3[CH:34]=[C:33]([NH:35][C:10]([C:2]4[S:1][C:5]5[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=5[CH:3]=4)=[O:12])[CH:32]=[CH:31][C:29]=3[N:30]=2)[CH2:22]1
Reactant: CN(C)C1CCN(c2nc3ccc(N)cc3s2)C1
Reactant: O=C(O)c1cc2ccccc2s1
Agent: O=C(Cl)C(=O)Cl
Product: CN(C)C1CCN(c2nc3ccc(NC(=O)c4cc5ccccc5s4)cc3s2)C1
Yield: 31.1 %

Procedure:
Prepare according to Method C (Example 9), using benzothiophene-2-carboxylic acid (123 mg, 0.685 mmol), oxalyl chloride (300 μL, 3.44 mmol), and 2-(3-dimethylamino-pyrrolidin-1-yl)-benzothiazol-6-ylamine (100 mg, 0.381 mmol) to afford the title compound (50 mg, 31%). mass spectrum (m/e): 423.0 [M+H]. 1H NMR (400 MHz, DMSO-d6) δ 10.53 (s, 1H), 8.35 (s, 1H), 8.25 (d, 1H, J=2.2 Hz), 8.06 (dd, 1H, J=6.5, 1.9 Hz), 8.01 (dd, 1H, J=6.2, 2.7 Hz), 7.55 (dd, 1H, J=8.8, 2.2 Hz), 7.50-7.43 (m, 3H), 3.72 (m, 1H), 3.63 (m, 1H), 3.48 (m, 1H), 3.31 (m, 1H), 2.90 (m, 1H), 2.22-2.17 (m, 7H), 1.92 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([Cl:15])[N:12]=[CH:11][C:10]=2[NH2:16])[C:5](F)=[N:6][CH:7]=1.[Na].C[Si]([NH-])(C)C>C1COCC1>[Br:1][C:2]1[CH:7]=[N:6][C:5]2[NH:16][C:10]3[CH:11]=[N:12][C:13]([Cl:15])=[CH:14][C:9]=3[C:4]=2[CH:3]=1
Reactant: Nc1cnc(Cl)cc1-c1cc(Br)cnc1F
Agent: C[Si](C)(C)[NH-]
Agent: [Na]
Solvent: C1CCOC1
Product: Clc1cc2c(cn1)[nH]c1ncc(Br)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.8 %

Procedure:
A solution of 5-bromo-6′-chloro-2-fluoro-[3,4′]-bipyridinyl-3′-ylamine (2.21 g, 7.32 mmol) in THF (124 mL) was added dropwise over 10 minutes to sodium his-(trimethylsilyl)amide ON solution in THF, 14.6 mL, 14.6 mmol). The reaction mixture was stirred for 1 h at ambient temperature and then quenched by the addition of water (2 mL). The resultant brown solution was partitioned between ethyl acetate (75 mL) and brine (50 mL). An off-white solid precipitated and was collected by filtration to afford the title compound as a grey solid (1.01 g, 49%). 1H NMR (DMSO-D6, 300 MHz): 9.01 (d, J=2.3 Hz, 1H), 8.73 (s, 1H), 8.70 (d, J=2.3 Hz, 1H), 8.35 (s, 1H). LCMS (Method B): RT=3.33 min, M+H+=284.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C@H:6]([CH3:11])[C:7]([F:10])([F:9])[F:8])[CH2:4][OH:5].CN1CCOCC1.[Si](Cl)(C)(C)C.[Cl:24][C:25]1[S:29][C:28]([S:30](Cl)(=[O:32])=[O:31])=[CH:27][CH:26]=1>CN1CCNCC1.C(Cl)Cl>[Cl:24][C:25]1[S:29][C:28]([S:30]([NH:2][C@H:3]([CH2:4][OH:5])[C@H:6]([CH3:11])[C:7]([F:10])([F:9])[F:8])(=[O:32])=[O:31])=[CH:27][CH:26]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Reactant: C[C@@H]([C@H](N)CO)C(F)(F)F
Agent: CN1CCNCC1
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C[C@@H]([C@@H](CO)NS(=O)(=O)c1ccc(Cl)s1)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.4 %

Procedure:
(2S,3S)-2-Amino-4,4,4-trifluoro-3-methyl-butan-1-ol HCl (10) (385.5 g, 1.99 moles) was stirred with 3.8 L CH2Cl2 and 1007 g (9.96 mole, equivalents) 1-methylmorpholine was added with a wash of 200 mL CH2Cl2. At 20-30° C., Me3SiCl (443 g, 4.08 mole, 2.05 equivalents) was over 15-30 minutes. The solution was stirred for 1 h at 20-30° C., then cooled to 15-20° C. 454 g (2.09 moles, 1.05 equivalents) of 5-chloro-thiophene-2-sulfonyl chloride was added over 10-15 minutes at 18 to 24° C. and washed with 190 mL CH2Cl2. The temperature rose to 31.5° C. over 30 minutes with the reactor in a bath at 30° C. The mixture was stirred for 16 hours and tested by HPLC to assure that excess (1-10%) 5-chloro-thiophene-2-sulfonyl chloride remains. 22 mL 1-methylpiperazine (0.199 mole, 0.1 equivalents) was added. The solvent was removed by distillation under vacuum at 90 mm Hg in a bath at 20-30° C. 3.65 L isopropyl acetate and 2 N H2SO4 (2 L) were added, the mixture was stirred for 20 minutes and the layers separated. The aqueous layer was back extracted with 0.5 L isopropyl acetate. 2 L 2 N H2SO4, 2 L ½ saturated NaHCO3 and 2 L water were used as a wash. The layers were clarified by filtration through 0.2 μM filter. The isopropyl acetate was removed under vacuum (40 to <10 mm Hg) to dryness giving 675 g of crude 5-Chloro-N-[(1S,2S)-3,3,3-trifluoro-1-(hydroxymethyl)-2-methylpropyl]thiophene-2-sulfonamide. The product was recrystallized from 10 volumes of 1:4 EtOAc/Heptanes giving 499 g after drying at 55° C. for 16 hours. A second crop of 49 g may be obtained from the mother liquors for a total yield of 548 g, 81%.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][O:6][CH2:5][CH2:4][NH:3]1.C(N(CC)CC)C.[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[C:15]([N:3]1[CH2:4][CH2:5][O:6][CH2:7][C:2]1=[O:1])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C1COCCN1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C1COCCN1C(=O)c1ccccc1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A 100 ml, three neck round bottom flask is equipped with a stir bar, a condenser, an addition funnel, a thermometer, and a temperature control device (Therm-O-Watch™, I2R). To this reaction flask is added the 3-oxomorpholine synthesized above (5.5 g, 0.054 moles), triethylamine (Aldrich, 6.0 g, 0.059 moles), and toluene (Baker, 15.0 g). To the addition funnel is added benzoyl chloride (Aldrich, 7.6 g, 0.054 moles). The reaction is heated to 90° C. under argon, and the benzoyl chloride is charged dropwise into the flask. After the addition is complete, the reaction is heated under reflux for 10 hours under argon as a white precipitate forms. The reaction mixture is then cooled and the precipitate is removed by vacuum filtration. Solvent is stripped from the resulting filtrate on a Kugelrohr apparatus at 2 mmHg and 70° C. for 1 hour to obtain the desired N-benzoyl-3-oxomorpholine as an oil.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].[H-].[Na+].[CH3:17]I>CN(C)P(N(C)C)(N(C)C)=O>[CH2:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH3:17])=[O:13])=[CH:7][CH:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCNc1ccc(CC(=O)O)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: C=CCNc1ccc(CC(=O)OC)cc1
Reaction time: 1 h

Procedure:
A solution of 20.7 g. of 4-(allylamino)phenylacetic acid in 25 ml. of hexamethylphosphoramide is added to a stirred mixture of 0.800 g. of sodium hydride (57% in mineral oil) and 25 ml. of hexamethylphosphoramide. The solution which forms after one hour is treated with 11.0 g. of methyl iodide and is then stirred at 25° C. for 18 hours. Dilution with water followed by filtration affords a white solid which is crystallized from ethanol to yield methyl 4-(allylamino)phenylacetate.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]CO)=[N+:2]=[N-:3].S(Cl)(C)(=O)=O.[CH3:16][S:17]([O:20][CH2:21]CN=[N+]=[N-])(=[O:19])=[O:18]>>[CH3:16][S:17]([O:20][CH2:21][CH:4]([N:1]=[N+:2]=[N-:3])[CH2:5][CH2:6][CH2:7][CH3:8])(=[O:19])=[O:18]
Reactant: CS(=O)(=O)OCCN=[N+]=[N-]
Reactant: [N-]=[N+]=NCCCCCCO
Agent: CS(=O)(=O)Cl
Product: CCCCC(COS(C)(=O)=O)N=[N+]=[N-]

Procedure:
Reaction of 6-azidohexanol (0.74 g, 5.22 mmol) and mesyl chloride (0.61 mL, 7.83 mmol) within 3 h as described for synthesis of 156a gave compound 156e (0.87 g) as a crude colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:29](=[O:30])[N:28]([CH3:31])[C:12]2[N:13]([CH3:27])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20](=O)[CH:21]=[CH:22][N:23](C)C)=[CH:16][CH:15]=3.[CH3:32][NH:33]N>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:29](=[O:30])[N:28]([CH3:31])[C:12]2[N:13]([CH3:27])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[N:33]([CH3:32])[N:23]=[CH:22][CH:21]=1)=[CH:16][CH:15]=3
Reactant: CNN
Reactant: CN(C)C=CC(=O)c1ccc2c(c1)c1cc(-c3ccc(Cl)cc3Cl)c(=O)n(C)c1n2C
Product: Cn1nccc1-c1ccc2c(c1)c1cc(-c3ccc(Cl)cc3Cl)c(=O)n(C)c1n2C

Procedure:
The process is carried out as in Example 37 above, with the compound from preparation 1.10F, 3-(2,4-dichlorophenyl)-6-(3-dimethylaminoacryloyl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one and methylhydrazine
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH:6]2[CH:8]([C:9](O)=O)[CH:3]1[CH2:4][CH2:5]2.[CH2:12]([N:15]1[C:22]([NH2:23])=[C:21]([NH2:24])[C:19](=[O:20])[N:18]([CH2:25][CH2:26][CH3:27])[C:16]1=[O:17])[CH2:13][CH3:14].Cl>>[O:1]=[C:2]1[CH2:7][CH:6]2[CH:8]([C:9]3[NH:24][C:21]4[C:19](=[O:20])[N:18]([CH2:25][CH2:26][CH3:27])[C:16](=[O:17])[N:15]([CH2:12][CH2:13][CH3:14])[C:22]=4[N:23]=3)[CH:3]1[CH2:4][CH2:5]2
Reactant: O=C1CC2CCC1C2C(=O)O
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Agent: Cl
Product: CCCn1c(=O)c2[nH]c(C3C4CCC3C(=O)C4)nc2n(CCC)c1=O

Procedure:
2-Oxo-bicyclo[2.2.1]heptane-7-carboxylic acid (308 mg) was couple to 1,3-Dipropyl-5,6-diaminouracil.HCl (576 mg) and cyclized using the procedures from Example 1. Yield: 320 mg. Mass (ES+ 345).
Reaction SMILES: [BH4-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[S@:14](=[O:15])[CH2:13][CH2:12][CH2:11][CH:10]=2)[CH:4]=1.O.CC(C)=O>C(O)C>[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C@H:9]2[CH2:10][CH2:11][CH2:12][CH2:13][S@:14]2=[O:15])[CH:4]=1
Reactant: O=[S@@]1CCCC=C1c1cccnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: CCO
Product: O=[S@@]1CCCC[C@@H]1c1cccnc1
Reaction time: 3 h
Yield: 30.6 %

Procedure:
A stirred suspension of sodium borohydride (11.44 g) in ethanol (935 ml) is treated with a solution of crude (R)-6-(3-pyridyl)-3,4-dihydro-2H-thiopyran 1-oxide (116.9 g; prepared as described in Example 10) in ethanol (117 ml) at room temperature under nitrogen. The mixture is stirred for 3 hours and is then treated with water (935 ml) and acetone (93 ml), with cooling. The solution is extracted with dichloromethane (3×800 ml), the combined extracts are washed with aqueous sodium chloride solution (2×800 ml;25% w/v), dried over magnesium sulphate, and evaporated under reduced pressure to give a paste (96.2 g). This paste is recrystallised from a mixture of tert-butyl methyl ether and methyl ethyl ketone, to give (1R,2R)-2-(3-pyridyl)tetrahydro-2H-thiopyran 1 -oxide (36.16 g), in the form of a pale yellow powder, m.p. 121°-126° C., enantiomeric excess 99.6%. [NMR (CDCl3):- 1.6(m, 1H), 1.8(m,2H),2.0(m,1H),2.4(m,1H),2.7(m,2H), 3.2(m,1H),3.5(dd,1H),7.3(m,1H),7.7(dt, 1H), 8.6(m,2H)].
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:7]2[N:8]([CH3:24])[CH:9]=[C:10]([C:13]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)=[O:14])[C:11](=[O:12])[C:6]=2[S:5][C:4]=1[CH2:25][N:26]([CH2:28][C@@H:29]([OH:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1)[CH3:27].C(N(C(C)C)CC)(C)C.[CH3:46][S:47](Cl)(=[O:49])=[O:48]>C(Cl)Cl>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][NH:15][C:13]([C:10]2[C:11](=[O:12])[C:6]3[S:5][C:4]([CH2:25][N:26]([CH2:28][C@@H:29]([OH:36])[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=4)[CH3:27])=[C:3]([CH2:2][NH:1][S:47]([CH3:46])(=[O:49])=[O:48])[C:7]=3[N:8]([CH3:24])[CH:9]=2)=[O:14])=[CH:22][CH:21]=1
Reactant: CN(Cc1sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c2c1CN)C[C@@H](O)c1ccccn1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(Cc1sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c2c1CNS(C)(=O)=O)C[C@@H](O)c1ccccn1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a cold (0° C.), stirred solution of 96 mg of 3-(aminomethyl)-N-(4-chlorobenzyl)-2-{[[(2R)-2-hydroxy-2-pyridin-2-ylethyl](methyl)amino]methyl}-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide and 40 μL of diisopropylethylamine in 2 mL of CH2Cl2 is added 15 μL of methanesulfonyl chloride. The solution is stirred at 0° C. for 20 min, then quenched with dil. HCl and aqueous NaHCO3 to pH 7.0. The mixture is extracted three times with CHCl3, and the combined extracts dried (Na2SO4) and concentrated under reduced pressure. Flash chromatography of the residue on silica using 3-4% MeOH in CH2Cl2 furnishes 114 mg of the title compound as a white foam. Recrystallization from EtOAc provides white crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:41])[CH2:5][CH2:6][C:7]1[O:8][C:9]2[CH:40]=[CH:39][CH:38]=[CH:37][C:10]=2[C:11]=1[CH2:12][CH:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:18](=[O:36])[CH:19]([NH:23][C:24](=[O:35])[CH:25]([NH:27]C(OC(C)(C)C)=O)[CH3:26])[CH:20]([CH3:22])[CH3:21])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:41])[CH2:5][CH2:6][C:7]1[O:8][C:9]2[CH:40]=[CH:39][CH:38]=[CH:37][C:10]=2[C:11]=1[CH2:12][CH:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:18](=[O:36])[CH:19]([NH:23][C:24](=[O:35])[CH:25]([NH2:27])[CH3:26])[CH:20]([CH3:22])[CH3:21])[CH3:2]
Reactant: CCOC(=O)CCc1oc2ccccc2c1CC1CCCN1C(=O)C(NC(=O)C(C)NC(=O)OC(C)(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CCc1oc2ccccc2c1CC1CCCN1C(=O)C(NC(=O)C(C)N)C(C)C
Reaction time: 2.5 h
Yield: 42.4 %

Procedure:
To a solution of 51 (160 mg, 0.28 mmol) in DCM (10 mL) was added TFA (2 mL) at ambient temperature. After 2.5 h, the solvent was removed under reduced pressure. The residue was dissolved in EtOAc and washed with aqueous NaHCO3, brine, dried over anhydrous Na2SO4, filtered and concentrated. A portion (˜50%) of the crude material was purified by reverse-phase HPLC (C18, 10-100% ACN/water containing 0.1% HOAc) to afford 56 mg of 52 as a white solid. 1H NMR (DMSO, 300 MHz) 58.03 (d, J=8.7 Hz, 1H), 7.77 (m, 1H), 7.43-7.41 (m, 1H), 7.21 (m, 2H), 4.37 (app t, J=8.1 Hz, 1H), 4.19 (m, 1H), 4.01 (q, J=7.2 Hz, 2H), 3.65 (m, 1H), 3.56 (app d, J=6.6 Hz, 1H), 3.28 (m, 1H), 3.06-3.01 (m, 3H), 2.68 (app t, J=7.2 Hz, 2H), 2.07-1.96 (m, 1H), 1.63 (m, 1H), 1.54 (m, 1H), 1.13-1.09 (m, 6H), 0.90 (d, J=6.3 Hz, 3H), 0.85 (d, J=6.3 Hz, 3H) ppm. Mass spectrum: m/z 472 [M+H]+; and, 494 [M+Na]+.
Reaction SMILES: Cl.[NH2:2][C:3]1[S:4][CH:5]=[C:6]([CH2:8][Cl:9])[N:7]=1.[CH3:10][N:11]=[C:12]=[O:13].N1C=CC=CC=1.O>CN(C)C=O>[CH3:10][NH:11][C:12](=[O:13])[NH:2][C:3]1[S:4][CH:5]=[C:6]([CH2:8][Cl:9])[N:7]=1
Reactant: Nc1nc(CCl)cs1
Reactant: CN=C=O
Agent: Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)Nc1nc(CCl)cs1
Temperature: 50 °C
Reaction time: 4 h
Yield: 41.4 %

Procedure:
To a solution of 2-amino-4-chloromethylthiazole hydrochloride (0.5 g) in N,N-dimethylformamide (5 ml) was added methyl isocyanate (0.17 g) in the presence of pyridine (0.24 ml). After 4 hours, methyl isocyanate (0.1 g) was further added. After 1 hour, methyl isocyanate (0.1 g) was added again and the reaction mixture was heated at 50° C. for 3.5 hours. The reaction mixture was then poured into water (20 ml) and extracted with ethyl acetate (30 ml×2). The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was distilled off and the residue was crystallized from a mixture of ethanol and n-hexane to give 2-(3-methylureido)-4-chloromethylthiazole (230 mg).
Reaction SMILES: CC1C(N=C=O)=CC([N:8]=[C:9]=[O:10])=CC=1.CC1C(N=C=O)=CC(N=C=O)=CC=1.CC1C(N=C=O)=CC=CC=1N=C=O.[CH3:40][C:41]([C:43]([O:45][CH2:46][CH2:47][OH:48])=[O:44])=[CH2:42].C(NCCCC)CCC.Cl>>[N-:8]=[C:9]=[O:10].[CH3:42][C:41]([C:43]([O:45][CH2:46][CH2:47][OH:48])=[O:44])=[CH2:40]
Reactant: Cc1ccc(N=C=O)cc1N=C=O
Agent: C=C(C)C(=O)OCCO
Agent: Cc1c(N=C=O)cccc1N=C=O
Agent: Cl
Solvent: CCCCNCCCC
Product: [N-]=C=O
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
Tolylene diisocyanate (2,4-tolylene diisocyanate/2,6-tolylene diisocyanate=80/20, hereinafter referred to as "TDI", 174 g) and EGA (130 g) are mixed, and to the stirred mixture is added dropwise HEMA (130 g, wherein phenothiazine (0.13 g) is dissolved) under nitrogen gas at 20°-45° C. over a period of 1 hour. After finishing the dropping of HEMA, the mixture is heated to 60° C. in 30 minutes and is stirred at the same temperature for 1.5 hour. It is confirmed that the product contains NCO of 9.6% (measured by di-n-butylamine-hydrochloric acid titration method) and an isocyanate product semi-blocked with HEMA is produced.