Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[CH:11]=[N:10][N:9]2[CH2:12][CH2:13][NH:14][C:8]=12.C(N(C(C)C)C(C)C)C.[C:24]([O:28][C:29]([NH:31][CH2:32][C:33](ON1C(=O)CCC1=O)=[O:34])=[O:30])([CH3:27])([CH3:26])[CH3:25]>C(Cl)Cl>[C:24]([O:28][C:29]([NH:31][CH2:32][C:33]([NH:6][C:7]1[CH:11]=[N:10][N:9]2[CH2:12][CH2:13][NH:14][C:8]=12)=[O:34])=[O:30])([CH3:27])([CH3:26])[CH3:25]
Reactant: Nc1cnn2c1NCC2
Reactant: CC(C)(C)OC(=O)NCC(=O)ON1C(=O)CCC1=O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCC(=O)Nc1cnn2c1NCC2
Temperature: 25 °C
Reaction time: 22 h
Yield: 59.5 %

Procedure:
To a solution of 7-amino-2,3-dihydro-1H-imidazo[1,2-b]pyrazole sulfuric acid salt (1.42 g) and N-ethyldiisopropylamine (2.73 g) in methylene chloride (50 ml) was added N-[2-(tert-butoxycarbonylamino)acetoxy]succinimide (1.90 g). The mixture was stirred at room temperature for 22 hours. The reaction mixture was washed with saturated aqueous sodium hydrogen carbonate solution, and the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The oily residue was purified by column chromatography on silica gel eluting with 5% methanol/chloroform to give 7-[2-(tert-butoxycarbonylamino)acetyl]amino-2,3-dihydro-1H-imidazo[1,2-b]pyrazole (1.07 g) as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([OH:10])[CH3:9].S(C1C=CC([N+]([O-])=O)=CC=1)(O[CH2:15][C@@H:16]1[O:18][CH2:17]1)(=O)=O.[H-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:10][CH2:15][C@H:16]1[CH2:17][O:18]1)[CH3:9]
Reactant: C[C@@H](O)c1ccccc1Br
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](OC[C@H]1CO1)c1ccccc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.8 %

Procedure:
(R)-1-(2-Bromophenyl)ethanol (30.0 g) and (R)-glycidyl nosylate(50.3 g) were dissolved in N,N-dimethylformamide (300 ml), sodium hydride (7.76 g, 60% in oil) was added and the mixture was stirred at room temperature for 2 hr. 10% Aqueous citric acid (600 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=6:1) to give the title compound (32.9 g).
Reaction SMILES: [OH:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47]([OH:49])=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][CH:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15][C:16](=[O:29])[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44].O.ON1C2C=CC=CC=2N=N1.[CH2:61](O)[C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1>C1COCC1>[OH:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47]([O:49][CH2:61][C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1)=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][CH:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15][C:16](=[O:29])[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44]
Reactant: CO[C@@H]1[C@@H](O)[C@@H](OC)C(NC2=CC(=O)c3c(cc4c(c3O)C(=O)[C@]3(OC)[C@H](O)Cc5cc(C)c(C(=O)O)c(O)c5[C@]3(O)C4=O)C2=O)O[C@H]1C
Reactant: OCc1ccccc1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: CO[C@@H]1[C@@H](O)[C@@H](OC)C(NC2=CC(=O)c3c(cc4c(c3O)C(=O)[C@]3(OC)[C@H](O)Cc5cc(C)c(C(=O)OCc6ccccc6)c(O)c5[C@]3(O)C4=O)C2=O)O[C@H]1C
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of (6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylic acid (80 mg, 0.12 mmol) in THF (1 mL) was added polystyrene-carbodiimide (208 mg, 0.24 mmol), 1-hydroxybenzotriazole hydrate (32 mg, 0.24 mmol) and benzyl alcohol (0.5 mL). The reaction mixture was stirred at room temperature under nitrogen for 17 h. The reaction was filtered through a micro filter and concentrated. The crude material was purified by preparative HPLC (10:90 acetonitrile/water to 60:40 acetonitrile/water with 0.05% TFA over 10 min, then isocratic) to afford (6R,6aS,14aR)-benzyl 1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate as a mixture of diastereomers (14 mg, 20%) and as a dark red solid: 1H NMR (500 MHz, CDCl3) δ 14.26 (s, 0.3H), 14.17 (s, 0.7H), 12.09 (s, 0.3H), 12.08 (s, 0.7H), 8.32 (br s, 6H), 8.27 (s, 0.3H), 8.21 (s, 0.7H), 6.86 (d, J=8.0 Hz, 1H), 6.52 (s, 1H), 5.87 (s, 0.7H), 5.86 (s, 0.3H), 5.28 (s, 2H), 4.96 (d, J=8.0 Hz, 1H), 4.67 (d, J=8.0 Hz, 1H), 3.80 (s, 3H), 3.74-3.70 (m, 2H), 3.61 (s, 3H), 3.58-3.53 (m, 2H), 3.40 (s, 3H), 3.37-3.30 (m, 3H), 3.13 (t, J=9.0 Hz, 1H), 2.41 (s, 2H), 3.39 (s, 1H), 1.36 (d, J=6.5 Hz, 3H); MS (ESI+) m/z 774 (M+H); HPLC >99% (AUC), tR 15.52 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]2[C:15](=[O:16])[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[C:25][CH2:26][NH:27]C(OCC4C=CC=CC=4)=O)[CH:19]=3)([CH3:17])[NH:13][C:12]2=[O:38])[CH:5]=1.C(O)(=O)C>CO.[Pd]>[CH3:1][O:2][C:3](=[O:39])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]2[C:15](=[O:16])[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][CH2:25][CH2:26][NH2:27])[CH:19]=3)([CH3:17])[NH:13][C:12]2=[O:38])[CH:5]=1
Reactant: COC(=O)c1cccc(CN2C(=O)NC(C)(c3cccc(C#CCNC(=O)OCc4ccccc4)c3)C2=O)c1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1cccc(CN2C(=O)NC(C)(c3cccc(CCCN)c3)C2=O)c1
Yield: 101.2 %

Procedure:
A solution of the Cbz-protected propargylamine 3 (580 mg, 1.1 mmol) and acetic acid (50 μL) in MeOH (10 mL) was stirred over 10% Pd/C (284 mg) under an atmosphere of hydrogen (50 psi) for 18 h. The suspension was passed through a PTFE-filter and the resulting filtrate concentrated under vacuum to give the desired material as a yellow solid (440 mg, 100%). 1H NMR (400 MHz, CDCl3) δ 8.32 (bs, 1H), 8.05 (bs, 2H), 7.83-7.88 (m, 2H), 7.34-7.41 (m, 3H), 7.27 (m, 1H), 7.14 (m, 1H), 6.95 (m, 1H), 4.57 (s, 2H), 3.79 (s, 3H), 3.39 (m, 2H), 2.86 (m, 2H), 2.60 (m, 2H), 2.00 (m, 2H), 1.65 (s, 3H). MS (ES+): 396 (M+H), 418 (M+Na).
Reaction SMILES: Cl[CH:2]1[C:8]2[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]=2[S:6][C:5]2[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:4]=2[CH2:3]1.[CH2:19]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[C:20]#[CH:21]>C(Cl)(Cl)Cl>[F:13][C:10]1[CH:11]=[CH:12][C:7]2[S:6][C:5]3[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:4]=3[CH2:3][CH:2]([N:25]3[CH2:26][CH2:27][N:22]([CH2:19][C:20]#[CH:21])[CH2:23][CH2:24]3)[C:8]=2[CH:9]=1
Reactant: C#CCN1CCNCC1
Reactant: Cc1ccc2c(c1)CC(Cl)c1cc(F)ccc1S2
Solvent: ClC(Cl)Cl
Product: C#CCN1CCN(C2Cc3cc(C)ccc3Sc3ccc(F)cc32)CC1

Procedure:
7 G. of 10-chloro-8-fluoro-10,11-dihydro-2-methyl-dibenzo[b,f]thiepin are heated under reflux for 20 hours with 7.8 g. of N-(2-propynyl)-piperazine and 40 ml. of chloroform. The chloroform is removed by evaporation and the residue is treated with ether and aqueous sodium hydroxide solution and mixed well. The ether phase is acidified with ethanolic hydrochloric acid. The precipitate which forms is removed by filtration, made alkaline with aqueous sodium hydroxide solution and taken up in benzene. The benzene phase is dried over sodium sulfate, evaporated, and there is obtained 1-[8-fluoro-10,11-dihydro-2-methyl-dibenzo[b,f]-thiepin-10-yl]-4-(2-propynyl)-piperazine which is converted into the dihydrochloride by reaction with ethanolic hydrogen chloride. The dihydrochloride melts at 230°-231° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]([F:17])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26]Br>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:10]2([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:26][CH2:25]2)=[O:16])=[C:4]([F:17])[CH:3]=1
Reactant: BrCCBr
Reactant: CCOC(=O)CC(=O)Nc1ccc(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(C(=O)Nc2ccc(Cl)cc2F)CC1
Yield: 60.5 %

Procedure:
In a manner similar to the procedure described in Example B, 31.0 grams (119.0 mmol) of ethyl 3-[(4-chloro-2-fluorophenyl)amino]-3-oxopropanoate, 41.4 grams (300.0 mmol) of anhydrous potassium carbonate, 100 milliliters anhydrous dimethylformamide and 10.4 milliliters (120.0 mmol) of 1,2-dibromoethane were reacted for a period of 3 days to give 20.6 grams (72.0 mmol) of ethyl 1-(4-chloro-2-fluorophenylaminocarbonyl)cyclopropanecarboxylate as a colorless solid having a melting point of 94.0° C.-95.5° C. The total yield was 61 percent. NMR analysis of the product indicated the following:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:16])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][C:3]=1[Br:17].Br[CH2:19][C:20]1[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=1[C:22]([O:24][CH3:25])=[O:23].C(N(C(C)C)CC)(C)C>C(O)C>[Br:17][C:3]1[CH:4]=[C:5]([CH:8]([CH3:16])[C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])[CH:6]=[CH:7][C:2]=1[NH:1][CH2:19][C:20]1[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=1[C:22]([O:24][CH3:25])=[O:23]
Reactant: COC(=O)c1ccccc1CBr
Reactant: CC(C(=O)OC(C)(C)C)c1ccc(N)c(Br)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: COC(=O)c1ccccc1CNc1ccc(C(C)C(=O)OC(C)(C)C)cc1Br
Temperature: 120 °C
Yield: 48.5 %

Procedure:
A mixture of tert-butyl 2-(4-amino-3-bromophenyl)propanoate (6.50 g, 21.7 mmol), methyl 2-(bromomethyl)benzoate (4.97 g, 21.7 mmol), diisopropylethylamine (2.80 g, 21.7 mmol), and ethanol (180 mL) was heated at 120° C. in a sealed vial overnight. After cooling to room temperature, the mixture was concentrated and the residue purified by flash chromatography (92:8 hexanes/ethyl acetate) to afford methyl 2-((2-bromo-4-(1-tert-butoxy-1-oxopropan-2-yl)phenylamino)methyl)benzoate (4.72 g, 48%) as thick oil: 1H NMR (500 MHz, CDCl3) δ 7.98 (m, 1H), 7.47 (m, 2H), 7.37-7.31 (m, 2H), 7.01 (dd, J=8.4, 2.0 Hz, 1H), 6.50 (d, J=8.4 Hz, 1H), 5.03 (br t, J=6.1 Hz, 1H), 4.75 (d, J=6.2 Hz, 2H), 3.92 (s, 3H), 3.43 (q, J=7.2 Hz, 1H), 1.38 (s, 9H), 1.37 (d, J=7.2 Hz, 3H); ESI MS m/z 450 [(M+2)+H]+.
Reaction SMILES: [Si:1]([O:18][C@@H:19]1[CH2:24][C@H:23]([O:25][Si](CC)(CC)CC)[CH2:22][C@@H:21]([OH:33])[C:20]1=[CH2:34])([C:14]([CH3:17])([CH3:16])[CH3:15])([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.N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:49]([C:52]([CH3:55])([CH3:54])[CH3:53])([CH3:51])[CH3:50])(=O)=O>ClCCl>[Si:49]([O:33][C@H:21]1[C:20](=[CH2:34])[C@H:19]([O:18][Si:1]([C:14]([CH3:17])([CH3:16])[CH3:15])([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:24][C:23](=[O:25])[CH2:22]1)([C:52]([CH3:55])([CH3:54])[CH3:53])([CH3:51])[CH3:50]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: C=C1[C@H](O)C[C@@H](O[Si](CC)(CC)CC)C[C@H]1O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: C=C1[C@H](O[Si](C)(C)C(C)(C)C)CC(=O)C[C@H]1O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
The compound of Example 13D (8.5 g, 17 mmol) was dissolved in 50 mL of dichloromethane; 4.4 mL of 2,6-lutidine was added, and the resultant solution was cooled to 0° C. tert-Butyldimethylsilyl trifluoromethanesulfonate (5.9 mL) was added, and the mixture was stirred for 1 hour. The reaction was quenched by the addition of saturated aqueous NH4Cl, the solvents were removed in vacuo, and the residue was partitioned between ethyl acetate and water. The organic phase was washed with 1 N aqueous HCl, then brine, and dried over Na2SO4. The solvents were removed in vacuo; the residue was purified by chromatography on an Analogix IntelliFlash 280™, eluting with a gradient of 2% to 5% ethyl acetate in hexanes. The product (9.3 g) was dissolved in 75 mL of ethanol; pyridinium p-toluenesulfonate (390 mg) was added, and the mixture was stirred at ambient temperature for 1 hour. The solvents were removed in vacuo; the residue was purified by chromatography on an Analogix Intelliflash 280™, eluting with a gradient of 9% to 17% ethyl acetate in hexanes. A sample of this product (5.8 of 6.8 g) was dissolved in 30 mL of dichloromethane; 3.0g of NaHCO3 was added, and the mixture was cooled to 0° C. Dess-Martin reagent (5.9 g) was added, and stirring was continued for 2 hours. The solvents were removed in vacuo, and the residue was partitioned between ethyl acetate and water. The organic phase was washed with 1 N aqueous HCl, then brine, and dried over Na2SO4. The organic phase was passed through a plug of silica gel and concentrated in vacuo, giving the titled compound (5.5 g, 71%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:18]3[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:17]=3[O:16][N:15]=2)[CH2:10][CH2:9]1.[CH2:24]1[O:32][C:31]2[CH:30]=[CH:29][C:28]([N:33]=[C:34]=[O:35])=[CH:27][C:26]=2[O:25]1>>[CH2:24]1[O:32][C:31]2[CH:30]=[CH:29][C:28]([NH:33][C:34]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]3[CH2:9][CH2:10][CH:11]([C:14]4[C:18]5[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:17]=5[O:16][N:15]=4)[CH2:12][CH2:13]3)=[O:35])=[CH:27][C:26]=2[O:25]1
Reactant: O=C=Nc1ccc2c(c1)OCO2
Reactant: OCCCCCCN1CCC(c2noc3cc(F)ccc23)CC1
Product: O=C(Nc1ccc2c(c1)OCO2)OCCCCCCN1CCC(c2noc3cc(F)ccc23)CC1
Yield: 51.7 %

Procedure:
Starting from 3-[1-(1-hydroxyhex-6-yl]-4-piperidinyl]-6-fluoro-1,2-benzisoxazole (270 mg, 0.84 mmol) and 3,4-methylenedioxyphenylisocyanate (297 mg, 1.69 mmol) using the procedure described in example 12B was prepared 210 mg (51.8%) of the title compound as an amorphous solid.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[Br:10]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>ClC(Cl)(Cl)Cl>[Br:10][CH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C#N)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(CBr)cc1

Procedure:
Bromo-4-methyl-benzene of general formula H-1, where B, R1, R2, R3 and R4 are as defined above is reacted with copper cyanide in a polar solvent as dimethylformamide at elevated temperature to obtain the 4-methyl-benzonitrile of general formula H-2. The 4-methyl-benzonitrile of general formula H-2 is brominated by the treatment with N-bromosuccinimide in refluxing tetrachloromethane in the presence of a radical initiator like AIBN to obtain the 4-Bromomethyl-benzonitrile of general formula H-3.
Reaction SMILES: CO[C:3](=[N:12][N+:13]([O-:15])=[O:14])[NH:4][CH2:5][C:6]1[S:10][C:9]([Cl:11])=[N:8][CH:7]=1.[CH3:16][NH2:17].Cl>O>[Cl:11][C:9]1[S:10][C:6]([CH2:5][NH:4][C:3]([NH:17][CH3:16])=[N:12][N+:13]([O-:15])=[O:14])=[CH:7][N:8]=1
Reactant: COC(=N[N+](=O)[O-])NCc1cnc(Cl)s1
Reactant: CN
Agent: Cl
Solvent: O
Product: CNC(=N[N+](=O)[O-])NCc1cnc(Cl)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.5 %

Procedure:
To a suspension of O-methyl-N-(2-chloro-5-thiazolylmethyl)-N'-nitroisourea (87% purity, 47.2 g, 0.164 mol) in water (410 ml) was added 40% aqueous solution of methylamine (25.5 g, 0.328 mol, 2.0 equivalents) dropwise at 23° C. After 2 hours of stirring at room temperature, the mixture was allowed to stand under ice-cooling and then, 36% hydrochloric acid (14.3 mol, 0.168 mol) was added dropwise at 13-20° C. The resulting crystals were collected by filtration to provide 39.1 g (95.6% yield) of 1-(2-chloro-5-thiazolylmethyl)-3-methyl-2-nitroguanidine.
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:7][NH:8][C:9]([C:11]1[N:18]2[C:14]([S:15][CH:16]=[CH:17]2)=[N:13][C:12]=1[CH3:19])=[O:10].[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[S:31][C:30]([CH3:32])=[N:29][C:28]=1[C:33](O)=[O:34]>>[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[S:31][C:30]([CH3:32])=[N:29][C:28]=1[C:33]([N:3]1[CH2:4][C@H:5]2[C@H:1]([CH2:6]2)[C@H:2]1[CH2:7][NH:8][C:9]([C:11]1[N:18]2[C:14]([S:15][CH:16]=[CH:17]2)=[N:13][C:12]=1[CH3:19])=[O:10])=[O:34]
Reactant: Cc1nc(C(=O)O)c(-c2ccccc2F)s1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2C[C@@H]21
Product: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)c(-c2ccccc2F)s1

Procedure:
prepared by reaction of 6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid [(1S,2S,5R)-1-(3-aza-bicyclo[3.1.0]hex-2-yl)methyl]-amide with 5-(2-Fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:2]1.Br[CH2:14][CH2:15][N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[O:26]=[C:17]1[C:18]2[C:19](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20](=[O:21])[N:16]1[CH2:15][CH2:14][N:1]1[CH:5]=[CH:4][C:3]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:2]1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: CC(C)(C)OC(=O)c1cc[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccn(CCN2C(=O)c3ccccc3C2=O)c1
Reaction time: 12 h
Yield: 12.6 %

Procedure:
To a solution of 2.62 g of tert-butyl 1H-pyrrole-3-carboxylate and 7.96 g of N-(2-bromoethyl)phthalimide in DMF (100 ml) was added 10.2 g of cesium carbonate at room temperature, followed by stirring for 12 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The extract was washed with saturated brine and then dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography using hexane/chloroform as an eluent solvent, and washed with diethyl ether to obtain 670 mg of tert-butyl 1-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-1H-pyrrole-3-carboxylate as a colorless solid.
Reaction SMILES: [N+:1]([C:4]1[C:9](F)=[CH:8][CH:7]=[CH:6][C:5]=1[NH:11][S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:14])=[O:13])([O-])=O.[C:21]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:31]2[CH2:30][CH2:29][N:28]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:33][CH2:32]2)=[CH:6][C:5]=1[NH:11][S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:14])=[O:13]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1c(F)cccc1NS(=O)(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N)c(NS(=O)(=O)c3ccccc3)c2)CC1
Temperature: 70 °C
Reaction time: 24 h
Yield: 29.5 %

Procedure:
A mixture of N-(2-nitro-3-fluorophenyl)-benzenesulfonamide (4.68 g, 15.7 mmol), Boc-piperazine (3.5 g, 18.9 mmol) and K2CO3 (3.8 g, 27.8 mmol) in DMF was stirred at 70° C. for 24 h. The mixture was filtered and purified by column chromatography (SiO2, CH2Cl2/MeOH/heptane/NH3 4:1:5:0.2%) to give 2.0 g of desired product. 1H-NMR δ 7.98 (d, 1H), 7.89-7.84 (m, 2H), 7.63-7.50 (m, 3H), 7.00 (d, 1H), 6.68 (dd, 1H), 3.59-3.45 (m, 8H), 1.49 (s, 9H); MS (posES-FIA) m/z=found: 485.0. (M++Na+). The product (1.85 g, 4.00 mmol) was dissolved in EtOH:THF (4:1) followed by addition of Raney-Ni and hydrazine (1.0 mL, 20 mmol). The reaction was stirred at room temperature for 3 h until the yellow color disappeared. Filtration through wet Celite, followed by removal of the solvent afforded 1.26 g of N-(2-amino-5-(4-tert-butoxycarbonyl-1-piperazinyl)-phenyl)-benzenesulfonamide which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([O-:13])=O)[S:10][C:3]=12.[Li+].[OH:15][C@@H:16]1[CH2:20][CH2:19][NH:18][CH2:17]1>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:18]3[CH2:19][CH2:20][C@@H:16]([OH:15])[CH2:17]3)=[O:13])[S:10][C:3]=12
Reactant: O=C([O-])c1cc2nccc(Cl)c2s1
Reactant: O[C@@H]1CCNC1
Agent: [Li+]
Product: O=C(c1cc2nccc(Cl)c2s1)N1CC[C@@H](O)C1
Yield: 36 %

Procedure:
This material was prepared by the coupling of lithium 7-chlorothieno[3,2-b]pyridine-2-carboxylate and (R)-3-hydroxypyrrolidine in a manner as previously described for example 2a to give 3.06 g (36%) of an off-white solid. 1H NMR (DMSO-d6): δ8.73 (1H, d, J=5.1 Hz), 8.15, 8.09 (1H, s), 7.69 (1H, d, J=5.1 Hz), 5.10-5.06 (1H, m), 4.43-4.29 (1H, m), 4.05-3.89 (2H, m), 3.72-3.43 (2H, m), 2.08-1.79 (2H, m).
Reaction SMILES: [Si]([O:18][CH2:19][C@@H:20]1[CH2:24][O:23][C@@H:22]([P:25]([O:30][CH2:31][CH3:32])([O:27][CH2:28][CH3:29])=[O:26])[S:21]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(O)(=O)C>O1CCCC1>[CH2:28]([O:27][P:25]([O:30][CH2:31][CH3:32])([C@H:22]1[S:21][C@H:20]([CH2:19][OH:18])[CH2:24][O:23]1)=[O:26])[CH3:29]
Reactant: CCOP(=O)(OCC)[C@@H]1OC[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)S1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)[C@@H]1OC[C@@H](CO)S1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 95.7 %

Procedure:
To a solution of cis and trans 4-(t-butyldiphenylsilyloxymethyl)-2-(diethyloxyphosphinoyl)-1,3-oxathiolane (example 42) (5.00 g, 10.07 mmol) in tetrahydrofurane (300 mL) was added tetrabutylammonium fluoride (15.0 mL, 15.0 mmol, 1.5 eq) at room temperature. The solution was stirred at room temperature for 45 min and acetic acid was added (850 μL) followed by evaporation under reduced pressure. The crude material was purified by flash chromatography with ethyl acetate to give the pure compound (2.47 g) in 96% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[OH:9])=[CH:4][CH:3]=1.[CH2:23]([O:25][C:26](=[O:39])[NH:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37]Br)=[CH:30][CH:29]=1)[CH3:24]>>[CH2:23]([O:25][C:26](=[O:39])[NH:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][N:13]2[CH2:12][CH2:11][CH:10]([C:8]([C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[OH:9])[CH2:15][CH2:14]2)=[CH:30][CH:29]=1)[CH3:24]
Reactant: CCOC(=O)Nc1ccc(OCCCBr)cc1
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCNCC1
Product: CCOC(=O)Nc1ccc(OCCCN2CCC(C(O)(c3ccc(F)cc3)c3ccc(F)cc3)CC2)cc1

Procedure:
Following the procedure of Example 1, [α,α-bis(p-fluorophenyl)]-4-piperidinemethanol and [4-(3-bromopropoxy)phenyl]carbamic acid ethyl ester are reacted to give the title compound.