Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[CH2:5][N:4]1[C:11](=[O:27])[C:12]([OH:26])=[C:13]([C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[O:16])[N:14]=[C:3]21.[CH2:28]([N:30]([CH2:36][CH3:37])[C:31](=[O:35])[C:32](O)=[O:33])[CH3:29].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C.CN(C)C1C=CN=CC=1>[CH2:28]([N:30]([CH2:36][CH3:37])[C:31](=[O:35])[C:32]([NH:1][C:2]12[CH2:8][CH2:7][CH:6]([CH2:9][CH2:10]1)[CH2:5][N:4]1[C:11](=[O:27])[C:12]([OH:26])=[C:13]([C:15](=[O:16])[NH:17][CH2:18][C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)[N:14]=[C:3]21)=[O:33])[CH3:29]
Reactant: NC12CCC(CC1)Cn1c2nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O
Reactant: CCN(CC)C(=O)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)C(=O)NC12CCC(CC1)Cn1c2nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.2 %

Procedure:
To a stirred solution of 10-amino-N-(4-fluorobenzyl)-3-hydroxy-4-oxo-4,6,7,8,9,10-hexahydro-7,10-ethanopyrimido[1,2-a]azepine-2-carboxamide (50 mg, 0.122 mmol) in DMF (3 mL) was added 2-(diethylamino)-2-oxoacetic acid (35.5 mg, 0.245 mmol), diisopropyl-ethylamine (0.128 mL, 0.734 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (93 mg, 0.245 mmol) and 4-(dimethylamino)pyridine (DMAP) (2.99 mg, 0.024 mmol) and the resulting mixture stirred at room temperature for 3 h. After work-up, the crude was then purified by prep HPLC to afford the title compound as a white solid (30 mg, 49% yield). 1H NMR (500 MHz, CDCl3) δ: 12.0 (1 H, brs), 8.7 (1 H, brs), 8.2 (1 H, s), 7.4 (2 H, dd, J=8.09, 5.65 Hz), 7.0 (2 H, t, J=8.55 Hz), 4.6 (2 H, d, J=6.41 Hz), 4.2 (2 H, d, J=3.66 Hz), 3.6 (2 H, q, J=6.82 Hz), 3.3 (2 H, q, J=7.02 Hz), 2.5-2.6 (3 H, m), 2.0-2.1 (2 H, m), 1.9-2.0 (2 H, m), 1.7-1.7 (2 H, m), 1.2 (3 H, t, J=7.02 Hz), 1.1 (3 H, t, J=7.02 Hz). LCMS (M+H)=500.45. HPLC purity: >95%.
Reaction SMILES: Br[Zn][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:9][C:10]1[C:11](=[O:18])[C:12]([CH3:17])=[CH:13][C:14](=[O:16])[CH:15]=1.Cl.C(OCC)(=O)C>C1COCC1>[OH:16][C:14]1([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH:13]=[C:12]([CH3:17])[C:11](=[O:18])[C:10]([CH3:9])=[CH:15]1
Reactant: CCOC(=O)C[Zn]Br
Reactant: CC1=CC(=O)C=C(C)C1=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CC1(O)C=C(C)C(=O)C(C)=C1
Yield: 80 %

Procedure:
Under nitrogen atmosphere, 6 mL of THF was added to 1.22 g (2 mmol, 0.6 equivalent) of (BrZnCH2COOEt.THF)2. Under argon atmosphere, a solution of 0.45 g (3.33 mmol) of 2,6-dimethyl-p-benzoquinone in 3 mL of THF was added dropwise while stirring at 0˜5° C. The mixture was stirred at 20˜25° C. for 1 hour. 5 mL of 1N hydrochloric acid was added dropwise at 20° C. or lower, followed by dilution with 25 mL of ethyl acetate. Then, the layers were separated. The organic layer was washed successively with 5 mL (×2) of 1N hydrochloric acid, 5 mL of water, 10 mL (×2) of an aqueous saturated sodium bicarbonate solution, and 5 mL (×2) of an aqueous saturated sodium chloride solution. After washing, the organic layer was dried with anhydrous magnesium sulfate. After concentration under reduced pressure, purification with silica gel column (developing solvent; ethyl acetate/n-hexane=1/3) afforded 0.60 g of the desired product (yield 80%).
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:10])[C:4]([O:6]C)=[O:5].[OH-].[Li+]>O1CCCC1.CO>[OH:1][CH2:2][CH:3]([NH:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:10])[C:4]([OH:6])=[O:5]
Reactant: COC(=O)C(CO)NC(=O)N1CCCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C(CO)NC(=O)N1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
200 mg (0.869 mmol) of methyl 3-hydroxy-2-[(1-piperidinylcarbonyl) amino]propionate was dissolved in 6 ml of a solvent mixture of methanol tetrahydrofuran (1:1). 1.04 ml (1.04 mmol) of 1 N aqueous lithium hydroxide solution was added to the obtained solution, and they were stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the concentrate was acidified with 1 N aqueous hydrochloric acid solution. After extracting with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain the title compound.
Reaction SMILES: C(OCCCC)(=O)C.C(N(CC)CC)C.[CH2:16]([C:20]1[N:24]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[C:38]#[N:39])=[CH:28][CH:27]=2)[C:23](=[O:40])[C:22]2([CH2:44][CH2:43][CH2:42][CH2:41]2)[N:21]=1)[CH2:17][CH2:18][CH3:19].[N-:45]=[N+:46]=[N-:47].[Na+]>C(O)(=O)C>[CH2:16]([C:20]1[N:24]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[C:38]3[NH:47][N:46]=[N:45][N:39]=3)=[CH:28][CH:27]=2)[C:23](=[O:40])[C:22]2([CH2:41][CH2:42][CH2:43][CH2:44]2)[N:21]=1)[CH2:17][CH2:18][CH3:19]
Reactant: CCCCC1=NC2(CCCC2)C(=O)N1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: CCCCOC(C)=O
Product: CCCCC1=NC2(CCCC2)C(=O)N1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 117.5 °C

Procedure:
A RB flask was charged with n-butyl Acetate (50 ml), triethyl amine (22 ml) and acetic acid (9 ml) and stirred. 2-(n-butyl)-3-[[2′-(cyano)biphenyl-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-one (10 g) and sodium Azide (3.4 g) was added to the flask and the reaction mixture was heated at 115-120° C. for 24 hrs, followed by cooling. The reaction was then quenched by addition of water (30 ml). The pH of the aqueous layer was adjusted between 10 to 11 with 30% Sodium hydroxide and then stirred for 10 min. Layers were separated and oily layer was treated with water and xylene. The pH of the aqueous layer was adjusted between 2 and 3 by the addition of hydrochloric acid and then stirred for 1 hour, filtered to obtain solid material which was washed with water (20 ml) and ethyl Acetate (5 ml) and dried at 90-100° C.
Reaction SMILES: [C:1]1([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:16])[CH3:15])=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[BH4-].[Na+]>CO.O>[OH:16][CH:14]([C:11]1[CH:12]=[CH:13][C:8]([C:1]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=2)=[CH:9][CH:10]=1)[CH3:15]
Reactant: CC(=O)c1ccc(C2=CCCCCC2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(O)c1ccc(C2=CCCCCC2)cc1
Reaction time: 16 h

Procedure:
A solution of 49 g of this ketone in 100 ml of methanol is stirred dropwise into a solution, cooled to 0° C, of 11 g of sodium borohydride in 500 ml of methanol and 100 ml of water. The reaction solution is stirred for another hour and a half at 5° to 10° C and then allowed to stand at room temperature for 16 hours. Finally, 600 ml of water are added and the batch is extracted with methylene chloride, dried over sodium sulfate and evaporated. In this manner, 1-hydroxy-1-[para-(1-cycloheptenyl)-phenyl]-ethane is obtained as an oily, colorless residue.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]1[CH:14]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:16](=[N:23]/[C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[CH2:26][O:27][C:28]2=[O:33])\[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[CH3:34][O-:35].[Na+].C(OCC)(=O)CC>>[CH2:1]([N:8]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]1[CH:14]1[C:34](=[O:35])[C:25]2[C:29]([C:28]([O:27][CH3:26])=[O:33])=[CH:30][CH:31]=[CH:32][C:24]=2[NH:23][CH:16]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[O-]
Reactant: Cc1cn(Cc2ccccc2)c(C=O)n1
Reactant: O=C1OCc2c(/N=C/c3ccccc3)cccc21
Agent: [Na+]
Solvent: CCOC(=O)CC
Product: COC(=O)c1cccc2c1C(=O)C(c1nc(C)cn1Cc1ccccc1)C(c1ccccc1)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.6 %

Procedure:
A mixture of 1-benzyl-4-methyl-1H-imidazole-2-carbaldehyde (450 mg, 2.25 mmol), (E)-4-(benzylideneamino)isobenzofuran-1(3H)-one (640 mg, 2.7 mmol), sodium methanolate (207 mg, 9 mmol) and ethyl propionate (25 mL) were stirred at room temperature overnight. Then the resulting mixture was evaporated under reduced pressure and extracted with ethyl acetate (4×100 mL) and concentrated to give methyl 3-(1-benzyl-4-methyl-1H-imidazol-2-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate (250 mg, yield 25%). LC-MS (ESI) m/z: 438 (M+1)+.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[C:14](=[O:19])[CH2:13]2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[CH2:9][CH:10]([N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[C:14](=[O:19])[CH2:13]2)[CH2:11]1
Reactant: CN1CCN(C2CN(C(=O)OC(C)(C)C)C2)CC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCN(C2CNC2)CC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.7 %

Procedure:
A mixture of 3-(4-methyl-3-oxopiperazin-1-yl)azetidine-1-carboxylic acid tert-butyl ester (211 mg, 0.78 mmol) and TFA (2 mL) in DCM (4 mL) was stirred at room temperature for 2 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH affording 4-Azetidin-3-yl-1-methylpiperazin-2-one as a white solid (125 mg, 95%). 1H NMR (CDCl3, 300 MHz): δ 3.63 (m, 4 H); 3.37-3.27 (m, 3 H); 3.03 (s, 2 H); 2.96 (s, 3 H); 2.58 (t, J=5.6 Hz, 2 H); 2.13-1.97 (m, 1 H).
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH:3]=[CH2:4].[C:6]([O:14][C@@H:15]1[C@@H:38]([O:39][C:40](=[O:47])[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C@H:37]([O:48][C:49](=[O:56])[C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C@@H:36]([CH2:57][O:58][C:59](=[O:66])[C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[O:35][C@H:16]1[O:17][C:18]1[C:22]([CH2:23][C:24]2[CH:29]=[CH:28][C:27](Br)=[CH:26][C:25]=2[CH3:31])=[C:21]([CH:32]([CH3:34])[CH3:33])[NH:20][N:19]=1)(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)C.C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:6]([O:14][C@@H:15]1[C@@H:38]([O:39][C:40](=[O:47])[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C@H:37]([O:48][C:49](=[O:56])[C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C@@H:36]([CH2:57][O:58][C:59](=[O:66])[C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[O:35][C@H:16]1[O:17][C:18]1[C:22]([CH2:23][C:24]2[CH:29]=[CH:28][C:27](/[CH:4]=[CH:3]/[CH2:2][CH2:1][OH:5])=[CH:26][C:25]=2[CH3:31])=[C:21]([CH:32]([CH3:34])[CH3:33])[NH:20][N:19]=1)(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Cc1cc(Br)ccc1Cc1c(O[C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H](OC(=O)c3ccccc3)[C@H]2OC(=O)c2ccccc2)n[nH]c1C(C)C
Reactant: C=CCCO
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(/C=C/CCO)ccc1Cc1c(O[C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H](OC(=O)c3ccccc3)[C@H]2OC(=O)c2ccccc2)n[nH]c1C(C)C
Temperature: 90 °C
Yield: 70.6 %

Procedure:
Add 3-buten-1-ol (0.58 mL, 6.8 mmol) to a solution of 4-(4-bromo-2-methylbenzyl)-5-(propan-2-yl)-1H-pyrazol-3-yl 2,3,4,6-tetra-O-benzoyl-beta-D-glucopyranoside (3 g, 3.4 mmol) in acetonitrile (30 mL) and triethylamine (20 mL). Degas the solution with nitrogen over 10 minutes. Add tri-o-tolylphosphine (205 mg, 0.67 mmol) and palladium acetate (76 mg, 0.34 mmol). Reflux at 90° C. for 2 hours. Cool to room temperature and concentrate to remove the solvent under the reduced pressure. Purify the residue by flash chromatography to yield the title compound (2.1 g, 2.4 mmol). MS (m/z): 878.4 (M+1).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:12]([NH:14][C@H:15]([C:25](ON1C(=O)CCC1=O)=[O:26])[CH2:16][CH2:17][C:18](=[O:24])[O:19]C(C)(C)C)=[O:13])[CH2:3][CH2:4][C:5](=[O:11])[O:6]C(C)(C)C.[NH2:42][C@H:43]([C:48]([OH:50])=[O:49])[C@H:44]([CH2:46][CH3:47])[CH3:45].[CH3:51][N:52]1[C@@H:69]2[CH2:70][C:57]3[CH:58]=[CH:59][C:60]([O:71][CH3:72])=[C:61]4[O:62][C@H:63]5[C:64]([CH2:66][CH2:67][C@@H:68]2[C@:55]5([C:56]=34)[CH2:54][CH2:53]1)=[O:65]>>[NH2:1][C@H:2]([C:12]([NH:14][C@H:15]([C:25]([NH:42][C@H:43]([C:48]([OH:50])=[O:49])[C@H:44]([CH2:46][CH3:47])[CH3:45])=[O:26])[CH2:16][CH2:17][C:18](=[O:19])[OH:24])=[O:13])[CH2:3][CH2:4][C:5](=[O:6])[OH:11].[CH3:51][N:52]1[C@@H:69]2[CH2:70][C:57]3[CH:58]=[CH:59][C:60]([O:71][CH3:72])=[C:61]4[O:62][C@H:63]5[C:64]([CH2:66][CH2:67][C@@H:68]2[C@:55]5([C:56]=34)[CH2:54][CH2:53]1)=[O:65]
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Reactant: CC[C@H](C)[C@H](N)C(=O)O
Agent: COc1ccc2c3c1O[C@H]1C(=O)CC[C@H]4[C@@H](C2)N(C)CC[C@]314
Product: CC[C@H](C)[C@H](NC(=O)[C@H](CCC(=O)O)NC(=O)[C@@H](N)CCC(=O)O)C(=O)O

Procedure:
Glu-Glu-Ile-Hydrocodone was prepared by a similar method to Example 9 except the amino acid starting material was Boc-Glu(OtBu)-Glu(OtBu)-OSu and the conjugate starting material was Ile-Hydrocodone.
Reaction SMILES: [CH:1]1([N:7]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])C(=O)CC)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([Mg]Cl)(CC)C.C(O[C@H:32]1[NH:35][C:34](=[O:36])[C@@H:33]1[C@H:37]([O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41])[CH3:38])(=O)C.[C:47](O)(=O)[CH2:48][C:49](CC(O)=O)(C(O)=O)[OH:50]>O1CCCC1.C(OCC)(=O)C>[Si:40]([O:39][C@@H:37]([C@@H:33]1[C@@H:32]([C@@H:48]([CH3:47])[C:49]([C:20]2[CH:19]=[C:18]([CH3:21])[CH:17]=[CH:16][C:15]=2[S:12]([NH:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)(=[O:13])=[O:14])=[O:50])[NH:35][C:34]1=[O:36])[CH3:38])([C:43]([CH3:44])([CH3:45])[CH3:46])([CH3:41])[CH3:42]
Reactant: CC(=O)O[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Reactant: CCC(=O)N(C1CCCCC1)S(=O)(=O)c1ccc(C)cc1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: CCC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)NC2CCCCC2)c(C(=O)[C@H](C)[C@H]2NC(=O)[C@@H]2[C@@H](C)O[Si](C)(C)C(C)(C)C)c1
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 63 %

Procedure:
Under a nitrogen atmosphere, 309 mg (1.0 mmol) of N-cyclohexyl-N-p-toluenesulfonylpropionamide was charged in a 30-ml three-necked flask to dissolve it in 2 ml of tetrahydrofuran. To the resulting solution, 2.2 ml (2.2 mmol) of a tetrahydrofuran solution (0.99M) of sec-butylmagnesium chloride was slowly added dropwise at room temperature. The resulting mixture was reacted for 25 minutes under the same conditions. After cooling to 5° C., 2 ml of a tetrahydrofuran solution of 287 mg (1.0 mmol) of (3R,4R)-4-acetoxy-3-[(R)-1-tert-butyldimethylsilyloxyethyl]azetidin-2-one was added at the same temperature. The resulting mixture was stirred for 10 minutes, added with 10 ml of ethyl acetate and then added dropwise with 2 ml of a 10% aqueous solution of citric acid. After separation, the organic layer was washed with 2 ml of a saturated aqueous solution of sodium bicarbonate and 2 ml of a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and distilled to remove the solvent. The residue was purified by column chromatography, whereby 339 mg of a condensation product was obtained (yield: 63%, β:α=92:8).
Reaction SMILES: C([C:8]1[S:12][C:11]([CH2:13][NH2:14])=[N:10][C:9]=1[C:15]([NH2:17])=O)(OC(C)(C)C)=O.C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O.O.C(Cl)[Cl:40]>>[ClH:40].[NH2:14][CH2:13][C:11]1[S:12][CH:8]=[C:9]([C:15]#[N:17])[N:10]=1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)c1sc(CN)nc1C(N)=O
Solvent: O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Product: Cl
Product: N#Cc1csc(CN)n1
Temperature: 22.5 °C
Reaction time: 1 h

Procedure:
Boc-2-aminomethylthiazole-4-carboxamide (75.0 g, 0.29 mol) was suspended in 524 ml of methylene chloride and, at from −5 to 0° C., admixed with triethylamine (78.9 g, 0.78 mol) and 79.5 g (0.38 mol) of trifluoroacetic anhydride. The mixture was stirred for another 1 h and then allowed to warm to 20-25° C., 1190 ml of water were added and the phases were separated. 160 ml of 5-6 N isopropanolic hydrochloric acid were added to the organic phase, the mixture was heated to the boil for 3 h, stirred at 20-25° C. overnight and cooled to from −5 to 0° C. for 2.5 h, and the solid was filtered off, washed with methylene chloride and dried. This gave 48.1 g of 2-aminomethyl-4-cyanothiazole of an HPLC purity of 99.4 area %, which corresponds to a yield over these two steps of 94.3%.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](C=O)=[N:2]1.NN1C=CC=C1.C(O)(=O)C>C(O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=Cc1n[nH]c2ccccc12
Agent: Nn1cccc1
Solvent: CCO
Solvent: CC(=O)O
Product: c1ccc2[nH]ncc2c1
Yield: 200.9 %

Procedure:
A solution of 6-pyridin-4-yl-1-(2-trimethylsilanyl)-ethoxymethyl)-1H-indazole-3-carbaldehyde (208 mg, 0.59 mmol), N-aminopyrrole (145 mg, 1.76 mmol), and acetic acid (5.8 μl) in ethanol (1 ml) was held at 95° C. for 16 h. The solution was then evaporated under reduced pressure, and purified by silica gel chromatography to give 1H-indazole as an oil (140 mg, 57%). 1H NMR (300 MHz, CDCl3) 9.08 (s, 1H), 8.71 (d, 2H, J=6.1 Hz), 8.46 (d, 1H, J=85 Hz), 834 (s, 1H), 7.85 (d, 2H, J=6.2 Hz), 7.80 (d, 1H, J=8.5 Hz), 7.56 (t, 2H, J=23 Hz), 6.25 (t, 2H, J=2.3 Hz), 5.93 (s, 1H), 5.74 (s, 2H), 3.64 (t, 2H, J=7.9 Hz), 0.86 (t, 2H, J=7.9 Hz), 0.00 (s, 9H).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[OH:8][CH2:9][CH2:10][SH:11].N1CCCCC1.C(NC(C)C)(C)C>>[O:5]=[C:4]1[CH:3]([CH2:2][C:1]([OH:6])=[O:7])[S:11][CH2:10][CH2:9][O:8]1
Reactant: O=C1C=CC(=O)O1
Reactant: OCCS
Solvent: C1CCNCC1
Solvent: CC(C)NC(C)C
Product: O=C(O)CC1SCCOC1=O

Procedure:
Analogously to Example 1, by reaction of maleic acid anhydride with 2-hydroxyethanethiol in the presence of piperidine (instead of diisopropylamine) and the usual working up, 2-oxo-1,4-oxathiane-3-acetic acid, m.p. = 96°-98° is obtained.
Reaction SMILES: C([O:5][C:6](=O)[NH:7][C:8]1[S:9][CH:10]=[C:11]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:12]=1[NH:13][C:14](OC(C)(C)C)=[O:15])(C)(C)C.O>C(O)(=O)C.C(OCC)(=O)C(OCC)=O>[C:21]1([C:11]2[C:12]3[NH:13][C:14](=[O:15])[C:6](=[O:5])[NH:7][C:8]=3[S:9][CH:10]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)Nc1scc(-c2ccccc2)c1NC(=O)OC(C)(C)C
Solvent: CC(=O)O
Solvent: CCOC(=O)C(=O)OCC
Solvent: O
Product: O=c1[nH]c2scc(-c3ccccc3)c2[nH]c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Di-t butyl-4-phenylthiophene-2,3-dicarbamate (0.9 g crude oil from the preceding step) was dissolved in a mixture of 7 ml of acetic acid and 7 ml of diethyl oxalate and heated to reflux for three hours. While still hot, 7 ml of water was added, and the mixture stirred overnight at room temperature to precipitate 0.27 g of crude title compound. Three crystallisations from acetic acid combined with charcoal (Norit SU 18) and one from ethanol/acetic acid (1:1) produced 65 mg of pure title compound, m.p.>300° C. 1H-NMR (DMSO-D6, δ): 7.1 (s, 1H), 7.4 (m, 5H), 11.5 (br.s, 1H), 12.5 (br.s, 1H). MS: 244.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH:7]2[CH2:16][C:15](=O)[C:10]3[C:11](C)=[CH:12][O:13][C:9]=3[CH2:8]2)=[CH:4][CH:3]=1.[C:18]([NH:21][NH2:22])([NH2:20])=[NH:19].[ClH:23].Cl.[CH2:25](O)C>>[ClH:23].[NH:21](/[N:22]=[C:15]1\[CH:16]([CH3:25])[CH:7]([C:5]2[S:6][C:2]([CH3:1])=[CH:3][CH:4]=2)[CH2:8][C:9]2[O:13][CH:12]=[CH:11][C:10]\1=2)[C:18]([NH2:20])=[NH:19]
Reactant: Cc1ccc(C2CC(=O)c3c(C)coc3C2)s1
Reactant: CCO
Reactant: N=C(N)NN
Agent: Cl
Product: Cc1ccc(C2Cc3occc3/C(=N/NC(=N)N)C2C)s1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a mixture of 6-(5-methyl-2-thienyl)-3-methyl-4,5,6,7-tetrahydrobenzofuran-4-one (0.18 g) and aminoguanidine hydrochloride (81 mg) were added ethanol (15 ml) and 6N hydrochloric acid (0.063 ml), and the mixture was stirred at 90° C. for 2 hours and cooled. The reaction solution was concentrated under reduced pressure, and the residue was washed with ethanol, ethyl acetate and isopropylether, and dried to give (E)-4-guanidinoimino-6-(5-methyl-2-thienyl)-5-methyl-4,5,6,7-tetrahydrobenzofuran hydrochloride (Compound 49) (0.18 g).
Reaction SMILES: [N:1]([CH2:4][C:5]([NH:7][C@H:8]1[C@@H:14]([OH:15])[C@H:13]([OH:16])[C@@H:12]([CH2:17][OH:18])[O:11][CH:9]1[OH:10])=[O:6])=[N+:2]=[N-:3].C(O[C:23](=[O:25])[CH3:24])(=O)C>N1C=CC=CC=1.CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:5]([O:10][CH:9]1[O:11][C@H:12]([CH2:17][O:18][C:23](=[O:25])[CH3:24])[C@@H:13]([O:16][C:12](=[O:11])[CH3:13])[C@H:14]([O:15][C:9](=[O:10])[CH3:8])[C@@H:8]1[NH:7][C:5](=[O:6])[CH2:4][N:1]=[N+:2]=[N-:3])(=[O:6])[CH3:4]
Reactant: CC(=O)OC(C)=O
Reactant: [N-]=[N+]=NCC(=O)N[C@@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OC[C@H]1OC(OC(C)=O)[C@@H](NC(=O)CN=[N+]=[N-])[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 190.8 %

Procedure:
A solution of 20 (25 mg, 0.095 mmol) in pyridine (2 mL) was cooled to 0° C. To this solution was added acetic anhydride (1.0 mL, 11 mmol) and a catalytic amount of DMAP. The reaction mixture was stirred overnight and allowed to warm to rt. The resulting light yellow solution was diluted with CH2Cl2 (100 mL) and washed with 1 N HCl (3×50 mL), sat. NaHCO3 (1×50 mL), water (1×50 mL) and sat. NaCl (1×50 mL). The combined aqueous layers were back extracted with 50 mL of CH2Cl2. The combined organic layers were dried over Na2SO4 and concentrated. The crude product was purified by silica gel chromatography eluting with a gradient of 1:10 to 1:2 EtOAc/hexanes to afford 39 mg (95%) of a light yellow oil. IR (thin film): 3317, 2106, 1744, 1677, 1529 cm−1. 1H NMR (500 MHz, CDCl3): δ 2.05 (app s, 6H), 2.10 (s, 3H), 2.12 (s, 3H), 3.82 (ddd, 1H, J=2.4, 4.5, 9.6), 3.93 (s, 2H), 4.13 (dd, 1H, J=2.4, 12.6), 4.29 (dd, 1H, J=4.5, 12.6), 5.15 (app t, 1H, J=9.6), 5.21 (app t, 1H, J=5.7), 5.78 (app t, 1H, J=4.5), 6.37 (d, 1H, J=5.7). 13C NMR (125 MHz, CDCl3): δ 20.5, 20.5, 20.6, 20.6, 20.6, 20.8, 20.8, 51.2, 52.4, 52.5, 53.2, 61.4, 61.5, 67.4, 67.6, 69.8, 70.3, 72.0, 72.1, 72.9, 90.2, 92.1, 166.9, 168.6, 169.1, 169.2, 170.6, 170.8, 171.5. HRMS (FAB) m/z 437.1496 (MLi+ C16H22LiN4O10 requires 437.1496).
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1.C([Li])CCC.[CH3:14][N:15]([C:25]1[CH:30]=[CH:29][C:28]([C:31](=[O:36])[C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=1)[S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:18])=[O:17]>C1COCC1>[CH3:14][N:15]([C:25]1[CH:30]=[CH:29][C:28]([C:31]([OH:36])([C:5]2[N:4]([CH2:3][O:2][CH3:1])[CH:8]=[CH:7][N:6]=2)[C:32]([F:34])([F:35])[F:33])=[CH:27][CH:26]=1)[S:16]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)(=[O:18])=[O:17]
Reactant: COCn1ccnc1
Reactant: CN(c1ccc(C(=O)C(F)(F)F)cc1)S(=O)(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCn1ccnc1C(O)(c1ccc(N(C)S(=O)(=O)c2ccccc2)cc1)C(F)(F)F
Reaction time: 14 h

Procedure:
To a solution of 55 mg (0.49 mmol) of 1-methoxymethyl-1H-imidazole in 5 ml of THF at −78° C. was added 0.20 ml (0.50 mmol) of a 2.5 M solution of n-butyllithium in hexanes and the resultant mixture was stirred at −78° C. for 30 mins. After this time, a solution of 160 mg (0.47 mmol) of N-methyl-N-(4-trifluoroacetyl-phenyl)benzenesulfonamide (Example 22, Step A) in 2 ml of THF was added and the resultant mixture stirred at −78° C. for a further 2 h, and then at room temperature for 14 h. After this time the reaction was quenched by the addition of a saturated aqueous solution of ammonium chloride and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography on silica gel (hexanes:EtOAc, 4:1) to give the title compound. 1H-NMR (CDCl3) δ 3.09 (s, 3H), 3.19 (s, 3H), 4.90 (s, 2H), 5.16 (brs, 1H), 7.07-7.16 (m, 4H), 7.42-7.62 (m, 7H). Mass Spectrum (CI+) m/e=456.1 (M+1).