Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH:12]1[S:18][CH2:17][CH2:16][NH:15][C:14]2[N:19]([CH3:28])[N:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[C:13]1=2)[C:5]([O:7]C)=O.[C-]#[N:30].[K+].N>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH:12]1[S:18][CH2:17][CH2:16][NH:15][C:14]2[N:19]([CH3:28])[N:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[C:13]1=2)[C:5]([NH2:30])=[O:7]
Reactant: [C-]#N
Reactant: COC(=O)c1ccc(C2SCCNc3c2c(-c2ccccn2)nn3C)c(Cl)c1
Agent: N
Agent: [K+]
Solvent: CO
Product: Cn1nc(-c2ccccn2)c2c1NCCSC2c1ccc(C(N)=O)cc1Cl
Temperature: 110 °C

Procedure:
A mixture of methyl 3-chloro-4-[1-methyl-3-(2-pyridyl)-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepin-4-yl]benzoate (0.14 g, 0.32 mmol, Example #E.1), methanol (15 mL), potassium cyanide (0.02 g, 0.3 mmol), and ammonia (10 mL, 7 M in MeOH, 70 mmol) was heated, in a sealed flask, for about 18 h at about 110° C. After cooling to rt the mixture was concentrated in vacuo. The residue was dissolved in DCM (100 mL) and washed with water (2×40 mL). The organic layer was dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by prep-HPLC (Table 2, Method a,) to give 3-chloro-4-[1-methyl-3-(2-pyridyl)-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepin-4-yl]benzamide as an off white solid (0.018 g, 0.05 mmol, 16%): LC-MS (Table 1, Method b) Rt=4.5 min; m/z 400 (M+H)+; 1H-NMR (CDCl3, Bruker 400 MHz) δ 2.63-2.72 (1H, m) 2.75-2.86 (1H, m) 3.18-3.28 (1H, m) 3.75-3.75 (1H, m) 3.83 (3H, s) 4.78 (1H, br.d, J=5.5 Hz) 6.23 (1H, br. s) 6.91 (1H, s) 7.08 (1H, ddd, J=8.0, 5.0, 1.0 Hz) 7.32-7.49 (2H, m) 7.56-7.65 (2H, m) 7.77 (1H, d, J=8.5 Hz) 7.94 (1H, d, J=1.5 Hz) 8.46-8.51 (1H, m).
Reaction SMILES: Br[CH:2]([CH3:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[CH3:12][C:13]1[C:14]2[N:15]([N:19]=[C:20]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH2:28])[CH:23]=3)[N:21]=2)[CH:16]=[CH:17][N:18]=1.C(N(CC)C(C)C)(C)C>C(O)C>[CH3:12][C:13]1[C:14]2[N:15]([N:19]=[C:20]([C:22]3[CH:27]=[CH:26][N:25]4[C:2]([CH3:11])=[C:3]([C:5]5[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=5)[N:28]=[C:24]4[CH:23]=3)[N:21]=2)[CH:16]=[CH:17][N:18]=1
Reactant: CC(Br)C(=O)c1ccccc1
Reactant: Cc1nccn2nc(-c3ccnc(N)c3)nc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1nccn2nc(-c3ccn4c(C)c(-c5ccccc5)nc4c3)nc12
Temperature: 80 °C
Yield: 18 %

Procedure:
2-Bromopropiophenone (0.034 ml, 0.221 mmol) was added to a solution of 4-(8-methyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)pyridin-2-amine (0.025 g, 0.111 mmol) in Ethanol (2.2 ml) and the mixture was heated at 80° C. for 40 hours. LC/MS analysis of the reaction mixture indicates reaction approximately 40% complete. The reaction mixture was transferred to a microwave reaction tube and N,N-diisopropylethylamine (0.059 ml, 0.332 mmol) was added. The reaction mixture was heated at 110° C. under standard microwave conditions for 2 hours. LC/MS analysis indicates reaction completion. The reaction mixture was concentrated in vacuo. The crude product was purified by flash chromatography (silica gel; 30-100% EtOAc/hexanes) to afford a tan solid (0.007 g, 0.020 mmol, 18.05% yield). 1H NMR (400 MHz, METHANOL-d4) δ 8.76 (d, J=4.5 Hz, 1H), 8.51 (s, 1H), 8.42 (d, J=6.5 Hz, 1H), 8.08 (d, J=4.5 Hz, 1H), 7.90 (dd, J=7.2, 1.6 Hz, 1H), 7.82-7.75 (m, 2H), 7.52 (t, J=7.5 Hz, 2H), 7.42 (s, 1H), 2.97 (s, 3H), 2.73 (s, 3H), LC/MS: (Method 2) Anal. Calcd. for [M+H]+C20H17N6: 341.15. Found: 341.07.
Reaction SMILES: [N:1]1([C:6]2[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][OH:24])=[CH:19][CH:18]=1.ON1C2C=CC=CC=2N=N1.C(Cl)CCl>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[OH:24][CH2:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][NH:15][C:10](=[O:12])[C:9]2[CH:8]=[CH:7][C:6]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[CH:14][CH:13]=2)=[CH:18][CH:19]=1
Reactant: O=C(O)c1ccc(N2CCCC2)cc1
Reactant: NCc1ccc(CO)cc1
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: c1ccncc1
Solvent: ClCCCl
Product: O=C(NCc1ccc(CO)cc1)c1ccc(N2CCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.5 %

Procedure:
To a mixture of 4-pyrrolidin-1-ylbenzoic acid (2.0 g, 10.5 mmol), (4-aminomethylphenyl)methanol (4.3 g, 31.4 mmol), 1-hydroxybenzotriazole (1.7 g, 12.6 mmol), and DMAP (256 mg, 2.1 mmol) in pyridine (50 mL) was added EDC (3.0 g, 15.7 mmol), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and an aqueous NaHCO3 solution (50 mL) was added. The mixture was extracted with 5% MeOH in CHCl3 (150 mL×2), and the organic layer was dried (MgSO4) and evaporated under reduced pressure. The crude product was purified by MPLC on silica gel (3% MeOH in CHCl3) to afford the titled compound (2.56 g, 79%) as a white solid.
Reaction SMILES: [CH2:1]([O:11][CH2:12][CH:13](Cl)[C:14]([OH:16])=[O:15])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH3:10].[NH3:18]>>[CH2:1]([O:11][CH2:12][CH:13]([NH2:18])[C:14]([OH:16])=[O:15])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH3:10]
Reactant: N
Reactant: COCCOCCOCCOCC(Cl)C(=O)O
Product: COCCOCCOCCOCC(N)C(=O)O
Yield: 70 %

Procedure:
This product is obtained with a melting point of 184°-185° and a yield of 70% by treatment of 3-(3,6,9-trioxadecyloxy)-2-chloropropionic acid (Ex. 11A) with 25% ammonia (1 mol/3.5 mol) at 115° C. for two hours and removal of the salts by passage through an ion exchange resin column.
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]([C:13]([O:15][CH3:16])=[O:14])=[C:7]([C:9]([O:11][CH3:12])=[O:10])[N:8]=1)[CH2:2][CH3:3].[Br:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:12][O:11][C:9]([C:7]1[N:8]=[C:4]([CH2:1][CH2:2][CH3:3])[N:5]([CH2:22][C:21]2[CH:24]=[CH:25][C:18]([Br:17])=[CH:19][CH:20]=2)[C:6]=1[C:13]([O:15][CH3:16])=[O:14])=[O:10]
Reactant: BrCc1ccc(Br)cc1
Reactant: CCCc1nc(C(=O)OC)c(C(=O)OC)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1nc(C(=O)OC)c(C(=O)OC)n1Cc1ccc(Br)cc1
Yield: 88.3 %

Procedure:
A solution of 40.0 g (0.177 mole) of 2-propyl-4,5-bis(methoxycarbonyl)-imidazole and 44.6 g (0.178 mole) of 4-bromobenzyl bromide in 350 mL of DMF was stirred in the presence of 37.5 g (0.271 mole) of K2CO3 overnight at room temperature. The reaction mixture was then poured into 1200 mL of water and extracted with 3×300 mL of ether. The combined ether extracts were washed with 8×1000 mL of water and once with brine, then dried over MgSO4. The solvent was removed under reduced pressure to yield 61.8 g (88%) of the title compound as a solid. 1H NMR (300 MHz, CDCl3): δ 0.94 (t, J=7.6 Hz, 3H); 1.73 (m, 2H); 2.63 (t, J=7.9 Hz, 2H); 3.81 (s, 3H); 3.93 (s, 3H); 5.37 (s, 2H); 6.86 (d, J=8.8 Hz, 2H); 7.45 (d, J=8.8 Hz, 2H). MS [DCI (NH3)]: m/z 395/397 (M+H, 1 Br).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:10]([O:14][CH3:15])(=[O:13])[CH:11]=[CH2:12].C1CCN2C(=NCCC2)CC1>CC#N>[N:1]1([CH2:12][CH2:11][C:10]([O:14][CH3:15])=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: C=CC(=O)OC
Reactant: c1ccc2[nH]ccc2c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COC(=O)CCn1ccc2ccccc21
Temperature: 50 °C
Yield: 43.3 %

Procedure:
To the solution of indole (1.20 g, 10.24 mmol) and methyl acrylate (1.384 mL, 15.37 mmol) in MeCN (20 mL) was added DBU (0.772 mL, 5.12 mmol). The mixture was heated at 50° C. overnight. Purification via flash chromatography then afforded the title compound (1.0 g, 4.43 mmol, 90% purity, 43.2% yield). LCMS: rt=3.04 min, [M+H+]=204
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:26])([CH3:25])[CH:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[C:12]([OH:14])=[O:13])(=[O:7])=[O:6].C(Cl)(=O)C(Cl)=O.[CH2:33](O)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.N1C=CC=CC=1>ClCCl>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:26])([CH3:25])[CH:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[C:12]([O:14][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:13])(=[O:7])=[O:6]
Reactant: COc1ccc(COC(C(=O)O)C(C)(C)COS(=O)(=O)CCCCl)cc1
Reactant: OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(COC(C(=O)OCc2ccccc2)C(C)(C)COS(=O)(=O)CCCCl)cc1
Yield: 38.4 %

Procedure:
Following the general procedure for the preparation of carboxylic esters from carboxylic acids of Description 15, (2R/S)-4-[(3-chloropropyl)sulfonyloxy]-2-[(4-methoxyphenyl)methoxy]-3,3-dimethylbutanoic acid (14) (0.50 g, 1.2 mmol) dissolved in 5 mL of anhydrous dichloromethane (DCM) was reacted with 0.14 mL (0.2 g, 1.5 mmol) of oxalyl chloride. After completion of the reaction, a solution of 0.34 mL of benzyl alcohol (0.25 mL, 0.26 g, 2.4 mmol) and 0.26 mL of pyridine (0.15 g, 1.9 mmol) in dichloromethane (DCM) was added to the acid chloride. After work-up, the crude material was purified by silica gel column chromatography using a mixture of ethyl acetate (EtOAc) and hexane (Hxn) as eluent (EtOAc/Hxn=1:2) to provide 0.23 g (38% yield) of the title compound (32a) as a colorless oil. The analytical data was consistent with the proposed structure and with the data obtained for the enantiopure compound (31a).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:11]=[C:10]([CH3:20])[C:9]=2/[CH:21]=[CH:22]/[CH:23]([OH:32])[CH2:24][C:25](=[O:31])[CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:4][CH:3]=1.C(B(CC)CC)C.[BH4-].[Na+].CO>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:11]=[C:10]([CH3:20])[C:9]=2[CH:21]=[CH:22][CH:23]([OH:32])[CH2:24][CH:25]([OH:31])[CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:6][CH:7]=1
Reactant: COC(=O)CC(=O)CC(O)/C=C/c1c(-c2ccc(F)cc2)cc(-c2ccccc2)nc1C
Agent: CCB(CC)CC
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)CC(O)CC(O)C=Cc1c(-c2ccc(F)cc2)cc(-c2ccccc2)nc1C
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 79.9 %

Procedure:
A solution of (E)-7-[4-(4-fluorophenyl)-2-methyl-6-phenyl-3-pyridinyl]-5-hydroxy-3-oxo-6-heptenoic acid, methyl ester (235 mg, 0.54 mmol) in THF (8 ml) was treated with triethylborane (1.0M in THF, 1.13 ml, 1.13 mmol). Twenty milliliters of air was bubbled through the solution and the mixture was stirred at room temperature for 25 minutes. The solution was cooled to -78° C. and treated with NaBH4 (20.7 mg, 0.55 mmol) followed by dropwise addition of dry methanol (1.25 ml). After stirring at -78° C. for 1.5 hours, the mixture was quenched with 30% H2O2 (3.5 ml) in H2O (8 ml). The mixture was kept at -78° C. for 15 minutes, then warmed to room temperature and stirred for 30 minutes. The solution was poured into 50% saturated NaHCO3 and extracted with Et 2 O (3×). The combined Et2O extracts were washed with H2O, saturated NaHCO3 and brine, then dried (Na2SO4), filtered and stripped. Purification of the resulting oil (Flash, Merck SiO2, 70% EtOAc/30% hexane) gave (3R*, 5S*, 6E)-7-[4-(4-fluorophenyl)-2-methyl-6-phenyl-3-pyridinyl]-3,5-dihydroxy-6-heptenoic acid, methyl ester (188 mg, 80%) as a colorless oily foam.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:10](Cl)(=[O:14])[C:11]([Cl:13])=[O:12]>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10](=[O:14])[C:11]([Cl:13])=[O:12])=[CH:2]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: O=C(Cl)C(=O)Cl
Product: O=C(Cl)C(=O)c1c[nH]c2ccccc12

Procedure:
reacting indole with oxalyl chloride to give 3-indoleglyoxylyl chloride;
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([NH:15][NH2:16])=[O:14].[N:17]1[C:21]2[CH:22]=[CH:23][C:24]([C:26](O)=O)=[CH:25][C:20]=2[NH:19][CH:18]=1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[O:14][C:26]([C:24]2[CH:23]=[CH:22][C:21]3[NH:17][CH:18]=[N:19][C:20]=3[CH:25]=2)=[N:16][N:15]=1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NN
Reactant: O=C(O)c1ccc2nc[nH]c2c1
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc3[nH]cnc3c2)o1
Yield: 5 %

Procedure:
As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (400 mg, 1.84 mmol) was converted using benzimidazole-5-carboxylic acid instead of o-toluic acid to the title compound (SiO2, heptane:ethyl acetate:dichloromethane:methanol=70:20:10:0 to 0:80:10:10, 33 mg, 5%) which was obtained as an off-white solid. MS: m/e=344.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C@H:5]([CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)[NH2:6])[CH3:2].[CH3:18][N:19]([CH3:28])[C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1>>[CH3:18][N:19]([CH3:28])[C:20]1[CH:27]=[CH:26][C:23]([CH:24]2[C:9]3[NH:10][C:11]4[C:16]([C:8]=3[CH2:7][CH:5]([C:4]([O:3][CH2:1][CH3:2])=[O:17])[NH:6]2)=[CH:15][CH:14]=[CH:13][CH:12]=4)=[CH:22][CH:21]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: CCOC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Product: CCOC(=O)C1Cc2c([nH]c3ccccc23)C(c2ccc(N(C)C)cc2)N1

Procedure:
The same method but starting from racemic tryptophan ethyl ester and 4-dimethylaminobenzaldehyde gave the title compound as white crystals m.p. 170° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9](=[O:11])[CH3:10])=[C:4]([CH3:12])[CH:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].I[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C.[Cu]I>[CH3:12][C:4]1[CH:3]=[C:2]([NH:1][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:7]=[C:6]([CH3:8])[C:5]=1[C:9](=[O:11])[CH3:10]
Reactant: Ic1ccccc1
Reactant: CC(=O)c1c(C)cc(N)cc1C
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1c(C)cc(Nc2ccccc2)cc1C
Temperature: 110 °C

Procedure:
To a solution of 1-(4-amino-2,6-dimethylphenyl)ethanone (3.26 g, 20.0 mmol), K3PO4 (9.2 g, 40 mmol), and 1-iodobenzene (4.08 g, 20.0 mmol) in DMF (35.0 mL) was added CuI (761.8 mg, 40 mmol). The reaction was heated at 110° C. overnight under N2. The solution was cooled to room temperature and filtered through a small pad of diatomaceous earth. The cake was washed with ethyl acetate (50 mL) and the combined filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give 1-(2,6-dimethyl-4-(phenylamino)phenyl)ethanone as red-brown syrup: 1H NMR (500 MHz, CDCl3) δ 7.30 (d, J=8.2 Hz, 2 H), 7.10 (d, J=7.7 Hz, 2 H), 6.99 (d, J=4.2 Hz, 1 H), 6.71 (s, 1 H), 2.47 (s, 3 H), 2.18 (s, 6 H); ESI-MS: m/z 239.5 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]([O:20][CH2:21][CH2:22]Br)([C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:24][C:25]1([CH3:33])[CH2:31][C:30](=[O:32])[NH:29][C:27](=[O:28])[CH2:26]1.[Na]>>[CH3:24][C:25]1([CH3:33])[CH2:31][C:30](=[O:32])[N:29]([CH2:2][CH2:3][O:4][C:5]([O:20][CH2:21][CH2:22][N:29]2[C:30](=[O:32])[CH2:31][C:25]([CH3:33])([CH3:24])[CH2:26][C:27]2=[O:28])([C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:27](=[O:28])[CH2:26]1
Reactant: CC1(C)CC(=O)NC(=O)C1
Reactant: O=C(c1ccccc1)C(OCCBr)(OCCBr)c1ccccc1
Agent: [Na]
Product: CC1(C)CC(=O)N(CCOC(OCCN2C(=O)CC(C)(C)CC2=O)(C(=O)c2ccccc2)c2ccccc2)C(=O)C1
Yield: 97.8 %

Procedure:
When 13.26 g of benzil-di-(β-bromoethyl)ketal and 10.63 g of sodium 3,3-dimethylglutarimide were reacted and worked up in the same way as in Example 4, 16.5 g (yield 95.8%) of benzil-di-(3,3-dimethyl glutarimidoethyl)ketal was obtained. Recrystallization from ethanol afforded crystals having a melting point of 130° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([N:22]3[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]3)=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[ClH:35]>C1COCC1.C(OCC)C>[ClH:35].[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)c3ccccc23)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)Nc2ccc(N3CCNCC3)c3ccccc23)cc1

Procedure:
1-tert-Butyl 4-(4-{[(4-methylphenyl)sulfonyl]amino}-1-naphthyl)-1-piperazinecarboxylate (intermediate 10) (0.4 g, 0.8 mmol) was dissolved in THF (20 mL) and treated with a 1N solution of HCl in diethyl ether (30 mL) for twelve hours. The product was collected as a pale pink solid. Yield 0.2 g (60%). mp 181° C. (dec); 1H NMR (DMSO-d6) δ 2.80 (s, 3H), 3.1 (br, 4H), 3.3 (br, 4H), 7.00 (q, J=8.06 Hz, 2H), 7.27 (ab, J=8.30 Hz, 2 H), 7.4-7.5 (m, 2H), 7.53 (ab, J=8.30 Hz, 2H), 7.99 (d, J=8.06 Hz, 1H), 8.07 (d, J=7.57 Hz, 1H), 9.2 (br, 2H); MS (ESI+) for C21 H23 N3 O2 S Found m/z 381.1499. M+ Calc. 381.1611.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O.[F:18][C:19]([F:27])([F:26])[C:20](=[O:25])[CH2:21][C:22](=O)[CH3:23]>C(O)(=O)C.S(=O)(=O)(O)O>[F:18][C:19]([F:27])([F:26])[C:20]([C:21]1[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:3]2[C:4]3[CH2:9][CH2:8][CH2:7][C:5]=3[S:6][C:2]2=[N:1][C:22]=1[CH3:23])=[O:25]
Reactant: CC(=O)CC(=O)C(F)(F)F
Reactant: Nc1sc2c(c1C(=O)c1ccccc1)CCC2
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1nc2sc3c(c2c(-c2ccccc2)c1C(=O)C(F)(F)F)CCC3
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 27.7 %

Procedure:
To a stirred solution of 50 mg (0.20 mmol) (2-amino-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)-phenyl-methanone (the preparation of which is described in example 2) in 2 ml acetic acid was added 0.026 ml (0.20 mmol) of 1,1,1-trifluoro-pentane-2,4-dione and one drop of sulfuric acid. The mixture was then stirred at 100° C. for 10 minutes in a microwave and then concentrated in vacuo. Flash chromatography (heptane/ethyl acetate 20:1) afforded 20 mg (27%) 2,2,2-trifluoro-1-(2-methyl-4-phenyl-6,7-dihydro-5H-cyclopenta[4,5]thieno [2,3-b]pyridin-3-yl)-ethanone as an orange oil. ES-MS m/e (%): 362 (M+H+, 100).
Reaction SMILES: [NH2:1][C@H:2]([CH2:5][CH2:6][CH2:7][CH3:8])[CH2:3][OH:4].[C:9]([N:13]=[C:14]=[S:15])([CH3:12])([CH3:11])[CH3:10]>C(O)C>[C:9]([NH:13][C:14]([NH:1][C@H:2]([CH2:5][CH2:6][CH2:7][CH3:8])[CH2:3][OH:4])=[S:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: CCCC[C@@H](N)CO
Reactant: CC(C)(C)N=C=S
Solvent: CCO
Product: CCCC[C@H](CO)NC(=S)NC(C)(C)C
Temperature: 20 °C
Reaction time: 18 h

Procedure:
The process is performed as in Example 2, starting with 1.14 g of (2R)-2-amino-2-butyl-1-ethanol and 1.36 cm3 of tert-butyl isothiocyanate in 15 cm3 of ethanol, with stirring for 18 hours at a temperature in the region of 20° C. and then for 3 hours in the region of 60° C. After concentration of the reaction medium under reduced pressure (5 kPa) at a temperature in the region of 40° C. 2.38 g of N-(tert-butyl)-N′-[(1R)-1-butyl-2-hydroxyethyl]thiourea are obtained in the form of a yellow oil. Infrared spectrum (CH2Cl2): 3620; 4430; 4410; 2960; 1560; 1500; 1395; 1375 and 1205 cm−.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9]1(=[O:15])[O:14][C:12](=[O:13])[CH:11]=[CH:10]1>>[CH:1]([C:10]1=[CH:11][C:12]([O:14][C:9]1=[O:15])=[O:13])=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=Cc1ccccc1
Reactant: O=C1C=CC(=O)O1
Product: O=C1C=C(C=Cc2ccccc2)C(=O)O1

Procedure:
U.S. Pat. No. 4,145,375 teaches a process for copolymerizing styrene and maleic anhydride by the steps of gradually mixing maleic anhydride with styrene in a mass stage under polymerizing conditions to form styrene-maleic anhydride polymer and then suspending the styrene-rich mixture in water, the styrene polymerization is completed as in a conventional mass/suspension polymerization system. Following polymerization, polymeric beads are separated from the water and dried. The disclosure indicates that after drying, the beads are likely to contain internal moisture and in addition approximately 15% of the bound maleic anhydride may be present in the acid rather than anhydride form, and, consequently, during extrusion, the acid portion reverts to the anhydride with the elimination of water. The disclosure indicates that a well-vented extruder is needed to produce a bubble-free extrudate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=1)[C:24]([NH:26][NH2:27])=[O:25]>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:27][NH:26][C:24](=[O:25])[C:23]1[CH:28]=[CH:29][CH:30]=[C:21]([O:20][CH3:19])[CH:22]=1)=[O:14]
Reactant: COc1cccc(C(=O)NN)c1
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Product: COc1cccc(C(=O)NNC(=O)c2ccncc2Nc2ccc(I)cc2F)c1

Procedure:
3-[(2-fluoro-4-iodophenyl)amino]-N′-(3-methoxybenzoyl)isonicotinohydrazide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.4 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 0.55 mmol of 3-methoxy-benzohydrazide. LC/MS [9.23 min; 507 (M+1)]
Reaction SMILES: [C:1]([CH2:7][C:8]#[N:9])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Br:10]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:10][CH:7]([C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])[C:8]#[N:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)C(=O)CC#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)C(=O)C(Br)C#N
Yield: 87.7 %

Procedure:
Pivaloylacetonitrile (1.00 g, 7.99 mmol) was dissolved in carbon tetrachloride (15 mL). N-Bromosuccinimide (1.42 g, 7.99 mmol) was added, and the mixture was refluxed for 15 minutes. After cooling, the insoluble matter was filtered off, and the residue obtained by evaporation of the filtrate under reduced pressure was purified by chromatography on silica gel (n-hexane:ethyl acetate=4:1) to give the title compound (1.43 g, 87.9%) as an yellowish brown oil.
Reaction SMILES: [NH:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:9]2[N:8]=[CH:7][NH:6][C:5]=2[C:4](=[O:16])[NH:3]1.[NH2:17]N>O>[NH2:17][N:3]1[C:4](=[O:16])[C:5]2[NH:6][CH:7]=[N:8][C:9]=2[N:10]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:2]1=[NH:1]
Reactant: CCCCCn1c(=N)[nH]c(=O)c2[nH]cnc21
Reactant: NN
Solvent: O
Product: CCCCCn1c(=N)n(N)c(=O)c2[nH]cnc21

Procedure:
A solution of 2-imino-3-pentyl-1,2,3,7-tetrahydro-6h-purin-6-one (750 mg, 3.39 mmol) and 18 m of hydrazine in water (30 ml) was stirred at 150° C. for 30 min on a microwave reactor. The reaction was diluted with water and extracted with ethyl acetate three times, dried with sodium sulfate, filtered, and concentrated in vacuo to yield the crude product for next step without further purification. LCMS calculated for C10H17N6O (M+H): 237.1. Found: 237.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][CH:6]1[CH2:11][CH:10]([C:12]([O:14][CH3:15])=[O:13])[CH2:9][CH2:8][NH:7]1.CCN(C(C)C)C(C)C.[C:28](Cl)(=[O:31])[O:29][CH3:30]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][CH:6]1[CH2:11][CH:10]([C:12]([O:14][CH3:15])=[O:13])[CH2:9][CH2:8][N:7]1[C:28]([O:29][CH3:30])=[O:31]
Reactant: COC(=O)Cl
Reactant: COC(=O)C1CCNC(Cc2cccc(F)c2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1CCN(C(=O)OC)C(Cc2cccc(F)c2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.4 %

Procedure:
Methyl 2-(3-fluorobenzyl)piperidine-4-carboxylate (7.6 g, 30.24 mmol) was dissolved in DCM (200 mL) and DIPEA (6.32 mL, 36.29 mmol), then methyl carbonochloridate (3.3 mL, 41.91 mmol) was added. The solution was stirred at room temperature for 2 h. The reaction mixture was washed with 0.1 M HCl and satd NaHCO3. The organic phase was passed through a phase separator and evaporated to yield dimethyl 2-(3-fluorobenzyl)piperidine-1,4-dicarboxylate (9.30 g, 99%) as a brown oil. MS m/z 310 (M+H)+