Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:13])[CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[C:4]([NH2:6])=[S:5].[CH:14]1(N)[CH2:16][CH2:15]1>O>[CH:14]1([NH:6][C:4](=[S:5])[CH:3]([N:2]([CH3:13])[CH3:1])[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:16][CH2:15]1
Reactant: CN(C)C(C(N)=S)c1ccccn1
Reactant: NC1CC1
Solvent: O
Product: CN(C)C(C(=S)NC1CC1)c1ccccn1

Procedure:
A mixture of 2-dimethylamino-2-(2-pyridyl)thioacetamide and 40% aqueous solution of cyclopropylamine is heated at reflux for 45 minutes. The mixture is cooled and water is added. The mixture is then extracted with chloroform and the extracts are dried, concentrated and the residue is recrystallized to give N-cyclopropyl-2-dimethylamino-2-(2-pyridyl)thioacetamide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:6][CH:7]=1.[C:16]1([C@@H:22]2[CH2:24][C@H:23]2[C:25](O)=[O:26])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[N:4][C:5]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([C:25]([C@@H:23]3[CH2:24][C@H:22]3[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:26])[CH2:12][CH2:11]2)=[N:6][CH:7]=1
Reactant: Fc1cnc(NCC2CCNCC2)nc1
Reactant: O=C(O)[C@@H]1C[C@H]1c1ccccc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C([C@@H]1C[C@H]1c1ccccc1)N1CCC(CNc2ncc(F)cn2)CC1

Procedure:
A solution of 5-fluoro-N-(piperidin-4-ylmethyl)pyrimidin-2-amine (1.00 g, 4.76 mmol), (1R,2R)-2-phenylcyclopropanecarboxylic acid (T. Riley et al., J. Med. Chem., 15, 1187, 1972) (0.77 g, 4.76 mmol), EDC (1.37 g, 7.13 mmol) and HOBt (0.96 g, 7.13 mmol) in DMF (10 mL) was stirred at rt for 2 h. The reaction mixture was diluted with ethyl acetate (200 mL), washed with aqueous saturated NaHCO3 (50 mL), water (5×50 mL), brine (20 mL), dried over Na2SO4, filtered and concentrated. The residue was chromatographed on silica gel 60 (90 g), eluting with 10:1–15:89–75 CH2Cl2:2-propanol:hexane to give the title compound. M.S. (M+1): 355.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[C:3]=1[C:12](=[O:14])[CH3:13].C([NH:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1)(=O)C.[OH-].[K+].O>C(O)C>[NH2:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[CH:13][C:12]([C:3]2[C:4]([O:10][CH3:11])=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=2[OH:1])=[O:14])=[CH:21][CH:20]=1
Reactant: COc1cc(O)c(C(C)=O)c(OC)c1
Reactant: CC(=O)Nc1ccc(C=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cc(O)c(C(=O)C=Cc2ccc(N)cc2)c(OC)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 8 %

Procedure:
A mixture of 98 mg of 2'-hydroxy-4',6'-dimethoxyacetophenone, 85 mg of 4-acetamidobenzaldehyde and 1 g of potassium hydroxide in 4 ml of 50% aqueous ethanol was stirred at room temperature for 3 days. The mixture was poured into 30 ml of cold water and then extracted with three 30 ml portions of ethyl acetate. The combined extracts were washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by preparative thin layer chromatography using a silica gel plate (Kiesel gel 60 F254, Merck Co.) and cyclohexane/ethyl acetate (1:1, v/v) as the developing solvent, whereby 12 mg of 4-amino-2'-hydroxy-4',6'-dimethoxychalcone as a yellow powder were obtained: Rf value 0.22; 1H-nmr spectrum (in CDCl3): δ3.6(2H), 3.72(3H), 3.82(3H), 5.90(1H), 6.06(1H), 6.56(1H), 6.70(1H), 7.50(1H), 7.62(1H) and 14.4 ppm (1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](I)[C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:10][Si:11]([C:14]#[CH:15])([CH3:13])[CH3:12].C(N(CC)CC)C>C1COCC1.[Cu]I>[F:1][C:2]1[CH:3]=[C:4]([C:15]#[C:14][Si:11]([CH3:13])([CH3:12])[CH3:10])[C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: Nc1ncc(F)cc1I
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cc(F)cnc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.3 %

Procedure:
A solution of 5-fluoro-3-iodo-pyridin-2-ylamine (4 g, 16.8 mmol) in THF (50 mL) and trimethylsilylacetylene (4.7 mL, 33.6 mmol) is treated with PdCl2(PPh3)4 (353 mg, 0.5 mmol), CuI (96 mg, 0.5 mmol) and triethylamine (7 mL, 50.4 mmol) and stirred at rt for 2 h. The mixture is filtered through Celite and concentrated. The residue is purified by silica gel chromatography eluting with 10%-35% EtOAc in heptane to afford 5-fluoro-3-trimethylsilanylethynyl-pyridin-2-ylamine (3.3 g, 94%). MS: 209 (M+H); 1H NMR (300 MHz, CDCl3): δ 7.90 (d, 1H), 7.30 (m, 1H), 4.89 (s, NH2, 2H), 0.25 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8](O)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)[CH:5]=[CH:6][CH:7]=1.FC(F)(F)C(O)=O.[BH4-].[Na+]>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(-c2ccccc2C(O)c2cccc(F)c2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1ccc(-c2ccccc2Cc2cccc(F)c2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 82.2 %

Procedure:
The product of the Example 25b (140 mg, 0.393 mmol) was dissolved in anhydrous dichloromethane (10 mL) and under nitrogen atmosphere was added trifluoroacetic acid (5 mL) at 0° C. The reaction mixture was stirred at 0° C. for 10 minutes and to the resulting dark orange solution was then added, in small portions sodium borohydride (290 mg, 7.86 mmol). The reaction mixture was stirred at 0° C. for 15 minutes and then at room temperature for 5 minutes. The solvent and trifluoroacetic acid were evaporated under reduced pressure and the residue was extracted with dichloromethane. The combined organic extracts were washed with water, brine, dried over sodium sulfate and filtered. The filtrate was evaporated under reduced pressure to give the crude which upon trituration with hexane yielded the title compound as a white solid, (110 mg, 83%), mp 97-98° C. 1H NMR (CDCl3) δ7.97 (d, J=8.3 Hz, 2H), 7.45 (d, J=8.3 Hz, 2H), 7.45-7.15 (m, 5H), 6.98 (dt, J=8.4 and 2.2 Hz, 1H), 6.75 (d, J=7.6 Hz, 1H), 6.63 (d, J=10 Hz, 1H); 13C NMR (CDCl3) δ164.4, 161.2, 147.2, 143.3 (d, J=7 Hz), 140.3, 139.2, 137.2, 130.7, 130.1 (2×C), 129.9, 129.7 (d, J=2.5 Hz), 128.6, 127.1 (2×C), 126.9, 124.3 (d, J=2.5 Hz), 115.4 (d, J=21 Hz), 112.9 (d, J=21 Hz), 44.5, 38.9; LRMS (APIMS) m/z 358 (M+NH4)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=2[CH:19]=1.[SH:20][C:21]1[N:25]=[CH:24][NH:23][N:22]=1>>[NH:23]1[CH:24]=[N:25][C:21]([S:20][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=3[CH:19]=2)=[N:22]1
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCCl)cc21
Reactant: Sc1nc[nH]n1
Product: CC1(C)OC(=O)Nc2ccc(OCCCCSc3nc[nH]n3)cc21

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 3-mercapto-1,2,4-triazole.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C@@H:13]([C@H:17]([NH:26]C(=O)OC(C)(C)C)[C:18]([N:20]2[CH2:24][CH2:23][C@H:22]([F:25])[CH2:21]2)=[O:19])[CH2:12][CH2:11]3)=[CH:4][CH:3]=1.[ClH:34]>O1CCOCC1>[ClH:34].[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C@@H:13]([C@H:17]([NH2:26])[C:18]([N:20]2[CH2:24][CH2:23][C@H:22]([F:25])[CH2:21]2)=[O:19])[CH2:12][CH2:11]3)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)N1CC[C@H](F)C1)[C@H]1CCc2cc(-c3ccc(F)cc3)ccc21
Agent: Cl
Solvent: C1COCCO1
Product: N[C@H](C(=O)N1CC[C@H](F)C1)[C@H]1CCc2cc(-c3ccc(F)cc3)ccc21

Procedure:
A solution of 24.5 mg of the compound from Step H in 1 mL of 4N hydrogen chloride in dioxane was stirred at ambient temperature for 1 h and then concentrated. The resultant solid was washed with ether and dried in vacuo to give the title compound. Mass spectrum (MS): m/z 357 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[C:18](=[O:19])[C:17]2[C:12](=[C:13]([OH:23])[CH:14]=[CH:15][C:16]=2[O:20][CH2:21][CH3:22])[S:9]1(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24](Br)[CH:25]=[CH2:26].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH2:1]([N:8]1[C:18](=[O:19])[C:17]2[C:12](=[C:13]([O:23][CH2:26][CH:25]=[CH2:24])[CH:14]=[CH:15][C:16]=2[O:20][CH2:21][CH3:22])[S:9]1(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOc1ccc(O)c2c1C(=O)N(Cc1ccccc1)S2(=O)=O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C=CCOc1ccc(OCC)c2c1S(=O)(=O)N(Cc1ccccc1)C2=O
Temperature: 80 °C
Yield: 96 %

Procedure:
A mixture of 2-benzyl-4-ethoxy-7-hydroxysaccharin (1.0 g), allyl bromide (0.36 g), potassium carbonate (0.62 g) and methyl ethyl ketone (about 20 mL) was heated at 80° C. for one hour. More allyl bromide (0.36 g) was added and heating at 80° C. was continued for one and one-half hours. The mixture was cooled and poured into ice-water (500 mL). The solid was collected affording 2-benzyl-4-ethoxy-7-allyloxysaccharin, 1.08 g, 96% yield, mp 148°-149° C.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCN(CC)CC.CS(Cl)(=O)=O.[Br:28][C:29]1[N:34]=[CH:33][C:32](O)=[CH:31][CH:30]=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.CN(C=O)C>[Br:28][C:29]1[N:34]=[CH:33][C:32]([O:15][CH2:14][CH:11]2[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][CH2:10]2)=[CH:31][CH:30]=1
Reactant: Oc1ccc(Br)nc1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc(Br)nc2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 43.5 %

Procedure:
A mixture of N-Boc-4-piperidinemethanol (4.8 g, 22.3 mmol), Et3N (3.4 mL, 24.5 mmol) in CH2Cl2 (100 mL) at 0° C. was treated dropwise with methanesulfonyl chloride (1.8 mL, 23.4 mmol). The reaction mixture was stirred at 0° C. for 1 h, and then was washed with water twice. The CH2Cl2 layer was dried over MgSO4, filtered, and the filtrate was concentrated. The residue was mixed with 6-bromo-3-pyridinol (3.88 g, 22.3 mmol) and K2CO3 (6.2 g, 44.6 mmol) in DMF (50 mL). The resulting mixture was heated at 90° C. overnight, cooled to ambient temperature, sat overnight, then was quenched with water and stirred at room temperature for 4 h. The resulting precipitate was collected, washed with water, and air-dried. The crude product was purified by chromatography on a silica gel column using 0 to 10% MeOH/CH2Cl2 to give 3.6 g (43%) of 1,1-dimethylethyl 4-{[(6-bromo-3-pyridinyl)oxy]methyl}-1-piperidinecarboxylate as a white solid along with some impure material. The impure material was repurified by chromatography on a silica gel column using 0 to 2.5% MeOH/CH2Cl2 to give an additional 2.8 g (77% overall yield) of 1,1-dimethylethyl 4-{[(6-bromo-3-pyridinyl)oxy]methyl}-1-piperidinecarboxylate as an off-white solid.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[C:6]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:5]=1.[Li+].[BH4-]>C1COCC1>[OH:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[C:6]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:5]=1
Reactant: COC(=O)c1ccc(C#N)c(OCCCCc2ccccc2)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1ccc(CO)cc1OCCCCc1ccccc1
Temperature: 70 °C

Procedure:
4-Cyano-3-(4-phenyl-butoxy)-benzoic acid methyl ester from step 1 (285.1 mg, 0.92 mmol) was dissolved in THF (4.6 ml). LiBH4 in THF (2M, 923 μl, 1.85 mmol) was added. The reaction mixture was heated to 70° C. for 3 hours. The reaction mixture was quenched carefully with 3N HCl and then extracted with EtOAc (3×10 mL). The organic layers were combined, washed with brine, dried (MgSO4), filtered and concentrated to yield the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:11]=[CH:10][C:9]=1[NH:20][CH3:21].C(N(CC)CC)C.[F:29][C:30]([F:48])([F:47])[C:31]1[CH:32]=[C:33]([C:41]([CH3:46])([CH3:45])[C:42](Cl)=[O:43])[CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1.O>ClCCl>[F:39][C:37]([F:40])([F:38])[C:35]1[CH:34]=[C:33]([C:41]([CH3:46])([CH3:45])[C:42]([N:20]([C:9]2[CH:10]=[N:11][C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[CH:13][C:8]=2[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH3:21])=[O:43])[CH:32]=[C:31]([C:30]([F:48])([F:29])[F:47])[CH:36]=1
Reactant: CNc1cnc(N2CCOCC2)cc1-c1ccccc1Cl
Reactant: CC(C)(C(=O)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(N2CCOCC2)cc1-c1ccccc1Cl
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 86.2 %

Procedure:
8.56 g (28.1 mmol) [4-(2-Chloro-phenyl)-6-morpholin-4-yl-pyridin-3-yl]-methyl-amine were dissolved in 50 ml dichloromethane in the presence of 5.5 ml (1.4 eq.) triethylamine and cooled to 0° C. A solution of 10.8 g (1.05 eq.) 2-(3,5-bistrifluoromethyl-phenyl)-2-methyl-propionyl chloride (step a) in 10 ml dichloromethane was added slowly and after 2 hours, 80 ml water was added. After 15 minutes stirring, the phases were separated, the aqueous phase was extracted with 2 portions of 80 ml dichloromethane and the combined organic extracts were washed with 80 ml water, 80 ml 2% aqueous NaOH, 80 ml water and 80 ml 5% aqueous NaHCO3, dried over Na2SO4 and concentrated under reduced pressure. Crystallization from 40 ml 2-propanol and 20 ml ethanol at −20° C. yielded 14.2 g (86%) of 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-morpholin-4-yl-pyridin-3-yl]-N-methyl-isobutyramide as a white powder of m.p.=134.4-135.5° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:19]([OH:21])=[O:20])=[C:8]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[N:9]=1)(=[O:3])[CH3:2].C[Si](C([Si](C)(C)C)C(N)=O)(C)C.[C:34]([O:38][C:39]([NH:41][C:42](N1C=CC=N1)=[N:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])=[O:40])([CH3:37])([CH3:36])[CH3:35]>C1COCC1>[C:1]([NH:4][C:5]1[S:6][C:7]([C:19]([OH:21])=[O:20])=[C:8]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18]/[C:42](/[NH:41][C:39]([O:38][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:40])=[N:43]/[C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])=[CH:14][CH:13]=2)[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)n1cccn1
Reactant: CC(=O)Nc1nc(CCc2ccc(N)cc2)c(C(=O)O)s1
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(CCc2ccc(N/C(=N/C(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc2)c(C(=O)O)s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 60.9 %

Procedure:
2-(Acetylamino)-4-[2-(4-aminophenyl)ethyl]-1,3-thiazole-5-carboxylic acid (106 mg) was suspended in THF (2 ml) under N2 atmosphere. Bis(trimethylsilyl)acetamide (0.253 ml) was added to the suspension at r.t., and the mixture was stirred at r.t. for 15 minutes. Then, N,N′-bis(tert-butoxycarbonyl)-1H-pyrazole-1-carboxamidine (119 mg) was added to the solution at r.t. The reaction mixture was stirred at r.t. for 20 hours, and concentrated in vacuo. The residue was dissolved in CHCl3. The organic solution was washed with 1N—HCl, water and brine, dried over anhydrous MgSO4, and concentrated in vacuo. The residual solid was washed with ethyl ether to give 2-(acetylamino)-4-{2-[4-({(Z)-[(tert-butoxycarbonyl)amino](tert-butoxycarbonyl)iminomethyl}amino)phenyl]ethyl}-1,3-thiazole-5-carboxylic acid (115.8 mg) as a pale brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:38])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([C:33]#[N:34])([CH3:32])[CH3:31])=[CH:26][C:25]=3[O:35][CH2:36][CH3:37])=[N:9]2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[N:46]1([CH:52]2[CH2:57][CH2:56][N:55]([C:58](=[O:60])[CH3:59])[CH2:54][CH2:53]2)[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1>>[C:58]([N:55]1[CH2:54][CH2:53][CH:52]([N:46]2[CH2:47][CH2:48][N:49]([C:21]([N:11]3[C@@:12]([C:14]4[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=4)([CH3:13])[C@@:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)([CH3:38])[N:9]=[C:10]3[C:24]3[CH:29]=[CH:28][C:27]([C:30]([CH3:32])([CH3:31])[C:33]#[N:34])=[CH:26][C:25]=3[O:35][CH2:36][CH3:37])=[O:22])[CH2:50][CH2:51]2)[CH2:57][CH2:56]1)(=[O:60])[CH3:59]
Reactant: CCOc1cc(C(C)(C)C#N)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CC(=O)N1CCC(N2CCNCC2)CC1
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cc(C(C)(C)C#N)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(C2CCN(C(C)=O)CC2)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-[4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-(4-piperazin-1-yl-piperidin-1-yl)-ethanone trifluoroacetate to give the title compound as a racemic mixture. The enantiomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 35% methanol in carbon dioxide). LR-MS: 743.4 [(M+H)+]
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][S:10][C:6]=2[CH2:5][CH2:4][CH:3]1[C:11]([O:13][CH3:14])=[O:12].[Br:15]Br.O>CCOCC.C(Cl)(Cl)(Cl)Cl>[Br:15][C:3]1([C:11]([O:13][CH3:14])=[O:12])[C:2](=[O:1])[C:7]2[CH:8]=[CH:9][S:10][C:6]=2[CH2:5][CH2:4]1
Reactant: COC(=O)C1CCc2sccc2C1=O
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOCC
Solvent: O
Product: COC(=O)C1(Br)CCc2sccc2C1=O
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 99.7 %

Procedure:
Methyl 4-oxo4,5,6,7-tetrahydro-1-benzothiophene-5-carboxylate (Preparation 11, 3.50 g) is dissolved in anhydrous ether (30 mL) and carbon tetrachloride (20 mL). This solution is cooled to −10° C. and a solution of bromine (2.66 g) in carbon tetrachloride (5 mL) with 3 drops of ether. Each drop of the bromine solution is added only after the orange color dissipated from the prior drop. After completion of addition, the solution is allowed to stir for 15 minutes at −10° C., 15 minutes at 0° C., and then overnight at rt. This reaction mixture is poured into water (100 mL) and extracted with ether (100 mL). The ether phase is washed with brine, dried over Na2SO4, filtered, and concentrated to give 4.80 g (99%) of the title compound as a yellow oil. Physical characteristics: MS (ESI+) m/z 289.0/291.0 (M+H)+.
Reaction SMILES: BrCCBr.Cl[Si](C)(C)C.I[CH2:11][CH2:12][CH2:13][N:14]1[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]2[C:15]1=[O:24].I[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-:34])=[O:33])[CH:27]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C)C=O.[Zn].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N+:32]([C:28]1[CH:27]=[C:26]([CH2:11][CH2:12][CH2:13][N:14]2[C:18](=[O:19])[C:17]3[C:16](=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:15]2=[O:24])[CH:31]=[CH:30][CH:29]=1)([O-:34])=[O:33]
Reactant: O=C1c2ccccc2C(=O)N1CCCI
Reactant: O=[N+]([O-])c1cccc(I)c1
Agent: [Pd]
Agent: C[Si](C)(C)Cl
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: BrCCBr
Product: O=C1c2ccccc2C(=O)N1CCCc1cccc([N+](=O)[O-])c1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 20.4 %

Procedure:
Under an atmosphere of nitrogen, a stirred suspension of 1.6 g (24 mg.atom) of zinc dust (<10 micron diameter) in 20 ml of dimethylformamide was treated with 0.11 ml (1.2 mmol) of 1,2-dibromoethane and the mixture was heated to 60° C. then allowed to cool to room temperature. The heating and cooling was repeated twice more. 0.04 ml (0.24 mmol) of chlorotrimethylsilane was added and the mixture stirred at ambient temperature for 30 minutes. The mixture was then treated with 1.26 g (4 mmol) of N-(3-iodopropyl)phthalimide and the resulting suspension stirred for 30 minutes at ambient temperature and then heated at 35° C. for 1 hour and cooled. To the mixture were then added sequentially 750 mg (3 mmol) of 1-iodo-3-nitrobenzene, 60 mg (0.06 mmol) of tris(dibenzylideneacetone)dipalladium and 70 mg (0.23 mmol) of tri(o-tolyl)phosphine and the resulting mixture stirred at ambient temperature for 1 hour. The suspension was filtered and the filtrate diluted with 50 ml of ethyl acetate, washed twice with 40 ml of water, dried over magnesium sulfate, filtered and evaporated. The product was purified by flash chromatography on silica gel using ethyl acetate/isohexane in a ratio of 1:2 as eluent. Product containing fractions were combined and evaporated to give 190 mg (20%) of 2-[3-(3-nitrophenyl)-propyl]-isoindole-1,3-dione as a pale pink solid. [Mass spectrum (ESI) MH+ =311].
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1.[CH3:10][NH2:11].CCO>>[CH3:10][NH:11][CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1
Reactant: CN
Reactant: ClCc1ccncc1
Agent: Cl
Solvent: CCO
Product: CNCc1ccncc1
Yield: 79 %

Procedure:
Using 4-chloromethyl-pyridine hydrochloride salt and 33% methylamine/EtOH the title compound was obtained as a colourless liquid (0.1 mm Hg, 60-62° C.) (79% yield), MS: m/e=122.1 (M+).
Reaction SMILES: [S:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3](=[O:11])[CH2:2]1.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([CH:21]=O)=[CH:13]1>N1CCCCC1>[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](/[CH:21]=[C:2]2\[S:1][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[NH:4][C:3]\2=[O:11])=[CH:13]1
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: O=C1CSc2ccccc2N1
Solvent: C1CCNCC1
Product: O=C1Nc2ccccc2S/C1=C\c1c[nH]c2ccccc12

Procedure:
A solution of 2H-1,4-benzothiazin-3(4H)-one (1.65 g, 10 mmol) and indole-3-carboxaldehyde (1.45 g, 10 mmol) in piperidine (30 ml) was heated under reflux for 5 days. The solvent was removed in vacuo, ethanol (20 ml) was added to the residue and the solid was filtered off. This solid was boiled in ethanol (20 ml) and filtered hot to give a yellow solid.
Reaction SMILES: [CH3:1][C:2]([CH3:31])([CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:15]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:14]=2[CH:30]=1)[C:3]#[N:4].[OH-:32].[Na+]>S(=O)(=O)(O)O>[CH3:1][C:2]([CH3:31])([CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:15]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:14]=2[CH:30]=1)[C:3]([NH2:4])=[O:32]
Reactant: [OH-]
Reactant: CC(C)(C#N)CCCCOc1ccc2nc(-c3ccccc3)n(-c3ccccc3)c2c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CC(C)(CCCCOc1ccc2nc(-c3ccccc3)n(-c3ccccc3)c2c1)C(N)=O
Temperature: 0 °C

Procedure:
500 mg of 2,2-dimethyl-6-[(1,2-diphenyl-1H-benzimidazol-6-yl)oxy]hexanonitrile was refluxed for 2 hours in 5 ml of 80% sulfuric acid. After cooling, it was carefully added to ice water, the pH was set at 8 with sodium hydroxide solution, it was extracted three times with ethyl acetate, the extracts were dried on sodium sulfate, and it was concentrated by evaporation in a vacuum. The residue was chromatographed on silica gel.
Reaction SMILES: C([C:6]1[C:7](=[O:15])[NH:8][C:9]([CH2:13][CH3:14])=[CH:10][C:11]=1[OH:12])(OCC)=O.[OH-].[K+].Cl>O>[CH2:13]([C:9]1[NH:8][C:7](=[O:15])[CH:6]=[C:11]([OH:12])[CH:10]=1)[CH3:14]
Reactant: CCOC(=O)c1c(O)cc(CC)[nH]c1=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCc1cc(O)cc(=O)[nH]1

Procedure:
119 g (0.564 mol) of 3-carbethoxy-6-ethyl-4-hydroxy-1H-2-pyridone are heated under reflux for two hours in a mixture of 1l of water with 155 g (2.77 mol) of KOH. After cooling, the mixture is adjusted to pH 4 using concentrated HCl, cooled again and filtered with suction.